Abstract: BACKGROUND: Blood pressure (BP) affects hypertensive left ventricular mass (LVM), explaining 10-25% of its variation. Thus, it is plausible that other factors operate in this process. Reduced kidney function is associated with increased LVM. METHODS: We enrolled 1000 untreated hypertensives with serum creatinine ≤1.5mg/dL and without proteinuria. BP was measured by standard sphygmomanometer. LVM was calculated with the Devereux formula and indexed by body surface area (LVMI). Anthropometric and the following laboratory parameters were measured: plasma glucose, serum insulin, cholesterol, triglyceride, creatinine and e-GFR (CKD-EPI equation). RESULTS: On univariate analysis, both insulin (r=0.44, P<0.0001) and creatinine (r=0.37, P<0.001) were directly related to LVMI. In multivariate regression analysis insulin resulted the first factor in rank explaining the variability in LVMI (semipartial r=0.34,P<0.001), followed by creatinine. Fasting insulin interacts with creatinine in explaining LVM variability: 0.1mg/dL increase in creatinine produces an increase of 8.1g/m(2) in LVMI in patients with higher plasma insulin (upper quartiles). CONCLUSIONS: Independently of other risk factors, fasting insulin and serum creatinine contribute to explain LVM development in hypertensives with preserved renal function; insulin interacts with creatinine in explaining LVM variability in these patients.
Abstract: BACKGROUND: Both uric acid and endothelial dysfunction are associated with new occurrence of type-2 diabetes but, at this moment, there is no evidence about a possible interaction between them. We tested, in untreated hypertensive patients, without clinical evidence of vascular damage, the hypothesis that serum uric acid and endothelial dysfunction may interact in predicting new diabetes. METHODS: In 500 uncomplicated hypertensive non diabetic (ADA criteria) patients we evaluated endothelial function, by strain-gauge plethysmography, and uric acid. RESULTS: During the follow-up (median 87.1months), there were 54 new cases of diabetes (1.8%/year). On univariate analysis, incident diabetes was inversely related with ACh-stimulated FBF (HR=0.65, 95%CI=0.52-0.82; P<0.001) and directly with serum CRP (HR=1.22, 95%CI=1.09-1.37; P<0.001), HOMA-index (HR=1.20, 95%CI=1.05-1.37; P=0.007), fasting insulin (HR=1.05, 95%CI=1.01-1.09; P=0.006) and age (HR=1.03, 95%CI=1.00-1.05; P=0.014). At multiple regression analysis, the interaction between ACh-stimulated FBF and uric acid resulted statistically significant. Similar results were observed for the interaction between FBF and CRP. CONCLUSIONS: Our data clearly demonstrate that the coexistence of both hyperuricemia and reduced endothelium-dependent vasodilation increases the risk to develop new diabetes in hypertensive patients. In addition, mild-inflammation seems to be the mediator of the interaction between endothelial dysfunction and uric acid.
Abstract: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase, which was associated with insulin resistance. Dimethylarginine dimethylaminohydrolase (DDAH) is the major determinant of plasma ADMA. Examining data from the DIAGRAM+ (Diabetes Genetics Replication And Meta-analysis), we identified a variant (rs9267551) in the DDAH2 gene nominally associated with type 2 diabetes (P = 3 × 10(-5)).
Abstract: We evaluated whether cardiometabolic risk profiles differ for subjects identified as having prediabetes by A1C, fasting glucose (FPG), or 2-h postchallenge glucose (2-PG) criteria.
Abstract: BACKGROUND: Subclinical organ damage is a condition with an increased risk for fatal and nonfatal cardiovascular events. Particularly, endothelial dysfunction and left ventricular mass (LVM) are recognized as independent predictors of cardiovascular events in hypertensive patients. Besides, LVM in hypertensives is inversely related to forearm blood flow (FBF) responses to the endothelium-dependent vasodilating agent. We evaluated the role of endothelium-dependent vasodilation in the progression/regression of LVM in a group of hypertensive subjects. METHODS: We enrolled 170 hypertensive outpatients (88 men, 92 women; age 47±11years). LVM was calculated with the Devereux formula and indexed by surface area (LVMI). Endothelium-dependent vasodilation was investigated by intra-arterial infusions of acetylcholine (ACh). RESULTS: During the follow-up blood pressure (BP) decreased from 150/91±17/11 to 135/80±14/9mm Hg (P=0.0001), and LVMI from 120±28 to 118±28g/m(2) (P=0.194). The mean annual rate of variation of LVMI was -0.38±3.9g/m(2), which was not statistically different in men and women. It was correlated with baseline ACh-stimulated FBF (r=-0.272, P=0.0001) and BMI (r=0.164, P=0.016). At multivariate analysis, FBF was the only baseline covariate that remained significantly associated with LVMI variation, also after correction for antihypertensive treatment and BP reduction. The interaction between baseline LVM and ACh-stimulated FBF was investigated in a multiple linear regression model showing that a fixed reduction in ACh-stimulated FBF (100%) induces different variation of annual rate of LVMI at different levels of baseline LVM. CONCLUSIONS: Our data demonstrate, for the first time, the role of endothelial function in the progression/regression of LVMI, independently of traditional cardiovascular risk factors and antihypertensive therapy.
Abstract: In the field of cardiovascular diseases, elevated levels of serum uric acid (UA) reflect a marked activation of the xanthine oxidase pathway with increase in free radicals production; it is often associated with an inflammatory state, oxygen consumption and endothelial dysfunction. All these associations have been also confirmed in heart failure (HF) but the pathophysiological role of UA in this setting is not well understood. The aim of this study was to evaluate the prognostic role of UA in outpatients enrolled in the Italian Registry of Congestive Heart Failure (IN-CHF).
Abstract: Subjects who are normal glucose tolerant (NGT) are considered at low risk, even if a plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) is able to identify NGT subjects at high risk for type 2 diabetes and subclinical organ damage. Hyperuricemia is associated with several risk factors for cardiovascular diseases such as hypertension, insulin resistance, and diabetes. However, it is unknown whether uric acid (UA) is able to affect 1-h postload plasma glucose in hypertensive NGT subjects.
Abstract: To assess the antihypertensive efficacy of olmesartan medoxomil and ramipril on 24-h ambulatory blood pressure (ABP) in elderly hypertensive patients by pooled data analysis of two studies with identical designs (one Italian, one European).
Abstract: Individuals with normal glucose tolerance (NGT), whose 1-h postload plasma glucose is ≥155 mg/dL (NGT 1h-high), have an increased risk of type 2 diabetes. The purpose of this study was to characterize their metabolic phenotype.
Abstract: Essential hypertension, as well as other established cardiovascular risk factors, is associated with endothelial dysfunction. Hypertensive patients with a nondipper circadian pattern have a greater risk of cerebrovascular and cardiovascular complications in comparison with those with a dipper circadian pattern. In this study, we evaluated the association between nondipper pattern and endothelial function in patients with essential hypertension.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is associated with insulin resistance and cardiovascular disease. Among the potential factors that may account for the increased cardiometabolic risk, IGF-I is a plausible candidate because the liver is the main site of its production.
Abstract: Glucose-tolerant subjects who have 1-h post-load glucose levels ≥155 mg dl(-1) (normal glucose tolerance (NGT)-1h-high) are at an increased risk of developing type 2 diabetes. Prospectively conducted studies indicated that high levels of liver enzymes are predictors of a tendency to develop type 2 diabetes; however, it is unknown whether the NGT-1h-high subjects are at increased risk for secreting higher levels of liver biomarkers.
Abstract: Two subtypes of angiotensin II (ATII) receptor have been defined on the basis of their differential pharmacological and biochemical properties: ATII-type1 receptors (AT(1)-R) and ATII-type2 receptors (AT(2)-R). It has been hypothesized that part of the protective effects on the cardiovascular system of AT(1)-R blockers is mediated by an ATII-mediated overstimulation of AT(2)-R. We hypothesized that the inhibition of AT(1)-R has a stronger impact on insulin-induced nitric oxide (NO) production than ATII-mediated overstimulation of AT(2)-R. Therefore we studied the effect of the inhibition of AT(1)-R and AT(2)-R on ATII-mediated actions in Human Umbilical Vein Endothelial Cells (HUVECs).
Abstract: To address whether glucose tolerance status, and in particular 1-h postload plasma glucose levels, may affect diastolic function in 161 never-treated hypertensive white subjects. Impaired left ventricular relaxation, an early sign of diastolic dysfunction, represents the first manifestation of myocardial involvement in diabetic cardiomyopathy. A plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) is able to identify subjects with normal glucose tolerance (NGT) at high risk for type 2 diabetes and with subclinical organ damage.
Abstract: BACKGROUND: Normotolerant subjects (NGT) are considered at low risk, even if a plasma glucose value ≥155mg/dl for the 1-hour post-load plasma glucose during an oral glucose tolerance test (OGTT) is able to identify NGT at high-risk for type-2 diabetes and subclinical organ damage. Insulin resistance (IR) contributes to the pathogenesis of impaired glucose tolerance and participates to the development of subclinical organ damage. However, it is unknown whether NGT<155 subjects are at low risk for the development of subclinical organ damage independently from other metabolic variables, such as IR/hyperinsulinemia. METHODS: From a large cohort of about 1200 uncomplicated hypertensive outpatients underwent to OGTT, we selected 645 NGT subjects, 319 men and 326 women aged 47.6±10.6. All subjects underwent standard echocardiography for measurement of left ventricular mass (LVM), and carotid ultrasonography for evaluation of intima media thickness (IMT). Finally, we estimated glomerular filtration rate (e-GFR) by using the new equation proposed by investigators in the chronic kidney disease epidemiology (CKD-EPI) collaboration. RESULTS: NGT<155 subjects into upper tertile of 1-h post-load insulin had a worse lipemic profile, a higher hs-CRP, creatinine, LVM, e-GFR and IMT. Comparing the NGT groups, we observed that metabolic and hemodynamic parameters of NGT<155 subjects into upper tertile of 1-h post-load insulin were similar to that observed in NGT≥155 subjects. Similarly, fasting and both 1-h and 2-h post-load insulin values were similar to that observed in NGT≥155. CONCLUSIONS: We documented that hypertensive NGT subjects have different phenotypic patterns, particularly in their metabolic profile and in presence of subclinical organ damage.
Abstract: Increased heart rate (HR) is a risk factor for cardiovascular morbidity and mortality in the general population and in some clinical conditions. Endothelial dysfunction is an adverse prognostic factor for cardiovascular events. The aim of the study was to evaluate the effect of HR on central hemodynamic parameters and endothelial function in hypertension. We evaluated forearm blood flow (FBF) response to intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) in 30 patients with HR ≤60 min(-1) and 30 with HR ≥80 min(-1). The FBF was measured by strain-gauge plethysmography. Transesophageal atrial pacing was used to increase the HR. Radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressures and correlate hemodynamic indices. The FBF response to ACh is lower in hypertensives with HR ≤60 min(-1) than in those with HR ≥80 min(-1) (10.6 ± 4.2 vs. 13.6 ± 5.1 ml × 100 ml(-1) of tissue × min(-1), P < 0.001). Vascular resistance decreases to 9.3 ± 2.8 U in patients with lower HR versus 7.2 ± 2.1 U in those with higher HR (P = 0.002). The FBF response to SNP is similar in both groups. Central systolic and pulse pressure are higher in bradycardic patients than in those with HR ≥80 min(-1) (140 ± 8 vs. 131 ± 8 mmHg, P = 0.0001 and 49 ± 10 vs. 39 ± 11 mmHg, P = 0.0001). All central hemodynamic parameters decrease during incremental atrial pacing. Augmentation index is the strongest predictor of endothelial dysfunction at multivariate analysis. These findings demonstrate that low HR affects endothelium-dependent vasodilation in hypertension. Increased central aortic pressure and hemodynamic correlates seem to be the underlying mechanisms by which bradycardia interferes with endothelium-dependent reactivity.
Abstract: We compared the performance of hemoglobin A1c (HbA1c) versus the fasting plasma glucose (FPG) in diagnosing the metabolic syndrome and assessed the diagnostic accuracy of the metabolic syndrome definition using HbA1c in identifying insulin-resistant subjects. The cardiometabolic risk factors, HbA1c, and glucose tolerance were analyzed in 774 nondiabetic white subjects. Insulin sensitivity was estimated with an oral glucose tolerance test-derived insulin sensitivity index. Insulin resistance was defined as the lower quartile of insulin sensitivity index. A 90.9% agreement existed between the use of HbA1c and the FPG for diagnosis of the metabolic syndrome (κ coefficient = 0.813); however, the proportion of subjects who met the metabolic syndrome criteria using the HbA1c was greater (42.1% vs 39.7%). Compared to the subjects who met the metabolic syndrome criteria using the FPG alone, those with the metabolic syndrome using the HbA1c-alone criterion were younger, had greater visceral adiposity, greater levels of inflammatory markers and liver enzymes, and lower blood pressure. In a logistic regression analysis with adjustment for age and gender, the subjects with the metabolic syndrome using the HbA1c criterion only had a 3.6-fold increase risk of having insulin resistance, defined as the lowest quartile of the insulin sensitivity index. A similar risk (3.8-fold) was observed in those who met the metabolic syndrome criteria using FPG alone. Insulin-resistant subjects who did not meet the criteria for the metabolic syndrome using the HbA1c had an unfavorable cardiovascular disease risk profile. In conclusion, although a good agreement existed between the HbA1c and FPG criteria for the diagnosis of the metabolic syndrome, appreciably different groups of subjects were classified using each method.
Abstract: TRIB3, a mammalian tribbles homologue, affects insulin signalling and action by inhibiting Akt phosphorylation. A TRIB3 Q84R gain-of-function polymorphism has been associated with insulin resistance both in vitro and in vivo and with several atherosclerotic phenotypes, including increased carotid intima-media thickness (IMT). We wanted to replicate this latter association and, if so, to get deeper insights about the molecular mechanisms underlying the role of the TRIB3 Q84R polymorphism in atherosclerosis.
Abstract: Anaemia is a risk factor for cardiovascular morbidity and mortality. Among factors responsible for anaemia, insulin-like growth factor-1 (IGF-1) is a plausible candidate. We evaluated the association of IGF-1 with haemoglobin (Hb) concentration and anaemia in a cohort of 1,039 Caucasians subjects. Subjects with anaemia exhibited lower IGF-1 (p=0.006), and higher hsCRP levels (p=0.003). To estimate the independent contribution of variables to Hb concentration, a multivariable regression analysis was modeled including age, gender, body mass index (BMI), waist circumference, blood pressure, fasting glucose, fasting insulin, IGF-1, fibrinogen, hsCRP, mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), serum iron, estimated glomerular filtration rate (eGFR), and treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). The variables significantly associated with Hb concentration were gender (p<0.0001), IGF-1 (p<0.0001), waist circumference (p=0.02), hsCRP (p<0.04), MCH (p<0.0001), MCV (p<0.0001), serum iron (p=0.001), IGF-1 (p=0.003), hsCRP (p=0.008), and waist circumference (p=0.01), accounting for 54.0% of its variation. Hb concentration was significant lower in subjects in the lowest IGF-1 quartile as compared with those in the third (p=0.02) and fourth (p=0.001). In a logistic regression model adjusted for age, gender, BMI, waist circumference, blood pressure, fasting glucose, fasting insulin, fibrinogen, hsCRP, MCH, MCV, serum iron, eGFR, and treatment with ACE inhibitors or ARBs, subjects in the first quartile of IGF-1 had a 2.49-fold higher risk of having anaemia as compared with those in the fourth (odds ratio 2.70, 95% confidence interval 1.02-7.16). Our data suggest that low IGF-1 may be an important contributor to mild anaemia.
Abstract: A broad spectrum of concomitant disorders may complicate heart failure adding further morbidity and mortality risk. Comorbidities may be subdivided into cardiovascular and noncardiovascular. The first group includes hypertension, coronary artery disease, peripheral artery disease, cerebrovascular disease, arrhythmias and valvular heart disease. Noncardiovascular comorbidities include respiratory, endocrine, metabolic, nutritional, renal, hematopoietic, neurological as well as musculoskeletal conditions. In recent years, advances in the treatment of heart failure have not been attended by important changes in management of its comorbidities. They now seem to be major causes of the poor prognosis of heart failure patients. In this review we provide an updated summary of the epidemiological, pathophysiological and clinical characteristics of comorbidities as well as their potential impact for heart failure treatment.
Abstract: Hemoglobin (Hb) is an important nitric oxide (NO) buffer and a modulator of NO bioavailability. In addition, endothelial dysfunction is common in hypertensive patients, suggesting a pivotal role of hemoglobin concentration ([Hb]) in vascular function. To investigate the potential role of [Hb] in endothelium-dependent vasodilation, the relationship between Hb and endothelial function was tested in a group of patients with essential hypertension.
Abstract: Non-alcoholic fatty liver disease, characterized by insulin resistance, has been correlated with several clinical and pathological manifestations, such as intima-media thickness. At present, no data are available regarding endothelial dysfunction, the first step in atherosclerosis, and non-alcoholic fatty liver disease. The aim of this study was to test a possible association between non-alcoholic fatty liver disease and endothelium-dependent vasodilation in a group of hypertensive patients.
Abstract: Left ventricular hypertrophy (LVH), an independent risk factor for cardiovascular (CV) morbidity and mortality, recognizes a multifactorial pathogenesis. A plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) identifies subjects with normal glucose tolerance (NGT) at high risk for type 2 diabetes. We addressed the question if glucose tolerance status, particularly 1-h postload plasma glucose levels, affects left ventricular mass (LVM) and cardiac geometry in essential hypertension.
Abstract: BACKGROUND AND AIMS: The American Diabetes Association (ADA) has revised criteria for diagnosis of type 2 diabetes recommending an A1C cut point of ≥6.5% in addition to criteria based on glucose levels. We compared A1C, fasting plasma glucose (FPG) or 2-h post-challenge glucose (2-hPG) criteria for the diagnosis of diabetes in a cohort of Italian Caucasians. METHODS AND RESULTS: A total of 1019 individuals without known diabetes completed an oral glucose tolerance test (OGTT) and had A1C measured. Moderate agreement existed for A1C and FPG criteria for diagnosis of type 2 diabetes (κ coefficient = 0.522), with 85.5% of individuals classified as not having diabetes by both A1C and FPG criteria, and 5.8% classified as having diabetes by both A1C and FPG criteria. Discordant classifications occurred for 5.5% of individuals who had an A1C ≥ 6.5% and FPG <126 mg dl(-1), and for 3.2% who had an A1C <6.5% and FPG ≥126 mg dl(-1). Modest agreement existed for A1C and 2-hPG criteria for diagnosis of type 2 diabetes (κ coefficient = 0.427), with 81.8% of individuals classified as not having diabetes by both A1C and 2-hPG criteria, and 6.0% classified as having diabetes by both A1C and 2-hPG criteria. The area under the receiver operating characteristic curve of A1C for identifying subjects with diabetes according to FPG or 2-hPG criteria was 0.856 and 0.794, respectively. Modest agreement existed for A1C and FPG and/or 2-hPG criteria for diagnosis of type 2 diabetes (κ coefficient = 0.446). CONCLUSIONS: A1C ≥ 6.5% demonstrates a moderate agreement with fasting glucose and 2-hPG for diagnosing diabetes among adult Italian Caucasians subjects.
Abstract: Left atrial (LA) dilation precedes or appears early after the onset of atrial fibrillation (AF) and factors in perpetuating the arrhythmia. Angiotensin receptor blockers were proposed for reversing LA remodeling. We evaluated the effect of valsartan on LA remodeling in patients with a recent episode of AF and the effect of LA size on AF recurrence (AFr).
Abstract: Metabolically healthy but obese (MHO) subjects have a favourable cardio-metabolic risk profile, but whether they are also at lower risk for kidney dysfunction is still questionable.
Abstract: Increased urinary excretion of albumin is an early sign of kidney damage and a risk factor for progressive cardiovascular and renal diseases and heart failure. There is, however, only limited information on the prevalence and prognostic role of urinary albumin excretion in patients with established chronic heart failure.
Abstract: Endothelial dysfunction and insulin resistance (IR) are associated with essential hypertension and other cardiovascular risk factors. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction in different setting of patients. However, at this moment no data are available about the role of ADMA and IR to induce endothelial dysfunction in an independent way or combined between them. In this study, we investigated, in 63 hypertensives and 21 normotensive healthy subjects, the relationship between ADMA and IR and their possible interaction on endothelial function.
Abstract: Low IGF1 levels have been associated with an increased cardiovascular risk. It is unknown however whether IGF1 mediates the atherosclerotic process by modulating high-density lipoprotein cholesterol (HDL-C) independently from confounders. To address this issue, we evaluated the association between IGF1 levels and HDL-C in nondiabetic subjects.
Abstract: A cutoff of 155 mg/dl for 1-hour postload plasma glucose (1hPG) during the oral glucose tolerance test (OGTT) is able to identify patients who are at high risk for type 2 diabetes and vascular atherosclerosis. We aimed to examine whether individuals with 1hPG ≥155 mg/dl are also at increased risk for chronic kidney disease (CKD).
Abstract: The role of atrial fibrillation (AF) in older patients with heart failure (HF) is controversial because many variables seem to influence their outcome. We investigated the predictivity of AF in 3 age groups of outpatients with HF.
Abstract: It has recently emerged that endothelial dysfunction is an early step in the development of atherosclerosis and is mainly characterised by a reduction in the bioavailability of nitric oxide. All of the traditional cardiovascular (CV) risk factors (dyslipidemia, arterial hypertension, hyperglycemia and diabetes) are associated with endothelial dysfunction, and oxidised low-density lipoproteins, the renin-angiotensin axis and insulin resistance play important roles in the pathogenesis of impaired endothelial function. The increased expression of adhesion molecules and pro-inflammatory cytokines leads to abnormal endothelium-dependent vasodilation which could be investigated using vasoreactivity tests such as flow-mediated dilation in the brachial artery. Recently, new evidences showed that the immune system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis with a particular regard towards autoimmunity. The high prevalence of the atherosclerotic process in systemic autoimmune diseases supports the hypothesis of the immune pathogenesis. Evaluating coronary microvascular dysfunction by means of transthoracic echocardiography with non-invasive coronary flow reserve assessment is particularly interesting as it could detect preclinical impairment of coronary microvascular function. The discovery that the mechanisms responsible for endothelial damage have a genetic basis could improve the approach to CV diseases. This review summarises the most important aspects of the pathogenesis and development of endothelial dysfunction, with particular attention to the role of traditional CV risk factors, the usefulness of vasoreactivity tests, and the future perspectives opened by genetic studies.
Abstract: The metabolic syndrome (MetS) has previously been associated with an early marker of atherosclerosis, the carotid intima-media thickness (IMT). From the ISMIR (Ispessimento Medio Intimale e Rischio cardiovascolare [media-intima thickness and cardiovascular risk]) study population of 479 asymptomatic participants, we identified 80 participants with MetS. Carotid IMT and plaques were evaluated by ultrasonography. Blood samples were obtained from all participants. Participants with MetS had a significantly higher prevalence of a carotid IMT > 0.80 mm (P = .004) and of carotid plaques (P < .001) as compared with participants without MetS. Carotid IMT was significantly correlated with fasting triglycerides and fibrinogen levels both in participants with MetS and in those without MetS (all P < .01). In contrast, IMT correlated with fasting plasma glucose, serum creatinine, and uric acid levels only in participants without MetS. Our study confirms the association between MetS and carotid atherosclerosis. In MetS, a significant correlation between carotid IMT and triglycerides and fibrinogen levels was found.
Abstract: Chronic kidney disease is a risk factor for cardiovascular disease, increasing all-cause mortality. Some evidence suggests that endothelial dysfunction is present in the early stages of renal insufficiency, but no data exist about its possible role in the progression of renal disease. Thus, we prospectively evaluated the effect of endothelial function on estimated glomerular filtration rate (eGFR) in essential hypertension.
Abstract: The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established.
Abstract: OBJECTIVE: To examine whether individuals with normal glucose tolerance (NGT), whose 1-h post-load plasma glucose is >or=155 mg/dl, or with impaired glucose tolerance (IGT) have an increased carotid intima-media thickness (IMT), as compared with NGT individuals with 1-h post-load plasma <155 mg/dl. METHODS: Atherosclerosis risk factors, oral glucose tolerance test (OGTT), and ultrasound manual measurement of IMT were analyzed in 400 non-diabetic Caucasians. RESULTS: As compared with individuals with a 1-h post-load plasma glucose <155 mg/dl, NGT individuals with a 1-h post-load plasma glucose >or=155 mg/dl exhibited higher hsCRP (2.0+/-1.5 vs. 1.5+/-1.0, P=0.008), and IMT (0.82+/-0.20 vs. 0.71+/-0.16; P=0.006), and lower insulin sensitivity (71+/-39 vs. 105+/-57; P<0.0001), and IGF-1 levels (214+/-88 vs. 176+/-49; P<0.03). No significant differences were observed in metabolic and cardiovascular risk factors between IGT and NGT subjects with a 1-h post-load glucose >or=155 mg/dl. Of the three glycemic parameters, 1-h and 2-h post-load glucose, but not fasting glucose, were significantly correlated with IMT. In a stepwise multivariate regression analysis in a model including age, gender, and a variety of atherosclerosis risk factors, the three variables that remained significantly associated with IMT were age (P<0.0001), BMI (P<0.0001), and 1-h post-load glucose (P=0.02) accounting for 20.2% of its variation. CONCLUSIONS: NGT subjects with a 1-h post-load glucose >or=155 mg/dl have an atherogenic profile similar to IGT individuals. These data suggest that a cutoff point of 155 mg/dl for the 1-h post-load glucose during OGTT may be helpful in the identification of NGT subjects at increased risk for cardiovascular disease.
Abstract: Carotid intima-media thickness (IMT) and aortic valve sclerosis (AVS) have recently emerged as important predictive factors for cardiovascular (CV) events. However, few data are available on their association and the respective roles of major CV risk factors in determining either condition. In this study, 479 asymptomatic subjects (mean age 58 +/- 13 years, 62% men) were assessed, without histories of CV disease, consecutively referred for comprehensive evaluations by echocardiography and carotid ultrasonography because of the presence of > or = 1 risk factor. Common carotid artery IMT and aortic valve morphology and function were analyzed. The mean IMT was 0.82 +/- 0.19 mm. The prevalence of increased carotid IMT (>0.80 mm) and AVS was 60.8% and 18.4%, respectively. The prevalence of increased IMT was 79.6% in subjects with AVS and 56.5% in those without AVS (relative risk 2.99, 95% confidence interval 1.72 to 5.21, p <0.001). On multivariate analysis, increased IMT was significantly and independently associated with hypertension, dyslipidemia, obesity, family history of CV disease, and age. Only age emerged as an independent predictor of AVS. The presence of both markers was independently associated only with hypertension and age. In conclusion, increased carotid IMT was strongly associated with AVS in a population of asymptomatic patients. IMT and AVS were differently related to individual CV risk factors, and their association seems to be correlated mainly with age and hypertension.
Abstract: BACKGROUND: Postmenopausal women have an increased risk of adverse cardiovascular (CV) events. Similarly, chronic kidney disease (CKD) is a well established risk factor for CV disease and mortality. DESIGN: We evaluated the effect of renal function on the risk of death and CV events in 1500 southern Italian postmenopausal women. METHODS AND RESULTS: Renal function was estimated (e) by glomerular filtration rate (e-GFR) by Modification of Diet in Renal Disease equation. We classified postmenopausal women in two groups of e-GFR (ml/min per 1.73 m(2)): > or =60 (group 1) and less than 60 (group 2). The primary endpoint was major adverse CV events (MACE). The secondary endpoints were total events (MACE + death from any cause), coronary events, and stroke. During the follow-up (mean=72.6 months), there were 200 new CV morbid events. The rate of MACE (per 100 patient-years) was 1.88 and 2.98 in the two groups of e-GFR (P<0.0001). On univariate analysis, the incident risk of CV events was inversely related with the e-GFR values; similarly, in multiple Cox regression model, only the e-GFR maintained an independent association with MACE and secondary end-points. CONCLUSION: For the first time, we demonstrated that the reduction of e-GFR was associated with the increased risk of death and CV events, independently of traditional CV risk factors, menopause duration, and presence of metabolic syndrome.
Abstract: OBJECTIVE: Insulin resistance induces increased pulse pressure (PP), endothelial dysfunction (ED), and reduced bioavailability of endothelium-derived nitric oxide (NO). The genetic background of these 3 cardiovascular risk factors might be partly common. The ENPP1 K121Q polymorphism is associated with insulin resistance and cardiovascular risk. METHODS AND RESULTS: We investigated whether the K121Q polymorphism is associated with increased PP in white Caucasians and with ED in vitro. In 985 individuals, (390 unrelated and 595 from 248 families), the K121Q polymorphism was associated with PP (P=8.0 x 10(-4)). In the families, the Q121 variant accounted for 0.08 of PP heritability (P=9.4 x 10(-4)). This association was formally replicated in a second sample of 475 individuals (P=2.6 x 10(-2)) but not in 2 smaller samples of 289 and 236 individuals (P=0.49 and 0.21, respectively). In the individual patients' data meta-analysis, comprising 1985 individuals, PP was associated with the Q121 variant (P=1.2 x 10(-3)). Human endothelial cells carrying the KQ genotype showed, as compared to KK cells, reduced insulin-mediated insulin receptor autophosphorylation (P=0.03), Ser(473)-Akt phosphorylation (P=0.03), and NO synthase activity (P=0.003). CONCLUSIONS: Our data suggest that the ENPP1 Q121 variant is associated with increased PP in vivo and reduced insulin signaling and ED in vitro, thus indicating a possible pathogenic mechanism for the increased cardiovascular risk observed in ENPP1 Q121 carriers.
Abstract: The AMP-activated protein kinase (AMPK) lies upstream of Akt in the pathway leading to endothelial NO synthase (eNOS) activation. Whether leptin promotes eNOS activation via AMPK-dependent activation of Akt, and which of the two AMPKalpha catalytic subunits is involved, remains unknown. Leptin resistance may be partly attributed to interaction between leptin and C-reactive protein (CRP). We hypothesized that leptin effect on eNOS activation in human aortic endothelial cells might be blunted by direct interaction with human recombinant CRP. Small interfering RNAs (siRNAs) were used to knock down expression of alpha1- or alpha2-AMPK in transient transfection assay to evaluate which is involved in this pathway and whether leptin effect on eNOS activation in human aortic endothelial cells might be blunted by direct interaction with human CRP. siRNA-mediated down-regulation of AMPKalpha1, but not AMPKalpha2, abolished leptin-induced Akt-Ser(473) phosphorylation, eNOS-Ser(1177) phosphorylation, eNOS activation, and cGMP accumulation. By contrast, siRNA-mediated knockdown of Akt1 did not affect AMPKalpha1 phosphorylation, but it abolished leptin-induced phosphorylation of Akt-Ser(473) and eNOS-Ser(1177), suggesting that Akt functions downstream of AMPKalpha1. Preincubation of leptin with human recombinant CRP impaired leptin-induced AMPK activation, eNOS-Ser(1177) phosphorylation, eNOS activity, and intracellular cGMP accumulation. The data are consistent with a model implicating an AMPKalpha1-->Akt-->eNOS pathway leading to NO production in response to leptin supporting the idea that interaction between leptin and CRP may have a role in impairing leptin effect on eNOS activation, suggesting a link between leptin resistance, low-grade inflammation, and endothelial dysfunction.
Abstract: Atrial fibrillation is the most common cardiac arrhythmia, and no current therapy is ideal for control of this condition. Experimental studies suggest that angiotensin II-receptor blockers (ARBs) can influence atrial remodeling, and some clinical studies suggest that they may prevent atrial fibrillation.
Abstract: OBJECTIVE: Essential hypertension is a clinical condition associated with insulin resistance and progressive impairment of renal function that increases cardiovascular events. Insulin-like growth factor (IGF)-1, which is inversely related to insulin levels, increases renal blood flow and glomerular filtration rate (GFR). The aim of the present study was to investigate the relationship between circulating IGF-1 levels and GFR in a group of never treated hypertensive patients. METHODS: The study population consisted of 537 outpatients presenting at Catanzaro University Hospital. To participate in this study, patients have to had a systolic clinic blood pressure (BP) of more than 140 and less than 180 mmHg or a diastolic BP of more than 90 and less than 100 mmHg or both on at least two separate visits. Blood samples were at least obtained after 8-10 h in fasting conditions. The GFR was estimated by the modification of diet in renal disease equation. Serum creatinine was measured in the laboratory by an automated technique. Insulin sensitivity was estimated by using the homeostasis model assessment index calculated from the fasting glucose and insulin concentrations. RESULTS: Both fasting insulin and homeostasis model assessment significantly (P < 0.0001) show an inverse relationship with GFR decline, whereas IGF-1 presents a significant and direct relationship with it. As expected, IGF-1 and fasting insulin resulted in an inverse relationship between them (r = -0.318; P < 0.0001). The strongest predictor of GFR resulted IGF-1, accounting for a 9.8% of its variation; the addition of fasting insulin and systolic BP accounts for another 3.7% of the variation. CONCLUSION: We demonstrate a significant relationship between IGF-1 and GFR in a large sample of never treated hypertensive patients, probably as consequence of insulin resistance/hyperinsulinemia, which is a very frequent condition in high BP.
Abstract: BACKGROUND: It has been shown that subjects with normal glucose tolerance (NGT), whose plasma glucose (PG) levels do not return to their fasting PG level within 2 h during an oral glucose tolerance test (OGTT) (Group I), have a significantly higher risk to develop type 2 diabetes than NGT subjects whose 2-h glucose returns to, or drops below, the fasting level (Group I). However, it is still unsettled whether individuals in Group II have a more atherogenic profile than Group I subjects. METHODS: To address this issue, we examined 266 non-diabetic offspring of type 2 diabetic patients, recruited in the context of EUGENE2 cross-sectional study. All subjects underwent an euglycaemic-hyperinsulinemic clamp to assess glucose tolerance and insulin sensitivity. Furthermore, cardiovascular risk factors and ultrasound measurement of carotid intima-media thickness (IMT) were evaluated. RESULTS: Individuals in Group II exhibited significantly higher waist circumference, blood pressure, triglycerides, 2-h post-load PG, hsC-reactive protein, interleukin-6, insulin-like growth factor-1 (IGF-1), IMT, and lower insulin sensitivity than subjects in Group I. CONCLUSIONS: Subjects with NGT, whose PG concentration does not return to their fasting PG level within 2 h during OGTT, have an atherogenic profile, suggesting that performing OGTT with measurement of PG every 30 min may be useful to assess the risk for cardiovascular disease in glucose-tolerant subjects.
Abstract: BACKGROUND AND AIM: Weight gain is associated with a decline in insulin sensitivity and a compensatory increase in insulin secretion. IGF-1 is a plausible candidate to explain these divergent phenomena. In this cross-sectional study, we analyzed the relationship between IGF-1 levels, insulin sensitivity and secretion in 110 nondiabetic subjects with a wide range of BMI to verify this hypothesis. METHODS AND RESULTS: Subjects underwent OGTT, IVGTT and euglycemic-hyperinsulinemic clamp. HOMA-beta, IVGTT-derived and OGTT-derived indexes for first-phase and second-phase insulin secretion were higher in obese as compared with overweight and normal-weight groups, while glucose disposal was lower. IGF-1 levels were negatively correlated with IVGTT-derived and OGTT-derived indexes first-phase and second-phase insulin secretion, and positively correlated with glucose disposal. These correlations were no longer significant after adjustment for BMI. In a multivariate analysis, the variables associated with glucose disposal were IGF-1, age, triglycerides, and 2-h post-load glucose accounting for 23.4% of its variation. When BMI was entered into the model, the variables associated with glucose disposal were triglycerides, 2-h post-load glucose and BMI accounting for 27.2% of variation. In a multivariate analysis, the only variable associated with IVGTT-derived first-phase and second-phase insulin secretion was IGF-1 accounting for 10.4% and 15.1% of variation, respectively. When BMI was entered into the model, it became the only variable associated with both first-phase and second-phase insulin secretion accounting for 25.7% and 37.6% of variation, respectively. CONCLUSION: These data suggest that progressive reduction in IGF-1 levels may be involved in obesity-related changes in both insulin sensitivity and secretion.
Abstract: We analyzed in NYHA I hypertensives the interactions between Carotid Intima-Media Thickness (IMT), Hypertension and Cardiovascular (CV) risk factors and relationships between IMT, CV risk factors and left ventricular (LV) geometric remodelling. 198 asymptomatic, never treated, essential hypertensives (age: 58.2 +/- 13) and 67 (age-gender matched) healthy subjects, were studied. Complete clinical examination, 2D Doppler echocardiography and vascular echography were performed in all study subjects. Major values of IMT are present in concentric LVH. Distribution of IMT among risk factors groups shows an higher IMT respect to increasing number of risk factors (P < 0.001). Significant correlation are present between pulse pressure and IMT (P < 0.006; r = 0.19) and IMT and LVM (P < 0.0001; r = 0.35). Altered patterns of LV geometry and carotid structural changes occur in many patients with essential hypertension. LVH or carotid remodeling are greater in elderly, in patients with higher systolic BP and with associated CV risk factors.
Abstract: The level to which systolic blood pressure should be controlled in hypertensive patients without diabetes remains unknown. We tested the hypothesis that tight control compared with usual control of systolic blood pressure would be beneficial in such patients.
Abstract: CONTEXT: The prevalence of type 2 diabetes (T2D), particularly among young adults, has been rising steadily during the past 2 decades. T2D, especially in its early-onset subtype, is under genetic control. TRIB3 inhibits insulin-stimulated Akt phosphorylation and subsequent insulin action. A TRIB3 gain-of-function polymorphism, Q84R (rs2295490), impairs insulin signaling. OBJECTIVE: The objective of the study was to verify the association of TRIB3 Q84R with: 1) T2D, either subtyped or not according to age at diagnosis (early-onset, <45 yr, or >or= 45 yr); 2) insulin secretion and sensitivity in nondiabetic individuals; or 3) in vitro insulin secretion from isolated human islets. DESIGN: Four different case-control samples comprising a total of 5,469 whites were examined. Insulinogenic and insulin sensitivity indexes and their interplay (disposition index) were assessed in 645 nondiabetic individuals at oral glucose tolerance test, glucose (16.7 mmol/liter)-induced in vitro insulin secretion was assessed in islets isolated from 54 nondiabetic donors. RESULTS: In the whole sample, the R84 variant was nominally associated with T2D (odds ratio 1.17, 95% confidence interval 1.00-1.36, P = 0.04). When stratifying according to age of diabetes onset, R84 carriers had an increased risk of early-onset T2D (odds ratio 1.32, 95% confidence interval 1.10-1.58, P = 0.002). Among 645 nondiabetic subjects, R84 carriers had higher glucose levels (P = 0.005) and lower insulinogenic (P = 0.03) and disposition index (P = 0.02) during the oral glucose tolerance test. R84 islets were more likely to display relatively low glucose-stimulated insulin release (P = 0.04). CONCLUSIONS: The TRIB3 R84 variant is associated with early-onset T2D in whites. Alteration in the insulin secretion/insulin sensitivity interplay appears to underlie this association.
Abstract: BACKGROUND AND PURPOSE: It is recognized that arteries can enlarge to compensate atherosclerosis. The role of diameter enlargement of unaffected arteries is not well known. We hypothesized that brachial and common carotid arteries diameters were larger in subjects with carotid atherosclerosis compared to subjects without these lesions. METHODS: We measured diameters in the common carotid and brachial arteries. Intimal medial thickness (IMT) of carotid arteries and carotid atherosclerosis were also evaluated using ultrasound in 83 cases and 83 disease-free control subjects. RESULTS: Common carotid and brachial diameter was greater in cases (subjects with carotid atherosclerosis) than controls (subjects without carotid atherosclerosis) after adjustment for confounding variables (P<0.02). Common carotid diameter was also larger in individuals with greater IMT (P<0.0001), whereas brachial artery diameter was not. Subjects with more than one carotid plaque had larger arterial diameters than those with one or without plaques. CONCLUSIONS: Common carotid and brachial artery diameters are both larger in cases than controls. This result suggests that vascular remodeling is a systemic process and not only a local response to atherosclerosis. The relationship between diameters and burden of disease could also suggest a link between vascular remodeling and severity of disease. Finally, if confirmed in prospective studies, brachial artery diameter could help to identify subjects at high cardiovascular risk, at least in postmenopausal women.
Abstract: CONTEXT: Accumulating evidence suggests that IGF-I has protective vascular effects, supporting the possibility that IGF-I deficiency may contribute to atherosclerosis. However, the relationship between plasma IGF-I levels and endothelium-dependent vasodilatation is still unsettled. OBJECTIVE: We designed this present study to test the hypothesis that low-plasma IGF-I levels are associated with reduced endothelial function independently classical cardiovascular risk factors. SETTING: Outpatients were included in the study. PATIENTS: A total of 100 never-treated hypertensive Caucasian subjects participating in the CAtanzaro MEtabolic RIsk factors Study was recruited. INTERVENTIONS: Subjects underwent forearm blood flow (FBF) evaluation by strain-gauge plethysmography in response to increasing doses of acetylcholine (ACh) (Sigma, Milan, Italy) and sodium nitroprusside (Malesci, Florence, Italy). Insulin sensitivity was estimated by the homeostasis model assessment index. RESULTS: Plasma IGF-I levels were significantly correlated with age (r = -0.300; P = 0.001), high-density lipoprotein serum cholesterol (r = 0.211; P = 0.017), homeostasis model assessment index (r = -0.355; P <0.0001), systolic blood pressure (r = -0.174; P = 0.042), glomerular filtration rate (r = 0.228; P = 0.011), and ACh-stimulated FBF (r = 0.565; P <0.0001). In a stepwise forward multivariate regression analysis, the strongest predictors of ACh-stimulated FBF response were plasma IGF-I levels, accounting for 31.9% of its variation. CONCLUSIONS: These results demonstrate, for the first time, that low-plasma IGF-I levels are highly associated with reduced endothelial function, an early step in atherogenesis process.
Abstract: Epidemiological, clinical and laboratory studies have provided definitive evidence that physical activity is able to improve fitness and reduce cardiovascular morbidity and mortality. Moreover, physical exercise also seems to significantly reduce the risk of developing other chronic diseases such as obesity, osteoporosis, diabetes, tumours and depression. Promoting physical activity in the general population is therefore one of the primary objectives of our healthcare institutions. Although the benefits of an active lifestyle have been demonstrated by numerous scientific data, only a few numbers of Italians and Europeans take up regular physical exercise. To promote physical activity, both in the general population and in subjects affected by cardiovascular diseases, the Italian Federation of Sports Medicine, the Italian Society of Sports Cardiology, the Italian Association of Hospital Cardiologists, the Italian Society of Cardiology, the Italian Association of Out-of-Hospital Cardiologists and the Italian Group of Cardiac Rehabilitation have promoted the constitution of a Task Force made up of experts in the fields of sports cardiology. The document produced by the Task Force is intended for healthcare professionals, and deals with the role of physical activity in the prevention and treatment of cardiovascular diseases. It examines the beneficial effects of physical activity on the cardiovascular system, while analysing the possible risks involved and how they can be avoided. The rational principles underlying the prescription of physical activity in the cardiologic setting are described, as are the modalities for prescribing such activity.
Abstract: OBJECTIVE: Type 2 diabetes and essential hypertension are major risk factors for cardiovascular diseases. Endothelial dysfunction is an early step in the development of atherosclerosis and has been demonstrated in hypertensive and diabetic patients. RESEARCH DESIGN AND METHODS: We designed this study to determine whether forearm endothelial dysfunction is an independent predictor of type 2 diabetes in patients with essential hypertension. We enrolled 400 white never-treated hypertensive outpatients, free of type 2 diabetes at the time of the first evaluation. Endothelium-dependent vasodilation was investigated by intra-arterial infusion of acetylcholine. Insulin resistance was estimated by homeostasis model assessment. RESULTS: During the follow-up (4.5 +/- 1.6 years), 44 patients developed type 2 diabetes. The event rate was 2.4 events/100 patient-years. In a multivariate Cox regression analysis, the peak percentage increase in acetylcholine-stimulated forearm blood flow (hazard ratio [HR] 0.77 [95% CI 0.61-0.99]; P = 0.04) and C-reactive protein (1.16 [1.03-1.32]; P = 0.01) resulted in the only independent predictors of type 2 diabetes. CONCLUSIONS: An impaired vasodilatory response to acetylcholine predicts development of type 2 diabetes in patients with essential hypertension. Present data also extend recent findings regarding a possible inflammatory pathogenesis of type 2 diabetes and suggest a new approach in treatment of essential hypertension.
Abstract: OBJECTIVE: To examine the relationship between plasma IGF-1 and interleukin-6 (IL-6) levels in Caucasian nondiabetic subjects and evaluate the association of IGF-1 and IL-6 with the cardiometabolic risk factors characterizing metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS: The study group consisted of 186 Caucasian nondiabetic subjects who underwent an oral glucose tolerance test and an euglycemic-hyperinsulinemic clamp. A logistic regression analysis, adjusted for age and sex, was used to determine the association between tertiles of IGF-1 and IL-6 and the MetS and its components. RESULTS: After adjusting for age and sex, both IGF-1 and IL-6 were correlated with insulin resistance and individual components of MetS, but in opposite directions. In the logistic regression model adjusted for age and sex, higher IL-6 and lower IGF-1 levels confer increased risk of having MetS and its two underlying pathophysiological abnormalities, i.e., visceral obesity and insulin resistance. CONCLUSIONS: The present results raise the possibility that lowered protection against inflammation, i.e., lower IGF-1 levels, may have a role in the development of MetS and its features, resulting in an imbalance between proinflammatory and anti-inflammatory proteins.
Abstract: Metabolically obese but normal-weight (MONW) individuals present metabolic disturbances typical of obese individuals. Additionally, metabolically healthy but obese (MHO) individuals have been identified who are relatively insulin sensitive and have a favorable cardiovascular risk profile. We compared insulin secretion patterns of MONW and MHO with those of two age-matched groups comprising nonobese individuals or obese insulin-resistant subjects, respectively. To this end, 110 nonobese subjects and 87 obese subjects were stratified into quartile based on their insulin-stimulated glucose disposal (M(FFM)). Insulin secretion was estimated by acute insulin response (AIR) during an intravenous glucose-tolerance test (IVGTT), and the disposition index was calculated as AIR x M(FFM). We found that, as defined, M(FFM) was lower in MONW, who exhibited higher triglycerides, free-fatty acid (FFA), and 2-h postchallenge glucose levels compared to normal nonobese group. Insulin secretion was higher in MONW than in normal nonobese subjects, but disposition index was lower in MONW. Disposition index did not differ between MONW and insulin-resistant obese. M(FFM) was higher in MHO who exhibited lower waist circumference, blood pressure (BP), triglycerides, FFA, insulin levels, and higher high-density lipoprotein (HDL) cholesterol compared to insulin-resistant obese. Insulin secretion did not differ between insulin-resistant obese and MHO, but disposition index was lower in the former group. In conclusion, MONW and insulin-resistant obese showed decreased compensatory insulin secretion compared to normal nonobese and MHO subjects, respectively. Because these subjects also exhibited a worse metabolic risk profile, these findings may account for their increased risk for type 2 diabetes.
Abstract: BACKGROUND: Left ventricular (LV) hypertrophy and decreased kidney function are well-established cardiovascular risk factors in hypertensive patients. STUDY DESIGN: We investigated the relationship between creatinine level, creatinine clearance, and estimated glomerular filtration rate (eGFR) with LV mass (LVM) in a cross-sectional study. PREDICTORS: eGFR and serum creatinine level. OUTCOME: LVM index (LVMI). SETTING & PARTICIPANTS: 400 patients with untreated uncomplicated essential hypertension. MEASUREMENTS: LVMI, eGFR (Modification of Diet in Renal Disease Study equation), Framingham risk factors, and a series of specific risk factors, ie, endothelial function (acetylcholine [ACh]-stimulated forearm blood flow [FBF]), insulin sensitivity (Homeostatic Model Assessment for insulin resistance [HOMA-R] index), C-reactive protein (CRP), and uric acid. RESULTS: Both eGFR and creatinine level were significantly related to LVMI (r = -0.34 and r = 0.35; P < 0.001). In a multiple regression model adjusting for Framingham risk factors, eGFR was independently associated with LVMI. However, this association, although highly significant, lost substantial strength after adjustment for such specific risk factors as HOMA-R index, ACh-stimulated FBF, CRP level, and uric acid level. eGFR interacted with insulin resistance in explaining the variability in LVMI (P = 0.007). LIMITATIONS: The cross-sectional nature of this study precludes cause-effect conclusions. CONCLUSIONS: Independently of other risk factors, decreased kidney function contributes to explain the variability in LVMI in patients with untreated uncomplicated essential hypertension. This association is attributable in part to the link between eGFR and such specific risk factors as HOMA-R index, ACh-stimulated FBF, CRP level, and uric acid level. Decreased kidney function and insulin resistance interact in explaining the variability in LVMI in these patients.
Abstract: The hypothesis that a therapeutic strategy aimed at lowering systolic blood pressure (SBP) below 130 mm Hg is superior to a conventional strategy targeted at below 140 mm Hg in hypertensive subjects has never been tested in randomized intervention studies. The Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica (Cardio-Sis) is a multi-centre study in non-diabetic, treated hypertensive subjects aged >55 years with uncontrolled SBP (>or=150 mm Hg) and at least one additional cardiovascular risk factor (ClinicalTrials.gov identifier: NCT00421863). Subjects are randomized to an SBP goal <140 mm Hg (conventional) or <130 mm Hg (aggressive), independently of baseline and achieved diastolic blood pressure (BP). Anti-hypertensive drugs dispensed for the study are restricted to a list of specific drugs. The primary outcome of the study is based on regression of left ventricular hypertrophy (LVH) using electrocardiography (ECG). The hypothesis is that subjects without LVH regression or with new development of LVH 2 years after randomization are 19% with conventional strategy and 12% with aggressive strategy. Secondary outcome is a composite pool of pre-specified fatal and non-fatal events. Randomization of 1111 subjects was completed by February 2007. Mean age of subjects (41% men) at entry was 67 years. BP was 158/87 mm Hg (systolic/diastolic) and prevalence of LVH by ECG was 21.0%. Cardio-Sis is the first randomized study specifically designed to compare two different SBP goals. Results will be broadly applicable to subjects with uncontrolled SBP under anti-hypertensive treatment.
Abstract: Monocyte-chemoattractant-protein (MCP)-1 and its receptor CCR2 have been shown to play a pivotal role in vascular inflammation and atherosclerotic plaque formation. However, it is currently unclear whether MCP-1/CCR2 triggered inflammation affects nitric oxide (NO)-bioavailability, hence influencing vascular function, a sign of early atherosclerosis. Therefore, we sought to investigate the association between serum levels of MCP-1 and NO-bioavailability, expressed as flow mediated dilation (FMD) in vivo, and the impact of CCR2 gene variations on FMD. We studied a German population of 242 prediabetic individuals (144 women, 98 men; mean age 45+/-0.8 years) via FMD by high-resolution ultrasound (13MHz). In order to replicate our findings, a second, independent population (n=115; 44 women, 77 men; mean age 48+/-1.0 years) (total=357 individuals) from Italy was studied. Vascular function in the Italian population was studied via intra-arterial application of acetylcholine. MCP-1 serum-levels were assessed by ELISA and CCR2 polymorphisms were determined by sequencing. MCP-1 serum levels showed no association with FMD (p=0.90), whereas the CCR2 promoter polymorphism was associated with elevated FMD (T/T: 5.6+/-0.3%; T/A: 6.7+/-0.4%; A/A: 8.3+/-0.8%; p=0.01) after adjusting for possible confounders. These results were confirmed in the independent Italian population (A/A: 97.1+/-20.3 vs. T/T: 60.5+/-5.6% forearm blood-flow increase; p<0.05). When testing for the functional relevance of the T-960A (rs3918359) polymorphism, we found that the A/A-genotype was associated with moderately increased protein binding in EMSA, increased promoter activity in luciferase assays and reduced transendothelial monocyte migration. In conclusion, MCP-1 serum levels do not reflect endothelial function in vivo in prediabetic individuals. However, the functionally relevant CCR2 promoter polymorphism T-960A (rs3918359) is associated with elevated vascular function. This might be due to reduced subendothelial inflammation, mediated by reduced transendothelial monocyte-migration ability.
Abstract: Epidemiological, clinical and laboratory studies have provided definitive evidence that physical activity is able to improve fitness and reduce cardiovascular morbidity and mortality. Moreover, physical exercise also seems to significantly reduce the risk of developing other chronic diseases such as obesity, osteoporosis, diabetes, tumours and depression. Promoting physical activity in the general population is therefore one of the primary objectives of our healthcare institutions. Although the benefits of an active lifestyle have been demonstrated by numerous scientific data, only a few numbers of Italians and Europeans take up regular physical exercise. To promote physical activity, both in the general population and in subjects affected by cardiovascular diseases, the Italian Federation of Sports Medicine, the Italian Society of Sports Cardiology, the Italian Association of Hospital Cardiologists, the Italian Society of Cardiology, the Italian Association of Out-of-Hospital Cardiologists and the Italian Group of Cardiac Rehabilitation have promoted the constitution of a Task Force made up of experts in the fields of sports cardiology. The document produced by the Task Force is intended for healthcare professionals and deals with the role of physical activity in the prevention and treatment of cardiovascular diseases. It examines the beneficial effects of physical activity on the cardiovascular system, while analysing the possible risks involved and how they can be avoided. The rational principles underlying the prescription of physical activity in the cardiologic setting are described, as are the modalities for prescribing such activity.
Abstract: OBJECTIVES: Endothelium-dependent vasodilatation is impaired in essential hypertension. Besides traditional and emerging cardiovascular risk factors, genetic factors may also promote deleterious alterations of endothelial physiology. The aim of the present study was to investigate the relationship between the 460Trp allele of ADD1 and endothelium-dependent vasodilation in 110 never-treated hypertensive patients. METHODS: Forearm blood flow (FBF) was measured during intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) at increasing doses. Analysis of endothelium-dependent and endothelium-independent vasodilation was tested according to ADD1 genotype. RESULTS: The FBF values at the three incremental doses of ACh were 5.22 +/- 0.24 (+76%), 8.64 +/- 0.45 (+193%) and 14.74 +/- 0.71 (+395%) ml/100 ml of tissue per min for Gly460Gly and 4.63 +/- 0.20 (+51%), 6.84 +/- 0.36 (+123%) and 11.22 +/- 3.8 (+269%) ml/100 ml of tissue per min for 460Trp. Thus, ACh-stimulated FBF was significantly reduced in hypertensive subjects carrying the 460Trp allele of ADD1 (P < 0.001). SNP-stimulated FBF was not affected by ADD1. CONCLUSIONS: The main finding in this study was that in essential hypertensives the 460Trp allele of ADD1 is strongly associated with an impaired endothelium-dependent vasodilation, a powerful predictor of cardiovascular risk.
Abstract: BACKGROUND: The interpretation of serial electrocardiographic (ECG) changes in hypertensive subjects is uncertain. We tested the hypothesis that serial changes in repolarization and voltage are independent determinants of outcome. METHODS: The Hypertrophy at ECG And its Regression during Treatment (HEART) Survey was a prospective observational study performed at 61 centers. We studied 711 subjects with hypertension and ECG left-ventricular hypertrophy (LVH) at entry. Tracings from 496 subjects at entry and one or more visits during follow-up were available for central reading. RESULTS: The prevalence of ECG LVH progressively decreased by 49.6% at 3 years. The crude rate of a prespecified primary composite end point of cardiovascular events was 4.17 per 100 subjects per year (95% confidence interval [CI], 3.27 to 5.33). We used Cox regression models of ECG LVH indexes as time-varying covariates at baseline and at follow-up. Time-varying LVH, defined as an absence of ST-T alterations ("strain"), was associated with a lower event rate hazard ratio (HR), 0.47; 95% CI, 0.28 to 0.78; P = .0035), whereas the LVH changes defined in terms of ECG voltages did not achieve significance (HR, 0.91; 95% CI, 0.74 to 1.13; P = .39). The crude event rate in subjects with versus without in-treatment ST-T alterations on the last available ECG before the event or before censoring was 8.38 versus 3.17 per 100 subjects per year (P < .0001). CONCLUSIONS: In this study of subjects with hypertension and ECG LVH at entry, serial changes in repolarization significantly predicted the prognosis, independent of voltage change (which was not significantly predictive in this study). The persistence or new development of ST-T alterations identifies subjects at very high risk of cardiovascular events.
Abstract: We investigated the relationship between microalbuminuria (an indicator of systemic and renal endothelial dysfunction), inflammation (high-sensitivity C-reactive protein [CRP]) and endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm) in 110 never-treated subjects with uncomplicated essential hypertension and serum creatinine within the normal range. Microalbuminuria was associated with the hemodynamic response to ACh (r=0.27, p=0.006) and with serum creatinine (r=0.34, p<0.001), and these associations held true in multivariate analyses. On the other hand, microalbuminuria was largely independent of serum CRP. Since microalbuminuria, response to ACh and serum CRP are all considered risk factors for renal insufficiency and since these factors were significantly related to creatinine at univariate analysis, we tested their association with creatinine in a multiple regression model including also the full set of Framingham risk factors. In this analysis, serum CRP and microalbuminuria maintained a significant association with serum creatinine, while the hemodynamic response to ACh lost substantial predictive value for serum creatinine. In conclusion, microalbuminuria in essential hypertension is weakly related to the vasodilatory response to ACh and unrelated to inflammation but maintains an independent link with serum creatinine. Collectively, these associations suggest that microalbuminuria reflects a local (renal) endothelial dysfunction and that it may contribute to renal impairment independently of inflammation and hemodynamic endothelial dysfunction in hypertensive patients.
Abstract: To clarify the role of gene polymorphisms on the effect of losartan and losartan plus hydrochlorothiazide on blood pressure (primary end point) and on cardiac, vascular and metabolic phenotypes (secondary end point) after 4, 8, 12, 16 and 48 weeks treatment, an Italian collaborative study - The Study of the Pharmacogenomics in Italian hypertensive patients treated with the Angiotensin receptor blocker losartan (SOPHIA) - on never-treated essential hypertensives (n = 800) was planned. After an 8 week run-in, losartan 50 mg once daily will be given and doubled to 100 mg at week +4 if blood pressure is more than 140/90 mmHg. Hydroclorothiazide 25 mg once daily at week +8 and amlodipine 5 mg at week +16 will be added if blood pressure is more than 140/90 mmHg. Cardiac mass (echocardiography), carotid intima-media thickness, 24 h ambulatory blood pressure, homeostatic model assessment (HOMA) index, microalbuminuria, plasma renin activity and aldosterone, endogenous lithium clearance, brain natriuretic peptide and losartan metabolites will be evaluated. Genes of the renin-angiotensin-aldosterone system, salt sensitivity, the beta-adrenergic system and losartan metabolism will be studied (Illumina custom arrays). A whole-genome scan will also be performed in half of the study cohort (1M array, Illumina 500 GX beadstation).
Abstract: OBJECTIVE: It is well known that coronary heart disease incidence increases in women after menopause. This phenomenon was related to reduced levels of female sex hormones. Estrogen decline, however, is not the only hormonal change during the postmenopausal period and estrogen administration did not protect women from cardiovascular disease. Therefore, it is justified to explore other hormonal changes. The role of androgens is still controversial. The aim of the present study was to investigate the relationship between endogenous sex hormones and endothelial function, measuring the brachial artery flow-mediated dilation. METHODS AND RESULTS: Sixty postmenopausal women were consecutively enrolled and underwent a clinical and biochemical examination. Brachial artery flow-mediated dilation was also evaluated by ultrasound. After correction for confounding variables, testosterone was positively correlated to flow-mediated dilation (beta=0.277, P=0.03). Indeed, women in the lowest testosterone tertile had a flow-mediated dilation smaller than that in the highest tertile (P=0.02). CONCLUSIONS: This result could suggest that the development of cardiovascular disease after menopause is due not only to estrogen decline but also to androgen decline. More studies are needed to evaluate the role of androgen replacement therapy on postmenopausal women with low level of this hormone.
Abstract: OBJECTIVES: Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) interfere with cardiac mass (left ventricular mass; LVM) development. We investigated the role of the GH/IGF-1 axis on LVM and ventricular geometry in a group of 230 never-treated hypertensive patients. METHODS: Partition values for left ventricular hypertrophy (LVH) were 125 g/m2 for both women and men. Insulin resistance was estimated by the homeostasis model assessment (HOMA) index. RESULTS: A significant inverse correlation was observed between IGF-1 and both fasting insulin (r = -0.249; P < 0.0001) and GH (r = -0.218; P < 0.0001). Systolic blood pressure (157.3 +/- 13.6 versus 149.4 +/- 12.8 mmHg; P < 0.001), fasting insulin (17.4 +/- 8.5 versus 11.4 +/- 6.0 microU/l; P < 0.0001), HOMA (4.4 +/- 2.3 versus 2.9 +/- 1.6; P < 0.0001) and GH (1.0 +/- 1.0 versus 0.4 +/- 0.5 ng/ml; P < 0.0001) were significantly higher in patients with LVH; on the contrary, IGF-1 values (119.1 +/- 47.8 versus 160.1 +/- 75.5 ng/ml; P < 0.0001) were higher in patients without LVH. In a logistic regression analysis, the strongest independent predictors of LVH were GH [relative risk (RR) = 2.078; 95% confidence interval (CI) = 1.364-3.163], HOMA (RR = 1.345; 95% CI = 1.133-1.596), IGF-1 (RR = 0.993; 95% CI = 0.998-0.999) and systolic blood pressure (RR = 1.036; 95% CI = 1.013-1.060). IGF-1 showed an opposite trend in patients with eccentric and concentric hypertrophy. CONCLUSIONS: Present data demonstrate that the increase in LVM prevalent in human essential hypertension is directly associated with serum GH levels and inversely related to circulating IGF-1.
Abstract: OBJECTIVE: Serum uric acid (SUA) is associated with cardiovascular disease (CVD). However it is still disputed whether the relationship is mediated by other risk factors such as obesity, dyslipidaemia, hypertension and insulin resistance. We explored the association of the uric acid level with carotid intima-media thickness (IMT), a well known marker of CVD, in postmenopausal healthy women. METHODS: We consecutively enrolled postmenopausal women undergoing a screening for health evaluation. After an accurate clinical examination, and a biochemical evaluation, the enrolled subjects underwent B mode ultrasonography to assess common carotid intima media thickness. RESULTS: Among 234 women aged 45-70 years, the uric acid level is associated with carotid IMT independently of other prognostic factors (p=0.03). In particular, women in the highest tertiles of uric acid level have a greater IMT than women in the lowest tertile (p=0.007). CONCLUSIONS: Independently of other cardiovascular risk factors, SUA levels are associated with carotid IMT even in subjects without the metabolic syndrome. This confirms and expands the role of uric acid in the determinism of CVD. Prospective trials would be useful to evaluate interventions aimed at lowering the uric acid level.
Abstract: The aim of this study was to investigate whether insulin resistance is independently associated with early manifestations of atherosclerosis. To this end, 176 normotensive offspring of type 2 diabetic patients were subjected to euglycemic hyperinsulinemic clamp to assess insulin sensitivity. Early atherosclerosis was studied by ultrasonography of the common carotid artery. Of the total 176 subjects, 145 were glucose tolerant, 18 had impaired fasting glucose, and 13 had impaired glucose tolerance. Univariate correlations showed that age, body mass index, waist, blood pressure, 2-h postchallenge glucose, fasting insulin, triglycerides, interleukin-6, fibrinogen, and white blood cell count were significantly correlated with carotid intima-media thickness (IMT), whereas HDL cholesterol and glucose disposal showed a negative correlation. A stepwise multivariate regression analysis including sex, age, waist circumference, smoking status, systolic blood pressure, diastolic blood pressure, triglyceride, HDL cholesterol, 2-h postchallenge glucose, plasma IL-6, fibrinogen, white blood cell count, insulin-stimulated glucose disposal, and fasting insulin showed that the four variables that remained significantly associated with carotid IMT were waist circumference, insulin-stimulated glucose disposal, white blood cell count, and diastolic blood pressure, accounting for 33.7% of its variation. These findings support the concept that insulin sensitivity, rather than plasma insulin levels, is associated with early atherosclerosis in nondiabetic normotensive offspring of type 2 diabetic patients.
Abstract: BACKGROUND: While the relationship between impaired glucose tolerance (IGT) and circulating interleukin-6 (IL-6) is well established, there is no information whether IL-6 levels are elevated in impaired fasting glucose (IFG). METHODS: To this end, we examined the relationship between plasma IL-6 concentration and different degrees of glucose homeostasis in a cohort of 470 Italian Caucasian subjects comprising 236 normal glucose tolerant (NGT), 49 IFG, 51 IGT, and 134 type 2 diabetic subjects. RESULTS: We observed that IL-6, CRP and fibrinogen levels were higher in subjects with IGT or type 2 diabetes as compared with NGT and IFG subjects. Univariate correlations between IL-6 concentrations and metabolic variables in the whole cohort showed that IL-6 levels were positively correlated with age, BMI, waist, systolic and diastolic blood pressure, fasting plasma glucose, triglycerides, CRP, fibrinogen, and negatively correlated with insulin sensitivity, IGF-I and HDL. In a subgroup analysis including NGT, IFG and IGT (n = 336), IL-6 levels were positively correlated with age, BMI, waist, systolic and diastolic blood pressure, triglycerides, CRP, fibrinogen, fasting insulin, 2 h post-load glucose, and negatively correlated with insulin sensitivity, IGF-I and HDL. Stepwise linear regression analysis in a model including gender, age, BMI, waist, glucose tolerance status, fasting plasma glucose, 2 h post-load glucose, triglycerides, HDL, fasting insulin, and insulin sensitivity revealed that waist was the only independent variable associated with IL-6 levels accounting for 21.0% of its variation (P < 0.0001). CONCLUSIONS: These data show that IGT and type 2 diabetes, but not IFG, are associated with elevated plasma IL-6 levels.
Abstract: BACKGROUND: Clinical, echocardiographic results and determinants of atrial fibrillation (AF) recurrence following AF ablation during mitral valve surgery (AFAMVS) were evaluated. METHODS: Fifty-two patients undergoing radiofrequency AFAMVS between January 2003 and December 2005, underwent serial echocardiographies with tissue Doppler imaging to assess atrio-ventricular function. Recurrence of AF, hospital readmission, episodes of congestive heart failure (CHF) were recorded. Predictors for AF-recurrence were evaluated. RESULTS: At a 29.5+/-8.6 months of follow-up (100% complete), 78.8% patients were in sinus rhythm (SR). Freedom from AF-recurrence was 64.6+/-0.76%, from hospital readmission 88.9+/-0.47%, from CHF 91.6+/-0.63%. SR-patients demonstrated better freedom from hospital readmission (97.4 vs 60.6%; p=0.0003) and from CHF (100 vs 72.7%; p=0.008) during follow-up. At follow-up SR-patients demonstrated left atrial (preoperative 5.8+/-0.8 cm vs follow-up 5.1+/-0.9; p=0.013) and ventricular reverse remodelling (preoperative LVDd 5.7+/-1.1cm vs follow-up 5.2+/-1.1; p=0.048 - preoperative LVDs 4.0+/-1.4 vs follow-up 3.6+/-1.1; p=0.036). E/A ratio was normal in 73.1% (92.7% of SR-patients). TDI at the level of the left lateral annulus showed an improved left ventricular systole (Sm), and diastole (Em, E/Em) of SR-patients, compared with AF-patients (Sm 9.40+/-1.74 vs 7.72+/-1.5, p=0.0001; Em: 10.45+/-1.98 vs 7.68+/-0.72, p=0.001; E/Em: 0.07+/-0.02 vs 0.10+/-0.04, p=0.0001). Large preoperative atrial diameter (OR=5.81; p=0.002), preoperative NYHA-IV (OR=3.55; p=0.001), high diuretics at discharge (OR=1.27; p=0.03), tricuspid insufficiency at follow-up (OR=2.31; p=0.02) were independent predictors of AF-recurrence. CONCLUSIONS: Radiofrequency AFAMVS achieves 78.8% of SR recovery. Maintenance of SR improves clinic, haemodynamic and echocardiographic endpoints. Pre- and post-operative cardiac failure is the main determinant of AF-recurrence.
Abstract: BACKGROUND: Obesity and the metabolic syndrome (MS) frequently coexist. Both are apparently associated to cardiovascular disease. However, the contribution of obesity to cardiovascular risk, independent of the presence of the metabolic syndrome, remains controversial. The purpose of this study was to investigate whether the subclinical carotid atherosclerosis prevalence is different in obese postmenopausal women with and without the metabolic syndrome. METHODS: On the basis of consecutive recruitment, 313 postmenopausal women underwent a clinical, biochemical and ultrasound characterization. Women affected by cardiovascular disease or diabetes were excluded from the study. RESULTS: Among enrolled women the metabolic syndrome and body mass index (BMI) resulted strongly associated, but only metabolic syndrome was associated with carotid atherosclerosis, a well-known marker of cardiovascular disease. Similarly, increases in BMI unit (normal to overweight to obese) were not associated with carotid atherosclerosis whereas metabolic status (normal to metabolic syndrome) conferred an approximate three-fold adjusted odds of carotid atherosclerosis. CONCLUSIONS: The metabolic syndrome but not obesity is associated to carotid atherosclerosis in postmenopausal women. Although it remains prudent to recommend weight loss in overweight and obese women, evaluation and control of metabolic risk factors should be considered the main goal to prevent cardiovascular and cerebrovascular disease.
Abstract: BACKGROUND: Recent randomized trials on hormone replacement therapy in postmenopausal women raised many doubts about their role in cardiovascular disease prevention. Therefore the role of other sex hormones needed to be investigated. In particular androgens seem to have a protective role on atherosclerosis. The present study was performed to assess the role of endogenous sex hormones on carotid atherosclerosis in postmenopausal women. METHODS AND RESULTS: We consecutively enrolled 101 postmenopausal women aged 45-75 (mean age 57.4) years referred to our University hospital menopausal health-screening clinic. The subjects underwent a medical history, a physical examination and biochemical analysis. Extracranial carotid arteries were assessed by ultrasound. Fifty percent of our sample had carotid plaques. On the multivariate logistic regression analysis age, glycaemia (positively) and testosterone (negatively) (P=0.02) were significantly correlated to carotid atherosclerosis. In non-obese subjects we found that participants in the third tertile had a significantly lower prevalence of carotid atherosclerosis (P=0.02) compared to those in the first tertile of testosterone. CONCLUSIONS: These results suggest a possible protective role of endogenous androgens at least on carotid atherosclerosis. Of course these preliminary results should be supported by prospective studies. Also the different role of these hormones on obese and non-obese subjects needs to be clarified.
Abstract: Interleukin 6 (IL-6) is an independent predictor of type 2 diabetes and cardiovascular disease and is correlated with insulin resistance. Insulin stimulates nitric oxide (NO) production through the IRS-1/PI3-kinase/Akt/eNOS pathway (where IRS-1 is insulin receptor substrate 1, PI3-kinase is phosphatidylinositol 3-kinase, and eNOS is endothelial NO synthase). We asked if IL-6 affects insulin vasodilator action both in human umbilical vein endothelial cells (HUVEC) and in the aortas of C57BL/6J mice and whether this inhibitory effect was caused by increased Ser phosphorylation of IRS-1. We observed that IL-6 increased IRS-1 phosphorylation at Ser(312) and Ser(616); these effects were paralleled by increased Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and reversed by JNK and ERK1/2 inhibition. In addition, IL-6 treatment resulted in impaired IRS-1 phosphorylation at Tyr(612), a site essential for engaging PI3-kinase. Furthermore, IL-6 treatment reduced insulin-stimulated phosphorylation of eNOS at the stimulatory Ser(1177) site and impaired insulin-stimulated eNOS dephosphorylation at the inhibitory Thr(495) site. Insulin-stimulated eNOS activation and NO production were also inhibited by IL-6; these effects were reversed by inhibition of JNK and ERK1/2. Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin-dependent activation of the Akt/eNOS pathway in the aorta as a result of JNK and ERK1/2 activation. Our data suggest that IL-6 impairs the vasodilator effects of insulin that are mediated by the IRS-1/PI3-kinase/Akt/eNOS pathway through activation of JNK and ERK1/2.
Abstract: BACKGROUND: In 2003, the American Diabetes Association (ADA) established a new cutoff for impaired fasting glucose (IFG) by reducing it from 110 to 100 mg/dL. This change was challenged as to its appropriateness. A few studies have examined the impact of the ADA(2003) threshold of IFG on metabolic and cardiovascular risk factors. METHODS: We examined whether metabolic and cardiovascular risk factors, including inflammatory biomarkers, differ in subjects with the new ADA(2003) threshold of IFG (IGF100) as compared with subjects with the old ADA(1997) threshold of IFG (IFG110) in a cohort of 946 nondiabetic Italian Caucasians (fasting plasma glucose < 126 mg/dL). RESULTS: As compared with normal fasting glucose (NFG), subjects with IFG100 and IFG110 had higher body mass index (BMI), waist circumference, total and low density lipoprotein (LDL) cholesterol, triglyceride, fasting and 2-h post-challenge plasma glucose, fasting insulin, systolic blood pressure, and lower levels of high density lipoprotein (HDL) and insulin-like growth factor I (IGF-I). In a logistic regression analysis with adjustment for age and gender, IFG110 was associated with higher risk of post-challenge glucose intolerance as compared with IFG100. As compared with IFG100, subjects with IFG110 have significantly lower levels of circulating IGF-I. As compared with NFG, IFG110, but not IFG100, showed a significant association with increased levels of inflammatory markers including white blood cell count (WBCC), and C-reactive protein (CRP). Both CRP and WBCC were correlated with 2-h plasma glucose but not with fasting plasma glucose (FPG). CONCLUSIONS: The data show that IFG110 is associated with a worse metabolic and cardiovascular risk profile as compared with IFG100.
Abstract: BACKGROUND AND AIM: Insulin resistance and increased left ventricular mass (LVM) characterize patients with essential hypertension. Some genetic polymorphisms play a role in the modulation of both insulin resistance and LVM. The aim of this work was to investigate whether the PC-1 and ACE genes exert a polygenic control of insulin resistance and LVM in hypertensive patients. METHODS AND RESULTS: In 158 never-treated hypertensive patients, we evaluated insulin resistance by HOMA index [insulin (microU/mL) x glucose (mmol/L)]/22.5 and LVM by echocardiograms. Genetic polymorphisms were obtained by polymerase chain reaction. PC-1 X121Q genotype carriers (K121Q+Q121Q, n=46) had higher HOMA (3.14+/-1.28 vs. 2.49+/-1.25; p=0.002) and LVM (137+/-34 vs. 127+/-24 g/m2; p=0.02) than K121K patients (n=112). Similarly, ACE DD carriers (n=56) showed higher HOMA (3.94+/-1.13 vs. 1.98+/-0.72; p<0.00001) and LVM (142+/-26 vs. 123+/-25 g/m2; p=0.00004) than XI (ID+II, n=102) patients. When considering both PC-1 and ACE polymorphisms, HOMA (p<0.00001) and LVM (p=0.00003) progressively increased from K121K/XI to X121Q/XI, K121K/DD and X121Q/DD patients. The association of both gene polymorphisms with LVM was no longer significant after adjusting for HOMA values. As compared to K121K/XI patients (i.e. no at risk alleles), X121Q/DD patients had a significantly increased risk (OR: 4.4, 95% C.I. 1.4-14.0, p=0.011) to have left ventricular hypertrophy. CONCLUSIONS: In hypertensive patients PC-1 K121Q and ACE I/D polymorphisms have an additive deleterious effect on insulin resistance and, consequently, on LVM, thus increasing the global cardiovascular risk. Identification of carriers of the at-risk genotypes may help set up prevention strategies to be specifically targeted at these patients.
Abstract: Interleukin (IL)-10 is a major anti-inflammatory cytokine that has been associated with obesity and type 2 diabetes. The three polymorphisms -1082G/A, -819C/T, and -592C/A in the IL10 promoter were reported to influence IL10 transcription. We investigated whether these polymorphisms were associated with type 2 diabetes and related traits in a cohort of Italian Caucasians comprising 551 type 2 diabetic and 1,131 control subjects. The -819C/T and -592C/A polymorphisms were in perfect linkage disequilibrium (r(2) = 1.0). The -1082G/A polymorphism was not associated with type 2 diabetes or related traits. Although the -592C/A polymorphism was not associated with type 2 diabetes, nondiabetic homozygous carriers of the A allele showed increased BMI and insulin resistance and lower plasma IL-10 levels compared with the other genotypes. In the nondiabetic group, the ATA haplotype was associated with an increased risk for obesity (odds ratio 1.28 [95% CI 1.02-1.60]; P = 0.02). The ATA/ATA composite genotype was associated with an increased risk for obesity (1.96 [1.16-3.31]; P = 0.01) and insulin resistance (1.99 [1.12-3.53]; P = 0.01). This study suggests that polymorphisms and haplotypes of the IL10 promoter may be associated with obesity and insulin resistance in a large sample of Italian Caucasians.
Abstract: Recent epidemiologic and experimental evidence suggests that serum uric acid (UA) is an independent risk factor for cardiovascular and renal diseases. However, endothelial dysfunction is an early predictor of cardiovascular events, particularly in hypertensive patients. For assessment of the association between UA and endothelial function, 217 (108 men, 109 women; aged 48.0 +/- 10.6 yr) white never-treated hypertensive patients were studied. All patients underwent the following procedures: BP measurements, laboratory tests (C-reactive protein [CRP], insulin resistance by homeostasis model assessment, serum creatinine, and UA), and endothelial function evaluated by intra-arterial infusion of acetylcholine (ACh). Serum creatinine, CRP, and maximal vasodilatory response to ACh were related to the UA (all P < 0.0001). In the multiple regression analysis, serum UA ranked as the third correlate of peak of forearm blood flow predictor, after homeostasis model assessment and CRP. The data show an independent link between UA and endothelial function, also in a statistical model that included CRP. In conclusion, the data demonstrate an inverse and significant relationship between UA and ACh-stimulated vasodilation in patients with uncomplicated, untreated essential hypertension, independent of traditional cardiovascular risk factors. Probably, the chronic inflammation that was documented in these patients may be considered the mechanistic link between serum UA and vascular damage.
Abstract: The relationship among inflammation (plasma high-sensitivity C-reactive protein [CRP]), endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm), and renal function (serum creatinine and GFR [Modification of Diet in Renal Disease formula]) was investigated in 264 never-treated individuals with uncomplicated essential hypertension and serum creatinine within the normal range. Multiple regression models of renal function (creatinine) were constructed in sequence including Framingham risk factors as well the hemodynamic response to ACh and plasma CRP. The inclusion of endothelial function into a model based on Framingham risk factors added highly significant (P < 0.001) power to this model (+5%). Of note, in an alternative model that included CRP (instead of endothelial function), the creatinine variance explained by this factor was two times higher (+10%) than that associated with endothelial function in the first model. In the full model that included both endothelial function and CRP, CRP maintained a much stronger independent link with the outcome measure than endothelial function. In individuals with untreated, uncomplicated essential hypertension, multivariate modeling indicated that inflammation is a crucial mechanism mediating the endothelial-renal function link. The proatherogenic potential of inflammation associated with subtle impairment in renal function may contribute to the cardiovascular risk of essential hypertension.
Abstract: BACKGROUND: Endothelin is elevated in heart failure and contributes to neurohormonal activation, hemodynamic deterioration, and cardiovascular remodeling. Here, we examined its prognostic value in a large population of patients with chronic heart failure. METHODS AND RESULTS: Big endothelin-1 (Big ET-1) and 4 other neurohormones were measured at study entry in 2359 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) and their concentrations related to outcome over a median follow-up of 23 months. Baseline concentration of Big ET-1 (median 0.80 pmol/L) was proportional to severity of disease (New York Heart Association class, left ventricular structure and function). High circulating concentrations of brain natriuretic peptide (BNP), creatinine and bilirubin, advanced New York Heart Association class, elevated body mass index, and the presence of atrial fibrillation were independently associated to higher concentrations of Big ET-1. Big ET-1 (ranking second just behind BNP among neurohormonal factors) was an independent predictor of outcome defined as all-cause mortality (hazard ratio 1.49, 95% CI 1.20-1.84, P = .0003) or the combined endpoint of mortality and morbidity (hazard ratio 1.43, 95% CI 1.20-1.69, P < .0001) and provided incremental prognostic value compared with BNP. CONCLUSIONS: In a large population of patients with symptomatic heart failure, the circulating concentration of Big ET-1, a precursor of the paracrine and bioactive peptide ET-1, was an independent marker of mortality and morbidity. In this setting, BNP remained the strongest neurohormonal prognostic factor.
Abstract: OBJECTIVE: To evaluate circulating serum ionized magnesium (i-Mg) concentrations in patients with type 2 diabetes mellitus, and to investigate its relationship with the components of the metabolic syndrome. DESIGN: cross-sectional study. SETTING: Outpatients' service for diabetic patients at the University Hospital of Messina, Italy. SUBJECTS: 290 patients with type 2 diabetes mellitus. Measures of Outcome: Serum i-Mg was measured by ion selective electrode. Age, gender, body mass index (BMI), waist circumference, blood pressure, fasting glucose, HbA1c, HDL cholesterol, triglycerides, and urinary albumin excretion rate (UAER) were considered in the analyses. Patients with hypomagnesemia, defined as serum i-Mg <0.46 mmol/l, were compared with those having normal serum i-Mg levels, and variables proven to be associated with low i-Mg levels in the univariate analysis were entered in a multivariable logistic regression model to obtain a deconfounded estimate of the association between metabolic parameters and hypomagnesemia. RESULTS: In univariate analysis, serum i-Mg levels were significantly reduced in patients with low HDL cholesterol, high triglycerides values, high waist circumference, high blood pressure, microalbuminuria and clinical proteinuria. Hypomagnesemia was highly prevalent in our study population (N = 143, 49.3%). After adjusting for potential confounders, plasma triglycerides (OR = 4.71; 95% CI = 2.56-8.67), waist circumference (OR = 2.21; 95% CI = 1.21-4.04), microalbuminuria (OR = 2.43; 95% CI = 1.16-5.08) and clinical proteinuria (OR = 2.04; 95% CI = 1.02-5.68) were independently associated with hypomagnesemia. CONCLUSIONS: Hypomagnesemia is highly prevalent in diabetic outpatients. High plasma triglycerides, waist circumference and albuminuria are independent correlates of hypomagnesemia.
Abstract: HEARTFAID is a research and development project aimed at devising, developing and validating an innovative knowledge based platform of services, able to improve early diagnosis and to make more effective the medical-clinical management of heart diseases within elderly population. Chronic Heart Failure is one of the most remarkable health problems for prevalence and morbidity, especially in the developed western countries, with a strong impact in terms of social and economic effects. All these aspects are typically emphasized within the elderly population, with very frequent hospital admissions and a significant increase of medical costs. Recent studies and experiences have demonstrated that accurate heart failure management programs, based on a suitable integration of inpatient and outpatient clinical procedures, might prevent and reduce hospital admissions, improving clinical status and reducing costs. HEARTFAID aims at defining efficient and effective health care delivery organization and management models for the "optimal" management of the care in the field of cardiovascular diseases. The HEARTFAID innovative computerized system will improve the processes of diagnosis, prognosis and therapy provision, providing the following services: * electronic health record for easy and ubiquitous access to heterogeneous patients data;* integrated services for healthcare professionals, including patient telemonitoring, signal and image processing, alert and alarm system;* clinical decision support in the heart failure domain, based on pattern recognition in historical data, knowledge discovery analysis and inferences on patients' clinical data.The formalization of the pre-existing clinical knowledge and the discovery of new elicited knowledge represent the core of the HEARTFAID platform.
Abstract: We have investigated the relationships between plasma interleukin-6 (IL-6) levels and insulin sensitivity and insulin secretion in a cohort of Italian-Caucasian glucose-tolerant subjects. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp, and first-phase insulin secretion was measured by intravenous glucose tolerance test. Fasting plasma IL-6 concentration was negatively correlated with the rate of insulin-stimulated glucose disposal (M) (P = 0.001). The correlation remained statistically significant, while attenuated, after adjusting for sex, age, and BMI (P < 0.03); after an additional adjustment for free fatty acids (FFAs), a further attenuation was observed, but statistical significance was maintained (P < 0.044). Fasting plasma IL-6 concentration was positively correlated with first-phase insulin secretion assessed as acute insulin response (AIR) (P = 0.001). The correlation remained significant after adjusting for sex, age, and BMI (P = 0.003). To estimate the independent contribution of plasma IL-6 levels to AIR, we carried out forward stepwise linear regression analysis in a model that included sex, age, BMI, waist-to-hip ratio, FFAs, and insulin-stimulated glucose disposal. Only insulin sensitivity and plasma IL-6 concentration were independently associated with AIR, accounting, respectively, for 19.0 and 5.2% of its variation. These data indicate that IL-6 is associated in a reciprocal manner with the two pathophysiological components of type 2 diabetes, i.e., insulin resistance and insulin secretion.
Abstract: Hypertension, one of the most important risk factors for cardiovascular diseases, is associated with both left ventricular hypertrophy and endothelial dysfunction. Both have been recently recognized as independent predictors of clinical events in different groups of patients. In fact, a dysfunctioning endothelium loses its antiatherosclerotic and antithrombotic action, and, therefore, promotes the atherosclerotic process. Similarly, cardiac hypertrophy is recognized as a powerful and independent risk factor for cardiovascular morbidity and mortality because it predisposes to arrhythmias and maximizes the consequences of acute myocardial ischemia. Recently, an evident interaction has been demonstrated between endothelial dysfunction and left ventricular mass. In particular, the coexistence of both left ventricular hypertrophy and endothelial dysfunction almost doubles the risk for future vascular events in hypertensives. Thus, in hypertensive patients, it is clinically useful to choose an aggressive therapeutic strategy--to reduce left ventricular mass and to improve endothelial function.
Abstract: CONTEXT: Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy; however, conclusive evidence is still lacking. OBJECTIVE: The objective of the study was to investigate whether diabetic patients carrying the E23K variant in KCNJ11 are at increased risk for secondary sulfonylurea failure. DESIGN: Secondary sulfonylurea failure was defined as fasting plasma glucose greater than 300 mg/dl despite sulfonylurea-metformin combined therapy and appropriate diet, in the absence of other conditions causing hyperglycemia. SETTING: The study was conducted in an ambulatory care facility. PATIENTS: A total of 525 Caucasian type 2 diabetic patients were enrolled in the study. INTERVENTION: Sulfonylurea treatment was followed by sulfonylurea-metformin combined therapy and then insulin treatment. MAIN OUTCOME MEASURE: Secondary failure was the main outcome measure. RESULTS: Of the diabetic patients enrolled in the study, 38.5% were E23E homozygous, 51.4% were E23K heterozygous, and 10.1% were K23K homozygous. The frequency of carriers of the K allele was 58 and 66.8% among patients treated with oral therapy or secondary sulfonylurea failure, respectively (odds ratio, 1.45; 95% confidence interval, 1.01-2.09; P = 0.04). Adjustment for age, gender, fasting glycemia, glycosylated hemoglobin, age at diagnosis, and duration of diabetes in a logistic regression analysis did not change this association (odds ratio, 1.69; 95% confidence interval, 1.02-2.78; P = 0.04). Islets isolated from carriers of the K allele showed no differences in glucose-stimulated insulin secretion and a tendency toward reduced response upon glibenclamide stimulation (P = 0.09). After 24-h exposure to high (16.7 mmol/liter) glucose concentration, impairment of glibenclamide-induced insulin release was significantly (P = 0.01) worse with the E23K variant. Conclusions: These data suggest that the E23K variant in KCNJ11 may influence the variability in the response of patients to sulfonylureas, thus representing an example of pharmacogenetics in type 2 diabetes.
Abstract: BACKGROUND AND AIM: The metabolic syndrome is a highly prevalent condition associated with cardiovascular disease. However, the contribution of LDL to cardiovascular risk is not estimated since it is not part of ATP III criteria. METHODS AND RESULTS: This is an observational study evaluating the association between metabolic syndrome and carotid atherosclerosis, according to LDL cholesterol levels. Two hundred and sixty-five menopausal women were consecutively enrolled, they all underwent clinical examination, biochemical characterization and ultrasound evaluation. In particular, carotid atherosclerosis, a well known marker of cardiovascular disease, was evaluated. Women affected by cardiovascular disease were excluded from the study. The metabolic syndrome was found strongly associated with carotid atherosclerosis in our study population. In individuals with normal or near normal LDL, the incidence of carotid atherosclerosis was significantly lower than in subject with high LDL. A high plasma LDL concentration was independently associated with carotid atherosclerosis (p=0.026) among women with the metabolic syndrome. CONCLUSIONS: High LDL cholesterol levels are associated with carotid atherosclerosis in menopausal women with the metabolic syndrome. Although it remains prudent to recommend an integrated control of all modifiable risk factors to prevent cardiovascular disease, decreasing LDL levels should be considered a high priority.
Abstract: AIMS: To investigate the additive prognostic impact of both forearm endothelial dysfunction and left ventricular mass (LVM) for future cardiovascular events. METHODS AND RESULTS: We enrolled 324 Caucasian, never treated, hypertensive outpatients. Endothelial function, by intra-arterial infusion of acetylcholine (ACh), and echocardiographic LVM were investigated. Patients were divided into tertiles on the basis of their increase in ACh-stimulated forearm blood flow (FBF) and LVM indexed by body surface area (LVMI). Cardiovascular events assessed were: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, transient cerebral ischaemic attack, unstable angina, coronary revascularization procedures, and symptomatic aorto-iliac occlusive disease. During a mean follow-up of 45.2+/-23.6 months, there were 47 new cardiovascular events (3.8 events/100 patient-years). The event rate was 6.8, 2.8, and 1.6% in the tertiles of ACh-stimulated FBF (log-rank test, P=0.0009), and 1.4, 3.4, and 6.6% in the tertiles of LVMI (log-rank test, P=0.0002), respectively. Besides, a significant interaction was documented between FBF and LVMI. In fact, the cardiovascular risk increases up to 11.4% in patients with low FBF and high LVMI. CONCLUSION: For the first time, we demonstrate that the co-existence of LVH and endothelial dysfunction in hypertensive patients increases significantly the risk of subsequent cardiovascular events.
Abstract: OBJECTIVE: We studied the relationships between plasma IGF-I concentrations and insulin sensitivity in subjects with various degrees of glucose tolerance. RESEARCH DESIGN AND METHODS: A total of 357 nondiabetic subjects, 54 subjects with impaired glucose tolerance and 98 newly diagnosed type 2 diabetic subjects, were consecutively recruited, and anthropometric and biochemical characteristics were collected. RESULTS: IGF-I concentrations were negatively correlated with age, BMI, waist-to-hip ratio, triglyceride levels, and systolic and diastolic blood pressure. IGF-I concentrations were positively correlated with HDL cholesterol and homeostasis model assessment of insulin sensitivity (HOMA-S). The correlations remained significant after adjusting for sex, age, and BMI. Correlations for HOMA-S with these metabolic and anthropometric variables were of a similar degree and direction to those for IGF-I concentrations. Stepwise linear regression analysis in a model, which included well-known modulators of insulin sensitivity such as sex, age, BMI, glucose tolerance status, family history of diabetes, waist-to-hip ratio, systolic and diastolic blood pressure, HDL cholesterol, and triglyceride levels, revealed that IGF-I concentrations were independently associated with insulin sensitivity accounting for 10.8% of its variation (P < 0.0001). IGF-I concentrations were significantly lower in subjects with World Health Organization (WHO)-defined metabolic syndrome compared with subjects without metabolic syndrome (P < 0.0001). Logistic regression analysis showed that each unit increase in log-transformed IGF-I concentrations was associated with a 90.5% reduction in the risk of WHO-defined metabolic syndrome. CONCLUSIONS: These data indicate that IGF-I has the characteristics to be a marker for the insulin resistance syndrome. This suggests that low IGF-I levels may be a useful marker for identifying subjects at risk for cardiovascular disease.
Abstract: OBJECTIVES: We investigated the relationship between ADMA plasma levels and endothelium-dependent vasodilation in 36 never-treated essential hypertensives and in 8 normotensive healthy subjects. BACKGROUND: It has been demonstrated that endothelium-dependent vasodilatation is impaired in essential hypertension. The potential contribution of asymmetric dimethylarginine (ADMA) to endothelial dysfunction of hypertensive humans has received poor attention. METHODS: Endothelial function was measured during intra-arterial infusion of acetylcholine (ACh), alone and during co-infusion of L-arginine, and sodium nitroprusside at increasing doses. Concentrations of ADMA and L-arginine in plasma were measured by high-performance liquid chromatography. RESULTS: Hypertensive subjects had significantly higher ADMA and L-arginine plasma concentrations than normotensive healthy controls; ACh-stimulated forearm blood flow (FBF) was significantly reduced in hypertensive subjects in comparison to normotensive control subjects (p < 0.0001). Intra-arterial coinfusion of L-arginine induced a further significant enhancement in ACh-stimulated vasodilation in hypertensive patients. In these, ADMA was strongly and inversely associated with the peak increase in FBF. In a multivariate model, only ADMA and L-arginine were independent correlates, accounting for 33.9% and 8.9% of the variability in the peak FBF response to ACh (p < 0.0001), respectively. CONCLUSIONS: The main finding in this study is that in essential hypertensives the L-arginine and endogenous inhibitor of nitric oxide synthase, ADMA, are inversely related to endothelial function.
Abstract: It has been suggested that serine (Ser) phosphorylation of insulin receptor substrate-1 (IRS-1) decreases the ability of IRS-1 to be phosphorylated on tyrosine, thereby attenuating insulin signaling. There is evidence that angiotensin II (AII) may impair insulin signaling to the IRS-1/phosphatydilinositol 3-kinase (PI 3-kinase) pathway by enhancing Ser phosphorylation. Insulin stimulates NO production by a pathway involving IRS-1/PI3-kinase/Akt/endothelial NO synthase (eNOS). We addressed the question of whether AII affects insulin signaling involved in NO production in human umbilical vein endothelial cells and tested the hypothesis that the inhibitory effect of AII on insulin signaling was caused by increased site-specific Ser phosphorylation in IRS-1. Exposure of human umbilical vein endothelial cells to AII resulted in inhibition of insulin-stimulated production of NO. This event was associated with impaired IRS-1 phosphorylation at Tyr612 and Tyr632, two sites essential for engaging the p85 subunit of PI3-kinase, resulting in defective activation of PI 3-kinase, Akt, and eNOS. This inhibitory effect of AII was reversed by the type 1 receptor antagonist losartan. AII increased c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 activity, which was associated with a concomitant increase in IRS-1 phosphorylation at Ser312 and Ser616, respectively. Inhibition of JNK and ERK1/2 activity reversed the negative effects of AII on insulin-stimulated NO production. Our data suggest that AII, acting via the type 1 receptor, increases IRS-1 phosphorylation at Ser312 and Ser616 via JNK and ERK1/2, respectively, thus impairing the vasodilator effects of insulin mediated by the IRS-1/PI 3-kinase/Akt/eNOS pathway.
Abstract: Due to the lack of convincing data about the association between atherosclerosis and osteoporosis, we evaluated the association between carotid atherosclerosis and bone mineral density in a sample of apparently healthy postmenopausal women who underwent health-screening in our hospital. We also evaluated a bone turnover marker, osteocalcin; we divided the population into 2 groups according to osteocalcin levels. We found a high prevalence of carotid atherosclerosis in subjects with high osteocalcin levels and low bone mineral density.
Abstract: BACKGROUND: Mild to moderate renal insufficiency in individuals with essential hypertension is currently considered the expression of a renal microvasculopathy characterized by preglomerular arteriolar involvement and tubulo-interstitial changes. Whether endothelial dysfunction plays a role in this alteration is still undefined. METHODS AND RESULTS: We investigated the relationship between endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm) and renal function in 500 patients with uncomplicated, never-treated, essential hypertension and serum creatinine within the normal range (ie, < or =1.5 mg/dL). Serum creatinine, creatinine clearance, and estimated glomerular filtration rate (GFR, by the Modification of Diet in Renal Disease formula) were related to the forearm blood flow response to ACh (all P< or =0.003), and these relationships held true in multiple regression analyses that included age, gender, systolic pressure, serum cholesterol and glucose, smoking, and body mass index. Accordingly, on multiple logistic regression analysis, the risk of moderate renal dysfunction (ie, an estimated GFR <60 mL x min(-1) x 1.73 m(-2)) was 64% lower (OR 0.36, 95% CI 0.18 to 0.70) in patients in the third ACh tertile (ie, those showing the higher vasodilatory response) than in those in the first tertile (ie, showing the lower response). C-reactive protein was related directly to serum creatinine and inversely to GFR and vasodilatory response to ACh, which suggests that endothelial dysfunction is a possible mechanism linking inflammation and impaired renal function in essential hypertension. CONCLUSIONS: An impaired vasodilatory response to ACh appears to be associated with renal function loss in patients with essential hypertension. This association suggests that systemic endothelial dysfunction is involved in mild to moderate renal insufficiency in patients with uncomplicated essential hypertension.
Abstract: Some cardiovascular risk factors, such as hypertension and insulin resistance, are associated with endothelial dysfunction. Insulin regulates both in vitro and in vivo expression of endothelial nitric oxide synthase (eNOS) via a pathway involving insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3 kinase. Recently, we found that human endothelial cells obtained from carriers of the Arg(972) IRS-1 polymorphism exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. To investigate a possible relationship between Arg(972) IRS-1 polymorphism and endothelial dysfunction in vivo, we enrolled a cohort of 100 never-treated hypertensive subjects. Endothelium-dependent and endothelium-independent vasodilation were assessed by increasing doses of acetylcholine and sodium nitroprusside. IRS-1 polymorphism was detected by PCR. The allelic frequency of the Arg(972) IRS-1 variant was 8.0%. Stratifying subjects according to IRS-1 genotype, we observed that acetylcholine-stimulated forearm blood flow was significantly (P < 0.0001) lower in Gly/Arg heterozygous carriers than in Gly/Gly carriers (11.3 +/- 4.4 vs. 14.7 +/- 5.9 ml/100 ml(-1) of tissue per min(-1)). Sodium nitroprusside caused comparable increments in forearm blood flow in both groups (12.9 +/- 2.4 vs. 13.3 +/- 3.5 ml/100 ml(-1) of tissue per min(-1)). Our data strongly suggest that, by inducing endothelial dysfunction, the Arg(972) IRS-1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease.
Abstract: Uncoupling protein (UCP)-2 is a member of the mitochondrial inner membrane carriers that uncouple pro-ton entry in the mitochondrial matrix from ATP synthesis. The -866G/A polymorphism in the UCP2 gene, which enhances its transcriptional activity, was associated with enhanced risk for type 2 diabetes in obese subjects. We addressed the question of whether the -866G/A polymorphism contributes to variation in insulin sensitivity by genotyping 181 nondiabetic offspring of type 2 diabetic patients. Insulin sensitivity, assessed by the hyperinsulinemic-euglycemic clamp, was reduced in -866A/A carriers compared with -866A/G or -866G/G carriers (P = 0.01). To directly investigate the correlation between UCP2 expression and insulin resistance, UCP2 mRNA levels were measured by real-time RT-PCR in subcutaneous fat obtained from 100 obese subjects who underwent laparoscopic adjustable gastric banding. UCP2 mRNA expression was significantly correlated with insulin resistance as assessed by the homeostasis model assessment index (r = 0.27, P = 0.007). We examined the association of the -866A/A genotype in a case-control study including 483 type 2 diabetic subjects and 565 control subjects. The -866A/A genotype was associated with diabetes in women (odds ratio 1.84, 95% CI 1.03-3.28; P = 0.037), but not in men. These results indicate that the -866A/A genotype of the UCP2 gene may contribute to diabetes susceptibility by affecting insulin sensitivity.
Abstract: OBJECTIVE: The aim of this study was to investigate whether diabetic patients carrying the Arg(972) insulin receptor substrate-1 (IRS-1) variant are at increased risk for secondary failure to sulfonylurea. RESEARCH DESIGN AND METHODS: A total of 477 unrelated Caucasian type 2 diabetic patients were recruited according to the following criteria: onset of diabetes after age 35 years, absence of ketonuria at diagnosis, and anti-GAD(-) antibody. Type 2 diabetes was diagnosed according to the American Diabetes Association criteria. Patients with secondary sulfonylurea failure were defined as those requiring insulin due to uncontrolled hyperglycemia (fasting plasma glucose >300 mg/dl) despite sulfonylurea-metformin combined therapy, appropriate diet, and absence of any conditions causing hyperglycemia. RESULTS: Of the total patients, 53 (11.1%) were heterozygous for the Arg(972) IRS-1 variant, 1 (0.2%) was homozygous, and the remainder (88.7%) were homozygous for the wild-type allele. The genotype frequency of the Arg(972) IRS-1 variant was 8.7% among diabetic patients well controlled with oral therapy and 16.7% among patients with secondary failure to sulfonylurea (odds ratio 2.1 [95% CI 1.18-3.70], P = 0.01). Adjustment for age, sex, BMI, metabolic control, age at diagnosis, duration of diabetes, and Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma2 gene in a logistic regression analysis with secondary failure to sulfonylurea as a dependent variable did not change this association (2.0 [1.38-3.86], P = 0.038). CONCLUSIONS: These data demonstrate that the Arg(972) IRS-1 variant is associated with increased risk for secondary failure to sulfonylurea, thus representing a potential example of pharmacogenetics in type 2 diabetes.
Abstract: OBJECTIVE: To investigate the role of phospholipase C (PLC), phospholipase A(2) (PLA(2)), calcium, and protein kinase C (PKC) in mediating leptin-enhanced aggregation of human platelets. DESIGN: In vitro, ex vivo study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital of Messina, Italy. SUBJECTS: In total, 14 healthy normal-weight male (age 31.4+/-1.9 y; body mass index 22.7+/-0.6 kg/m2) subjects. MEASUREMENTS: Adenosine diphosphate-(ADP-) induced platelet aggregation and platelet free calcium were measured after incubation of platelets with leptin alone (5-500 ng/ml), or leptin (50 and 100 ng/ml) in combination with anti-human leptin receptor long form antibody (anti-ObRb-Ab, 1:800-1:100 dilutions), PLC inhibitor U73122 (3.125-25 microM), PLA(2) inhibitor AACOCF3 (1.25-10 microM), or PKC inhibitor Ro31-8220 (1.25-10 microM). RESULTS: Platelet stimulation with leptin leads to a significant and dose-dependent increase in ADP-induced platelet aggregation and platelet free calcium concentrations. Leptin effects on both platelet aggregation and calcium mobilization were completely abated by the co-incubation with leptin and anti-ObRb-Ab. Leptin-induced platelet aggregation was dose-dependently inhibited by U73122, AACOCF3, or Ro31-8220. The effect of leptin on intracellular calcium was inhibited in a dose-dependent manner by incubation with U73122 and AACOCF3, but not with Ro31-8220. CONCLUSIONS: Our study confirms that leptin is able to enhance ADP-induced aggregation of human platelets, and raise the possibility that PLC, PKC, PLA(2), and calcium could play a relevant role in mediating the proaggregating action of leptin.
Abstract: Many adverse effects of glucose were attributed to its increased routing through the hexosamine pathway (HBP). There is evidence for an autocrine role of the insulin signaling in beta-cell function. We tested the hypothesis that activation of the HBP induces defects in insulin biosynthesis by affecting the insulin-mediated protein translation signaling. Exposure of human pancreatic islets and RIN beta-cells to glucosamine resulted in reduction in glucose- and insulin-stimulated insulin biosynthesis, which in RIN beta-cells was associated with impairment in insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation at Tyr(608) and Tyr(628), which are essential for engaging phosphatidylinositol 3-kinase (PI 3-kinase). These changes were accompanied by impaired activation of PI 3-kinase, and activation of Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway. RIN beta-cells exposed to high glucose exhibited increased c-Jun N-terminal kinase (JNK) and ERK1/2 activity, which was associated with increased IRS-1 phosphorylation at serine (Ser)(307) and Ser(612), respectively, that inhibits coupling of IRS-1 to the insulin receptor and is upstream of the inhibition of IRS-1 tyrosine phosphorylation. Azaserine reverted the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser(307) and Ser(612). Glucosamine mimicked the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser(307) and Ser(612). Inhibition of JNK and MAPK kinase-1 activity reverted the negative effects of glucosamine on insulin-mediated protein synthesis. These results suggest that activation of the HBP accounts, in part, for glucose-induced phosphorylation at Ser(307) and Ser(612) of IRS-1 mediated by JNK and ERK1/2, respectively. These changes result in impaired coupling of IRS-1 and PI 3-kinase, and activation of the Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway.
Abstract: OBJECTIVES: This study sought to investigate whether pulse pressure (PP) is associated with endothelium-dependent vasodilation in a group of never-treated hypertensives. BACKGROUND: Pulse pressure represents a well-established independent predictor for cardiovascular morbidity and mortality. Forearm endothelial dysfunction, defined as impaired vasodilating response to acetylcholine (ACh), may be associated with several cardiovascular risk factors. Recently, the prognostic value of coronary and forearm endothelial dysfunction has been demonstrated. METHODS: All patients underwent measurement of blood pressure (BP) both clinically and in an ambulatory setting. Endothelium-dependent and -independent vasodilation was investigated by strain-gauge plethysmography in 262 hypertensive patients (age 30 to 55 years) during intra-arterial infusion of increasing doses of ACh and sodium nitroprusside. RESULTS: We observed that systolic BP rather than diastolic BP significantly induces the PP increase. Linear regression analysis revealed a significant inverse correlation between ACh-stimulated forearm blood flow (FBF) and age, body mass index, clinic and monitored systolic BP, and clinic and monitored PP. However, stepwise multivariate analysis showed that monitored PP was the strongest independent predictor of ACh-stimulated FBF, accounting for 33.6% of the variation. After adjustment for other covariates, ACh-stimulated FBF decreases by 8.7% for each mm Hg increment in monitored PP. CONCLUSIONS: Our data indicate that monitored PP is inversely correlated with ACh-stimulated vasodilation. It is possible to hypothesize that elevation in PP reduces FBF by increasing oxidative stress and reducing production of nitric oxide caused by reduced shear stress. In addition, the present findings demonstrate the accuracy of ambulatory BP as a prognostic predictor of hypertension-associated endothelial dysfunction.
Abstract: OBJECTIVE: To test whether weight loss may improve endothelial dysfunction in human obesity, we recruited 28 healthy obese subjects, aged 30-46 years, with BMI 30-43 kg/m(2). RESEARCH DESIGN AND METHODS: Endothelium-dependent and -independent vasodilation were investigated by intra-arterial infusion of increasing doses of acetylcholine (ACh; 7.5, 15, and 30 microg x ml(-1) x min(-1)) and sodium nitroprusside (0.8, 1.6, and 3.2 microg x ml(-1) x min(-1)). Insulin resistance was estimated by homeostasis model assessment (HOMA). Weight loss was obtained by caloric restriction and physical activity. RESULTS: We observed a significant reduction in BMI (from 33.1 +/- 4.2 to 27.5 +/- 4.5 kg/m(2), -16.9%, P < 0.0001) and in waist circumference (from 108.2 +/- 12.1 to 96.8 +/- 12.9 cm, -10.5%, P < 0.0001). Weight loss was also associated with a significant increase in ACh-stimulated forearm blood flow (FBF), from 7.4 +/- 2.8 to 12.9 +/- 3.4 ml. 100 ml(-1) of tissue x min(-1) kg/m(2) (P < 0.0001). Multivariate regression analysis demonstrated that the only independent predictor of FBF was HOMA, accounting for 44.5% of the variation, whereas the addition of BMI explained another 2.3% of the variation. CONCLUSIONS: Our data demonstrate that energy-restricted diet associated with physical activity induce a significant and clinically relevant improvement in ACh-stimulated vasodilation in obese healthy subjects.
Abstract: OBJECTIVE: To investigate the effects of leptin on platelet aggregation and platelet free calcium (Ca(2+)) concentrations, and the role of the long form of leptin receptor (ObRb) and the phospholipase C (PLC) in mediating leptin effects on platelet function. DESIGN: Cross-sectional, clinical study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital of Messina, Italy. SUBJECTS: A total of 19 healthy, 14 overweight, and 16 obese male subjects. MEASUREMENTS: ADP-induced platelet aggregation and platelet Ca(2+) were measured after incubation of platelet-rich plasma with leptin alone 5-200 ng/ml, leptin 200 ng/ml and anti-human leptin receptor long-form antibody (ObRb-Ab) 5-10 microl, or leptin 200 ng/ml and PLC inhibitor U73122 0.5-1 nmol/l. RESULTS: Platelet stimulation with leptin lead to a significant and dose-dependent increase in platelet aggregation in healthy subjects. This effect was blunted in overweight, and strongly reduced in obese subjects. Similarly, the incubation with leptin induced a significant and dose-dependent increase in platelet free calcium, which was blunted in overweight and obese patients. The effect of leptin on platelet aggregation and platelet Ca(2+) was completely abated by the anti-ObRb-Ab and the PLC inhibitor U73122. CONCLUSIONS: Leptin produces a dose-dependent enhancement of ADP-induced platelet aggregation in humans. Platelet aggregation response to leptin is blunted, but not completely abolished in overweight/obese subjects, thus suggesting that platelet may represent a site of leptin resistance in human obesity. Leptin increases platelet free calcium in a dose-dependent manner. The inhibition of PLC completely abates the effect of leptin on both platelet aggregation and Ca(2+) levels. These findings suggest that signaling pathway other than JAK-STAT tyrosine phosphorylation (ie PLC and calcium) may be involved in mediating the prothrombotic action of leptin.
Abstract: This multicenter, double-blind, parallel-group study compared the effects of three dihydropyridine calcium channel blockers (lercanidipine, felodipine, and nifedipine gastrointestinal therapeutic system) on blood pressure and heart rate in 250 patients with mild to moderate hypertension (diastolic blood pressure > or =95 and 109 mm Hg). Patients were randomized to 4 weeks of treatment with once-daily doses of lercanidipine 10 mg, felodipine 10 mg, or nifedipine gastrointestinal therapeutic system 30 mg. After 4 weeks of treatment, the dose was doubled in nonresponding patients. At 8 weeks, no significant differences in blood pressure were observed among the three groups. Increases in heart rate in all three groups induced by stressful conditions before and after treatment were not exacerbated during active treatment. The incidence of adverse drug reactions was lower in the lercanidipine and nifedipine groups than in the felodipine group (p<0.05); in particular, the incidence of edema for lercanidipine was 5.5% vs. 13% for felodipine and 6.6% for nifedipine.
Abstract: BACKGROUND: Left ventricular hypertrophy (LVH) detected at electrocardiography (ECG) is a predictor of an increased cardiovascular risk in essential hypertension. However, uncertainty remains concerning the reproducibility of ECG LVH and the prognostic relevance of its regression over time in hypertension. The aim of this study was to determine the prognostic value of baseline ECG LVH and its serial changes in a large cohort of hypertensive patients. METHODS: The Hypertrophy at ECG and its Regression during Treatment Survey (HEART Survey) is a prospective observational study conducted in 66 Italian centers. Inclusion criteria are essential hypertension with ECG LVH defined by the Perugia score (Cornell voltage criteria and/or a typical left ventricular "strain" pattern and/or a Romhilt-Estes score > or = 5 points) in subjects aged 45-84 years. The treatment of hypertension and other risk factors accords with current guidelines and is individually tailored. ECG is recorded twice at entry and periodically repeated over a 4-year follow-up period. Expert readers (unaware of the clinical findings) classify ECG. The incidence of major cardiovascular events in relation to baseline ECG and its changes over time are assessed, together with the reproducibility in the two baseline recordings. Overall, 708 patients aged 64 +/- 9 years have been enrolled in centers from northern (27%), central (32%) and southern (41%) Italy. Their baseline characteristics are presented. Follow-up is ongoing. CONCLUSIONS: The HEART Survey will examine the prognostic value of baseline ECG LVH and of its regression over time in a wide population of hypertensive patients.
Abstract: BACKGROUND AND AIMS: Blood pressure is known to be influenced by the season, particularly in the elderly. The association between cold weather and unrecognized hypertension has not been previously studied. The present study aimed at assessing whether recognition of hypertension in the elderly follows a seasonal pattern. METHODS: All patients over 64 with either first-listed or secondary diagnosis of hypertension at discharge (N = 4487) out of 24585 consecutively admitted to 69 wards of Geriatrics or Internal Medicine during ten bi-monthly observation periods (May-June and September-October) were enrolled. The main outcome of the study was the prevalence of unrecognized hypertension, defined as no mention of hypertension and/or antihypertensive drugs in clinical histories collected on admission, and a first-listed or secondary discharge diagnosis of hypertension. RESULTS: We found a total of 928 patients with unrecognized hypertension. Being admitted in the September-October period was independently associated with the outcome unrecognized hypertension (OR 1.25, 95% CI 1.08-1.46), as were smoking addiction (OR 1.57, 95% CI 1.23-2.0) and allocation to a medical ward (OR 1.21, 95% CI 1.04-1.41). Negative correlates of the outcome were multiple pathologies (OR 0.85, 95% CI 0.73-0.99), discharge diagnosis of coronary artery disease (OR 0.77, 95% CI 0.64-0.92) or diabetes mellitus (OR 0.81, 95% CI 0.67-0.97). CONCLUSIONS: Hypertension in the elderly may at least partly follow a seasonal pattern, and this finding may be relevant for screening and therapeutic decisions.
Abstract: Left ventricular (LV) mass that develops as cardiac adaptive remodeling represents a powerful independent predictor of cardiovascular morbidity and mortality in the general population and in several clinical conditions, including essential hypertension. However, many studies have shown that blood pressure explains only 10% to 25% of the variation in LV mass, supporting the hypothesis that other factors, such as genetics or metabolics (insulin-resistance/hyperinsulinemia), are involved in the cardiac growth in human hypertension. Essential hypertension is also characterized by insulin-resistance/hyperinsulinemia, which may directly induce LV hypertrophy through the stimulation of insulin-like growth factor-1 receptors, abundantly expressed in myocardium. Taken together, we investigated the growth effect of fasting insulin, associated with angiotensin-converting enzyme-gene polymorphism, on cardiac mass in a group of previously untreated hypertensive patients.
Abstract: BACKGROUND: Optimal glycemic control prevents the onset of diabetes complications. Identifying diabetic patients at risk of poor glycemic control could help promoting dedicated interventions. The purpose of this study was to identify predictors of poor short-term and long-term glycemic control in older diabetic in-patients. METHODS: A total of 1354 older diabetic in-patients consecutively enrolled in a multicenter study formed the training population (retrospective arm); 264 patients consecutively admitted to a ward of general medicine formed the testing population (prospective arm). Glycated hemoglobin (HbA1c) was measured on admission and one year after the discharge in the testing population. Independent correlates of a discharge glycemia > or = 140 mg/dl in the training population were assessed by logistic regression analysis and a clinical prediction rule was developed. The ability of the prediction rule and that of admission HbA1c to predict discharge glycemia > or = 140 mg/dl and HbA1c > 7% one year after discharge was assessed in the testing population. RESULTS: Selected admission variables (diastolic arterial pressure < 80 mmHg, glycemia = 143-218 mg/dl, glycemia > 218 mg/dl, history of insulinic or combined hypoglycemic therapy, Charlson's index > 2) were combined to obtain a score predicting a discharge fasting glycemia > or = 140 mg/dl in the training population. A modified score was obtained by adding 1 if admission HbA1c exceeded 7.8%. The modified score was the best predictor of both discharge glycemia > or = 140 mg/dl (sensitivity = 79%, specificity = 63%) and 1 year HbA1c > 7% (sensitivity = 72%, specificity = 71%) in the testing population. CONCLUSION: A simple clinical prediction rule might help identify older diabetic in-patients at risk of both short and long term poor glycemic control.
Abstract: BACKGROUND: Reactive oxygen species play a critical role in inducing apoptosis. The small GTPase p21 Ras and the ERK1/2 MAPK have been proposed as key regulators of the signaling cascade triggered by oxidative stress (H2O2). Harvey-Ras (Ha-Ras) and Kirsten-Ras (Ki-Ras) isoforms are so far functionally indistinguishable, because they activate the same downstream effectors, including ERK1/2. Moreover, ERK1/2 signaling has been involved in both protection and induction of apoptosis. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were subjected to H2O2, and apoptosis was detected by fluorescence-activated cell sorting analysis, fluorescence microscopy, and caspase-3 activation. Transfection of Ha-Ras and Ki-Ras genes in HUVECs was performed to evaluate the response to H2O2. We have found that, whereas Ha-Ras decreases tolerance to oxidative stress, Ki-Ras has a potent antiapoptotic activity. Both effects are mediated by ERK1/2. Tolerance to H2O2 is encoded by a unique stretch of lysines at the COOH terminus of the Ki-Ras, lacking in Ha-Ras, and it is relatively independent of the farnesylated anchor. Inhibition of p21 Ras signaling by farnesylation inhibitors increased the resistance to apoptosis in Ha-Ras-expressing cells. CONCLUSIONS: These findings explain the opposite effects of ERK1/2 stimulation on apoptosis found in different cell types and suggest that local activation of ERK1/2 signaling may account for the opposing response to oxidative stress by Ha-Ras or Ki-Ras-expressing cells. Modulation of cell reactivity to oxidative stress by p21 Ras points to the specific and predictive effects of Ras inhibitors in vivo as potential therapeutic drugs in disorders produced by increase of reactive oxygen species inside the cells.
Abstract: BACKGROUND: Granulocyte apoptosis is a key control process in the clearance of neutrophils from inflammatory sites, and its rate is modulated both in vitro and in vivo by a number of inflammatory mediators. In this study, we investigated the influence of cardiopulmonary bypass (CPB) on neutrophil apoptosis. METHODS: Twenty patients undergoing coronary operation with CPB were studied. Patients undergoing off-pump (OP) coronary bypass and healthy subjects served respectively as stressed and normal groups. Interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha were assessed on plasma collected preoperatively, at the end of CPB, and after intervals of 4, 8, 12, and 24 hours. Neutrophil apoptosis was detected by light microscopy as well as by the annexin-V assay on postoperative samples. The polymorphonuclear leukocyte (PMN) apoptotic receptors, Fas and FasL, were studied together with the activity of caspase 3 in postoperative neutrophils. RESULTS: Spontaneous apoptosis was significantly delayed in PMNs from CPB patients when compared with either the stressed or control patients. Neutrophils were activated, as indicated by increased surface expression of CD11b. Western blot analysis showed a normal expression of the apoptotic receptors Fas and FasL. Caspase 3 activity was found to be significantly reduced in neutrophils from CPB patients after 18 and 24 hours of culture. When control neutrophils were cultured in the presence of postoperative plasma from OP and CPB patients, apoptosis was significantly delayed. Depleting surgical plasma of IL-6 and IL-8 completely abolished this antiapoptotic effect. CONCLUSIONS: Inflammatory mediators during CPB prolong the functional lifespan of neutrophils through modulation of apoptosis, and potentiate the inflammatory response observed after coronary bypass operation.
Abstract: OBJECTIVE: The purpose of this study was to investigate the effectiveness of atrial and brain natriuretic peptides (ANP and BNP, respectively) as indicators of recovery of left ventricular (LV) function after coronary surgery. METHODS: We measured the concentrations of these peptides in 31 patients with poor LV function (ejection fraction, EF<35%) undergoing coronary artery bypass, and evaluated their correlation with the echocardiographic indexes of LV function. RESULTS: Pre-operatively, the plasma levels of both ANP and BNP were markedly higher in coronary patients than in normal control subjects, and strongly correlated with both EF (BNP: r=-0.8, P<0.001; ANP: r=-0.6, P<0.001) and wall motion score index (WMSI). At post-operative follow up, plasma levels of both natriuretic peptides were markedly reduced compared with pre-operative values in 21 patients. In addition, the post-operative-pre-operative differences of BNP (Delta(BNP)) and ANP (Delta(ANP)) plasma levels strongly correlated with the differences of both EF (r=-0.7, P<0.0001 vs. Delta(BNP); r=-0.6, P=0.0003 vs. Delta(ANP)) and WMSI (r=0.6, P=0.002 vs. Delta(BNP); r=0.6, P=0.04 vs. Delta(ANP)). Finally, by logistic regression analysis, BNP appeared a significant predictor of LVEF recovery after surgery. CONCLUSION: Plasma levels of ANP and BNP might be used in routine clinical practice as a support to echocardiography in detecting recovery of the LV function after coronary surgery.
Abstract: The association between angiotensin-converting enzyme (ACE) gene polymorphism and insulin resistance (IR) in hypertensive subjects remains controversial. Thus, we evaluated the possible association between IR and ACE gene polymorphism in a group of hypertensive, never-treated patients compared with that in a normotensive control group. We enrolled 200 (114 men and 86 women; age, 45.5 +/- 4.7 yr) hypertensive patients and 96 (54 men and 42 women; age, 44.0 +/- 4.7 yr) normotensive subjects. A double PCR assay was used to identify ACE genotypes. We determined fasting glucose and insulin by the glucose oxidase method and using a standard RIA technique. IR was estimated using the homeostasis model assessment (HOMA(IR)). Both fasting glucose (5.0 +/- 0.3 vs. 4.7 +/- 0.3 mmol/L; P < 0.0001), insulin levels (12.3 +/- 4.7 vs. 4.9 +/- 1.5 muU/mL; P < 0.0001), and HOMA(IR) (2.7 +/- 1.1 vs. 1.1 +/- 0.3; P < 0.0001) were significantly higher in hypertensive patients than in the normotensive control group. When we subdivided hypertensive patients according to ACE genotype, we observed that fasting insulin and HOMA(IR) were 16.3 +/- 3.3 and 3.6 +/- 0.8 in the DD genotype, 9.4 +/- 3.1 and 2.1 +/- 0.7 in the ID genotype, and 8.3 +/- 2.8 and 1.9 +/- 0.7 muU/mL in the II group (P < 0.0001, by ANOVA). No significant differences were observed in the normotensive control group. In conclusion, we extended previous data regarding the relationship of hypertension and IR by demonstrating a dependence of this relationship upon the ACE gene polymorphism.
Abstract: BACKGROUND: Forearm endothelial dysfunction, characterized by an impaired vasodilating response to acetylcholine (ACh), may be associated with several cardiovascular risk factors, including essential hypertension. Although the prognostic value of coronary endothelial dysfunction has been demonstrated, that of forearm endothelial dysfunction is still unknown. Methods and Results-- Endothelium-dependent and -independent vasodilation was investigated in 225 never-treated hypertensive patients (age, 35 to 54 years) by intra-arterial infusion of increasing doses of ACh and sodium nitroprusside. Patients were divided into tertiles on the basis of their increase in ACh-stimulated forearm blood flow (FBF) from basal: group 1, from 30% to 184%; group 2, from 185% to 333%; and group 3, from 339% to 760% increase from basal. During a mean follow-up of 31.5 of months (range, 4 to 84 months), there were 29 major adverse events at the cardiac (n=19), cerebrovascular (n=9), or peripheral vascular (n=1) level. Events included myocardial infarction, angina, coronary revascularization procedures, stroke, transient cerebral ischemic attack, and aortoiliac occlusive disease. Event rate per 100 patient-years was 8.17, 4.34, and 2.02 in the first, second, and third tertiles of peak percent increase in FBF during ACh infusion. The excess risk associated with an FBF increase in the first tertile was significant (relative risk, 2.084; 95% CI, 1.25 to 3.48; P=0.0049) after controlling for individual risk markers, including 24-hour ambulatory blood pressure. CONCLUSIONS: Our data suggest that forearm endothelial dysfunction is a marker of future cardiovascular events in patients with essential hypertension.
Abstract: Strain gauge plethysmography and brachial artery ultrasound are widely used to study endothelial function. No data on correlation between these two procedures are reported. The present study compared these two methods and investigated the correlation between vasodilation and brachial wall shear stress. In six healthy subjects and ten patients with hypertension or obesity, strain gauge plethysmography was performed in resting conditions and after infusion of 7.5,15 and 30 microg/min of acetylcholine, and brachial artery ultrasound in resting conditions and after 5 min hand ischemia. Wall shear stress was calculated as: blood viscosity x blood velocity/internal diameter. Forearm blood flow following acetylcholine infusion increased more in healthy subjects than in patients with hypertension or obesity. In addition, brachial artery dilated more in the former group. Change in brachial artery diameter correlated with change in forearm blood flow, calculated as area under the curve of acetylcholine infusion (r=0.739, P<0.001). Wall shear stress was higher in healthy subjects (67.8+/-20.0 dynes/cm(2)) than in patients with either hypertension or obesity (39.2+/-16.7, P<0.001), and correlated with variations of diameter (r=0.796, P<0.0002), and marginally of blood flow (r=0.516, P<0.05). The present findings demonstrate that there is a high correlation between endothelial function evaluated by strain gauge plethysmography and brachial artery ultrasound. Wall shear stress correlates with brachial artery diameter change following hand ischemia, and marginally with blood flow change following acetylcholine infusion.
Abstract: Endothelial dysfunction has been reported in obese subjects, but its mechanism has not been elucidated. We have therefore investigated 1) the possible relationship among BMI, waist-to-hip ratio (WHR), and endothelium-dependent vasodilation and 2) whether oxidative stress participates in endothelial dysfunction. We recruited 76 healthy subjects (50 men and 26 women aged 21-45 years) and measured their BMI (kg/m2), WHR, and insulin resistance (IR) estimated by the homeostasis model assessment (HOMA). Endothelium-dependent and -independent vasodilation were assessed by increasing doses of acetylcholine (ACh) (7.5, 15, and 30 pg x ml(-1) x min(-1)) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 microg x ml(-1) x min(-1)) during saline and vitamin C coinfusion (24 mg/min). The effects of cyclooxygenase activity were evaluated by a dose-response curve to intrabrachial coinfusion of ACh and indomethacin (500 microg/min). Three different groups have been identified according to their BMI: group A (BMI <25), consisting of 10 men and 5 women; group B (BMI between 25 and 29), consisting of 16 men and 8 women; and group C (BMI > or =30), consisting of 24 men and 13 women. Obese subjects had significantly lower forearm blood flow (FBF) during ACh infusions (means +/- SD): 19.8 +/- 2.8, 10.8 +/- 2.7, and 6.5 +/- 1.8 ml x 100 ml(-1) tissue x min(-1) (P < 0.0001) for groups A, B, and C, respectively. SNP caused comparable increments in FBF in all groups. Regression analysis revealed a significant negative correlation between BMI (r = -0.676, P < 0.0001), WHR (r = -0.631, P < 0.0001), fasting insulin (r = -0.695, P < 0.0001), HOMA-IR (r = -0.633, P < 0.0001), and percent peak increase in FBF during ACh infusion. In obese subjects, both vitamin C and indomethacin increased the impaired vasodilating response to ACh, whereas the SNP effect was unchanged. In conclusion, in obese subjects, ACh-stimulated vasodilation is blunted, and the increase in FBF is inversely related to BMI, WHR, fasting insulin, and HOMA-IR. The effects of both vitamin C and indomethacin on impaired ACh-stimulated vasodilation support the hypothesis that oxidative stress contributes to endothelial dysfunction in human obesity.
Abstract: The detection of left ventricular (LV) hypertrophy on echocardiography is a powerful risk indicator in essential hypertension. However, the prognostic impact of LV mass values within the "normal" range and the shape of the relation between LV mass and prognosis remain unclear. Thus, 1925 white subjects with uncomplicated essential hypertension underwent off-therapy 24-hour blood pressure monitoring and M-mode echocardiography. During 4. 0+/-2 years of follow-up, there were 181 major cardiovascular events (2.4/100 patient-years) and 49 deaths from all causes. In the 5 gender-specific quintiles of LV mass distribution (partition values: 92, 105, 120, and 138 g/m(2) in men and 79, 91, 102, and 116 g/m(2) in women), cardiovascular event rates were 0.8, 1.7, 2.2, 2.9, and 4. 3 per 100 patient-years. After adjustment for several risk factors, including 24-hour ambulatory blood pressure, the relative risk (RR) of developing a cardiovascular event increased progressively from the first quintile (RR 1) to the second (RR 1.6, 95% CI 0.8 to 3.1), third (RR 1.9, 95% CI 1.01 to 4.0), fourth (RR 3.0, 95% CI 1.5 to 5. 8), and fifth (RR 3.5, 95% CI 1.8 to 6.8) quintile. For all-cause death, the RR in the fifth quintile compared with the first quintile was 4.3 (95% CI 1.2 to 13.4). In conclusion, the powerful relation between LV mass and risk of cardiovascular disease in subjects with uncomplicated essential hypertension is continuous over a wide range of LV mass values, even below the current "upper normal" limits. The relation remains significant after control for traditional risk factors, including ambulatory blood pressure.
Abstract: We tested the effects of vitamin C and atorvastatin treatment on endothelium-dependent and endothelium-independent vasodilation in 18 hypercholesterolemic patients (ten men and eight women, aged 20-46 years) in comparison with 12 normal volunteers (seven men and five women, aged 20-45 years). The responses of the forearm blood flow (FBF) to acetylcholine (ACh) (7.5, 15 and 30 microg/min), sodium nitroprusside (SNP) (0.8, 1.6, 3.2 microg/min) and L-NMMA (2, 4, 8 micromol/min) were evaluated at baseline and after 1 month of atorvastatin (10 mg/day) treatment. Drugs were infused into the brachial artery and FBF was measured by strain-gauge plethysmography. At baseline, the response to ACh was significantly attenuated in hypercholesterolemics versus controls: at the highest dose (30 microg/min), FBF was 27.0+/-3.4 versus 11.5+/-1.9 ml.100 ml tissue(-1).min(-1) respectively (P<0.0001). No significant differences were found between groups during SNP infusion. The atorvastatin treatment significantly improved ACh-stimulated FBF: at highest dose the FBF increased to 14.9+/-1.5 ml.100 ml tissue(-1). min(-1) (P<0.0001). Similarly, the L-NMMA endothelial effects were significantly enhanced by lipid-lowering treatment, supporting the improvement of basal nitric oxide. Vitamin C increased ACh-vasodilation in the same way before and after atorvastatin treatment. In conclusion, the endothelial dysfunction in hypercholesterolemics is due to an oxidative stress and atorvastatin rapidly improves both basal and stimulated endothelium-dependent vasodilation.
Abstract: To determine the clinical impact of endogenous subclinical hyperthyroidism, specific symptoms and signs of thyroid hormone excess and quality of life were assessed in 23 patients (3 males and 20 females; mean age, 43 +/- 9 yr) and 23 age-, sex-, and lifestyle-matched normal subjects by using the Symptoms Rating Scale and the Short Form 36 Health Survey questionnaires. Because the heart is one of the main target organs of the thyroid hormone, cardiac morphology and function were also investigated by means of standard 12-lead electrocardiogram (ECG), 24-h Holter ECG, and complete Doppler echocardiography. Stable endogenous subclinical hyperthyroidism had been diagnosed in all patients at least 6 months before the study (TSH, 0.15 +/- 0.1 mU/L; free T(3), 6.9 +/- 1.1, pmol/L; free T(4), 17.2 +/- 2.3, pmol/L). Fifteen patients were affected by multinodular goiter, and eight patients by autonomously functioning thyroid nodule. The mean Symptoms Rating Scale score (9. 8 +/- 5.5 vs. 4.3 +/- 2.2, P: < 0.001) and both the mental (36.1 +/- 9.5 vs. 50.0 +/- 8.5, P: < 0.001) and physical (42.6 +/- 8.0 vs. 55. 6 +/- 4.1, P: < 0.001) component scores of Short Form 36 Health Survey documented a significant prevalence of specific symptoms and signs of thyroid hormone excess and notable impairment of quality of life in patients. Holter ECG showed a higher prevalence of atrial premature beats in endogenous subclinical hyperthyroid patients than in the controls, but the difference was not statistically significant, although the average heart rate was significantly increased in the patients (P: < 0.001). An increase of left ventricular mass (162 +/- 24 vs. 132 +/- 22 g, P: < 0.001) due to the increase of septal (P: = 0.025) and posterior wall (P: = 0.004) thickness was observed in patients. Systolic function was enhanced in patients as shown by the significant increase of both fractional shortening (P: = 0.005) and mean velocity of heart rate-adjusted circumferential fiber shortening (P: = 0.036). The Doppler parameters of diastolic function were significantly impaired in the patients as documented by the reduced early to late ratio of the transmitral flow velocities (P: < 0.001) and the prolonged isovolumic relaxation time (P: = 0.006). These data indicate that endogenous subclinical hyperthyroidism has a relevant clinical impact and that it affects cardiac morphology and function. Moreover, they suggest that treatment of persistent endogenous subclinical hyperthyroidism should be considered also in young and middle-aged patients to attenuate specific symptoms and signs of thyroid hormone excess, ameliorate the quality of life, and avoid the consequences to the heart of long exposure to a mild excess of thyroid hormone.
Abstract: BACKGROUND: Hypertensive patients are characterized by development of both left ventricular hypertrophy (LVH) and endothelial dysfunction METHODS AND RESULTS: We enrolled 65 never-treated hypertensive patients (36 men and 29 women aged 45.6+/-6.0 years) to assess the possible relationship between echocardiographic left ventricular mass (LVM) and endothelium-dependent vasodilation. Left ventricular measurements were performed at end diastole and end systole according to the recommendations of the American Society of Echocardiography and the Penn Convention. LVM was calculated with the Devereux formula and indexed by body surface area and height raised to the 2.7th power. The endothelial function was tested as responses of forearm vasculature to acetylcholine (ACh), an endothelium-dependent vasodilator (7.5, 15, and 30 microg. mL-1. min-1, each for 5 minutes), and sodium nitroprusside (SNP), an endothelium-independent vasodilator (0.8, 1.6, and 3.2 microg. mL-1. min-1, each for 5 minutes). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by strain-gauge plethysmography. A negative significant relationship between indexed LVM and peak of increase in FBF was found during ACh infusions (r=-0. 554; P<0.0001). In addition, hypertrophic patients had a significantly lower responsive to ACh than patients without LVH (the peak increase in FBF was 9.9+/-3.7 versus 16.1+/-8.1 mL per 100 mL of tissue per minute; P<0.0001). No significant correlation was observed between LVM and FBF during SNP infusion. CONCLUSIONS: Our data provide the first evidence that echocardiographic LVM in hypertensive patients is inversely related to FBF responses to the endothelium-dependent vasodilating agent ACh, but it is likely that both endothelium and LVM are damaged by hypertension.
Abstract: OBJECTIVE: To evaluate the relationship between ACE-gene polymorphism and left ventricular geometry in never treated hypertensives. METHODS: We enrolled 200 hypertensive outpatients that underwent clinical and ambulatory blood pressure measurements, echocardiographic evaluation and analysis for insertion (I)/deletion (D) polymorphism by PCR. Patients with normal or increased (> 125 g/m2 in males and > 110 g/m2 in females) left ventricular mass were considered to have concentric remodeling or concentric left ventricular hypertrophy if their relative wall thickness was > or = 0.45. RESULTS: The left ventricular mass index values (g/m2) were 136 +/- 30 in DD genotype, 124 +/- 26 in ID genotype, and 116 +/- 20 in II genotype (DD vs. ID P < 0.005; DD vs. II P < 0.05), and were unrelated to blood pressure. Ninety-six patients presented left ventricular hypertrophy (48.0%): 51 with concentric and 45 with eccentric hypertrophy. The eccentric left ventricular hypertrophy was detected in 32 (36.8%) DD patients, in ten (10.5%) ID patients (P < 0.05), and in three (16.6%) II patients. The relative septal thickness was 0.43 +/- 0.09 in DD genotype, 0.45 +/- 0.08 in ID genotype, and 0.43 +/- 0.10 in II genotype. In DD and ID genotypes, the relative posterior wall thickness (0.37 +/- 0.07 vs. 0.41 +/- 0.07; P < 0.0001) and the end-diastolic left ventricular internal dimension (52.8 +/- 3.3 mm vs. 48.3 +/- 2.8 mm; P < 0.0001) were statistically different. CONCLUSIONS: The DD genotype of the ACE-gene is associated with an increased left ventricular mass and with a significantly higher prevalence of eccentric left ventricular hypertrophy, when compared to ID genotype.
Abstract: OBJECTIVE: To examine whether middle (two months) and long-term (six months) isradipine sustained-release treatment improves endothelium-dependent vasodilation in never treated hypertensive patients. METHODS: The responses of the forearm vasculature to acetylcholine (7.5, 15 and 30 micrograms/min) and sodium nitroprusside (0.8, 1.6, 3.2 micrograms/min) were evaluated in 12 normotensive controls (seven men and five women, aged 25 to 49 years), and in 12 hypertensives (eight men and four women, aged 20 to 47 years) at baseline and after two and six months of isradipine sustained-release treatment. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. RESULTS: At baseline, the response to acetylcholine was significantly lower in hypertensives vs controls: at the highest dose (30 micrograms/min), forearm blood flow was 28.6 +/- 2.4 ml/100 ml of tissue per min in the controls vs 8.9 +/- 1.0 ml/100 ml of tissue per min in hypertensive (p < 0.0001). Similarly, vascular resistance was significantly (p < 0.0001) higher in hypertensives: 4.8 +/- 0.5 units (controls) vs 15.1 +/- 1.7 units (hypertensives). After isradipine treatment, the forearm blood flow in hypertensive patients changed from 8.9 +/- 1.0 ml/100 ml of tissue per min to 16.0 +/- 1.2 ml/100 ml of tissue per min (two months; p < 0.0001) and 15.2 +/- 1.4 ml/100 ml of tissue per min (six months; p < 0.0001). Isradipine treatment did not modify the vasodilating effect of sodium nitroprusside. CONCLUSIONS: Our data demonstrate for the first time that the calcium antagonist isradipine improves acetylcholine-induced vasodilation in hypertensives.
Abstract: BACKGROUND: The sudden infant death syndrome (SIDS) is multifactorial in origin, but its causes remain unknown. We previously proposed that prolongation of the QT interval on the electrocardiogram, possibly resulting from a developmental abnormality in cardiac sympathetic innervation, may increase the risk of life-threatening ventricular arrhythmias and contribute to this devastating disorder. We prospectively tested this hypothesis. METHODS: Between 1976 and 1994, we recorded electrocardiograms on the third or fourth day of life in 34,442 newborns and followed them prospectively for one year. The QT interval was analyzed with and without correction for the heart rate. RESULTS: One-year follow-up data were available for 33,034 of the infants. There were 34 deaths, of which 24 were due to SIDS. The infants who died of SIDS had a longer corrected QT interval (QTc) than did the survivors (mean [+/-SD], 435+/-45 vs. 400+/-20 msec, P<0.01) and the infants who died from causes other than SIDS (393+/-24 msec, P<0.05). Moreover, 12 of the 24 SIDS victims but none of the other infants had a prolonged QTc (defined as a QTc greater than 440 msec). When the absolute QT interval was determined for similar cardiac-cycle lengths, it was found that 12 of the 24 infants who died of SIDS had a QT value exceeding the 97.5th percentile for the study group as a whole. The odds ratio for SIDS in infants with a prolonged QTc was 41.3 (95 percent confidence interval, 17.3 to 98.4). CONCLUSIONS: Prolongation of the QT interval in the first week of life is strongly associated with SIDS. Neonatal electrocardiographic screening may permit the early identification of a substantial percentage of infants at risk for SIDS, and the institution of preventive measures may therefore be possible.
Abstract: The response of the forearm vasculature to acetylcholine (7.5, 15, and 30 microg/min, each for 5 minutes) and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min, each for 5 minutes) was evaluated in 32 never-treated hypertensive outpatients (17 men and 15 women, aged 43+/-7 years) and in 24 normotensive control subjects (14 men and 10 women, aged 42+/-6 years). Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. In both hypertensive and normotensive groups, a deletion (D)/insertion (I) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene was determined by polymerase chain reaction. The response to acetylcholine was significantly reduced in hypertensive patients versus control subjects: at the highest dose (30 microg/min), forearm blood flow was 13.9+/-6.3 mL x 100 mL tissue(-1) x min(-1) in hypertensives versus 27.1+/-9.7 mL x 100 mL tissue(-1) x min(-1) in the controls (P<.001); similarly, vascular resistance was 10.6+/-5.6 U in hypertensive patients and 4.9+/-1.9 U in normotensive subjects. In the hypertensive group, the patients with DD genotype showed significantly less endothelium-dependent vasodilation compared with ID+II genotypes (at the highest dose of acetylcholine, forearm blood flow was 12.1+/-4.2 versus 17.0+/-4.1 mL x 100 mL tissue(-1) x min(-1)) (P<.005). The vasodilator effect of sodium nitroprusside infusions was not statistically different in DD and ID+II hypertensive patients. In conclusion, our data suggest that ACE polymorphism affects endothelium-dependent vasodilation in hypertensive patients and confirm that hypertensive patients had a blunted response to the endothelium-dependent agent acetylcholine.
Abstract: In this study the seroepidemiology of H. pylori and Epstein-Barr virus was compared in the same setting. A sample of 705 subjects completed a structured questionnaire. A serum sample was drawn from each subject and assayed for H. pylori IgG. Antibodies to Epstein-Barr virus were determined in a subgroup of 466 subjects. Cross-tabulation of data showed that 274 (58.8%) subjects were seropositive and 20 (4.3%) were seronegative for both infections, 17 (3.6%) were seropositive for H. pylori, and 155 (33.3%) were seropositive for Epstein-Barr virus (odds ratio=2.08, 95% confidence interval: 1.008-4.3). Nevertheless, the agreement between H. pylori and Epstein-Barr virus seropositivity was no better than chance (kappa=0.067) and the age-related seroprevalence curve of Epstein-Barr virus was similar in H. pylori seropositive and seronegative subjects. Furthermore, multiple logistic regression analysis did not show any risk factor shared by both infections. The findings of this study do not support the hypothesis that H. pylori and Epstein-Barr virus share a common mode of transmission. It can be speculated that the oral cavity may not be an important reservoir for H. pylori.
Abstract: The impact of molecular genetics in the diagnosis and management of various forms of heritable cardiac or vascular disorders is continuously increasing thanks to the newly available laboratory tools. Familial hypertrophic cardiomyopathy (FHC), an autosomal dominant inherited disease characterized by unexplained left ventricular hypertrophy and a wide range of clinical symptoms, is the first cardiac disorder whose genetic bases have been elucidated. Linkage analysis studies have shown a statistically significant association between the disease status and at least seven genetic loci, all coding for sarcomeric proteins, in unrelated kindreds. A major challenge for physicians is to make an accurate and early diagnosis, not only on the basis of the traditional tools (i.e. physical examination and electro-echocardiography) but also to focus on the impact of genotype on clinical manifestations of FHC. In this review we present the more recent findings on the genetic basis of FHC and analyze the genotype-phenotype correlations of this disorder, whose expression may be modulated by additional factors (modifier genes, genetic background, environmental factors) other than mutations in any of the sarcometric proteins.
Abstract: OBJECTIVE: Diabetes mellitus is a well-known risk factor in patients undergoing coronary artery bypass grafting. Myocardial and pulmonary injury often occurs after cardiopulmonary bypass (CPB), mediated in part by neutrophil activation and adhesion to endothelial cells. The objectives of the present study are to compare the degree of neutrophil activation and neutrophil-endothelial cells adhesive interactions in diabetic patients after CPB. METHODS: Nitro-blu tetrazolium scores, CD 11b expression and neutrophil-endothelial cells adhesion were assessed in blood samples from 15 diabetic and 15 control patients who had undergone elective coronary bypass grafting. Blood samples were obtained at baseline, 30 min after beginning CPB, at the end of CPB and 60 min postoperatively. At the same sampling points as above, blood glucose levels were also checked in all patients. RESULTS: Diabetes was associated with a significant basal increase in neutrophil CD1 lb expression and adhesion to endothelial cells as well as with an increased superoxide anion production. The increased adhesion of diabetic neutrophils persisted by the end of the CPB to 60 min postoperatively independently of the blood glucose levels. Antibodies directed against CD1 lb and CD18 significantly reduced the degree of neutrophil adhesion observed 60 min postoperatively. CONCLUSIONS: These results indicate that diabetes mellitus is associated with an increased neutrophil-endothelial cell adhesion probably mediated by the CD1 1b/CD18 molecule; this, in turn, might be responsible for the increased risk of postoperative complications observed in diabetic patients undergoing coronary artery bypass grafting.
Abstract: OBJECTIVES: This study sought to evaluate the relation between the pattern of neutrophil-endothelial adhesion in saphenous vein (SV) and internal mammary artery (IMA) grafts and the endothelial production of nitric oxide (NO). BACKGROUND: Autologous IMA and SV grafts (SVGs) are increasingly used as conduits for coronary bypass grafting. Previous studies have demonstrated a greater production of endothelial-derived relaxing factor (NO) from IMA than from SVGs. Because of the well known role of NO in modulating the adhesion of polymorphonuclear leukocytes to the endothelium, we studied the pattern of neutrophil adhesion to the endothelium of IMA and SVs under basal conditions and after inhibition of NO synthesis. METHODS: Segments of IMA and SVs were obtained from 20 patients undergoing coronary artery bypass graft surgery. We evaluated the adhesion of both unstimulated and activated neutrophils to the endothelial surface of IMA and SVs in both basal conditions and after inhibition of NO synthesis with Nomega-nitro-L-arginine methyl ester. RESULTS: Under basal conditions, no difference in unstimulated neutrophil adhesion to endothelium was observed between the two vessel conduits. After neutrophil activation, a significantly (p < 0.05) greater adhesion of neutrophils was observed in the SV than in the IMA. After inhibition of NO release, the adhesion of activated neutrophils increased in both vessels, and no significant difference between them was observed. The increased adhesion was attenuated by both L-arginine and sodium nitroprusside. CONCLUSIONS: The lesser neutrophil adhesion to the endothelium of the IMA is a consequence of enhanced release of NO at this level; this effect could be responsible for the better early and long-term patency of this conduit over the SVG in coronary bypass grafting.
Abstract: BACKGROUND AND AIMS: Recent studies have shown that the age-specific seroprevalence of H pylori infection parallels hepatitis A (HAV), suggesting similar modes of transmission. The aim of this study was to investigate the seroepidemiology of H pylori and HAV in the same setting. PATIENTS: A sample of 705 resident subjects (273 men, age range 1-87 years, median 50) who attended the outpatient medical centre of the rural town of Cirò, Southern Italy (11,000 inhabitants) for blood testing were recruited. METHODS: All subjects completed a structured questionnaire. A serum sample was drawn from each subject and assayed for H pylori IgG by a validated in house enzyme linked immunosorbent assay. Antibodies to HAV were determined in 466 subjects (163 men, age range 1-87 years, median 49). A measure of agreement between H pylori and HAV seropositivity, the kappa statistic, was used. RESULTS: Overall, 446 (63%) subjects were seropositive for H pylori. Of the 466 subjects screened for both H pylori and HAV, 291 (62%) were seropositive for H pylori and 407 (87%) for HAV. Cross-tabulation of these data showed that 275 (59%) were seropositive and 43 (9%) seronegative for both H pylori and HAV, 16 (3%) were seropositive for H pylori, and 132 (28%) were seropositive for HAV (OR = 5.6, CI 3 to 10). There was a parallel, weakly correlated (r = 0.287) rise in the seroprevalence of the two infections with increasing age. However, the agreement between H pylori and HAV seropositivity was little better than chance (kappa = 0.21) and in those aged less than 20 years it was worse than chance (kappa = -0.064). Furthermore, multiple logistic regression analysis did not show any risk factor shared by both infections. CONCLUSIONS: The correlation between H pylori and HAV reflects the age-specific seroprevalence of both infections rather than a true association. This study provides evidence against a common mode of transmission of H pylori and HAV.
Abstract: OBJECTIVES: This study sought to evaluate the possible association of polymorphism of the angiotensin-converting enzyme (ACE) gene with blood pressure and left ventricular mass index (LVMI). BACKGROUND: The renin-angiotensin system seems to be involved in the pathogenesis of essential hypertension. Moreover, recent epidemiologic observations demonstrate that many subjects with left ventricular hypertrophy have normal blood pressure levels, suggesting that factors other than hemodynamic overload may contribute to the hypertrophy. METHODS: The study included 140 untreated hypertensive outpatients who underwent ambulatory blood pressure monitoring, echocardiographic evaluation and analysis for insertion (I)/ deletion (D) polymorphism in intron 16 of the ACE gene by polymerase chain reaction. Blood pressure was measured at 24 h, and LVMI was calculated by the Devereux formula, in each patient. RESULTS: Left ventricular mass index values (mean +/- SD) were 137 +/- 28 g/m2 in patients with the DD genotype, 125 +/- 27 g/m2 in those with the ID genotype and 115 +/- 27 g/m2 in those with II genotype. The frequencies of the DD, ID and II genotypes were 45.71% (n = 64), 46.42% (n = 65) and 7.85% (n = 11), respectively, and were in Hardy-Weinberg equilibrium. The strongest association between left ventricular mass and DD genotype in our cohort appeared to be an independent cardiovascular risk factor (DD vs. ID: odds ratio [OR] 2.497, 95% confidence interval [CI] interval 1.158 to 5.412, p < 0.05; DD vs. II: OR 6.577, 95% CI 1.169 to 28.580, p < 0.02). CONCLUSIONS: Our data show that the LVMI was significantly enhanced in patients with the DD genotype.
Abstract: In order to evaluate the antihypertensive effects of manidipine, at the dosage of 10 or 20 mg once daily, we studied 36 patients (12 males and 24 females, mean age 54.3 years) with mild hypertension. After a wash-out period of 2 weeks and another 2 week run-in period with placebo, all the patients were assigned to a treatment with manidipine 10 mg/ day. After 2 weeks of treatment, the non-normalized (diastolic BP > 90 mmHg) and the non-responders (BP fall < 10 mmHg) received an increase in dosage to 20 mg/day. The drug effects were assessed by casual blood pressure (BP) measurement at baseline and after 4, 8, 12, 24, 36 and 52 weeks. At baseline and after 1 year of treatment a 24-h BP monitoring and a Doppler echocardiogram were performed. Routine laboratory tests were performed at baseline, after 6 months and after 1 year of treatment. At the end of the observation period, both casual systolic (p < 0.01) and diastolic (p < 0.001) BP were significantly reduced; 24-h BP monitoring showed a significant decrease in systolic (p < 0.05) and diastolic (p < 0.01) pressure, systolic and diastolic (p < 0.001) daytime and night-time measurements. The peak to through ratio was 67%. No difference was found in heart rate. Reduced interventricular septum thickness (p < 0.05), increased fractional shortening (p < 0.02), reduced end-systolic stress (p < 0.005) and systemic vascular resistances (p < 0.001), and lower values of atrial filling fraction (AFF) (p < 0.001) after 1 year of treatment have been shown at the Doppler-Echo evaluation. A multilinear regression analysis showed a relation between delta %AFF and delta %24-h systolic BP (R = 0.74; F = 7.5: p < 0.05) and with delta % daytime systolic BP (R = 0.77; F = 9.2; p < 0.02). No abnormal changes were observed in laboratory tests. Three non-responder patients and three patients with adverse effects (1 flushing and 2 ankle oedema) dropped out and were excluded from the final analysis. In conclusion, manidipine at an individualized dose of 10 or 20 mg. was effective and safe in the management of arterial hypertension. Hemodynamic evaluations after 1 year of treatment confirmed an improvement of systolic and diastolic function, with an evident reduction of afterload.
Abstract: OBJECTIVE: To investigate whether patients with constrictive pericarditis have changes in collagen content and architecture that could influence left ventricular function. DESIGN: Cohort study. SETTING: University teaching hospital. PATIENTS: Biopsy specimens of myocardium from 13 patients admitted consecutively for treatment of chronic constrictive pericarditis were compared with normal heart tissue taken at necropsy from 15 patients free of cardiac disease. INTERVENTION: Pericardiectomy through median sternotomy. Biopsy specimens (4 or 5) were taken from the left ventricular free wall. MAIN OUTCOME MEASURES: Biochemical and histological assessment of total collagen content, relative proportion of type I and III collagen, and amount of orthogonal collagen fibre meshwork (crosshatching) in the left ventricular tissue. RESULTS: There was more collagen in the myocardium of patients with constrictive pericarditis than in controls when measured either biochemically by hydroxyproline content (89.4 v 50.4 mg/g dry weight) or by histological measurement of the collagen fraction of the myocardium (2.4% v 7.0%). Neither of these measurements, however, correlated with left ventricular ejection fraction, pulmonary wedge pressure, or right ventricular end diastolic pressure. The thickness of the fibrous trabeculae in the myocardium was, however, inversely related to both left ventricular ejection fraction (r = -0.76) and deceleration time (r = -0.68). Trabecular thickening was also related to NYHA class, with those in class III and IV having the greatest thickening. CONCLUSION: Changes in collagen content and architecture may contribute to impaired ventricular function in patients with chronic constrictive pericarditis.
Abstract: To test the hypothesis of association between heart failure and altered haemostatic balance in patients with a mechanical valve prosthesis, comparisons were made between 20 patients with mitral valve replacement and stable chronic heart failure (group A), 20 with the same prosthesis but satisfactory haemodynamics (group B) and 20 age-matched controls (group C). The left ventricular ejection fraction was significantly highest (p < 0.001) in group A. The pulmonary artery systolic pressure was also highest in group A (p < 0.001), without significant difference between groups B and C. Two group A patients had a transient ischaemic attack. The D-dimer plasma concentrations and the antigenic and biologic von Willebrand factor activities were significantly greatest in group A. Significant correlation was found between the plasma concentrations of these activities and pulmonary artery systolic pressure and between D-dimer and ejection fraction. Platelet-activating factor was detected only in six group A patients. The observed relationship between haemostatic factors and heart failure in patients with mechanical heart-valve prosthesis advocates careful evaluation of von Willebrand factor and D-dimer in order to prevent embolic events in such cases.
Abstract: A previously undescribed de novo insertion-deletion mutation in the beta cardiac myosin heavy chain gene was found in a kindred with familial hypertrophic cardiomyopathy. In the mutated allele there is an inserted-deleted guanine at nucleotides 8823 and 8850 of the beta myosin heavy chain gene, resulting in a dramatic change of the amino acid sequence (AA 395-404). such a mutation, detected in the proband and in his son but not in the proband's parents, is likely to produce major impairment of myosin function.
Abstract: We compared the efficacy and tolerability of isradipine (ISR) and fosinopril (FOS) once-a-day administration in 17 outpatients, 9 men and 8 women, aged 35-65 years (mean +/- SD = 58 +/- 10 years), affected by mild to moderate primary systemic hypertension. The patients were given single-blind placebo for 2 weeks and thereafter, in double-blind, randomized, crossover sequence, ISR (5 mg) and FOS (20 mg), both for 4 weeks. At the end of each period, patients underwent 24-h noninvasive blood pressure (BP) monitoring by means of an A&D TM 2420 Monitor Model 7, with readings taken very 10 min during the day (from 7 A.M. to 11 P.M.), and every 20 min during the night (from 11 P.M. to 7 A.M.) Similarly, BP load (BPL) as percentage of systolic and diastolic BP reading > 140 and > 90 mmHg was investigated. Both ISR and FOS induced a highly significant (p < 0.0001) decrease in BP from 158/96 +/- 7/6 mmHg to 133/86 +/- 6/6 and to 132/83 +/- 10/7 mmHg, respectively. Mean BP decreased from 117 +/- 6 mmHg to 102 +/- 6 mmHg (ISR) (p < 0.0001) and to 99 +/- 8 mmHg (FOS) (p < 0.0001). Both ISR and FOS significantly (p < 0.0001) reduced systolic BPL from 78 +/- 16% to 44 +/- 13% and 28 +/- 12%, respectively, and diastolic BPL from 70 +/- 15% to 40 +/- 13% (p < 0.0001) and 35 +/- 13% (p < 0.0001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: OBJECTIVES. To evaluate the effects of isradipine (ISR) and diltiazem (DIL) on exercise tolerance and ischemic ST depression in patients with stable effort angina. METHODS. Fourteen out-patients, 9 males and 5 females, aged 46-65 years (mean +/- SD = 57 +/- 8), with ischemic heart disease and reproducible ST-segment depression on two consecutive exercise stress tests in baseline conditions, underwent a study consisting of 4 periods: 1 and 3 placebo, 2 and 4 at random ISR (5 mg b.i.d.) and DIL (120 mg b.i.d.). At the end of each period a multistage treadmill exercise stress test (Bruce protocol) was performed. RESULTS. Both drugs significantly (p < 0.001) increased ischemia time (IT) (0.1 mV ST depression) as compared to placebo, from 438 +/- 132 s. to 620 +/- 164 s. (ISR) and 583 +/- 147 s. (DIL) without statistical difference between two drugs (p = 0.2), and significantly reduced (p < 0.002) the maximal ST depression, from -0.20 +/- 0.11 mV to -0.07 +/- 0.07 mV (ISR) and -0.09 +/- 0.11 mV (DIL). At the IT, systolic blood pressure increased (p = 0.02), from 180 +/- 19 mm Hg to 187 +/- 15 mm Hg (ISR) and 191 +/- 15 mm Hg (DIL); similarly, heart rate increased from 133 +/- 24 bpm to 144 +/- 18 bpm (ISR: p = 0.002) and 140 +/- 17 bpm (DIL: p = NS). CONCLUSIONS. ISR and DIL, at the above dosage have showed an important and significant anti-ischemic effect (IT = +41.5% during ISR and +33.1% during DIL).
Abstract: This study was designed to compare the efficacy and tolerability of amlodipine (AML) and ramipril (RAM) administered once a day in patients affected by mild to moderate primary systemic hypertension. Twenty outpatients, 12 men and 8 women (age range 35-64 years), were enrolled. The patients received single-blind placebo for 2 weeks and thereafter in a double-blind, randomized crossover sequence AML (10 mg) and RAM (5 mg), both for 4 weeks. At the end of each period, the patients underwent 24-hour noninvasive blood pressure monitoring with readings taken every 10 min during daytime (from 07.00 to 23.00 h) and 20 min during nighttime (from 23.00 to 07.00 h). Both AML and RAM induced a highly significant (p < 0.0001) decrease in blood pressure from 162/103 +/- 7/3 to 132/82 +/- 6/6 and 135/83 +/- 6/5 mm Hg, respectively. The mean blood pressure decreased from 122 +/- 5 to 99 +/- 6 (AML; p < 0.0001) and 100 +/- 5 mm Hg (RAM; p < 0.0001). No significant differences in heart rate were noted during drug administrations. Treatment did not have to be discontinued in any patient because of adverse reactions. In conclusion, both AML and RAM reduced the blood pressure markedly, even if AML proved to be significantly more effective than RAM.
Abstract: Left ventricular dysfunction has been identified as the strongest independent predictor of sudden death in patients with ventricular tachyarrhythmias. It has been suggested that some of these arrhythmias might be due to myocardial stretch which may alter cellular electrophysiological properties. In heart failure (HF) the abnormal mechanics of contraction may directly initiate an arrhythmia by mechano-electric feedback (MEF), defined as changes in mechanical state that precede and alter transmembrane potential. So far, the significance of MEF and its role in clinical arrhythmogenesis have received minimal attention. We report data of 3 patients, aged from 60 to 64 years (mean age 62 +/- 2), affected by HF from 28.3 +/- 3.5 months and ventricular arrhythmias recorded by Holter: premature contractions, couplets, nonsustained ventricular tachycardia (VT). Sinus rhythm was present in 2 patients, atrial fibrillation in the last one. Many VT episodes started after an abrupt spontaneous increase in ventricular cycle length or following an ectopic beat. A permanent VVI pacemaker (MEDTRONIC Legend) was implanted in each patient and programmed at different rate from 50 to 80 b/min. During the upper rates, 70 and 80 b/min, VT episodes decreased from 292 +/- 181 to 161 +/- 95 and 97 +/- 63 (p < 0.05), respectively. In fact, the permanent pacemaker could prevent the lengthening of ventricular cycle and the myocardial fibers stretch due to the increase in ventricular volume. In conclusion, in patients with HF and ventricular arrhythmias a pacemaker may be useful in preventing VT episodes and, probably, sudden death.
Abstract: In the setting of stable effort angina a single-blind, randomized, cross-over study to evaluate the effects of gallopamil (GAL) and amlodipine (AML) on exercise tolerance and ischemic ST depression was conducted. Fifteen outpatients, 12 males and 3 females, aged 40-65 years (57 +/- 9), with documented coronary atherosclerosis and reproducible ST-segment depression on 2 consecutive baseline exercise stress tests, completed the study, which consisted of 4 periods: 1 and 3 placebo, 2 and 4 at random GAL (50 mg tid) and AML (10 mg/daily). At the end of each period a multistage treadmill exercise stress test (Bruce protocol) was performed. Both drugs significantly (p = 0.0001) increased the ischemia time (IT) (0.1 mV ST depression) as compared to placebo, from 416 +/- 165 s to 635 +/- 161 s (GAL) and 607 +/- 152 s (AML) with significant difference (p = 0.2) between the 2 drugs, and reduced significantly (p = 0.001) the maximal ST depression from -0.25 +/- 0.09 mV to -0.11 +/- 0.08 mV (GAL) and -0.12 +/- 0.09 mV (AML). At the IT, the systolic blood pressure increased from 178 +/- 23 mmHg to 185 +/- 20 mmHg (GAL) and remained unchanged during AML treatment (178 +/- 15 mmHg); similarly, the heart rate increased from 126 +/- 22 b/min to 139 +/- 21 b/min (GAL) and 138 +/- 19 b/min (AML). In conclusion, both GAL and AML showed a good anti-ischemic effect (IT = +52.6% during GAL and +45.9% during AML), even if GAL proved to be significantly more effective than AML.
Abstract: A case of QT interval prolongation with ventricular tachycardia and torsade de pointes is reported. Arrhythmias occurred in a baby with persistent 2:1 atrioventricular block and long QT interval 2 days after birth and were self-limiting. No structural cardiac defect was present. Serum levels of sodium, potassium, magnesium and calcium were in the normal range. Finally, the pathogenetic mechanism of cardiac block is discussed.
Abstract: We report the electrocardiographic and electrophysiologic effects of magnesium (Mg) sulfate infusion in 25 normomagnesemic patients (16 men and 9 women, aged 22-74 years; mean +/- SD, 60.4 +/- 11.9) with different cardiac conduction impairments. Ten patients had chronic ischemic heart disease, two had idiopathic dilated cardiomyopathy, two had hypertensive heart disease, three had valvular heart disease, five had sclerodegenerative heart disease and three had no clinical evidence of cardiac disease. Five patients had trifascicular block [first degree atrioventricular (A-V) block+right bundle branch block (RBBB)+left anterior hemiblock (LAH)], eight had bifascicular block (6 RBBB+LAH, 2 first degree A-V block+RBBB), four had isolated first degree A-V block and eight had bundle branch block [5 RBBB, 3 left bundle branch block (LBBB)]. Before and during Mg infusion (50 mg/min/60 min) we evaluated the A-V (P-R), intraatrial (P-A), suprahisian (A-H), infrahisian (H-V) conduction times, electrical ventricular systole (Q-T), Q-T index (Q-Tc) intraventricular conduction time (QRS) and heart rate. At the end of infusion the P-R, P-A, A-H, H-V increased from 215.4 +/- 36.6, 33.6 +/- 9.1, 112.8 +/- 37.3, 69.0 +/- 12.8 ms to 217.6 +/- 37.1 (p less than 0.002), 33.8 +/- 9.4 (NS), 114.2 +/- 38.1 (p less than 0.005), 69.6 +/- 13.3 (NS) ms. QRS complex did not change (125 +/- 16.9 ms).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Antiarrhythmic magnesium (Mg) therapy was evaluated in 20 normomagnesaemic patients affected by ischaemic dilated cardiomyopathy (ID) and severe ventricular arrhythmias, and in 10 patients with torsade de pointes (TdP) occurring in the setting of acquired QT interval prolongation. In the group with IDC, magnesium sulphate was given as slow infusions (50 mg/min over 60 min) twice a day for 7 d. This was antiarrhythmic in all of the patients: ventricular premature contractions and couplets decreased from 13,979 +/- 8964 (mean +/- SD) to 382 +/- 265 (P < 0.001), and from 516 +/- 274 to 9 +/- 6 (P < 0.001), respectively; runs of ventricular tachycardia (41.9 +/- 14.2) disappeared by the fifth day of treatment. The efficacy of antiarrhythmic treatment was evaluated by 24 h Holter monitoring obtained in baseline conditions and after 3, 5 and 10 d from beginning of therapy. In patients with TdP, Mg infusions were instituted at a slow rate (50 mg/min) and continued for 2 h after disappearance of Tdp, which occurred within 20 to 30 min from the start of the Mg infusions. These were followed by prophylactic infusions at rate of 30 mg/min for 90 min twice a day over the next 3 to 4 d. No side effects were observed, and heart rate and QTc remained unchanged from baseline values. In conclusion, Mg infusions may be an effective antiarrhythmic treatment for short and medium-term control of severe ventricular arrhythmias associated with IDC, and may prove useful in the acute treatment of TdP, especially in situations where conventional therapy might prove deleterious or difficult.
Abstract: A prospective electrocardiographic study was performed in 1830 newborns to evaluate the predictive value of QT interval for sudden infant death syndrome (SIDS). Standard ECG, with babies asleep, was recorded at the ages of 4 days, 2, 4, 6 months, and 1 year. The QTc (+/- SD) was 392 +/- 22 at 4 days, 410 +/- 16 (p less than 0.0001) at 2 months (n = 1256), 404 +/- 16 at 4 months (n = 1015), 400 +/- 16 at 6 months (n = 895), and 398 +/- 15 at 1 year (n = 890). QTc values longer than the mean plus 3 standard deviations were considered prolonged. Heart rate values (beats/min) were 138 +/- 19 at 4 days, 141 +/- 13 at 2 months, 134 +/- 13 at 4 months, 133 +/- 13 at 6 months, and 128 +/- 14 at 1 year. In 34 babies the QT interval was prolonged (mean + 3SD) and 3 of these died suddenly: the first, at 3 months (QTc = 470 and HR = 147 at 4 days); the second after 7 weeks (QTc = 514, HR = 115); the third at 3 months (QTc = 464 and HR = 140 at 4 days).
Abstract: The sudden infant death syndrome (SIDS) is the most common cause of death in infancy. The pathophysiological mechanism leading to SIDS is still obscure. In the QT hypothesis, the mechanism must be an arrhythmogenic sympathetic imbalance: the infants die suddenly of cardiac arrhythmia. Recently, it has been suggested that analysis of heart rate variability (HRV), expressed as standard deviation or variance analysis, can provide adequate information on sympathovagal interaction. We studied 150 newborns enrolled in a previous prospective electrocardiographic study to evaluate the predictive value of QT interval for SIDS. We analyzed the ECGs recorded with infants alert on the fourth day of life and after 2 months. For each ECG, the HRV was calculated using the first standard deviation of of RR intervals (ms) measured for 1 minute. The average RR interval was 441 +/- 71 ms at the fourth day and 410 +/- 39 ms at the second month. The QTc and HRV mean values were 396 +/- 23 and 23 +/- 12 ms at the fourth day, 412 +/- 19 and 15 +/- 7 msec at the second month. Therefore, the SD values of heart rate were correlated with QTc in order to assess a possible relationship between the two variables. The correlation coefficient and regression equation were: -0.639 and y = 423.67 - 1.18*X (P less than 0.001) at the fourth day, -0.146 and y = 418.09 - 0.37*X (NS) at the second month. In conclusion, our data seems to confirm a delayed maturation or impaired functioning of the autonomic nervous system in the first weeks of life, reflecting a direct correlation with QT prolongation.
Abstract: The efficacy of magnesium sulfate (MgSO4) infusion in the treatment of ventricular arrhythmias was evaluated in 10 normomagnesemic patients: seven men and three women, aged 56-78 years (mean +/- SD, 63.8 +/- 9.3). All of the patients had ischemic dilated cardiomyopathy (IDC) and severe ventricular arrhythmias: multiform ventricular premature contractions (VPCs), couplets, runs of ventricular tachycardia (VT), and R-on-T phenomenon. Four had evidence of old myocardial infarction (MI), four had chronic ischemic cardiomyopathy, and two had effort angina pectoris. Dilated cardiomyopathy was diagnosed by chest X-ray (cardiothoracic ratio greater than 0.5) and echocardiogram (end-diastolic left-ventricular diameter greater than 56 mm). All of the patients underwent two successive 24-hr Holter monitoring at the time of admission and after 3, 5, and 10 days from the beginning of therapy. Ventricular arrhythmias were classified according to modified Lown criteria. Renal function was normal. Magnesium sulfate in 0.9% sodium chloride was given by slow infusions (50 mg/min/60 min) twice daily for 7 days. They were antiarrhythmic in all of the patients: VPCs and couplets mean values decreased from 7971 +/- 2612 to 321 +/- 141 (p less than 0.001) and from 405 +/- 113 to 7 +/- 4 (p less than 0.001), respectively; VT runs (33.8 +/- 5.8) disappeared by the fifth day of treatment. Both the heart rate and the QTc interval remained unchanged from baseline values. The slow magnesium infusion did not notably raise serum Mg when evaluated immediately after stopping the infusion, as compared with baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The permanent form of junctional reciprocating tachycardia (PJRT) is a very rare arrhythmia with the following clinical and electrocardiographic findings: (1) it occurs predominantly in infants and children; (2) it is almost incessant and refractory to pharmacological therapy; (3) the onset is commonly related to a critical shortening of the P-P cycle length without P-R prolongation; (4) during tachycardia the ECG shows an R-P longer than P-R interval, with a negative P wave in leads II, III, aVF. Recently, the anatomic and electrophysiological characteristics underlying PJRT have been identified: there is an accessory pathway of working myocardium with decremental properties, located in the posterior pyramidal space. A case of familial PJRT is reported: the arrhythmia has been documented in a 72-year-old female and in her 16-year-old grandson. Several triggering tachycardia mechanisms have been observed. Tachycardia was almost incessant and the heart rates were 115 and 135 beats/min, respectively. Typing according to the HLA system, performed in all members of the family, demonstrated the Bw41 antigen in both our patients as well as in the boy's paternal uncle. This is the first documented familial case of PJRT, but the possible significance and correlation with the Bw41 antigen should be further investigated.
Abstract: The ventricular rate during rapid atrial rhythms is related in Wolff-Parkinson-White (WPW) syndrome to antegrade effective refractory period of the accessory pathways. Among the many antiarrhythmic drugs available, amiodarone is most commonly used for its large therapeutic window and very long half-life. We report a case of cardiac pre-excitation syndrome in a young male patient in whom amiodarone therapy (3000 mg/weekly) was instituted to modify the dangerous ventricular response during atrial fibrillation (shortest R-R interval 190 ms, ventricular rate 210 beats/min). Four months later, starting pharmacological treatment, a new electrophysiological study documented a malignant ventricular arrhythmia: during atrial fibrillation the minimum R-R interval was 160 ms and the ventricular rate 280 beats/min. Finally, the possible mechanism of paradoxical effect observed in our patient is hypothesized. Amiodarone could favor conduction over the accessory pathways by slowing or blocking conduction into the atrioventricular node and decreasing concealed retrograde conduction into the accessory bypass tract by normally conducted beats.
Abstract: We report the results of magnesium sulphate (MgSO4) infusion in 10 patients with different ventricular arrhythmias: 6 torsade de pointes (2 with total A-V block, 1 with acute myocardial infarction and 3 with lengthening of the Q-Tc due to antiarrhythmic and/or diuretic treatment), 1 bidirectional ventricular tachycardia (on chronic treatment with digoxin (0.5 mg/day) and diuretics), and 3 polymorphic ventricular ectopic beats plus ventricular tachycardia runs (2 with hypertensive and 1 with ischemic cardiomyopathy). MgSO4 in normal saline was given at low rate (50 mg/min) and continued 2 hours after disappearance of arrhythmia, and the infusion was repeated at the same rate for 60-90 min twice daily for the next 3-4 days. In all patients the drug was effective and no side effects were observed. The heart rate and Q-Tc interval remained unchanged from baseline values. Serum creatinine concentration was normal. Serum Mg++, 60 minutes after the beginning of the infusion, was comparable to control values in all the patients, except 2 with hypomagnesemia. Finally, we can conclude that MgSO4 is an useful therapeutic tool for the treatment of various ventricular tachycardias.
Abstract: A case of permanent junctional reciprocating tachycardia with post-mortem documentation of an accessory atrioventricular pathway as the substrate of the arrhythmia is reported. Tachycardia had lasted for 15 years and showed a retrograde P wave (P') and R-P' longer than P'-R interval. The tachycardia circuit utilized a concealed posterior septal accessory pathway as the retrograde limb. Because the arrhythmia was disabling and unresponsive to pharmacological treatment, the patient underwent closed chest ablation of the His bundle. After the procedure, no anterograde or retrograde conduction over the normal conduction system was observed; anterograde conduction over the anomalous pathway showed decremental properties. Because of previous myocardial infarction, the patient developed a ventricular aneurysm and died suddenly 5 months after His bundle ablation. Histological examination of the heart revealed a group of tiny fibromuscular bundles joining the lower rim of the coronary sinus outlet to the summit of the interventricular septums; the anomalous atrioventricular connection pursued a sinuous, tortuous path. The geometrical disposition of the accessory pathway may have been responsible for the decremental properties of conduction observed during life.
Abstract: The usefulness and safety of intracardiac discharge of a synchronized DC shock through a catheter-electrode to ablate the His bundle has led the Authors to evaluate the use of this technique to interrupt bypass tracts located near the coronary sinus. Acute experiments were performed in 10 open chest dogs. A tripolar 6F catheter-electrode was placed in the coronary sinus and 2 or 3 unipolar shocks of 80-120 joules were delivered to each electrode. After the procedure the coronary sulcus was inspected and a lesion 2-3 cm wide and 2-4 mm deep with edema and haemorrhage was found in all cases. On the basis of the data obtained in dogs, the technique was successfully used in a woman with "incessant" supraventricular tachycardia due to reentry through a concealed anomalous pathway located in the posterior septum. A careful mapping of the coronary sinus allowed the localization of the earliest retrograde atrial activation. Two shocks of 120 joules were delivered in the coronary sinus at the site suggested by the electrophysiologic mapping. The patient has remained free from tachycardia since the time of the discharge (follow-up: three weeks).
Abstract: Intermittent preexcitation, block in the accessory pathway after intravenous injection of ajmaline or procainamide, and block in the accessory pathway during exercise usually exclude a short antegrade refractory period of an accessory pathway in patients with the Wolff-Parkinson-White syndrome. This report describes three patients with these findings suggestive of a relatively long antegrade effective refractory period of the accessory pathway in whom life-threatening ventricular response occurred during atrial fibrillation. In the first patient with a pattern of intermittent preexcitation, rapid ventricular response with wide QRS was present during atrial fibrillation. In the second patient in whom preexcitation disappeared after intravenous injection of ajmaline or procainamide as well as during exercise testing, atrial pacing showed 1:1 conduction over the accessory pathway at a cycle length of 220 msec and the shortest R-R interval during induced atrial fibrillation was 190 msec. The third patient, with no evidence of preexcitation during sinus rhythm, presented antidromic reciprocating tachycardia and atrial fibrillation with life-threatening ventricular response, the minimal R-R interval being 220 msec. Noninvasive tests in the preexcitation syndrome lack sufficient prognostic sensitivity. The evaluation of ventricular response during induced atrial fibrillation represents the most reliable means of identifying such patients at risk.
Abstract: Postmortem examination of the heart was done in a case with disabling supraventricular tachyarrhythmia successfully treated by closed-chest ablation of the His bundle. A ventricular aneurysm developed as a result of a previous myocardial infarction, and death occurred suddenly five months after the procedure. Histologic studies of the atrioventricular (AV) junctional tissue demonstrated severe damage to the nearby AV node and penetrating His bundle. No damage to the branching His bundle or either bundle branch was observed.
Abstract: A case of permanent junctional reciprocating tachycardia in a 36-year-old woman successfully treated with closed-chest interruption of the His bundle is reported. Tachycardia had lasted for 14 years and showed a retrograde P wave (P') and RP' longer than PR' interval. The tachycardia used an anomalous pathway with a long conduction time in the retrograde direction. The atrial end of the anomalous pathway was located near the coronary sinus orifice. His ablation was accomplished by delivering a direct-current shock from a cardioversion unit to the nodal-His zone by means of a conventional electrode catheter percutaneously introduced via the femoral vein. Two shocks were necessary to obtain the desired results. After the procedure, complete atrioventricular block below the His bundle was induced, while antegrade conduction was assured through the anomalous pathway that showed decremental properties. During 7 months of follow-up, stable sinus rhythm with a long PR interval has been observed; the patient has remained free from tachycardia. Furthermore, she is not pacemaker-dependent and requires no cardioactive medication. This case demonstrates the therapeutic value of closed-chest ablation of the His bundle in a patient with permanent junctional reciprocating tachycardia, as well as demonstrating for the first time that the underlying accessory pathway is capable, in some instances, of antegrade conduction.
Abstract: An esophageal lead was used to perform decremental atrial pacing and elective induction of atrial fibrillation (AF) in 5 patients with the Wolff-Parkinson-White (W-P-W) syndrome before and after amiodarone therapy. In the control state, 1:1 atrioventricular (AV) conduction over the accessory pathway ranged from 220 to 260 ms (mean 232). The shortest R-R interval during AF ranged from 190 to 210 ms (mean 198). The ventricular rate ranged from 175 to 212 beats/min (mean 196). After amiodarone therapy, the shortest cycle length with 1:1 AV conduction increased in all patients, ranging from 290 to 540 ms (mean 370); during AF, no preexcited beat was present in 2 patients, whereas the minimal preexcited R-R interval in the remaining 3 was 290, 240, and 370 ms, respectively. The ventricular response during AF decreased in all patients. Thus, esophageal pacing is a useful method for identifying patients at risk with the W-P-W syndrome and for assessing appropriate management in individual patients. Amiodarone provides protection against life-threatening arrhythmias in these patients.
Abstract: The AA. describe a technique for interrupting the A-V conduction using a direct-current shock delivered from a cardioversion unit to the A-V junctional tissue by means of a conventional electrode-catheter. The method was used in 2 patients with refractory supraventricular tachycardias. After the procedure both patients received a programmable A-V sequential pacemaker. The first patient, with cardiomyopathy and intermittent W-P-W syndrome, had a 2-year history of iterative reciprocating tachycardia and occasional episodes of atrial flutter-fibrillation. The second patient, with coronary heart disease, had recurrent episodes of atrial flutter for at least 2 years. In patient 1 the shock caused a suprahisian first-degree block. Atrial pacing at 580 ms cycle length provoked a 2:1 block and ventricular pacing showed no retrograde conduction. The patient, who is not pacemaker-dependent, is now free from reciprocating tachycardia and, during atrial flutter-fibrillation episodes, the ventricular rate varies from 62 to 75 bpm. In patient 2 the shock caused a persistent complete A-V block and neither antegrade nor retrograde conduction was observed during atrial and ventricular pacing. During a long episode of atrial flutter, there was a complete A-V block with a ventricular rate between 40 and 48 bpm. The follow-up is 9 months in both patients. We conclude that the technique used, which does not require open heart surgery, can be effectively used in patients with disabling supraventricular tachyarrhythmias resistant to drug treatment.
Abstract: In order to assess the effects of oxyfedrine in ischaemic heart disease, echocardiographic evaluation of left ventricular function was performed 2,5,10,15 and 20 minutes after the intravenous administration of 12 mg oxyfedrine in 15 patients with coronary artery disease without angiographic abnormalities of left ventricular wall motion. The following parameters were measured: heart rate, mean arterial blood pressure, internal dimension in diastole (LVIDd) and in systole (LVIDs) of the left ventricule and the percentage shortening of the LVID (%LVID). There was a significant increase in %LVID (peak 10 minutes after drug administration; p less than 0.001) indicating improved left ventricular function, associated with slight changes in pre-load (LVIDd) and in heart rate, and no variation in mean blood pressure. No abnormalities of contraction were observed after the administration of oxyfedrine. These results suggest that oxyfedrine exerts a direct positive inotropic effect of the myocardium in patients with significant coronary artery stenoses.
Abstract: Cardiac programmed stimulation in the control of tachyarrhythmias offers encouraging prospectives. We describe two devices which utilize radiofrequency as a means of synchronization and stimulation and can be triggered by the patient himself when tachycardia occurs. In addition we introduce a third anti-tachycardia device, completely automatic, which can be used in cardiologic departments. The first device described permits critical stimulation and can be programmed to deliver a single or double synchronized impulse. The second device, which utilizes the same implanted unit and electrode as used for critical stimulation, when activated searches the tachycardia interruption zone by scanning. The third device, based on the same principles, has a rate discriminator that activates the scanning stimulation. We treated 12 patients: 8 suffering from paroxysmal supraventricular tachycardia (4 with Wolff--Parkinson--White syndrome, 2 with intranodal reentry, 2 with brady--tachy syndrome); 2 patients with ventricular recurrent tachycardia; 1 with atrial flutter; and another with iterative junctional tachycardia. The follow-up varied for every patient from 6 yr to 3 mth.
Abstract: The use of radiofrequency as a means of synchronization and stimulation does not necessitate an external lead, and thus has allowed the construction of an implantable device for long-term treatment of reentry tachycardias. The device is used along with Amiodarone therapy and can be triggered by the patient himself.
Abstract: This study showed the effectiveness of magnesium sulphate during digitalis therapy complicated by ventricular hyperexcitability. 28 patients with cardiac disease and ventricular arrhythmias in heart failure were studied. Magnesium sulphate was given by slow intravenous infusion (30--50 mg/min) twice daily. The anti-arrhytmic action allowed treatment with digitalis until improvement in cardiac function was observed. The mechanism of the action of magnesium sulphate in digitalis--induced arrhythmias is discussed.
Abstract: The AA. described an external stimulator to be utilized instead of invasive pharmacological treatment, as a short and middle-time therapeutic approach to re-entry tachycardia, in Departments of cardiology. The device must be connected with an electrode placed in atrium or in coronary sinus or in ventricle, according to individual request. A frequency discriminant device recognizes tachycardia and activates automatic scanning stimulator, synchronized on R or P waves, with progressive 5 msec stop delay; tachycardia interruption zone is automatically individuated. Stimulation has an automatic stop when tachycardia is interrupted; in case of persistent tachycardia scanning-function cycle will star again automatically. The device, which can be programmed for a simple or a double impulse emission, is equipped with a demand stimulator working if post-tachycardia asystole is present. Frequency discriminant device activates the scanning function beyond a defined threshold which can be varied within a wide range of frequencies.
Abstract: The use of programmed electrical stimulation in the long term treatment of re-entry tachycardia offers encouraging perspectives. Among the others proposed, the "scanning" system seems to be the most effective. However, an implantable stimulator with these features is not yet available and, thus, a temporary external lead is required. These difficulties have been overcome by utilizing radiofrequency to synchronize and stimulate. An implantable device was therefore designed which is triggered by the patient and automatically searches the interruption zone of the tachycardia by exploring the R-R cycle. The external transmitter, which can produce one or two synchronized impulses, is programmed to scan the R-R cycle with progressive steps of 5 or 10 ms; when tachycardia is interrupted, further stimulation is inhibited. The implanted module connected to an endocavitary lead does not have any power supply and, therefore, is very small. The efficacy of this method has been demonstrated in 4 patients with supraventricular tachycardia (3 with WPW syndrome) resistant to conventional pharmacologic therapy.
Abstract: In 49 patients suffering of heart diseases we have studied the changes of radiologic cardiac measurements and systolic time intervals (STI) in the four functional classes of the New York Heart Association (NYHA) classification, investigating also the existence of any relationship between these different parameters. Only the patients in functional classes 3rd and 4th showed significant changes in STI and radiologic measurements as compared to the control group. Moreover, a significant negative correlation has been observed between relative heart volume and left ventricular ejection time (LVET) (r = 0.69, P less than 0.001) and LVETc (r = 0.82, P less than 0.001) and a positive correlation between relative heart volume and pre-ejection period (PEP) (r = 0.59, P less than 0.01) and PEP/LVET ratio (r = 0.75, P less than 0.001). These results seem to demonstrate that relative heart volumetry is a fairly accurate index of the cardiac conditions in non valvular heart diseases.
Abstract: A new model of radiofrequency stimulator is presented, which can be programmed for the transmission of one or two impulses synchronised and delayed on the endocardial electrogram. This pacemaker was successfully used in jounctional reciprocating tachycardias and in a case of recurrent ventricular tachycardia. The implanted device, connected to the electrode catheter in right ventricle, does not contain energy sources. This lets a little size and allows having outside the body all the program controls, which in the time can have to change, due to variations of the parameters of tachycardias interruption. The implanted receiver is designed to induce in the resonant coil of external transmitter a frequency modulation proportional to the endocavitary signal. A slope detector receives this signal and programs on them the stimulating impulses, transmitted to stop the tachycardia. It is possible to manufacture such a simple device that the same patient can use it. Of course, periodic controls on the patient must be made to assess the cause of the tachycardia.
Abstract: The use of programmed stimulation in the long-term treatment of re-entry tachycardia offers encouraging perspectives. Among the others proposed the "scanning" system seems to be the most effective. However, an implantable stimulator with such pictures is not yet available and a temporary electrode is thus required. These difficulties have been overcome utilizing the radiofrequency as a sincronizing and stimuli-producing means. An implantable appliance was therefore designed which is triggered by the patient himself and automatically researches the zone of interruption of tachycardia by exploring the R-R cycle. The program of external transmitter which can produce one or two sincronized impulses, seams the cycle with progressive steps of 10 msec each; when tachycardia is interrupted, further stimulation is inhibited. The implanted part of the appliance connected with a normal endocavitary electrode, does not have any power supply and thus is very small. The efficacy of this method has been shown in 4 junctional reciprocating and 1 ventricular recurrent chronic tachycardias, resistent to conventional pharmacologic therapy.
Abstract: This study was designed to evaluate the usefulness of non-invasive parameters in the follow-up of cardiopathic patients without valvular cardiac diseases. In 49 patients suffering from heart disease we have studied the changes of radiologic cardiac measurements and systolic time intervals (STI) in the 4 functional classes of the NYHA classification, investigating also the existence of any relationship between these different parameters. Only the patients in the 3rd and the 4th functional classes showed significant changes in STI and radiologic measurements, as compared with the control group. Moreover, significant negative correlations have been observed between relative heart volume and LVET (r = 0.69, P less than 0.001) and LVETc (r = 0.82, P less than 0.001) and positive correlations between relative heart volume and PEP (r = 0.59, P less than 0.01) and PEP/LVET ratio (r = 0.75, P less than 0.001). These results, while confirming the close correlation between STI and cardiac performance, seem to demonstrate that relative heart volumetry is a fairly accurate index of the cardiac conditions in non-valvular heart diseases.
Abstract: From among the theories which have been advanced to explain the finding on ECG of a shorter than normal PR interval, in addition to the short circuit theory we should mention the explanation given by Condorelli before the first publication on the "short PR-normal QRS" syndrome appeared. While studying the mechanism of conduction of a stimulus in the atrial myocardium, he showed that a short PR may result from a conduction defect in the sino-atrial pathways, while sino-nodal conduction remains normal. In this report there is an example which supports the validity of Condorelli's hypothesis. It involves a female patient with mitral valve disease beginning to affect the tricuspid. Her rheumatic disease had just relapsed, and after this there was a long period of attacks of tachycardia with arrhythmia during the course of which the surface electrocardiogram showed a short PR and normal QRS. Electrophysiological investigations allowed us to interpret these findings in the light of Condorelli's hypothesis (sino-atrial block with normal sino-nodal conduction). This study suggests that it is useful to separate off those cases with a short PR and normal QRS to a clinical entity of their own, as this syndrome may have a different pathogenesis. Therefore, if there is no electrocardiographic evidence of an accessory pathway, far from indicating accelerated conduction, the short PR may be due to an isolated defect of conduction in the atrial myocardium, as Condorelli suggested. It is also correct that this author should be given credit for describing the first cases. To him also should go credit for first describing the short PR.
Abstract: A pacemaker is described which uses radiofrequency signals for synchronisation and pacing, and seeks automatically the phase of the cycle at which the tachycardia may be interrupted. The patient himself can activate the pacemaker. The programme of the external transmitter, which scans nearly all the R-R cycles of the tachycardia, may be pre-set to transmit one or two synchronised stimuli, with a progressive delay of 5 or 10 ms. If the tachycardia is interrupted the pacing stops automatically. The implantable unit of the device may be connected to a normal endocardial electrode, has no batteries and is of small size and weight. The method has been used with success in 4 patients with reciprocal junctional tachycardia (3 of these patients had the Wolff-Parkinson-White syndrome), and in one case of chronic recurrent ventricular tachycardia. All of them were refractory to conventional therapy.
Abstract: A case is described of permanent atrial paralysis in a 68 year old female with diabetes and cirrhosis of the liver. Absence of electrical atrial activity was expected on the standard electrocardiogram, and confirmed by intracavitary electrophysiological investigation which showed the ineffectiveness of stimulation of both the right atrium and the coronary sinus. Recording of the His potentials showed that the resultant rhythm was of supra-ventricular origin. The absence of mechanical atrial activity was confirmed radiographically, on the jugular venogram, on the apexogram, and on the tracings of right atrial and pulmonary capillary pressure. A search was made for muscular or neuromuscular dystrophy which has often been found in association with this arrhythmia, but none was found. There may be an etio-pathological relationship between carbohydrate metabolism and atrial paralysis, as certain authors have suggested.
Abstract: The effect of magnesium sulphate administration on myocardial inotropism has been evaluated by means of the noninvasive indexes of myocardium contractility in 18 patients affected by myocardiosclerosis associated with signs of cardiac impairment of different degree. Magnesium has been administered via either a prolonged infusion (30-50 mg/min) or a single injection (2.5 g/30 sec). It is emphasized that the influence of this agent on systolic time intervals (STI) is dependent upon its route of administration. Thus, prolonged infusion does not modify significantly these parameters, whereas a single injection induces marked variations, i.e., decrease of LVET, increase of PEP, ICT and PEP/LVET ratio, which are all more marked in cases of severe cardiac impairment. In view of the strict correlation established between the STI and the invasive indexes of myocardial contractility, it is suggested that administration of magnesium sulphate via prolonged infusion does not induce a decrease of cardiac performance, while a single injection of this agent leads to this effect.
