Abstract: Magnesium is associated with several important cardiovascular diseases. There is an accumulating body of evidence verifying the important roles of Mg(2+)-permeable channels. In the present study, we estimated the intracellular free Mg(2+) concentration ([Mg(2+)](i)) using (31)P-nuclear magnetic resonance ((31)P-NMR) in porcine carotid arteries. pH(i) and intracellular phosphorus compounds were simultaneously monitored. Removal of extracellular divalent cations (Ca(2+) and Mg(2+)) in the absence of Na(+) caused a gradual decrease in [Mg(2+)](i) to approximately 60% of the control value after 125 min. On the other hand, the simultaneous removal of extracellular Ca(2+) and Na(+) in the presence of Mg(2+) gradually increased [Mg(2+)](i) in an extracellular Mg(2+)-dependent manner. 2-aminoethoxydiphenyl borate (2-APB) attenuated both [Mg(2+)](i) load and depletion caused under Na(+)- and Ca(2+)-free conditions. Neither [ATP](i) nor pH(i) correlated with changes in [Mg(2+)](i). RT-PCR detected transcripts of both TRPM6 and TRPM7, although TRPM7 was predominant. In conclusion, the results suggest the presence of Mg(2+)-permeable channels of TRPM family that contribute to Mg(2+) homeostasis in vascular smooth muscle cells. The low, basal [Mg(2+)](i) level in vascular smooth muscle cells is attributable to the relatively low activity of this Mg(2+) entry pathway.
Abstract: Aims The aim of this study was to perform quantitative analysis of the plaques of target lesions by integrated backscatter intravascular ultrasound (IB-IVUS) and to investigate the association between these data and the risk of post-procedural myocardial injury after stenting. Methods and results One hundred and fourteen consecutive patients who received elective stent implantations following IB-IVUS analysis were enrolled. The volume of each plaque component (lipid, fibrous, and calcified) was calculated for the target lesion. Creatine kinase-MB (CK-MB) and troponin-T (TnT) were also evaluated 18 h after procedure. We defined a post-procedural TnT level higher than three times the normal limit as a post-procedural myocardial injury. Lipid, fibrous, and calcified volumes were greater in patients with myocardial injury than in those without myocardial injury. Lipid and fibrous volumes correlated with post-procedural cardiac biomarkers, and the lipid volume fraction (lipid volume/total plaque volume) also correlated with post-procedural TnT and CK-MB. The fibrous volume fraction for plaques was found to be inversely correlated with post-procedural TnT and CK-MB. Hence, lipid volume and volume fraction were concluded to be independent predictors of post-procedural myocardial injury. Conclusion A larger plaque volume and lipid-rich plaque may be indicative of embolic events after stent implantation, resulting in myocardial injury.
Abstract: AIMS: Diabetic patients without clinical evidence of cardiovascular disease may develop left ventricular (LV) dysfunction. The present study was designed to test the hypothesis that coronary microvascular dysfunction affects LV function in type 2 diabetic patients. METHODS: The study subjects were 20 type 2 diabetic patients and 15 controls, who had been angiographically determined to have normal coronary arteries. LV ejection fraction (LVEF) and the percentage change in LVEF during dobutamine infusion (DeltaLVEF) were measured as an index of LV function. In order to evaluate coronary flow reserve, coronary flow velocity was recorded using a Doppler guide wire. RESULTS: There were no significant differences in LVEF. DeltaLVEF was significantly lower in the diabetic patients than in the control subjects (p<0.01). Although there was no significant difference in the baseline coronary volumetric flow between the two groups, values during maximal hyperemia were significantly less in the diabetic patients than in the controls (p<0.05). Consequently, coronary flow reserve was significantly lower (p=0.0001). A significant positive correlation between coronary flow reserve and DeltaLVEF was exhibited (r=0.68, p=0.0009). CONCLUSIONS: Coronary flow reserve, an indicator of coronary microvascular function, is significantly reduced in type 2 diabetes, and this is reflected in impairment of myocardial contractile reserve.
Abstract: Background Accelerated atherosclerosis is a major risk for long-term survivors receiving hemodialysis (HD), with coronary events being the leading cause of mortality. Methods and Results A total of 88 consecutive patients on HD (121 lesions) who underwent percutaneous coronary intervention (PCI) with sirolimus-eluting stents (SES) were compared with 78 patients on HD (95 lesions) who received bare metal stents (BMS) in the preceding 1 year. The primary endpoint was angiographic restenosis defined as >/=50% diameter stenosis at 6-8 months follow-up after PCI. The angiographic restenosis rate at follow-up was 22.2% in the SES group and 24.4% in the BMS group. No difference was detected in the restenosis rate between the 2 groups (p=0.73). When including both HD and non-HD patients, the independent predictors for restenosis after SES implantation were treatment with HD (hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.23-7.95; p=0.016), incidence of hyperlipidemia (HR 3.93; 95%CI 1.12-13.7; p=0.032), coronary calcification (HR 2.78; 95%CI 1.12-6.91; p=0.027), and implantation of multi-stents (HR 4.14; 95%CI 1.70-10.1; p=0.0017). Conclusions Even if treated with SES, patients with end-stage renal failure on HD are at high risk of restenosis after PCI. (Circ J 2008; 72: 56 - 60).
Abstract: OBJECTIVES: We assessed the impact of metabolic syndrome (MetS) on the tissue characteristics of coronary plaques using integrated backscatter intravascular ultrasound (IB-IVUS). BACKGROUND: Metabolic syndrome is associated with the increasing risk of cardiovascular disease. METHODS: We identified MetS by the definition of the National Cholesterol Education Program in Adult Treatment Panel III criterion. Non-target coronary lesions with mild to moderate stenosis were measured by conventional and IB-IVUS parameters using 40-MHz (motorized pullback 0.5 mm/s) intravascular catheter. A total of 20 IB-IVUS images were recorded at an interval of 0.5 mm for 10 mm length in each plaque. The 3-dimensional analyses were performed using commercially available software. RESULTS: The prevalence of MetS was 61 patients (50%) with 73 lesions (49%) among 122 patients with 148 lesions. Patients with MetS showed a significant increase in percentage lipid area (38 +/- 19% vs. 30 +/- 19%, p = 0.02) and percentage lipid volume (39 +/- 17% vs. 33 +/- 17%, p = 0.03), and they also showed a significant decrease in percentage of fibrous volume (57 +/- 14% vs. 61 +/- 13%, p = 0.03). Multivariate regression analysis after adjustment for potentially confounding risk factors showed that MetS remains correlated independently with the percentage of lipid volume (r = 0.223, p = 0.01). Logistic regression analysis after adjusting for confounding and non-MetS coronary risk factors showed that MetS (odds ratio 4.00, 95% confidence interval 1.33 to 12.0, p = 0.01) is proved to be an independent predictor of the lipid-rich plaque. CONCLUSIONS: Metabolic syndrome is associated with lipid-rich plaques, contributing to the increasing risk of plaque vulnerability.
Abstract: Published reports have indicated that prodromal angina before acute myocardial infarction (AMI) is associated with better outcomes and that nicorandil has cardioprotective effects on ischemic hearts. We compared cardioprotective effects of intravenous nicorandil with preconditioning effects by prodromal angina in patients with AMI who underwent percutaneous coronary intervention (PCI). In total, 368 patients with first ST-elevation AMI who underwent PCI were randomly assigned to receive nicorandil 12 mg or a placebo intravenously just before PCI. Subjects were assigned to 1 of 4 groups: 52 patients with prodromal angina were given placebo, 129 patients without prodromal angina were given nicorandil, 56 patients with prodromal angina were given nicorandil, and 131 patients without prodromal angina were given placebo. Coronary microvascular impairment after PCI was prevented at similar frequencies in groups with prodromal angina and groups on nicorandil. Five-year rates for freedom from major cardiac events were similar across groups with prodromal angina given placebo, without prodromal angina given nicorandil, and with prodromal angina given nicorandil (92.3%, 93.8%, and 92.9%, respectively) but were significantly lower in the group without prodromal angina given placebo (80.2%, p = 0.0019, 0.044, and 0.042, respectively). In conclusion, intravenous administration of nicorandil before PCI exerts pharmacologic cardioprotective effects similar to ischemic preconditioning in patients with AMI.
Abstract: OBJECTIVE: Stress hyperglycemia increases the risk of mortality and poor outcomes in patients with acute myocardial infarction (AMI). We aimed to assess effects of intravenous nicorandil administered before reperfusion on AMI patients with stress hyperglycemia. RESEARCH DESIGN AND METHODS: This study consisted of 158 consecutive first AMI patients with stress hyperglycemia who underwent percutaneous coronary intervention (PCI) within 24 h from the onset. They were randomly assigned to receive 12 mg of nicorandil (n = 81) or a placebo (n = 77) intravenously just before reperfusion. Stress hyperglycemia was defined as a blood glucose level > or =10 mmol/l (180 mg/dl). We examined various aspects of epicardial flow and microvascular function as immediate data and major adverse cardiac events (MACEs) (coronary heart disease death or unplanned readmission due to congestive heart failure) as late-phase data. RESULTS: The incidence of slow flow after PCI was lower in the nicorandil group (13.6 vs. 27.3%, P < 0.04). ST segment resolution >50% was observed in 70.4 and 53.2% on nicorandil and placebo, respectively (P < 0.03). Patients treated with nicorandil had a lower peak creatine kinase level (3,137 +/- 2,577 vs. 4,333 +/- 3,608, P < 0.02). Upon Kaplan-Meier analysis, 5 years' freedom from MACEs was 86.4% in the nicorandil group and 74.0% in the placebo (P < 0.05). CONCLUSIONS: Adjunctive therapy with administration of intravenous nicorandil before reperfusion on AMI patients with stress hyperglycemia significantly improves epicardial flow and prevents the occurrence of severe microvascular reperfusion injury, resulting in better outcomes in these patients.
Abstract: Aldosterone promotes vascular smooth muscle cell proliferation and endothelial dysfunction, suggesting the contribution to in-stent restenosis (ISR). This study evaluated any relation between plasma aldosterone levels and ISR 6 months after successful coronary stenting. We enrolled 156 consecutive patients with stable angina who underwent coronary bare metal stenting. Plasma aldosterone levels and other serum markers known to influence cardiovascular events were measured in all patients at baseline. Patients with restenosis were found to have significantly higher plasma aldosterone levels than their counterparts without restenosis (162 +/- 60 vs 122 +/- 60 pg/ml, p = 0.007). On logistic regression analysis, even after adjusting for clinical, angiographic, and other confounding variables, plasma aldosterone level per 10 pg/ml (odds ratio 1.34, 95% confidence interval 1.10 to 1.63, p = 0.006) proved to be the independent predictor of ISR. The area under the receiver-operating characteristic curve for plasma aldosterone level was 0.75, and the optimal cut-off value identified by receiver-operating characteristic analysis was 141.9 pg/ml, which had a predictive accuracy of 69%. In conclusion, the present findings indicate that plasma aldosterone levels at baseline are independent predictors of ISR and may constitute a potential therapeutic target.
Abstract: BACKGROUND: Studies have reported an association between receipt of statin therapy and a reduction in complications after elective percutaneous coronary intervention (PCI). However, there are limited data on the effects of chronic statin therapy before the occurrence of an acute myocardial infarction (AMI). OBJECTIVE: This study investigated whether administration of chronic statin therapy before AMI was associated with a reduction in reperfusion injury in AMI patients undergoing PCI. METHODS: This was a retrospective study of consecutive patients with a first AMI who underwent successful reperfusion therapy with PCI within 24 hours after the onset of AMI between April 1998 and October 2003. Patients were stratified according to whether they had or had not been receiving chronic statin therapy for > or = 1 month before the onset of AMI. The following end points were compared after PCI: electrocardiographic resolution of ST segment elevation, defined as a reduction of > or = 50% from the initial value; achievement of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow; corrected TIMI frame count (cTFC); maximum serum creatine kinase (CK) level; and the type and frequency of ventricular arrhythmias. RESULTS: The study enrolled 386 patients, 40 of whom had been receiving statin therapy before the onset of AMI. The clinical characteristics of the 2 groups were similar at baseline, with the exceptions of a significantly higher rate of hyperlipidemia in the statin group compared with the nonstatin group (P < 0.001), significantly greater chronic use of aspirin therapy (P < 0.001), and significantly greater chronic use of antihypertensive medications (beta-blockers: P = 0.004; angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers: P = 0.007; calcium channel blockers: P = 0.006). Electrocardiographic ST segment resolution after PCI was observed in 87.5% and 69.9% of the statin and nonstatin groups, respectively (hazard ratio [HR]: 3.01; 95% CI, 1.15-7.90; P = 0.025). Achievement of TIMI grade 3 flow after PCI was seen in 95.0% of the statin group and 83.5% of the nonstatin group (HR: 3.75; 95% CI, 0.88-16.0; P = NS). Patients treated with a statin had a significantly lower mean (SD) maximum CK level compared with the nonstatin group (2300 [1449] vs 3538 [3170] IU/mL, respectively; P = 0.015) and a lower cTFC after PCI (18.8 [4.0] vs 24.2 [14.2]; P = 0.017). The difference in reperfusion arrhythmias between groups was not statistically significant. After adjustment for baseline covariates, pretreatment with a statin was found to be an independent predictor of ST segment resolution after PCI (HR: 2.95; 95% CI, 1.08-8.09; P = 0.035) and prevention of impaired coronary flow (HR: 3.00; 95% CI, 1.63-5.55; P < 0.001). CONCLUSION: In this study, receipt of chronic statin therapy before the onset of AMI was associated with improvement in epicardial perfusion and a reduction in myocardial necrosis after PCI.
Abstract: BACKGROUND: Intravenous nicorandil, a hybrid compound of ATP-sensitive potassium channel opener and nitric oxide donor, has been reported to ameliorate early functional and clinical problems in patients with acute myocardial infarction. However, its effects on the late phase remain unclear. METHODS AND RESULTS: This follow-up study to 5 years of a randomized, double-blinded trial was conducted among 368 patients with first ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). They were randomly assigned to receive 12 mg of nicorandil or a placebo intravenously just before reperfusion. We analyzed incidence of cardiovascular death or rehospitalization for congestive heart failure after PCI as well as various aspects of epicardial flow and microvascular function. Mean follow-up was 2.4 years (SD, 1.4). A total of 12 (6.5%) patients receiving nicorandil and 30 (16.4%) receiving placebo had cardiovascular death or hospital admission for congestive heart failure (hazard ratio, 0.39; 95% CI, 0.20 to 0.76; P=0.0058). Postprocedural TIMI 3 flow was obtained in 89.7% of the nicorandil group and in 81.4% of the placebo (hazard ratio, 1.99; 95% CI, 1.09 to 3.65; P=0.025). Corrected TIMI frame count was furthermore lower in the nicorandil group (21.0+/-9.1 versus 25.1+/-14.1; P=0.0009). ST-segment resolution >50% was observed in 79.5% and 61.2% of the nicorandil and placebo groups, respectively (hazard ratio, 2.45; 95% CI, 1.54 to 3.90; P=0.0002). CONCLUSIONS: The addition of intravenous nicorandil to PCI leads to beneficial clinical outcomes and prevents cardiovascular events of long duration and death in patients with ST-segment-elevation myocardial infarction.
Abstract: BACKGROUND: Mineralocorticoid receptor antagonism reduces mortality associated with heart failure by mechanisms that remain unclear. The effects of the mineralocorticoid receptor antagonist spironolactone on left ventricular (LV) function and chamber stiffness associated with myocardial fibrosis were investigated in mildly symptomatic patients with idiopathic dilated cardiomyopathy (DCM). METHODS AND RESULTS: Twenty-five DCM patients with a New York Heart Association functional class of I or II were examined before and after treatment with spironolactone for 12 months. LV pressures and volumes were measured simultaneously, and LV endomyocardial biopsy specimens were obtained. Serum concentrations of the carboxyl-terminal propeptide (PIP) and carboxyl-terminal telopeptide (CITP) of collagen type I were measured. The patients were divided into 2 groups on the basis of the serum PIP/CITP ratio (< or =35, group A, n=12; >35, group B, n=13), an index of myocardial collagen accumulation. LV diastolic chamber stiffness, the collagen volume fraction, and abundance of collagen type I and III mRNAs in biopsy tissue were greater and the LV early diastolic strain rate (tissue Doppler echocardiography) was smaller in group B than in group A at baseline. These differences and the difference in PIP/CITP were greatly reduced after treatment of patients in group B with spironolactone, with treatment having no effect on these parameters in group A. The collagen volume fraction was significantly correlated with PIP/CITP, LV early diastolic strain rate, and LV diastolic chamber stiffness for all patients before and after treatment with spironolactone. CONCLUSIONS: Spironolactone ameliorated LV diastolic dysfunction and reduced chamber stiffness in association with regression of myocardial fibrosis in mildly symptomatic patients with DCM. These effects appeared limited, however, to patients with increased myocardial collagen accumulation.
Abstract: In the present study of rat heart using (31)P-nuclear magnetic resonance, we examined the interaction between beta-adrenergic and insulin receptors in terms of the intracellular free Mg(2+) concentration ([Mg(2+)](i)) regulation. [Mg(2+)](i) was estimated from the separation of the chemical shifts of the alpha- and beta-adenosine triphosphate (ATP) peaks, using the dissociation constant of MgATP 87 microM (established recently). In normal (phosphate-free Krebs-Henseleit) solution, [Mg(2+)](i) was approximately 1.02 mM. Insulin at physiological and pathological concentrations increased [Mg(2+)](i) and contractility in a dose-dependent manner. Insulin (more than 100 micro(u) ml(-1)) suppressed the decrease in [Mg(2+)](i) caused by isoprenaline (100 nM), and these effects of insulin on [Mg(2+)](i) and contractility were blocked by LY333531 (macrocyclic bis (indolyl) maleimide, 100 nM), a protein kinase C (PKC) inhibitor. The isoprenaline-induced decrease in the concentrations of ATP ([ATP]) with insulin application was significantly smaller than that without insulin. Insulin modulates [Mg(2+)](i) and haemodynamics, presumably via activation of PKC, thereby antagonizing the reduction of [Mg(2+)](i) induced by beta-adrenoceptor stimulation.
