Abstract: Chronic heart failure (CHF) is an illness mostly affecting elderly people. In Germany CHF is one of the most common causes of death and at the same time one of the most common diagnosis in inpatient care. Due to the expected increase in life expectancy in the next few years experts predict a further step-up of the incidence. Against this background development of a national guideline on chronic heart failure was prioritised and accordingly the National Disease Management Guideline (NDMG) Chronic Heart Failure was developed by a multi- and interdisciplinary group. The guideline group comprised experts from all relevant scientific medical societies as well as a patient expert. The National Disease Management Guideline (NDMG) on Chronic Heart Failure aims at supporting patients and health care providers with respect to decisions on a specific health care problem by giving recommendations for actions. Recommendations are informed by the best available scientific evidence on this topic.Patients with CHF often suffer from multiple conditions. Due to this fact and the old age patients do have very complex and demanding health care needs. Thus accounting for co-morbidities is paramount in planning and providing health care for theses patients and communication between doctor and patient but also between all health care providers is crucial.Basic treatment strategies in chronic heart failure comprise management of risk factors and prognostic factors as well as appropriate consideration of co-morbidities accompanied by measures empowering patients in establishing a healthy life style and a self-dependant management of their illness.Psycho-social aspects have a very strong influence on patients' acceptance of the disease and their self-management. In addition they have a strong influence on therapy management of the treating physician thus they have to be addressed adequately during the consultation.The National Disease Management Guideline (NDMG) Chronic Heart Failure (CHF) is an interdisciplinary guideline putting particular emphasis on giving recommendations for health care management at the interfaces of the health care system. The NDMG CHF provides a collection of evidence-based and consensus-based recommendations for diagnostics and therapy of patients with CHF. This CPG is meant to improve health care for all affected patients regardless of stage of disease or health care setting. Quality improvement though can only happen when the NDMG CHF is adopted into daily routine. To support implementation a patient version of the guideline was developed. The article compiles the most relevant recommendations and algorithms of the National Disease Management Guideline (NDMG) Chronic Heart Failure (CHF).
Abstract: BACKGROUND: Therapeutic and prognostic implications of subclinical thyroid dysfunction in patients with heart failure (HF) are unclear. We compared the prognostic impact of euthyroidism, subclinical thyroid dysfunction, and euthyroid sick syndrome (ESS) in systolic HF. METHODS: We included 1032 patients hospitalized for systolic HF (left ventricular ejection fraction [LVEF] ≤40%) who participated in a randomized trial assessing the effects of a HF disease management program. Patients with incomplete thyroid function tests or thyrotropic medication were excluded. In the remaining 758 subjects, the risk of all-cause death was estimated based on TSH only, or full thyroid function profile. Changes of thyroid function after six months were assessed in 451 subjects. RESULTS: Subclinical thyroid dysfunction was present in 103 patients at baseline (14%). No differences were found between groups regarding NYHA class (P=0.29), and LVEF (P=0.60). After a median follow-up of three years patients with ESS (n=13) had a 3-fold age-adjusted increased risk of death compared to euthyroid patients (P=0.001). However, neither subclinical hyperthyroidism (HR 1.18, 95%CI:0.82-1.70) nor hypothyroidism (HR 1.07, 95%CI:0.58-1.98) were associated with increased age-adjusted mortality risk. Subclinical thyroid dysfunction had normalized spontaneously at follow-up in 77% of patients. However, persistent subclinical thyroid dysfunction was also not associated with worse outcome. CONCLUSIONS: In this large well-characterized HF cohort, subclinical thyroid dysfunction did not predict an increased mortality risk. Thus, in patients with moderate to severe HF, further diagnostic and therapeutic procedures for subclinical thyroid dysfunction appear dispensable. ESS was an infrequent but important indicator of a poor prognosis in HF. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN23325295.
Abstract: AIMS: To investigate in detail the correlates of dysnatremia, and to estimate its differential prognostic relevance in patients with heart failure with reduced or preserved LVEF.BackgroundHyponatraemia has been shown to carry important prognostic information in patients with heart failure with reduced left ventricular ejection fraction (LVEF). However, exact serum sodium cut-off levels are not defined and the implications for heart failure with preserved ejection fraction (HF-pEF) are unclear. The prognostic value of hypernatraemia has not been investigated systematically. Therefore, the aim of this study was to investigate in detail the correlates of dysnatraemia, and to estimate its differential prognostic relevance in patients with heart failure with reduced or preserved LVEF. METHODS AND RESULTS: One thousand consecutive patients with heart failure of any cause and severity from the Würzburg Interdisciplinary Network for Heart Failure registry were included. Non-linear models for the association between serum sodium and mortality risk were calculated using restricted cubic splines and Cox proportional hazard regression. Median follow-up time for survivors was 5.1 years.ResultsIndependent correlates of dysnatraemia included guideline-recommended medication for chronic heart failure, indicators of renal function, and reverse associations with established cardiac risk factors. Overall mortality was 56%. Both hyponatraemia (n = 72) and hypernatraemia (n = 98) were associated with a significantly increased mortality risk: hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.60-2.77; and HR 1.91, 95% CI 1.49-2.45, respectively. A U-shaped association of serum sodium with mortality risk was found. Prognosis was best for patients with high normal sodium levels, i.e. 140-145 mmol/L. CONCLUSIONS: Both hypo- and hypernatraemia indicate a markedly compromised prognosis in heart failure regardless of LVEF. Sodium levels within the reference range carry differential information on survival, with serum levels of 135-139 mmol/L indicating an increased mortality risk.
Abstract: BACKGROUND: This cross sectional study provides a practical approach for the clinical assessment of Friedreich ataxia (FA) cardiomyopathy (FA-CM). METHODS AND RESULTS: A comprehensive cardiac assessment, including standard echocardiography, color Doppler myocardial imaging (CDMI), cardiac magnetic resonance imaging (cMRI), electrocardiography (ECG) and exercise stress testing was performed in 205 FA patients. To assess myocardial hypertrophy in FA-CM, the end-diastolic interventricular septal wall thickness (IVSTd) was found to be the best echocardiographic parameter when compared to cMRI-determined left ventricular mass. Using this parameter, four groups of FA-CM could be defined. Patients with normal values for IVSTd (31.7%) classified as "no FA-CM". Patients with an IVSTd exceeding the predicted normal IVSTd were classified as "mild FA-CM" (40%) if IVSTd exceeds the normal value by < 18% or as "intermediate FA-CM" (16.1%) if IVSTd exceeds by ≥18%. Patients with ejection fraction (EF) <50% were classified as "severe FA-CM" (12.2%). Besides increased myocardial mass, severe FA-CM was further characterized by dilatation of the left ventricle, reduced systolic strain-rate of the posterior wall, and ECG abnormalities. Regional myocardial function correlated negatively with FA-CM groups. Younger patients had a tendency for a more advanced FA-CM. Importantly, no clear correlation was found between FA-CM groups and neurological function. CONCLUSIONS: We provide and describe a readily applicable clinical grouping of the cardiomyopathy associated with FA based on echocardiographic IVSTd and EF data. As no distinct interrelations between FA-CM and neurological status could be determined, regular follow-up of potential cardiac involvement in FA patients is essential in clinical practice. CLINICAL TRIAL REGISTRATION INFORMATION: Clinicaltrials.gov; ID: NCT00905268.
Abstract: AIMS: Depression is common in heart failure (HF) and associated with adverse outcomes. This study aimed to investigate incidence rates and predictors of depression in patients sampled from four subprojects of the German Competence Network Heart Failure. METHODS: Eight hundred thirty nine symptomatic HF patients free of depression at baseline underwent repeat depression screening (Patient Health Questionnaire, PHQ-9) after 12months. Ordered logistic regression analysis was employed to search for predictors of incident depression. RESULTS: Incident minor (major) depression was observed in 61 (7.3%) and 47 (5.6%) of the population. Depression was recurrent in 15 (25%) and 16 (34%), respectively. Multiple regression analysis revealed seven variables predicting minor or major depression: Previous depressive episode (odds ratio [OR] 4.04, 95% confidence interval [CI] 2.37-6.89, p≤0.001), previous resuscitation (OR 2.44, CI 1.23-4.81, p=0.010), current smoking (OR 2.06, CI 1.08-3.50, p=0.008), >4 visits/year to general practitioner (OR 1.67, CI 1.06-2.63, p=0.026), New York Heart Association class (OR 1.54/class, 95% CI 1.05-2.25, p=0.027), PHQ-9 baseline sum-score (OR 1.18/point, CI 1.11-1.27, p<0.001), and SF-36 physical functioning (OR 1.08/-5 points, CI 1.03-1.13, p=0.002). CONCLUSIONS: In these HF patients initially free of depression annual incidence rates were high. Several independent predictors allowed identification of patients at particular risk. Although obtained in a selected cohort these findings call, in view of the grave prognosis of HF patients with comorbid depression, for regular depression screening and development of specific supportive strategies to improve patient care and outcomes in HF.
Abstract: ABSTRACT: BACKGROUND: The Global Initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed post-bronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Age-dependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. METHODS: In a prospective cohort study, 405 patients aged [greater than or equal to] 65 years with a general practitioner's diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. RESULTS: Compared to the expert panel diagnosis, 'GOLD-COPD' misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. CONCLUSIONS: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice.
Abstract: To evaluate the implementation of current pharmacotherapy guidelines of heart failure and to identify factors associated with high pharmacotherapy guideline adherence in heart failure patients.
Abstract: Noninvasive echocardiographic differentiation between old and fresh left ventricular thrombi after myocardial infarction would be of clinical importance to estimate the risk for embolization and the necessity of anticoagulation.
Abstract: Pulmonary restriction-a reduction of lung volumes-is common in heart failure (HF), rendering severity grading of chronic obstructive pulmonary disease (COPD) potentially problematic in subjects with both diseases. We compared pulmonary function in patients with either HF or COPD, or the combination to assess whether grading of COPD using the Global Initiative of Chronic Obstructive Lung Disease classification is hampered in the presence of HF.
Abstract: The recommendation to restrict the use of activated protein C (APC) to patients with severe sepsis and the highest risk of death originates from large trials that were subject to major exclusion criteria.
Abstract: Peripartum cardiomyopathy (PPCM) is a rare disease of the heart muscle that affects women with previously unknown heart diseases during pregnancy or in the first months after delivery. Cardinal symptoms are dyspnoea and fluid retention. However, tachycardia, cardiogenic thromboembolism and other clinical signs of cardiac dysfunction may also herald this uncommon cause of heart failure. The estimated incidence of PPCM shows large regional variations: in Europe and the United States it is between 1:2000 and 1:4000. The markedly higher incidence rates observed in Haitian or South African women (up to 1:300) suggest that genetic or environmental factors may play a pathogenetic role. However, the underlying aetiology of PPCM still is unclear. Besides genetic susceptibility an abnormal autoimmune response against cardiac tissue components, viral infections or an irregular activity of cathepsin D generating a potentially cardio-toxic splice variant of prolactin have been discussed. New therapeutic strategies as immune modulation or prolactin inhibition were therefore suggested, but are not yet established. Treatment strategies focus on the standard therapies for heart failure and its complications. During pregnancy heart failure therapy is limited to substances without fetotoxic effects. But even with optimal heart failure therapy the course of the disease exhibits large variations ranging from full recovery to deterioration of heart function and even early cardiac death. This review cumulates the current knowledge on PPCM and aims to raise awareness for this rare and potentially life-threatening disorder amongst all medical professionals involved in the care for pregnant women.
Abstract: Low gradient aortic stenoses (AS) represent a special challenge for physicians with respect to an exact diagnosis and optimal therapy. The difficulty lies in the estimation of the severity of AS which is decisive for subsequent treatment and the prognosis. Low flow and low gradient can be due to systolic or diastolic dysfunction by high-grade as well as by medium-grade AS and be of non-valvular origin. The latter group is to be interpreted as pseudoaortic stenosis as long as the low flow can successfully be raised by interventional means. However, only patients in the first group can be expected to profit from valve replacement and for patients in the second group the accompanying diseases must be the focus of therapeutic treatment. Therefore, according to recent European surveys up to 30% of patients with severe AS are undertreated due to false estimation of the severity of stenosis and perioperative risk stratification. Furthermore, follow-up investigations have shown that patients with low flow/low gradient stenosis and borderline-normal ejection fraction (EF) are in an advanced stage of the disease because they have often developed a severe reduction in longitudinal myocardial function and in addition have pronounced myocardial replacement fibrosis due to cardiac remodelling despite a preserved EF. Therefore, aortic valve area, mean pressure gradient and EF alone cannot be taken into consideration for the management of patients with severe AS but a comprehensive assessment of the hemodynamics, such as stroke volume, special functional parameters as well as individual clinical appearance is essential for precise diagnostic and therapeutic decision making.
Abstract: BACKGROUND: -Trials investigating efficacy of disease management programs (DMP) in heart failure reported contradictory results. Features rendering specific interventions successful are often ill defined. We evaluated the mode of action and effects of a nurse-coordinated DMP (HeartNetCare-HF(TM), HNC). METHODS AND RESULTS: -Patients hospitalized for systolic heart failure were randomized to HNC or Usual Care (UC). Besides telephone-based monitoring and education, HNC addressed individual problems raised by patients, pursued net-working of healthcare-providers and provided training for caregivers. Endpoints were time to death or rehospitalization (combined primary), heart failure symptoms and quality of life (SF-36). Of 1,007 consecutive patients, 715 were randomized (HNC:n=352, UC:n=363, 69±12years, 29% female, 40% NYHA III-IV). Within 180 days, 130 HNC and 137 UC patients reached the primary endpoint (hazard ratio[HR] 1.02, 95% confidence interval 0.81-1.30, p=0.89), since more HNC patients were readmitted. Overall, 32 HNC and 52 UC patients died (one UC and four HNC patients after dropout), thus uncensored HR was 0.62, 0.40-0.96, p=0.03. HNC patients improved more regarding NYHA class (p=0.05), physical functioning (p=0.03) and physical health component (p=0.03). Except for HNC, healthcare utilization was comparable between groups. However, HNC patients requested counselling for non-cardiac problems even more frequently than for cardiovascular or heart-failure-related issues. CONCLUSIONS: -The primary endpoint of this study was neutral. However, mortality risk and surrogates of well-being improved significantly. Quantitative assessment of patient requirements suggested that besides (tele)monitoring individualized care considering also non-cardiac problems should be integrated in efforts to achieve more sustainable improvement in heart failure outcomes. Clinical Trial Registration-URL: http://www.controlled-trials.com. Unique identifier: ISRCTN23325295.
Abstract: Fabry disease is often linked with a prominent papillary muscle. It remains unknown whether this sign could be used as a diagnostic marker to screen for Fabry patients. Standard echo was performed in 101 consecutive patients with concentric left ventricular (LV) hypertrophy (28 Fabry, 30 Friedreich, 34 isolated arterial hypertension, 9 amyloidosis) and 50 healthy controls. In addition, the areas of both papillary muscles, as well as the LV endocardial circumference, were manually traced in short axis views. A ratio of papillary muscle size to LV circumference was calculated (PM_LV_ratio). The papillary muscle area was positively correlated to LV wall thickness in this cohort (p < 0.0001; r = 0.58). In all patient subgroups, the absolute papillary muscle area was significantly enlarged and the PM_LV_ratio was significantly higher when compared with controls. However, Fabry patients showed a significantly larger absolute papillary muscle area than Friedreich and amyloidosis patients and a higher PM_LV_ratio than hypertensive and amyloidosis patients. Enlarged absolute papillary muscle area was evidenced in 21 (75%), and increased PM_LV_ratio was found in 22 (78%) of 28 Fabry patients. Combining these two parameters yields a sensitivity of 75% and specificity of 86% for diagnosing Fabry disease with LV hypertrophy. Only 10 of 73 non-Fabry patients (14%) (4 Friedreich, 1 amyloidosis, 5 hypertensive) showed an increased absolute papillary muscle area and PM_LV_ratio. In conclusion, this study confirmed the assumption that the prominent papillary muscle could be an echocardiographic marker for detection of Fabry patients with concentric LV hypertrophy.
Abstract: While acute myocardial infarction (MI) is associated with impaired clopidogrel responsiveness, systematic evaluation is lacking due to the inability of functional aggregation-based assays to analyse clopidogrel responsiveness in the presence of glycoprotein IIb/IIIa inhibitors. Using the P2Y12-specific, non-aggregation-based platelet-reactivity-index (PRI) we assessed clopidogrel responsiveness in patients with acute MI. Clopidogrel responsiveness was determined 24 hours (h) after loading with 600 mg clopidogrel in 54 patients with acute MI admitted for coronary intervention. A PRI >50% was considered as suboptimal inhibition. Overall response in MI patients was suboptimal with a median PRI of 58%. Diabetes, low high-density lipoprotein and pre-hospital clopidogrel loading were associated with impaired clopidogrel responsiveness. Patients loaded at first medical contact had a significantly weaker platelet inhibition by clopidogrel after 24 h (PRI 63%) compared to those loaded peri-interventionally (PRI 54%, p=0.014). Clinical outcome was assessed as a combination of cardiac death, non-fatal MI, stent thrombosis, ischaemic stroke, and urgent target vessel revascularisation after 12 months. The pre-selected cut-off of PRI ≤50% yielded a sensitivity of 87% at a specificity of 26%, whereas a PRI ≤57% determined by receiver-operating characteristics (ROC)-analysis yielded a sensitivity of 80% at a specificity of 56% (event rate: PRI ≤57%: 12.0%; PRI >57%: 41.4%, p=0.0136). In conclusion, PRI detects clopidogrel responsiveness in acute MI patients requiring glycoprotein IIb/IIIa antagonism; and impaired clopidogrel responsiveness predisposes to clinical events. Pre-hospital clopidogrel loading was associated with impaired response and more adverse events challenging the concept of earliest oral clopidogrel loading in MI patients.
Abstract: The recognition of the true prevalence of cardiac toxicity after mediastinal radiotherapy requires very long follow-up and a precise diagnostic procedure. Cardiac magnetic resonance imaging (MRI) permits excellent quantification of cardiac function and identification of localized myocardial defects and has now been applied to a group of 20-year Hodgkin's disease survivors.
Abstract: The water deprivation test (WDT) with direct or indirect measurement of plasma arginine vasopressin (AVP) is the method of choice for the differential diagnosis of the polydipsia-polyuria syndrome. In theory, direct measurement of AVP is highly attractive but is hampered by technical difficulties.
Abstract: OBJECT: To analyze the remodeling processes of the infarct territory in the time course of infarct healing. MATERIALS AND METHODS: Serial late enhancement (LE) studies were performed in 30 patients following reperfused myocardial infarction (MI) in the first and second week post-MI and after 3 months. To characterize infarct remodeling over time, the following variables were derived and analyzed in a blinded fashion: Infarct size (IS, in mm(3)), maximum infarct thickness (IT(max), mm), mean infarct thickness (IT(mean), mm) and the variability of infarct thickness (VIT=IT(max)/IT(mean)). Further, a new parameter for the assessment of infarct remodeling, the infarct extent (IE, mm(2)) was computed. IE quantifies IS in two dimensions along the heart's circumferential and longitudinal directions. IS was divided by the IE to obtain IT(mean). RESULTS: Overall infarct thickness was highly variable. Infarct shrinkage due to infarct thinning and IE reduction was found in the first months of healing. IS, IT(mean) and IT(max) significantly decreased during follow-up. There was a less consistent change of the IE: IE decreased in 75% of all infarcts from the first week up to 3 months post-MI, whereas 25% of infarcts expanded. Infarct thinning was found in almost all patients (92%), hence occurring in patients with infarct expansion and in patients without infarct expansion. CONCLUSION: Infarct thinning and-to a lesser extent-IE reduction, contribute to infarct shrinkage in the time course of infarct healing. Infarct thinning may occur without infarct expansion.
Abstract: Left ventricular hypertrophy is a non-specific physiological or maladaptive cardiac response to a large array of stimuli mediated by exercise and numerous cardiac and systemic diseases. The precise characterization and quantification of left ventricular hypertrophy may allow a more timely diagnosis of the underlying condition. The clinical reference standard to assess left ventricular hypertrophy is echocardiography, but a comprehensive description of how to approach this frequent finding in clinical practice is lacking. The current review systematically describes the typical echocardiographic patterns of important types of cardiac hypertrophy using both established and advanced imaging modalities. In hypertrophic obstructive cardiomyopathy a markedly reduced regional systolic function is found in the prominent thickened septum, whereas in essential arterial hypertension a typical concentric left ventricular hypertrophy with a less prominent basal septal bulge is present. The echocardiographic characteristics of cardiac amyloidosis are ventricular hypertrophy with sparkling granular myocardial texture and a small epicardial effusion. In addition, the strain rate curve for longitudinal function shows a typically reduced function which reaches maximum already in early systole. The typical feature of Friedreich cardiomyopathy is concentric left ventricular hypertrophy and sparkling granular texture with preserved regional systolic function. In Fabry cardiomyopathy a prominent papillary muscle is presented and a typical strain rate curve can be extracted from the basal lateral wall, indicating replacement fibrosis. Prominent hypertrabecularisation (ratio of non-compacted to compacted myocardium >2) in the apical and mid left ventricular segments is typical for non-compaction cardiomyopathy. Knowledge of these typical echocardiographic features enables the cardiologist to distinguish between the different hypertrophic entities, thus paving the way to early diagnosis.
Abstract: Androgen deficiency is a hormonal disorder that is frequently observed in advanced chronic conditions. A reduction of androgen blood levels may be cause or consequence of the disease, or both. Typical symptoms, such as fatigue or muscle weakness, may be particularly aggravated in heart failure, and disease severity may be indirectly affected by low levels of androgen. Recently, androgen replacement therapy has been suggested as a new treatment option of heart failure symptoms, and placebo-controlled pilot trials showed a modest improvement of physical performance. However, testosterone replacement in elderly patients is not without risks, and the benefit-risk ratio for such adjunct treatment is unclear. This review focuses on the general effects of androgens on the cardiovascular system and outlines expected benefits and suspected side effects of testosterone replacement therapy in patients with heart failure.
Abstract: This prospective cohort study in patients with aortic stenosis (AS) aimed to identify surrogates of myocardial fibrosis that are easy to derive in clinical practice, allow the differentiation of low-gradient severe AS from moderate AS, and have an impact on clinical outcome.
Abstract: TOPSTAR was a randomized, placebo-controlled trial studying the effects of adding the glycoprotein IIb/IIIa inhibitor tirofiban to conventional treatment with aspirin and clopidogrel in patients undergoing elective percutaneous coronary interventions (PCI). TOPSTAR demonstrated a lower periprocedural troponin release and a reduced 6-month mortality risk following PCI. The present study analyzed the corresponding long-term effects.
Abstract: The typical appearance of cardiac amyloidosis using standard echocardiographic techniques is usually a late finding only in patients with relatively advanced stages of the disease. Early noninvasive identification of cardiac amyloidosis is of growing clinical importance. Newer echocardiographic techniques, including tissue Doppler imaging and deformation imaging (strain rate imaging and 2-dimensional speckle tracking), are powerful tools for quantifying regional myocardial motion and deformation. Using these advanced techniques, early functional impairment in cardiac amyloidosis may be detectable when the results of standard echocardiography are still normal or inconclusive. This review provides a comprehensive overview of the different echocardiographic approaches for the assessment of systolic and diastolic function in patients with cardiac amyloidosis. Special attention is paid to regional myocardial function assessed by tissue Doppler imaging, strain rate imaging, and 2-dimensional speckle-tracking imaging.
Abstract: In December 2009, the first version of the German Disease Management Guideline (DM-CPG) for chronic heart failure was completed, including a set of proposed quality indicators for heart failure. This article explores whether proposed indicators can be derived from data collected routinely in general practices. For this purpose, previous experiences and data from the research project CONTENT (CONTinuous morbidity registration Epidemiologic NeTwork) conducted under guidance of the Department of General Medicine and Health Services Research at the University of Heidelberg, Germany, were applied. The availability of numerators and denominators needed for calculating the four quality indicators for diagnosis and pharmacotherapy proposed in the DM-CPG was checked within so-called "routine data" from the existing dataset of the CONTENT project. Within the given context, routine data are defined as data that are periodically transmitted from health care providers to cost units within the health care system. A thorough assessment has revealed that within the given context only one indicator could be deduced from routine data collection. This was the indicator measuring the proportion of patients receiving beta receptor antagonists, compared to all patients with heart failure NYHA class II to IV. Indeed, this single indicator will only be computable if the NYHA grade of heart failure severity and the presence or absence of contraindications to beta receptor antagonist therapy are routinely collected and the data merged into a central database. Against the background of these results it is obvious that a fully developed, transsectoral concept for data collection and data transfer needs to be implemented.
Abstract: BACKGROUND: Asymmetric dimethylarginine (ADMA) causes endothelial dysfunction by inhibiting endothelial nitric oxide synthase. Elevated ADMA plasma levels comprise a major risk factor for coronary artery disease (CAD) and predict coronary events. ADMA is metabolised by dimethylarginine dimethylaminohydrolases (DDAHs) to citrulline and dimethylamine (DMA) and is partly excreted unchanged via the kidney. Unlike circulating ADMA, very little is known about urinary ADMA and DMA concentrations and a predictive value in CAD patients. METHODS AND RESULTS: Seventy-seven consecutive patients admitted to hospital because of stable angina (mean age 65.9±1.1years) were enrolled and followed-up for 28 [1-28] months. All patients underwent cardiac catheterization and were divided into patients with no CAD or 1-3-vessel disease (CAD 1-3). Urinary ADMA levels (corrected for creatinine excretion) were lower in severely diseased patients (CAD 3, p<0.05) whereas the DMA/ADMA ratio was significantly increased (p<0.05 CAD 3 vs. CAD 0). In a stepwise multivariate regression analysis the ADMA/creatinine ratio correlated with cardiac function (r=0.5, p<0.0001) and LDL concentrations (r=0.27, p=0.01). A total of 12 patients died during follow-up, 9 due to cardiovascular causes. Importantly, low urinary ADMA concentrations predicted future cardiovascular death (p<0.01) and overall death (p<0.05). CONCLUSION: In CAD patients low urinary ADMA concentrations are associated with impaired cardiac function and predict cardiovascular as well as all-cause mortality. The potential clinical value of urinary ADMA as a new biomarker for the diagnosis of CAD or cardiac dysfunction is intriguing, but warrants further studies.
Abstract: Evidence for a pathophysiologic relevance of autoimmunity in human heart disease has substantially increased over the past years. Conformational autoantibodies stimulating the cardiac beta1-adrenoceptor (beta1-aabs) are considered of importance in heart failure development and clinical pilot studies have shown their prognostic significance in human 'idiopathic' cardiomyopathy.
Abstract: Left ventricular hypertrophy is a nonspecific physiologic or maladaptive cardiac response to a large array of stimuli mediated by exercise and numerous cardiac and systemic diseases. Hypertrophy, however, is not uniform. Rather, depending on the underlying pathologic mechanism, it may display unique morphologic and functional characteristics. The precise characterization and quantification of left ventricular hypertrophy may therefore allow a more timely diagnosis of the underlying condition. The clinical reference standard to assess left ventricular hypertrophy is echocardiography, but a comprehensive description of how to approach this frequent finding in clinical practice is lacking. The current review systematically describes the typical echocardiographic patterns of important types of cardiac hypertrophy using both established and advanced imaging modalities, thus guiding clinicians' path to early diagnosis.
Abstract: BACKGROUND: The differential diagnosis of hyponatremia is often challenging because of its association with multiple underlying pathophysiological mechanisms, diseases, and treatment options. Several algorithms are available to guide the diagnostic approach to hyponatremia, but their diagnostic and clinical utility has never been evaluated. We aimed to assess in detail the diagnostic utility as well as the limitations of the existing approaches to hyponatremia. METHODS: Each of the 121 consecutive subjects presenting with hyponatremia (serum sodium <130 mmoL/L) underwent 3 different and independent diagnostic and therapeutic approaches: inexperienced doctor applying an established Algorithm, intensive care senior physicians acting as Senior Physician, and senior endocrinologist serving as Reference Standard. RESULTS: The overall diagnostic agreement between Algorithm and Reference Standard was 71% (respective Cohen's kappa and delta values were 0.64 and 0.70), the overall diagnostic agreement between Senior Physician and Reference Standard was 32% (0.20 and 0.19, respectively). Regarding the therapeutic consequences, the diagnostic accuracy of the Algorithm was 86% (0.70 and 0.72, respectively) and of the Senior Physician was 48% (0.01 and 0.04, respectively). In retrospect, by disregarding the patient's extracellular fluid volume and assessing the effective arterial blood volume by determination of the fractional urate excretion, the Algorithm improved its diagnostic accuracy to 95%. CONCLUSION: Although the Algorithm performed reasonably well, several shortcomings became apparent, rendering it difficult to apply the Algorithm without reservation. Whether some modifications may enhance its diagnostic accuracy and simplify the management of hyponatremia needs to be determined.
Abstract: Background: Atherosclerosis has long been thought to develop over time in a linear manner from gradual wall thickening to advanced thick lesions. However, evidence has emerged indicating a phasic rather than linear progression with time. A major reason for this non-linear pattern appears to be the occurrence of hemorrhages in the arterial wall, although data on this issue are still scarce. We studied the occurrence of temporarily impressive thickenings of the carotid arterial wall in a cohort of healthy postmenopausal women who were followed up for 3 years with regular carotid ultrasound examinations. Methods: The women were the European participants of a randomized placebo-controlled trial into the effect of hormone replacement therapy on progression of carotid intima-media thickness (CIMT). For a period of 3 years, the women underwent a standardized carotid ultrasound protocol every 6 months. Common, bifurcation and internal carotid segments were scanned on both sides, stored on videotape, and the near and far wall CIMT was measured on defined angles and segments, also in areas of plaque. Adverse events were routinely recorded. At the completion of the study, all segment-specific measurements were evaluated for outliers. Images were retrieved from videotape and evaluated whether the outlier resulted from a real morphological change or 'measurement error'. Results: The 509 healthy postmenopausal women, free from previous symptomatic cardiovascular disease, underwent 3,812 carotid ultrasound scans during the study, and 44,924 carotid segments were evaluated. In 203 segments of 188 participants outliers were observed. True morphological changes were found in 12 participants, equivalent to a 3-year risk of 2.4%. These changes did not give rise to clinical symptoms. In the 6 women of whom we had follow-up measurements, the changes were reversed within 6-12 months. Conclusion: We observed acute increases in CIMT among 2.4% of healthy postmenopausal European women followed for 3 years. When assuming these were the result of vessel wall hemorrhages, our findings add to the body of evidence suggesting that vessel wall hemorrhages contribute to atherosclerosis development and also appear to occur clinically silent.
Abstract: BACKGROUND: Depression is highly prevalent in patients with chronic heart failure (CHF) and may bias patients' reports of their health-related quality of life (HRQoL). Depressed patients may rate their limitations of HRQoL worse even when their condition is rather good. We aimed to examine whether co-morbid depression alters the relationship between disease severity and HRQoL, thus compromising the validity of a CHF-specific HRQoL measure. METHODS: A sample of 233 outpatients with CHF (mean age 64.5 years, 70% male) was evaluated. Depression was measured with the Patient Health Questionnaire and CHF-specific HRQoL with the Kansas City Cardiomyopathy Questionnaire (KCCQ). CHF severity was assessed with physician ratings of the New York Heart Association (NYHA) functional class. RESULTS: Both NYHA functional class and depression independently impacted the various subscales of the KCCQ. Regarding the symptom- and function-related subscales, a dose-response relationship between disease severity and HRQoL was observed also in depressed patients. In contrast, in the quality of life subscale covering life satisfaction an interaction effect of disease severity and depression was found. In this subscale, a dose-response relationship between increasing disease severity and worsening HRQoL was no longer present among the depressed. CONCLUSIONS: Both disease severity and depression impacted each heart failure-specific HRQoL dimension while the presence of depression seemed to distort the relationship between disease severity and HRQoL in the quality of life subscale. As quality of life may depend more on the presence of depression than on the severity of CHF, assessing depression may help interpreting HRQoL scores.
Abstract: OBJECTIVE: Deficiency of anabolic sex steroids is common in heart failure (HF). The pathophysiological implications of this phenomenon, however, have not been fully elucidated. This clinical study investigated the significance of low serum androgen levels in HF. DESIGN: Prospective cohort study. Patients and Methods In 191 consecutively recruited men with HF (mean age 64 years; New York Heart Association (NYHA) class I-IV 24%/35%/35%/6%) and reduced (ejection fraction (EF) <or=40%, n=96) or preserved (EF >40%, n=95) left ventricular function total and free serum testosterone, dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured. The median observation period was 859 days. RESULTS: During follow-up 53 patients (28%) died. Whereas total serum testosterone was normal in most patients (91%), free testosterone and DHEAS were reduced in 79% and 23%, respectively. DHEAS and free testosterone, but not total testosterone, were inversely associated with NYHA class (both p<0.01). Lower free testosterone and DHEAS and higher SHBG predicted all-cause mortality risk (hazard ratio (HR) 0.89, 95% CI 0.82 to 0.96 per 1 ng/dl free testosterone, p=0.004; HR 0.95, 95% CI 0.89 to 1.00 per 10 microg/dl DHEAS, p=0.058; and HR 1.18, 95% CI 1.05 to 1.33 per 10 nmol/l SHBG, p=0.006, respectively; adjusted for age and NYHA class). However, further adjustment for carefully selected confounding factors abolished these associations. CONCLUSION: In male HF patients, low serum levels of androgens are associated with adverse prognosis, but this relation is confounded by indicators of a poor health state. The results suggest that low serum androgens develop as a sequel of this progressive multifaceted systemic disorder.
Abstract: Genetic research on heart failure (HF) requires large cohorts of well-phenotyped patients. The German Competence Network of Heart Failure (CNHF) organized a biobank in 2004 to supply the necessary infrastructure and standard operating procedures (SOPs) for a centralized collection of blood specimen. We centralized data and collected serum, plasma and DNA of well characterized HF subjects all over Germany. Different pseudonyms were created automatically to address data safety and other concerns about privacy. Thus far, we have collected 85,000 sample specimen from 9,500 prospectively evaluated patients with HF. Detailed medical data were prospectively acquired together with corresponding blood samples. In 2008 clinician-scientists can apply for access to the material. Our biobank represents a major facet of the CNHF and has already documented research and clinical utility.
Abstract: OBJECTIVE: To study the association of circulating markers of fibrosis: procollagen type III amino-terminal propeptide (PIIINP), procollagen type I carboxy-terminal propeptide (PIP) and collagen type I carboxy-terminal telopeptide (CITP): with left (LV) and right ventricular (RV) longitudinal and LV radial systolic function in patients with heart failure in the course of essential hypertension. METHODS: The study population consisted of 81 patients with hypertension divided into four groups according to NYHA classification and 20 healthy controls. Cardiac function was estimated by myocardial deformation indices assessed by tissue Doppler imaging. Serum PIIINP, PIP and CITP levels were quantified by radioimmunoassay. RESULTS: Progressive LV longitudinal function impairment was demonstrated in all hypertension groups as indicated by reduced peak systolic strain and strain rate and increased postsystolic strain index. The respective indicators of LV radial function were deteriorated only in NYHA classes III-IV. Concurrently, RV longitudinal function was found abnormal in NYHA classes II-IV. PIIINP concentration was higher in NYHA class III and IV, whereas CITP level was increased and PIP/CITP ratio was decreased in the NYHA IV individuals. PIIINP was an independent correlate of LV and RV longitudinal strain (R = 0.52, beta = -0.34, P < 0.001; R = 0.25, beta = -0.27, P < 0.01, respectively). PIP/CITP ratio independently determined LV radial strain in patients with LV ejection fraction less than 50% (R = 0.44, beta = 0.52, P < 0.008). CONCLUSION: In hypertensive patients, the progressive decline in cardiac longitudinal function is related to increased collagen III synthesis, whereas the changes in collagen I turnover favoring its increased degradation might contribute to LV radial and global systolic dysfunction seen in the advanced hypertensive heart disease.
Abstract: BACKGROUND: Major depression is 4-5 times more common in heart failure than in the general population, and associated with adverse outcomes. This prospective study investigated somatic correlates of comorbid depression in patients with heart failure aiming to better understand the interrelation of both conditions. METHODS: We enrolled 702 consecutive patients hospitalized for heart failure with a left ventricular ejection fraction (LVEF) </=40% (mean age 67years, 71% male). Suspected episodes of depression were identified using the Patient Health Questionnaire (PHQ-9). A score >11 (9-11) was defined as suspected major (minor) depression. RESULTS: The prevalence of major (minor) depression was 24% (15%). Major depression was more common in women (30%) than men (22%, p=0.02). In multivariable analysis, history of depression, (OR 3.09, 95%CI 1.98-4.82, p<0.001), New York Heart Association class (OR 2.07 per class, 95%CI 1.52-2.81, p<0.001), leukocyte count >8000/mm(3) (OR 1.50, 95%CI 1.03-2.17, p=0.032), and obstructive pulmonary disease (OR 1.61, 95%CI 1.04-2.50, p=0.033) correlated independently with higher prevalence rates of major depression. Hemoglobin (OR 0.87 per g/dL, 95%CI 0.79-0.96, p=0.005), and treatment with 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors (OR 0.66, 95%CI 0.45-0.98, p=0.039) correlated independently with lower prevalence rates. Female sex, diabetes, peripheral edema, hyperuricemia, cholesterol <150mg/dL, LVEF <30%, peripheral vascular disease, diuretics, and renal dysfunction were predictive only in univariable models. CONCLUSIONS: The high prevalence of major depression in patients with heart failure seems closely linked to various typical clinical features of this syndrome. Whether this implicates differential therapeutic needs in patients with comorbid compared with primary depression requires further investigation.
Abstract: BACKGROUND: Observational studies indicate that classical cardiovascular risk factors as body mass index, total cholesterol, and systolic blood pressure are associated with improved rather than impaired survival in heart failure ("reverse epidemiology"). We estimated the prognostic role of these risk factors in unselected patients with heart failure. METHODS AND RESULTS: Consecutive subjects with heart failure of any cause and severity were enrolled (n=867), and survivors were followed for a median period of 594 days (25th to 75th percentile, 435 to 840). Mean age was 70+/-13 years, 41% were female, New York Heart Association class distribution I through IV was 15%/29%/41%/15%, and 49% had preserved left ventricular ejection function. At follow-up, 34% of the patients had died. Low levels of any risk factor (ie, body mass index, total cholesterol, and systolic blood pressure in the low tertile) indicated the highest mortality risk. After adjustment for age, sex, New York Heart Association class, and ejection fraction, >/=2 risk factors in the high tertile indicated a relative reduction in mortality risk of 51% (hazard ratio, 0.49; 95% CI, 0.35 to 0.68; P=0.001) compared with subjects with 3 risk factors in the low tertile. Further adjustment for cause of heart failure, relevant comorbidities, medication, and biomarkers attenuated this association only modestly (hazard ratio, 0.63; 95% CI, 0.45 to 0.89; P=0.009). CONCLUSIONS: In patients with heart failure, mortality risk counterintuitively increased on a cumulative scale with lower levels of body mass index, total cholesterol, and systolic blood pressure, irrespective of the type and severity of heart failure. Future studies need to identify whether risk factor control as presently recommended should be advocated in all patients with heart failure.
Abstract: Rising prevalence and disease-related costs render chronic heart failure a rapidly growing socioeconomic challenge. Guideline-adjusted diagnosis and appropriate therapy are successful in improving mortality, morbidity, functional status and quality of life of patients with chronic left ventricular failure. Corresponding state-of-art recommendations were recently published in the updated European and American treatment guidelines. They determine a stepwise escalation of pharmacological and surgical treatment measures according to increasing disease severity. Still, the complexity of the heart failure syndrome demands to tailor diagnostic procedures and therapy to the patients' individual needs and circumstances.
Abstract: The management of heart failure patients (diagnosis, treatment monitoring, assessment of prognosis) crucially depends on the accuracy of the tools used for patient evaluation. While the diagnostic accuracy of anamnesis, clinical signs and symptoms is poor, "classic" tools like chest X-ray or electrocardiogram show reasonable specificity but poor sensitivity. Transthoracic echocardiography is well suited for the diagnosis of heart failure, but is relatively costly and depends on availability and the skills of the investigator. Over the last 2 decades, numerous biomarkers have emerged that potentially might aid in the complex decisionmaking processes for diagnosis, treatment and monitoring of heart failure. The ideal biomarker would possess a favorable diagnostic test profile and deliver pivotal information. In this respect, the currently best evidence base has been accumulated for the natriuretic peptide family. A large array of other heart failure biomarkers (i.e., markers of inflammation, extracellular matrix remodeling, and myocyte damage and stress) are still in earlier phases of testing. This short review will provide a balanced comparison of those "classic tools" and natriuretic peptides focusing on their diagnostic capacity in various clinical settings, factors influencing test values, cutoff values and their interpretation, and the capacity of these biomarkers to guide the diagnostic and therapeutic decision-making processes in patients with suspected and established heart failure.
Abstract: Heart failure (HF) has been identified as one of the most threatening diseases for the western civilisation, posing a risk to health for a rising number of patients. Acknowledging the medical problem of HF to be both economically and socially threatening the German Federal Ministry of Research and Education (BMBF) initiated a nationwide research network aiming to find new ways in prevention, alleviation and treatment of the widespread disease. The "Competence Network Heart Failure" (CNHF), initiated in 2003, bundles the scientific expertise in a large-scale research network; its aims are the coordination of basic and applied clinical research as well as dissemination of findings into clinical practice in order to consolidate and perpetuate the achieved improvements. The scope of this paper is to introduce the CNHF and to provide an overview of the tasks and hitherto attained achievements to a broad spectrum of health care providers.
Abstract: BACKGROUND: In this prospective follow-up study, the effect of myocardial fibrosis on myocardial performance in symptomatic severe aortic stenosis was investigated, and the impact of fibrosis on clinical outcome after aortic valve replacement (AVR) was estimated. METHODS AND RESULTS: Fifty-eight consecutive patients with isolated symptomatic severe aortic stenosis underwent extensive baseline characterization before AVR. Standard and tissue Doppler echocardiography and cardiac magnetic resonance imaging (late-enhancement imaging for replacement fibrosis) were performed at baseline and 9 months after AVR. Endomyocardial biopsies were obtained intraoperatively to determine the degree of myocardial fibrosis. Patients were analyzed according to the severity of interstitial fibrosis in cardiac biopsies (severe, n=21; mild, n=15; none, n=22). The extent of histologically determined cardiac fibrosis at baseline correlated closely with New York Heart Association functional class and markers of longitudinal systolic function (all P<0.001) but not global ejection fraction or aortic valve area. Nine months after AVR, the degree of late enhancement remained unchanged, implying that AVR failed to reduce the degree of replacement fibrosis. Patients with no fibrosis experienced a marked improvement in New York Heart Association class from 2.8+/-0.4 to 1.4+/-0.5 (P<0.001). Only parameters of longitudinal systolic function predicted this functional improvement. Four patients with severe fibrosis died during follow-up, but no patient from the other groups died. CONCLUSIONS: Myocardial fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe aortic stenosis and was not reversible after AVR over the 9 months of follow-up examined in this study. Because markers of longitudinal systolic function appear to indicate sensitively both the severity of myocardial fibrosis and the clinical outcome, they may prove valuable for preoperative risk assessment in patients with aortic stenosis.
Abstract: BACKGROUND AND OBJECTIVES: In hemodialysis, applicable guidelines recommend regular electrocardiogram (ECG) recordings. However, respective systematic evaluations are absent. Thus, the authors investigated whether routine ECG findings add prognostic information to standard risk assessment in hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The relationship between nine common baseline ECG variables and a combined cardiovascular endpoint (CVE; cardiac death, myocardial infarction, stroke), sudden death, stroke, MI, and all-cause death in 1253 patients from the German Diabetes and Dialysis Study was evaluated. All patients were on maintenance hemodialysis, had type 2 diabetes mellitus, and received randomized treatment with atorvastatin or placebo. RESULTS: During 4 yr of follow-up (March 1998 to March 2004), 469 patients reached the CVE, and 617 died. After adjustment for demographics, comorbidities, and biomarkers in multivariate analysis, patients presenting without sinus rhythm were 89% more likely to die, and the risk of CVE and stroke increased by 75% and 164%, respectively, compared with patients with preserved sinus rhythm. Left ventricular hypertrophy was associated with >2-fold increase in the risk of stroke and a 60% increase in the risk of sudden death. CONCLUSIONS: In hemodialysis patients with type 2 diabetes mellitus, the absence of sinus rhythm is a risk indicator for CVE, stroke, and all-cause death, and left ventricular hypertrophy is associated with stroke and sudden death. Thus, routine ECG recording adds prognostic information to standard risk assessment.
Abstract: BACKGROUND: Enzyme replacement therapy with recombinant alpha-galactosidase A reduces left ventricular hypertrophy and improves regional myocardial function in patients with Fabry disease during short-term treatment. Whether enzyme replacement therapy is effective in all stages of Fabry cardiomyopathy during long-term follow-up is unknown. METHODS AND RESULTS: We studied 32 Fabry patients over a period of 3 years regarding disease progression and clinical outcome under enzyme replacement therapy. Regional myocardial fibrosis was assessed by magnetic resonance imaging late-enhancement technique. Echocardiographic myocardial mass was calculated with the Devereux formula, and myocardial function was quantified by ultrasonic strain-rate imaging. In addition, exercise capacity was measured by bicycle stress test. All measurements were repeated at yearly intervals. At baseline, 9 patients demonstrated at least 2 fibrotic left ventricular segments (severe myocardial fibrosis), 11 had 1 left ventricular segment affected (mild fibrosis), and 12 were without fibrosis. In patients without fibrosis, enzyme replacement therapy resulted in a significant reduction in left ventricular mass (238+/-42 g at baseline, 202+/-46 g at 3 years; P for trend <0.001), an improvement in myocardial function (systolic radial strain rate, 2.3+/-0.4 and 2.9+/-0.6 seconds(-1), respectively; P for trend=0.045), and a higher exercise capacity obtained by bicycle stress exercise (106+/-14 and 122+/-26 W, respectively; P for trend=0.014). In contrast, patients with mild or severe fibrosis showed a minor reduction in left ventricular hypertrophy and no improvement in myocardial function or exercise capacity. CONCLUSIONS: These data suggest that treatment of Fabry cardiomyopathy with recombinant alpha-galactosidase A should best be started before myocardial fibrosis has developed to achieve long-term improvement in myocardial morphology and function and exercise capacity.
Abstract: Cardiac amyloidosis represents a prognostically relevant comorbidity in multiple myeloma. We report the case of a patient in whom severe heart failure symptoms as a consequence of cardiac AL-amyloidosis resolved after tandem high-dose melphalan therapy followed by autologous blood-stem cell transplantation. Partial regression of cardiac amyloid deposits and improvement of cardiac function were objectified.
Abstract: BACKGROUND: To examine whether depression and heart failure severity are independent predictors of both the physical and psychologic domains of health-related quality of life (HRQoL) in patients with chronic heart failure. METHODS AND RESULTS: A sample of 206 outpatients with chronic heart failure (mean age 64 years, 69% male) was evaluated. Depression was measured with the Patient Health Questionnaire and disease-specific HRQoL with the Kansas City Cardiomyopathy Questionnaire. Heart failure severity was assessed with physician ratings of the New York Heart Association (NYHA) functional class. The simultaneous effects of predictor variables on outcomes were estimated using structural equation modeling. Both depression and NYHA functional class independently predicted the physical domain of HRQoL. By contrast, the psychologic domain was only predicted by depression, but not by NYHA functional class. CONCLUSIONS: Our results suggest that comorbid depression has an independent impact on both physical and psychologic HRQoL in patients with chronic heart failure after controlling for the severity of heart failure symptoms, while heart failure severity only impacts physical HRQoL. Thus, assessment of comorbid depression may help interpreting reduced HRQoL in heart failure patients. Research seems warranted evaluating whether the amelioration of depression may enhance patients' HRQoL in chronic heart failure.
Abstract: BACKGROUND: Treatment of patients with hyponatremia varies widely; thus, convenient diagnostic parameters are needed to guide the correct treatment strategy. This study was designed to evaluate the diagnostic potential of copeptin, the C-terminal part of provasopressin, as a new marker in the differential diagnosis of hyponatremia. METHODS: In this prospective observational study, 106 consecutive hyponatremic patients were classified based on their history, clinical evaluation, and laboratory tests. In patients and 32 healthy control subjects, plasma copeptin concentration and standard biochemical parameters were tested for their utility of diagnosing the syndrome of inappropriate antidiuresis (SIAD). RESULTS: Four patients (4%) were diagnosed as primary polydipsia, nine (8%) as diuretic-induced hyponatremia, 42 (40%) as SIAD, 29 (27%) as hypovolemic hyponatremia, and 22 patients (21%) as hypervolemic hyponatremia. In controls, a close correlation between plasma copeptin and serum sodium (r(2) = 0.62, P < 0.001) or urine osmolality (r(2) = 0.39, P = 0.001) was observed. Plasma copeptin levels were significantly higher in patients with hypo- and hypervolemic hyponatremia compared with SIAD (P < 0.005, respectively) and primary polydipsia (P < 0.001). The copeptin to U-Na ratio differentiated accurately between volume-depleted and normovolemic disorders (area under the receiver-operating characteristic curve 0.88, 95% confidence interval 0.81-0.95; P < 0.001), resulting in a sensitivity and specificity of 85 and 87% if a cutoff value of 30 pmol/mmol was used. The combined information of plasma copeptin less than 3 pmol/liter and urine osmolality less than 200 mOsm/kg ensured primary polydipsia in 100% of suspected patients. CONCLUSION: Copeptin measurement reliably identifies patients with primary polydipsia but has limited utility in the differential diagnosis of other hyponatremic disorders. In contrast, the copeptin to U-Na ratio is superior to the reference standard in discriminating volume-depleted from normovolemic hyponatremic disorders.
Abstract: BACKGROUND: Oral oestrogen replacement therapy increases levels of C-reactive protein (CRP). CRP is an established strong predictor of cardiovascular events. It is unknown whether endogenous oestrogen levels are associated with CRP. We therefore studied the relationship between endogenous sex hormones and CRP in healthy postmenopausal women emphasizing the role of body composition as peripheral fat is both a main source of oestrogen production after menopause and an endocrine tissue with inflammatory activities. SUBJECTS AND METHODS: The study population comprised 889 women participating in the PROSPECT study, an ongoing population-based cohort study. Information on risk factors was collected by questionnaires and clinical examination. Endogenous sex hormone levels and CRP were measured with double antibody radio immuno assay (RIA) from fasting plasma samples. In this cross-sectional study, associations between risk factors and lnCRP were studied using linear regression models. RESULTS: Increases in oestrone and free oestradiol levels and the free androgen index were related to an increase in lnCRP of 1.19, 1.23 and 1.21 mg dL(-1) respectively. Body mass index (BMI), waist circumference and physical activity were strongly related to CRP levels, independent of age and other cardiovascular risk factors. Levels of all sex steroids but dehydroepiandrostenedione decreased with age. In age-adjusted analyses, an increase in waist circumference or BMI by one quartile was associated with a 1.28-fold and 1.26-fold increase in CRP. The relationship between endogenous hormones and CRP was modestly attenuated but remained highly significant after adjustment for body composition, physical activity and other traditional cardiovascular risk factors. CONCLUSIONS: Our findings show that in postmenopausal women high levels of endogenous oestrogenic and androgenic sex steroids coincide with high CRP levels. This was only explained in part by markers of body composition or intra-abdominal fat.
Abstract: Incomplete P2Y(12)-inhibition during clopidogrel treatment is associated with increased cardiovascular events and mortality after coronary intervention. We investigated the incidence of impaired individual clopidogrel-responsiveness using a P2Y(12)-specific and pre-treatment-independent assay in a real world situation. One hundred consecutive patients with coronary artery disease (CAD) on combined acetylsalicylic acid and clopidogrel treatment (75 mg/d) and 33 patients on aspirin only were screened for platelet ADP-induced signalling by conventional aggregometry, platelet P-selectin expression and the platelet reactivity index (PRI). Impaired P2Y(12)-specific inhibition by clopidogrel was defined as a PRI>50%. Functional platelet reactivity was significantly lower in clopidogrel-treated patients compared to controls. Impaired individual response to treatment was diagnosed in 69% of clopidogrel-treated patients. Conventional assessment of maximum ADP-induced platelet aggregation failed to detect impaired P2Y(12) inhibition in 36% of patients identified by PRI to have an impaired clopidogrel response. Impaired clopidogrel response was associated with lower HDL levels and a history of hyperlipidaemia. In conclusion, PRI as a P2Y(12)-specific assay to evaluate the treatment effect of clopidogrel in patients with CAD revealed insufficient P2Y(12)-inhibition in two thirds of patients in a real-world scenario indicating a markedly higher incidence than previously assumed. PRI detected significantly more patients with impaired response than conventional platelet aggregation.
Abstract: BACKGROUND: The effectiveness of chronic heart failure (CHF) pharmacotherapy in unselected cohorts is unknown. AIMS: To estimate the association between quality of CHF pharmacotherapy and all-cause mortality risk. METHODS AND RESULTS: In a prospective cohort study, 1054 unselected patients with CHF (61% with reduced and 39% with normal left ventricular ejection fraction (LVEF)) were consecutively enrolled. Quality of pharmacotherapy was assessed by calculating a guideline adherence indicator (GAI-3, range 0-100%) based on prescription of beta blockers, angiotensin converting enzyme inhibitors or angiotensin receptor II type-1 blockers, and mineralocorticoid receptor antagonists. Median follow-up in survivors was 595 days (100% complete). In patients with reduced LVEF the median GAI-3 was 67%, and inversely associated with age, CHF severity, and important comorbidities. Mortality rates in GAI-3 categories low/medium/high were 79/30/11 per 100 person-years. In multivariable Cox regression, high GAI-3 was independently predictive of lower mortality risk: hazard ratio (HR) 0.50 (95% confidence interval [CI] 0.32-0.74; P<0.001) vs low GAI-3. This association was also observed in subgroups of high age (HR 0.42, 95%CI 0.27-0.66; P<0.001) and women (HR 0.42, 95%CI 0.23-0.79; P=0.007). CONCLUSIONS: In this community-based cohort with CHF, better implementation of pharmacotherapy was associated with better prognosis in patients with reduced LVEF, irrespective of age and sex.
Abstract: OBJECTIVE: Two-dimensional (2-D) strain imaging is a novel echocardiographic technique for myocardial function evaluation. We sought to investigate left ventricular (LV) systolic function in patients with heart failure caused by hypertension using a 2-D strain approach and to validate this method against Doppler strain measurements. METHODS: The study population comprised 81 patients (66.4 +/- 7.4 years) with hypertension in New York Heart Association (NYHA) class I to IV and 20 healthy controls. RESULTS: Decreased longitudinal strain was demonstrated in the basal septal segment in NYHA I, in the basal and mid septal and basal lateral segments in NYHA II, and in all segments in NYHA III and IV. Radial and circumferential strain were reduced in patients with NYHA III and IV. Independent predictors of strain were duration of HT, LV mass index, LV end-diastolic volume index, and systolic blood pressure. The agreement between 2-D and Doppler strain remained within acceptable ranges (mean difference +/- 1 standard deviation: 0.61%-1.92% +/- 2.38%-2.92% for longitudinal strain in particular segments and 4.98% +/- 5.26% for radial strain). CONCLUSION: In hypertensive patients, (1) LV longitudinal systolic function progressively deteriorates from NYHA I to IV and abnormalities commence in the basal septum, (2) LV radial and circumferential systolic impairment appears in NYHA III and IV, and (3) 2-D strain measurement provides a feasible tool for the quantitation of LV systolic performance.
Abstract: In industrialized countries, heart failure has developed into a leading cause of death and hospitalization. It represents one of the most relevant drivers of health-related costs and is among the prime medical and societal challenges of future decades. Sleep-disordered breathing impacts adversely on quality of life and may further aggravate the heart failure syndrome, thus augmenting the high mortality risk associated with this disorder. This article reviews important pathophysiological interactions between both obstructive and central sleep apnea and coexistent heart failure and describes the available treatment options. Based on current evidence, an algorithm for the diagnosis and treatment of sleep-disordered breathing in heart failure is proposed, and future research perspectives are outlined.
Abstract: AIMS: Poor image quality remains a limitation of dobutamine stress echocardiography (DSE). This study aimed at investigating the effects of transpulmonary contrast application on endocardial border delineation and diagnostic yield of DSE in patients with intermediate coronary stenoses. The invasively measured fractional flow reserve (FFR) served as the reference standard. METHODS AND RESULTS: Seventy patients with an intermediate coronary stenosis entered the study. Cineloops were recorded during DSE before and after contrast application at rest and peak stress. Two observers blinded to angiography assessed wall motion. FFR was measured in the target vessel during repeat angiography and an FFR <or= 0.75 was considered pathological. Abnormal FFR findings were seen in 41% of the patients. Native DSE was abnormal in 36% and contrast-enhanced DSE in 50% of the patients. Luminal diameter narrowing measured by quantitative angiography was not significantly different between patients with normal and abnormal FFR. After contrast application, the number of non-interpretable segments [median (25-75th percentile)] decreased from 2 (1-3) to 0 (0-0) at rest and from 1 (0-3) to 0 (0-0) at stress (both P < 0.001). Compared with native imaging, sensitivity and accuracy increased with transpulmonary contrast from 48 [CI (confidence interval) 40-57%] to 83% (76-91%) and from 62 (CI 56-69%) to 77% (71-82%), respectively (both P = 0.05). CONCLUSION: Transpulmonary contrast application improves the interpretability and diagnostic yield of DSE in patients with intermediate coronary lesions.
Abstract: BACKGROUND: The syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hyponatremia. Its diagnosis requires decreased serum osmolality, inappropriately diluted urine (e.g. >100 mOsm/kg), clinical euvolemia, and a urinary sodium (Na) excretion (U-Na) more than 30 mmol/liter. However, in hyponatremic patients taking diuretics, this definition is unreliable due to the natriuretic effect of diuretics. Here, we examined the diagnostic potential of alternative laboratory measurements to diagnose SIAD, regardless of the use of diuretics. METHODS: A total of 86 consecutive hyponatremic patients (serum Na <130 mmol/liter) was classified based on their history, clinical evaluation, osmolality, and saline response to isotonic saline into a SIAD and a non-SIAD group. U-Na, serum urate concentration, and fractional excretion (FE) of Na, urea, and uric acid (UA) were measured in all subjects. The accuracy to diagnose SIAD was assessed using receiver operating characteristic analysis. RESULTS: A total of 31 patients (36%) had a diagnosis of SIAD, and 55 (64%) were classified as non-SIAD. There were 57 patients (68%) who were on diuretics (15 in the SIAD group, 42 in the non-SIAD group). In the absence of diuretic therapy, SIAD was accurately diagnosed using U-Na (area under the receiver operating characteristic curve 0.96; 0.92-1.02). However, in patients on diuretics, the diagnosis was unreliable (area under the curve 0.85; 0.73-0.97). There, FE-UA performed best compared with all other markers tested (area under the curve 0.96; 0.92-1.12), resulting in a positive predictive value of 100% if a cutoff value of 12% was used. CONCLUSION: FE-UA allows the diagnosis of SIAD with excellent specificity. Combining the information on U-Na and FE-UA leads to a very high diagnostic accuracy in hyponatremic patients with and without diuretic treatment.
Abstract: BACKGROUND: Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are involved in cardiac remodelling. The prognostic utility of TIMP is unknown in chronic heart failure (CHF). AIMS: We investigated the association of plasma levels of soluble MMP-9 and TIMP-1 with clinical, laboratory and echocardiographic parameters and estimated their prognostic value in the prediction of all-cause death. METHODS: MMP-9, TIMP-1, tumour necrosis factor-alpha, and amino-terminal pro-brain natriuretic peptide were measured in 249 consecutively enrolled CHF patients and 74 healthy individuals. RESULTS: After adjustment for age, sex and creatinine, levels of TIMP-1 (1640 vs. 735 ng/ml, P<0.001) but not MMP-9 were elevated in CHF patients compared to controls. During a median follow-up period of 2.5 years, 66 patients (27%) died. In multivariable Cox regression models TIMP-1 but not MMP-9 emerged as an independent predictor of all-cause death (hazard ratio per tertile, 3.5; 95% confidence interval [CI], 2.2-5.1). In addition to the full set of univariately predictive clinical and serological markers, information on TIMP-1 significantly increased the area under the receiver operating characteristic curve from 0.77 (95% CI, 0.71-0.84) to 0.87 (95% CI, 0.82-0.92). CONCLUSION: In stable CHF patients, TIMP-1 but not MMP-9 is of independent and incremental value regarding the prediction of all-cause death.
Abstract: Behçet's disease is a chronic relapsing systemic vasculitis of unknown etiology, affecting predominantly oral and genital mucocutaneous tissues and also the eyes. The disease is spread worldwide with a higher prevalence rate in countries along the ancient Silk Route, but it is rare (1-10/100,000) in Central and Northern Europe. Genetic, environmental, immunologic, inflammatory and rheologic factors are involved in the pathogenesis and the course of the disease. Any vascularized organ may be affected. Eye involvement is frequent, and may eventually result in loss of vision. Further important complications are cerebral manifestations, thrombotic syndromes, and arterial aneurysms with a high risk of rupture. Diagnosis and therapy of Behçet's disease are best managed by an interdisciplinary team. Skin lesions may be controlled by systemic treatment with colchicine, alternatively with dapsone, and in severe cases with thalidomide. Active systemic disease should be treated more aggressively using immunosuppressants. Despite advances in treatment relapses are still frequent, and systemic disease remains associated with an adverse prognosis.
Abstract: Amyloidoses are a heterogeneous group of multisystem disorders, which are characterized by an extracellular deposition of amyloid fibrils. Typically affected are the heart, liver, kidneys, and nervous system. More than half of the patients die due to cardiac involvement. Clinical signs of cardiac amyloidosis are edema of the lower limbs, hepatomegaly, ascites and elevated jugular vein pressure, frequently in combination with dyspnea. There can also be chest pain, probably due to microvessel disease. Dysfunction of the autonomous nervous system or arrhythmias may cause low blood pressure, dizziness, or recurrent syncope. The AL amyloidosis caused by the deposition of immunoglobulin light chains is the most common form. It can be performed by monoclonal gammopathy. The desirable treatment therapy consists of high-dose melphalan therapy twice followed by autologous stem cell transplantation. Due to the high peritransplantation mortality, selection of appropriate patients is mandatory. The ATTR amyloidosis is an autosomal dominant disorder caused by the amyloidogenic form of transthyretin, a plasmaprotein that is synthesized in the liver. Therefore, liver transplantation is the only curative therapy. The symptomatic treatment of cardiac amyloidosis is based on the current guidelines for chronic heart failure according to the patient's New York Heart Association (NYHA) state. Further types of amyloidosis with possible cardiac involvement comprise the senile systemic amyloidosis caused by the wild-type transthyretin, secondary amyloidosis after chronic systemic inflammation, and the beta(2)-microglobulin amyloidosis after long-term dialysis treatment.
Abstract: Diagnostic criteria of heart failure (HF) are the presence of typical signs, symptoms, and objective evidence of cardiac dysfunction. Exertional dyspnea is a key symptom but highly unspecific, calling for standardised focused diagnostic algorithms. These include 12-lead ECG, chest X-ray, routine laboratory values, measurement of natriuretic peptides, and the quantification of systolic and diastolic dysfunction by echocardiographic methods. Further options in the diagnostic armamentarium comprise laevocardiography, coronary angiography, scintigraphic techniques, cardiac computer tomography, cardiac magnetic resonance imaging, and endomyocardial biopsy. As a primary diagnostic aim, the underlying cause of heart failure should be determined in all subjects because the therapeutic strategy may depend on this information.
Abstract: A total of 52 pharmacologically untreated subjects with essential hypertension were randomly allocated to either 8 weeks of contemplative meditation combined with breathing techniques (CMBT) or no intervention in this observer-blind controlled pilot trial. CMBT induced clinically relevant and consistent decreases in heart rate, systolic and diastolic blood pressure if measured during office readings, 24-h ambulatory monitoring and mental stress test. Longer-term studies should evaluate CMBT as an antihypertensive strategy.
Abstract: BACKGROUND: Data regarding the influence of depression on outcome in chronic heart failure are conflicting and neglect possible gender differences. AIMS: To investigate prevalence and prognostic importance of depression in a cohort of patients with symptomatic heart failure and to compare findings in males and females. METHODS: Depression was measured at study entry using a self-reported 9-item Patient Health Questionnaire (PHQ-9) in 231 consecutive outpatients. The median follow-up time was 986 (IQR=664-1120) days. RESULTS: The prevalence of suspected major depression was 13% (minor depression, 17%) and was not different between the sexes. Major (but not minor) depression was associated with an increased mortality risk (hazard ratio [HR]=3.3, 95% confidence interval=1.8-6.1, p<0.001). This relationship remained significant after adjustment for other prognostically relevant factors as age, sex, heart failure aetiology, degree and type of left ventricular dysfunction, and New York Heart Association functional class. However, testing the effect of the interaction between gender and depression failed to reach significance (p=0.37). CONCLUSION: Our data confirm a high prevalence of depression in chronic heart failure. Further, they prove an independent prognostic impact of major, but not minor, depression. Possible gender differences regarding the prognostic impact of depression require further investigation in a larger patient cohort.
Abstract: BACKGROUND: Statins reduce cardiomyocyte hypertrophy in animal models of hypertrophic cardiomyopathy, aortic banding and heart failure after myocardial infarction. We investigated the effect of the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin on left ventricular (LV) mass in patients with hypertrophic cardiomyopathy in a randomized placebo-controlled double-blind pilot study. MATERIALS AND METHODS: Patients with hypertrophic cardiomyopathy were randomized to be treated once daily by atorvastatin 80 mg or placebo for nine months. LV mass was assessed by serial cardiac magnetic resonance imaging. LV systolic and diastolic function was determined by echocardiography. Markers of collagen metabolism and inflammation were also assessed. RESULTS: Out of 78 screened patients with hypertrophic cardiomyopathy 28 (2 x 14) patients were eligible for randomization. Eleven patients in each group completed the study with cardiac magnetic resonance imaging assessments meeting the evaluation standards at baseline and at follow-up. Low-density lipoprotein cholesterol levels in the atorvastatin group decreased from 3.24 +/- 1.14 mmol L(-1) (125 +/- 44 mg dL(-1)) at baseline to 1.37 +/- 0.49 mmol L(-1) (53 +/- 19 mg dL(-1)) at follow-up (P < 0.001), but were unchanged in the placebo group. Baseline LV mass was 228 +/- 51 g in the placebo and 232 +/- 67 g in the atorvastatin group. The primary endpoint of change in LV mass from baseline to follow-up was 2 +/- 10% in the atorvastatin group versus 0 +/- 13% in the placebo group (P = NS). Parameters of LV volumes and diameters, systolic and diastolic function, and markers of collagen metabolism were also unchanged in both groups. CONCLUSION: In patients with hypertrophic cardiomyopathy, this randomized placebo-controlled double-blind pilot study did not demonstrate an effect of 9-month treatment with atorvastatin 80 mg on LV mass reduction.
Abstract: OBJECTIVES: This study sought to develop a rapid method for the detection of activating autoantibodies directed against the beta1-adrenoceptor (anti-beta1-Abs) in patients with heart failure. BACKGROUND: The anti-beta1-Abs are supposed to play a pathophysiological role in heart failure. However, there is no reliable method for their detection. With a complex screening strategy (enzyme-linked immunosorbent assay, immunofluorescence, cyclic adenosine monophosphate [cAMP]-radioimmunoassay) we have previously identified antibodies targeting the second extracellular beta1-receptor loop (anti-beta1-EC(II)) in 13% of patients with ischemic cardiomyopathy (ICM) and in 26% with dilated cardiomyopathy (DCM). METHODS: To detect anti-beta1-Abs, we measured beta1-receptor-mediated increases in intracellular cAMP by fluorescence resonance energy transfer using a highly sensitive cAMP sensor (Epac1-based fluorescent cAMP sensor). RESULTS: The immunoglobulin G (IgG) prepared from 77 previously antibody-typed patients (22 ICM/55 DCM) and 50 matched control patients was analyzed. The IgG from all 22 previously anti-beta1-EC(II)-positive patients (5 ICM/17 DCM) induced a marked cAMP increase, indicating receptor activation (49.8 +/- 4.2% of maximal isoproterenol-induced signal). The IgG from control patients and 32 previously anti-beta1-EC(II)-negative patients (17 ICM/15 DCM) did not significantly affect cAMP. Surprisingly, our technology detected anti-beta1-Abs in 23 DCM patients formerly judged antibody-negative, but their cAMP signals were generally lower (31.3 +/- 6.8%) than in the previous group. "Low"-activator anti-beta1-Abs were blocked preferentially by peptides corresponding to the first, and "high"-activator anti-beta1-Abs by peptides corresponding to the second beta1-extracellular loop. Beta-blockers alone failed to fully prevent anti-beta1-EC(II)-induced receptor activation, which could be achieved, however, by the addition of beta1-EC(II) peptides. CONCLUSIONS: Our novel method of detecting anti-beta1-Abs proved to be fast and highly sensitive. It also revealed an insufficient ability of beta-blockers to prevent anti-beta1-EC(II)-induced receptor activation, which opens new venues for the research on anti-beta1-Abs and eventual treatment options in heart failure.
Abstract: OBJECTIVE: The aim of this study was to examine whether the physical and mental components of health-related quality of life (HRQoL) are independent predictors of survival in patients with chronic heart failure (CHF). METHODS: A cohort of 231 outpatients with CHF was followed prospectively for 986 days (median; interquartile range=664-1120). Generic HRQoL was measured with the Short Form-36 Health Survey (SF-36), disease-specific HRQoL was measured with the Kansas City Cardiomyopathy Questionnaire, and depression was measured with the self-reported Patient Health Questionnaire. RESULTS: Both generic and disease-specific HRQoL were predictive of survival on univariate analyses. After adjustment for prognostic factors such as age, gender, degree of left ventricular dysfunction, and functional status, only the mental health component of SF-36 and the disease-specific HRQoL remained significant. When depression was included, both measures also lost their predictive power. CONCLUSION: Our data suggest that the prognostic value of patients' HRQoL reflects confounding with the severity of disease and comorbid depression.
Abstract: AIMS: Regional myocardial fibrosis detected by magnetic resonance imaging (MRI) using late enhancement (LE) indicates an unfavorable prognosis. We investigated in a prospective study whether regional non-ischaemic fibrosis in hypertrophic myocardium can also be detected by ultrasonic strain-rate imaging based on specific visual features of the myocardial deformation traces. METHODS AND RESULTS: This diagnostic study aimed to define left ventricular fibrotic segments in 30 patients with hypertrophic cardiomyopathy (n = 10), severe aortic valve stenosis (n = 10), Fabry disease cardiomyopathy (n = 10), and 10 healthy controls. MRI and strain-rate imaging (=deformation imaging) was performed in all patients and controls to detect LE. In total, 42 segments showed LE according to MRI criteria. Using strain-rate imaging, all LE positive segments displayed a characteristic pattern consisting of a first peak in early systole followed by a rapid fall in strain rate close to zero and a second peak during isovolumetric relaxation. This 'double peak sign' was never seen in segments of healthy controls. However, it was detected in 10 segments without LE. These 'false-positive' segments belonged to Fabry patients who often develop a fast progressing fibrosis. In a follow-up MRI study after 2 years (available for 6/10 segments), all these segments had developed LE. CONCLUSION: The 'double peak sign' in strain-rate imaging tracings seems to be a reliable tool to diagnose regional fibrosis.
Abstract: BACKGROUND: Depression and chronic heart failure (CHF) are common conditions, both of which are clinically and economically highly relevant. Major depression affects 20-40% of CHF patients and predicts adverse outcomes in terms of quality of life, morbidity and mortality as well as health care expenditure, independent of other factors of prognostic relevance. AIMS: The purpose of the MOOD-HF trial is to clarify whether antidepressant pharmacotherapy improves outcome in CHF patients, and if so by which mechanism(s). METHODS: MOOD-HF is a prospective, randomised, double-blind, placebo-controlled, 2-armed, parallel-group multicenter trial investigating the effects of the serotonin re-uptake inhibitor (SSRI) escitalopram on morbidity and mortality (primary endpoint), severity of depression, anxiety, cognitive function, quality of life and health care expenditure in 700 patients with symptomatic systolic CHF and major depression diagnosed by structured clinical interview. All patients will receive optimised pharmacotherapy for CHF. Duration of follow-up, including close safety monitoring, is 12-24 months from randomisation. PERSPECTIVE: MOOD-HF is the first prospective randomised controlled trial to assess the effects of antidepressant pharmacotherapy on hard somatic endpoints, the mechanism(s) of action of SSRI treatment, as well as safety in New York Heart Association functional class II-IV CHF patients. The results are expected to promote the development of evidence-based recommendations for managing depression in the context of CHF. TRIAL REGISTRATION: (ISRCTN.org). Identifier: ISRCTN33128015.
Abstract: BACKGROUND: In severe aortic stenosis (AS), brain natriuretic peptide (BNP) and its precursor, the amino-terminal pro-hormone (NT-proBNP) are independent predictors of outcome. Deterioration of cardiac function in AS is currently assessed by symptomatology and echocardiography to determine the optimal time point for surgery. We investigated whether BNP or NT-proBNP may help to estimate the individual risk of patients for subendocardial ischaemia in patients with moderate and severe AS. DESIGN: In 71 patients with AS and 24 controls, the association of plasma natriuretic peptides with invasively measured haemodynamic parameters, including the myocardial oxygen supply-to-demand ratio [diastolic pressure time index/systolic pressure time index (DPTI/SPTI)] was cross-sectionally assessed. RESULTS: Levels of natriuretic peptides increased with severity of AS. In patients with moderate AS (n = 30), natriuretic peptides differentiated between symptomatic and asymptomatic status (P = 0.01). BNP and NT-proBNP values correlated negatively with DPTI/SPTI (r = -0.58 and -0.51, P < 0.001, respectively) and left ventricular (LV) ejection fraction (EF) (r = -0.52 and -0.59, P < 0.001, respectively). DPTI/SPTI correlated with aortic valve area (P < 0.0001) but not with EF. Receiver operating characteristic analysis determined cut-off values of > 450 pg mL(-1) for BNP and of > 1800 pg mL(-1) for NT-proBNP for those AS patients who were at highest risk for subendocardial ischaemia (i.e. DPTI/SPTI < 0.22) in combination with impaired LV systolic function (i.e. EF < 45%). CONCLUSIONS: Elevated natriuretic peptides show cardiac deterioration in AS and may help to identify those patients in need for early valve replacement.
Abstract: AIMS: The present study aims to compare the change of left ventricular deformation during dobutamine stress echocardiography (DSE) with the reference standard of invasive myocardial fractional flow reserve (FFR) to assess the haemodynamic significance of intermediate coronary lesions. METHODS AND RESULTS: In 30 patients with an intermediate coronary artery stenosis in one epicardial coronary artery, FFR measurements were performed during coronary catheterization. In case of an FFR < 0.75 after intracoronary adenosine administration, the stenosis was considered significant, indicating ischaemia. In addition, during DSE, peak systolic strain rate and systolic strain of the region of interest (supplied by the stenotic vessel) and of a non-ischaemic remote region were assessed at baseline and at peak stress. Thirteen patients had an FFR >or= 0.75, indicating normal flow reserve (non-ischaemic group). The remaining 17 patients with an FFR < 0.75 comprised the ischaemic group. At baseline DSE, mean values of strain rate (-1.2 +/- 0.3 s(-1)) and strain (-17 +/- 8%) were not significantly different between both groups. In the ischaemic group, in the target region, strain at peak stress decreased to - 10 +/- 8%, whereas strain rate remained unchanged. In contrast, in the non-ischaemic group, strain at peak stress remained unchanged (-18 +/- 7%), whereas strain rate increased to - 2.5 +/- 1.1 s(-1). The receiver operating characteristic curve analysis revealed the change in strain rate as the best parameter to detect ischaemia, with a sensitivity of 89% and a specificity of 86%. In the remote region, in both groups, strain rate (-1.4 +/- 0.4 s(-1)) and strain values (-20 +/- 7%) were not significantly different at baseline, and strain rate doubled and strain remained unchanged at DSE peak stress. CONCLUSION: Non-invasive evaluation of regional deformation, using strain rate imaging during DSE, predicted the relevance of intermediate coronary stenosis. In this context, strain rate is superior to strain measurements for the quantification of the contractile reserve.
Abstract: BACKGROUND: In patients with systolic heart failure, high levels of circulating aldosterone are associated with an adverse prognosis, and mineralocorticoid receptor blockade improves survival. The prognostic significance of cortisol that may also bind and activate the mineralocorticoid receptor in chronic heart failure is unknown. METHODS AND RESULTS: Serum levels of cortisol and aldosterone were quantified in a prospective cohort study of 294 consecutive patients with chronic heart failure [48% were in New York Heart Association functional class III or IV; 58% had systolic heart failure]. During a median follow-up of 803 days (interquartile range, 314 to 1098), 79 patients died (27.3% mortality rate). Cortisol and aldosterone were independent predictors of increased mortality risk in Cox regression analyses adjusted for age, sex, New York Heart Association functional class, C-reactive protein, N-terminal pro-brain natriuretic peptide, sodium, and hypercholesterolemia. The hazard ratio for highest versus lowest tertile of cortisol was 2.72 [95% confidence interval [CI], 1.38 to 5.36; P=0.004], and the hazard ratio for aldosterone was 2.19 (95% CI, 1.23 to 3.93; P=0.008). Patients with both cortisol and aldosterone levels above the respective medians had a 3.4-fold higher mortality risk compared with subjects with both corticosteroids below the median (95% CI, 1.54 to 7.46; P=0.0001). Addition of cortisol and aldosterone levels to the fully adjusted model significantly improved the discriminatory power [increase in Harrell's C-statistic from 0.80 (95% CI, 0.70 to 0.90) to 0.86 (95% CI, 0.79 to 0.94; P<0.001 for change]. CONCLUSIONS: In patients with chronic heart failure, higher serum levels of both cortisol and aldosterone were independent predictors of increased mortality risk that conferred complementary and incremental prognostic value.
Abstract: Adipocytokines are under investigation as mediators of cardiovascular risk. In 142 non-diabetic postmenopausal women, we investigated whether plasma levels of adiponectin and leptin are associated with changes in carotid intima-media thickness (IMT) and distensibility as assessed by high-resolution ultrasound. Adiponectin but not leptin correlated weakly with baseline measures of IMT and distensibility. After 12 months, carotid IMT showed a significant progression [0.023 mm (95% CI, 0.014-0.031 mm)] whereas stiffness was unaltered. A threshold was identified for the relation of adiponectin with both progression of IMT and stiffness. Age-adjusted adiponectin levels in the lowest quartile versus second to fourth quartile were related to progression of IMT (odds ratio, 2.99; 95% CI, 1.81-5.09) and stiffness (odds ratio, 1.71; 95% CI, 1.19-4.07). Adjustment for possible confounding factors and intermediates weakened this association only to a minor degree. No such associations were observed for leptin. We conclude that low levels of adiponectin are associated with adverse changes in morphology and function of central arteries over time independently of other cardiovascular risk factors in postmenopausal non-diabetic women.
Abstract: PURPOSE: Ways to predict the risk of cardiovascular (CV) events or all-cause mortality have largely been derived from populations in which old and very old subjects were underrepresented. We set out to estimate the incremental prognostic utility of inflammation and atherosclerosis markers in the prediction of all-cause and CV mortality in elderly men. METHODS: In a prospective population-based cohort study, conventional CV risk factors were documented in 403 independently living elderly men. C-reactive protein (CRP) and interleukin (IL)-6 levels were measured. Carotid plaques were assessed by ultrasound. Analyses were performed with proportional hazards analyses, and bootstrapping was used for internal validation. Main outcome was CV and all-cause mortality occurring during 4 years of follow-up. RESULTS: Increasing tertiles of CRP, IL-6, and number of plaques were independently associated with all-cause and CV mortality. With information on age, carotid plaques, IL-6, and CRP yielded good discriminatory power for all-cause and CV mortality: area under the receiver operating characteristic curve (95% confidence interval), 0.76 (0.70-0.82) and 0.74 (0.68-0.80), respectively. Combined use of only IL-6 and plaque burden allowed identification of subjects with low and high mortality risk. The Framingham PROCAM and a Dutch Risk Function poorly predicted mortality risk, similar or worse than a model using age alone. CONCLUSION: In the old and very old, IL-6 and number of carotid plaques are powerful predictors of mortality risk in the years to come. Conventional risk scores seem to perform unsatisfactorily.
Abstract: BACKGROUND: Cardiac allograft vasculopathy (CAV) represents a major prognostic factor in long-term survivors of heart transplantation (HTx). Reliable diagnosis of CAV late after HTx is important but remains the domain of invasive techniques such as coronary angiography. METHODS: To test alternative approaches, 54 consecutive HTx recipients (mean time since HTx: 52 months) were studied with intravascular ultrasound (IVUS), angiography, dobutamine stress echocardiography and immunofluorescence staining against anti-thrombin III (AT-III) in endomyocardial biopsies. Univariate and multivariate predictors as well as receiver-operating-characteristic (ROC) curves of different sets of predictors were calculated. RESULTS: Using IVUS as reference standard, CAV was present in 80% of subjects. Coronary angiography identified CAV correctly in only 44% of cases. If AT-III staining alone was used as a diagnostic criterion, CAV was correctly identified in 77% of subjects. In a multivariate analysis, only AT-III, donor age and echocardiography at rest emerged as independent predictors of CAV (p < 0.05 for all), yielding an excellent discriminative power. CONCLUSIONS: With almost equal reliability when compared with IVUS, CAV can be identified using information on donor age, wall motion score at rest and AT-III staining late after HTx. Coronary angiography may be limited to patients with a high probability score and should not be used routinely for surveillance of CAV.
Abstract: BACKGROUND: The aim of this study was to estimate the independent and incremental prognostic value of the presence of stimulating autoantibodies directed against the human beta1-adrenergic receptor (anti-beta1-AR) in patients with chronic heart failure. METHODS: One hundred five antibody-typed chronic heart failure patients with dilated cardiomyopathy (DCM, n = 65) or ischemic cardiomyopathy (ICM, n = 40) were prospectively followed for 10.7 +/- 2.5 years. Information on all-cause and cardiovascular mortality was collected throughout the observation period. RESULTS: Stimulating anti-beta1-AR were prevalent in 26% (17/65) of patients with DCM and 13% (5/40) with ICM. All-cause mortality in antibody-positive patients was 65% in those with DCM and 80% in those with ICM, and in antibody-negative patients 44% and 49%, respectively. In univariate and multivariable Cox regression analysis (P < .05), presence of stimulating anti-beta1-AR was associated with increased all-cause and cardiovascular mortality risk in DCM but not in ICM. Information on antibody status improved the prognostic capacity in models containing already extensive information on clinical profile, Holter electrocardiography, and invasive hemodynamic measurements (area under the receiver operating characteristic curve, 0.91; 95% confidence interval, 0.85-0.97; P < .05 for increase in receiver operating characteristic area). CONCLUSION: The presence of stimulating anti-beta1-AR autoantibodies independently predicts increased all-cause and cardiovascular mortality risk in DCM conferring incremental prognostic value in addition to established risk predictors. Our data indicate a clinical relevance of stimulating anti-beta1-AR in DCM and encourage further research into antibody-directed strategies as a therapeutic principle.
Abstract: INTRODUCTION: Left (LVEF) and right ventricular ejection fraction (RVEF) as well as LV regional wall motion at rest are valuable tools to monitor and tailor treatment of congestive heart failure (CHF) patients. Gated blood pool SPECT (GBPS) is under evaluation as an "all-in-one" technique, providing information on LVEF, RVEF, and wall motion derived from a single examination. Aim of the study was to evaluate a commercially available automated GBPS processing software for EF measurements and wall motion analysis in heart failure patients. METHODS: Thirty-two patients (12 female; mean age+/-SD: 53+/-13 years), suffering from dilated (63%), ischemic (25%) or hypertrophic (13%) cardiomyopathy, were studied. First-pass radionuclide ventriculography (FP-RNV), planar multigated radionuclide angiography (MUGA), and GBPS were performed at rest after in vivo labeling of red blood cells, and LVEF and RVEF was calculated with each method. Later on the same day LVEF was calculated by echocardiography. LV wall motion (summed motion score and wall motion index) was derived from GBPS and echocardiography using the standard 16-segment model. RESULTS: Mean LVEF measured by GBPS, echocardiography, MUGA and FP-RNV was 33+/-13%, 37+/-15%, 41+/-14% and 45+/-13%, respectively. LVEF values calculated from GBPS showed moderate to good correlation with FP-RNV (r=0.61), MUGA (r=0.65) and ECHO (r=0.74; all p<0.01). Mean RVEF calculated by GBPS, FP-RNV and MUGA was 45+/-14%, 46+/-9% and 38+/-9%, respectively. RVEF values calculated from GBPS showed weak correlation with FP-RNV (r=0.33) and MUGA (r=0.26; all p=n.s.). Assessment of GBPS wall motion was qualitatively possible in all patients. The agreement between GBPS and ECHO was 82% (kappa=0.73). The wall motion index showed good correlation between both methods (r=0.88; p<0.001). CONCLUSION: An automated algorithm for LVEF calculation and wall motion analysis using GBPS is feasible for clinical routine diagnostic in CHF patients. The RVEF calculation method needs to be improved before routine clinical application can be recommended.
Abstract: Patients' health-related quality of life is increasingly being included as an additional endpoint when evaluating the treatment of chronic heart failure. Although generic self-report instruments measuring health-related quality of life are available, there is a lack of disease-specific instruments covering various dimensions of quality of life with high reliability, validity and sensitivity to chance. Thus, the aim of the present study was to evaluate the German version of a new heart failure-specific quality of life measure, the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample consisted of 233 consecutively recruited outpatients of a university department in Germany. Test-retest-reliability was high (intraclass correlation coefficient 0.93 for both the Functional State and the Clinical Summary total scores). Construct validity was demonstrated with strong correlations to respective subscales of the SF-36. Known groups validity was shown by both statistically and clinically significant differences between NYHA classes. The examination of sensitivity to change yielded promising results. The questionnaire was well accepted by the participating patients. The KCCQ proved to be a reliable and valid self-report instrument for measuring disease-specific quality of life in chronic heart failure.
Abstract: AIMS: The aim of this clinical cross-sectional study was to investigate the cardiac interrelation of morphological and functional abnormalities in patients with Fabry disease. METHODS AND RESULTS: Fifty-one patients (5-78 years) were compared with 25 controls (8-77 years). In all subjects, end-diastolic thickness of the left ventricle was measured by echocardiography and ultrasonic peak systolic strain rate (SR) was extracted to assess regional myocardial function. Magnetic resonance imaging was performed to assess late-enhancement for the detection of myocardial fibrosis in Fabry patients (n=39). In patients, women <20 years of age had no hypertrophy, no late-enhancement, and normal radial and longitudinal function (SR longitudinal=-1.7+/-0.5 s(-1); P=n.s. compared with controls). Ten women, >20 years of age, had no hypertrophy, no late-enhancement, normal radial and longitudinal function in the septal wall, but reduced longitudinal function in the lateral wall (SR=-1.4+/-0.5 s(-1)). All male patients without hypertrophy and no late-enhancement had normal radial function but reduced longitudinal function in both the septal and lateral walls (SR=-1.3+/-0.3 s(-1)). Patients with hypertrophy but without late-enhancement (n=13) had reduced radial and longitudinal function. Twelve patients displaying hypertrophy and late-enhancement had severely reduced radial and longitudinal function (SR=-1.1+/-0.5 s(-1)). Two of them with the worst impairment of regional function (SR=-0.8+/-0.6 s(-1)) died in the follow-up period. CONCLUSION: These results illustrate the variation of morphological changes and its functional consequences in Fabry cardiomyopathy.
Abstract: The importance of sex- and gender-related features of various diseases regarding the impact of different risk factors on the natural course of disease, the response to therapy and outcome have only more recently been appreciated. Studies investigating sex- and gender-related aspects in rheumatoid arthritis (RA) are scarce. Unambiguous classification of factors of potential pathogenetic relevance or with the capacity to influence clinical course and disease management into sex- or gender- related aspects is difficult (Figure 1). The majority of RA patients is female. As illustrated by Figure 2, available evidence indicates a progressive decline in the incidence of this disease over the past 40 years in both men and women. There appears to be a cyclical pattern in the annual incidence rates with peaks and troughs occurring for both sexes, but at different times, which suggests the changing exposure to environmental factors which may promote or decrease RA. Current knowledge suggests that RA is characterized by chronic local and systemic inflammation which may trigger accelerated atherogenesis. Sex hormones may also play a pathogenetic role. Androgens and estrogens may stimulate the production of inflammatory cytokines in the synovial fluid. These cytokines then may influence sex hormone metabolism thus modifying sex hormone levels (Figure 3). Compared to the general population (Figures 4 and 5), the risk of cardiovascular morbidity and mortality is significantly increased in patients with rheumatic diseases and in particular in RA. This is evidenced by a higher incidence of congestive heart failure (Figure 6), coronary artery disease and (frequently silent) myocardial infarction, as well as sudden cardiac death. Several studies have demonstrated a significantly increased standardized mortality ratio in RA and identified cardiovascular events as the most frequent cause. Compared with expected mortality rates in the normal population, women with RA have a significantly more compromised life expectancy than men (Table 1). Amongst factors with uneven distribution between sexes are traditional cardiovascular risk factors (Table 2), but also more recently recognized potential risk indicators or risk modifiers such as inflammatory markers and sex hormones. Drugs directed against RA may influence the natural course of cardiovascular disease, as, e. g., indicated by the increased rates of cardiac events and stroke associated with cyclooxygenase-(COX-)2 inhibitor treatment. In contrast, the effect of pharmacotherapy for cardiovascular diseases on the course of RA is unexplored. Prospective cohort studies aiming at early detection of cardiovascular morbidity and precise and detailed characterization of disease manifestations will be required in order to more thoroughly understand the interplay of factors and conditions determining an individuals' risk for developing cardiovascular comorbidity in autoimmune diseases. This article summarizes the available evidence for sex- and gender-related differences in the disease manifestation of rheumatic disorders as well as in cardiovascular risk factors with an emphasis on the cardiovascular comorbidity observed in RA.
Abstract: Irrespective of improved medical and interventional therapeutic options, mortality among patients with acute heart failure and cardiogenic shock has remained disappointingly high. Early diagnosis and rapid initiation of basic treatment measures to improve hemodynamics and metabolism are of vital importance until causal therapy, e. g. revascularization, is initiated. Due to the principal difficulty to set up larger clinical trials, in patients with cardiogenic shock empirical rather than firm evidence supports the various treatment and management strategies currently in use. Continuous hemodynamic monitoring to tailor fluid therapy, new drugs, and prognostic markers have been developed for the treatment and monitoring of cardiogenic shock, all of which await testing in larger-scale studies. Ongoing challenges remain the right ventricular pump failure or hemodynamically compromising arrhythmia which may be either cause or consequence of cardiogenic shock.
Abstract: The widely shared enthusiasm about the cardioprotective potential of estrogenic compounds has come to an abrupt halt since randomized trials failed to show a cardiovascular risk reduction in postmenopausal women. This was unexpected because observational studies had strongly suggested that hormone replacement therapy would reduce the incidence of cardiovascular disease. Inflammatory activity is considered central in atherogenesis and atherosclerosis progression. Thus, parts of the striking discrepancy between observational and randomized data have been attributed to an estrogen-mediated adverse effect on inflammation. Here, we review the current clinical evidence with respect to the inflammation-modulating effects of different estrogenic compounds as one potential explanatory factor for these divergent findings. We conclude that it is still unclear whether estrogen-modulated inflammation is an important biological factor determining clinical outcome or a mere epiphenomenon.
Abstract: Nuclear factor kappa B (NF-kappaB) is a ubiquitous transcription factor activated by various stimuli that are implicated in the progression of chronic heart failure. Therefore, we examined the activation of NF-kappaB in peripheral leukocytes, the only nucleated cell population noninvasively accessible in patients with heart failure. In patients with stable heart failure with no obvious other reason for NF-kappaB activation, NF-kappaB was significantly activated.
Abstract: BACKGROUND: Indicators of carotid atherosclerosis may confer additional prognostic value and guide clinicians in cardiovascular risk assessment. Carotid artery morphology (plaque burden) and function (stiffness indexes) as predictors of all-cause and cardiovascular mortality were prospectively evaluated in elderly men. METHODS AND RESULTS: Cardiovascular risk profile was measured in 367 independently living men (mean+/- SD age, 78+/-4 years). The number of carotid plaques was assessed by B-mode ultrasound, and arterial stiffness was quantified with a wall tracker system. During 48 months of follow-up, 70 deaths (28 cardiovascular) occurred. The total number of carotid plaques was the parameter most closely related to prognosis. In the age-adjusted multivariate Cox model, all-cause mortality was predicted by number of plaques (hazard ratio [HR] per 1-unit increase, 1.35; 95% confidence interval [CI], 1.12 to 1.64). Predictors of cardiovascular mortality in the respective model were number of plaques (HR, 1.18; 95% CI, 1.04 to 1.33) and Young's elastic modulus (HR, 1.68; 95% CI, 1.26 to 2.26). Number of plaques improved the prognostic utility in any prognosis model when added to commonly available cardiovascular risk information. In contrast, stiffness indexes offered no consistent additive value. CONCLUSIONS: In elderly men, carotid artery plaque burden is a strong independent predictor of all-cause and cardiovascular mortality in the years to come. The additional value of carotid artery stiffness measurements as a pathophysiologically related entity appears to be limited in this age group and, if anything, confined to cardiovascular mortality risk.
Abstract: AIMS: This comparative prospective multi-centre study evaluated efficacy and safety of cyclosporine A downtitration in heart transplant recipients with chronic renal dysfunction potentially attributable to cyclosporine (n=161). METHODS: In the intervention arm (n=109, recruited from 9 centres), mycophenolate mofetil was introduced de novo or substituting azathioprine, followed by cyclosporine reduction (target trough levels 2-4 microg/ml and 50 ng/ml, respectively). In controls (n=52, recruited from 1 centre), immunosuppression remained unchanged. Renal function was recorded twelve, six, and three months before, and throughout the eight-month study period. RESULTS: At study entry, cyclosporine trough levels and renal function parameters were comparable. At study end, mean+/-SD cyclosporine in the intervention arm was 57+/-24 vs. 116+/-36 ng/ml in controls. During the study, creatinine decreased by 23.3+/-50.7 micromol/l (P<0.0001) in the intervention arm but increased by 7.3+/-46.9 micromol/l (P=0.992) in controls (P=0.0001 for comparison between groups). A creatinine reduction of at least 20% was found in 35% of subjects of the intervention arm but only in 4% in the control arm (P<0.0001 for comparison between groups). Improvement in renal function was not weakened after adjustment for baseline characteristics in multiple regression analysis. Renal function improved in strata of creatinine entry values from 150 to 310 micromol/l, regardless of the presence of diabetes. Myocardial biopsies at target levels for cyclosporine and mycophenolate mofetil showed three reversible subclinical rejection episodes. CONCLUSIONS: Cyclosporine downtitration improved renal dysfunction in diabetic and non-diabetic heart transplant recipients across a wide range of creatinine levels. The long-term benefit of this strategy deserves further study.
Abstract: Incidence and prevalence of chronic heart failure are continuously increasing. Today, heart failure of different etiologies represents the most frequent cause of death in industrialized countries. Improvements in heart failure diagnosis and treatment have decreased lethality. In this context, a valid diagnosis, causative therapy of treatable heart failure etiologies, and efficient pharmacological as well as non-pharmacological management strategies are of equal importance. The principal goals of therapy are prevention, maintenance or even improvement of quality of life and the decrease of heart-failure-related morbidity and mortality.
Abstract: BACKGROUND: Peak oxygen consumption at maximum exercise (peak VO(2)) predicts survival in chronic heart failure (CHF) patients. Right ventricular ejection fraction (RVEF) at rest has been reported to correlate with peak VO(2). We evaluated the strength and consistency of the association between peak VO(2) and RVEF measured by different radionuclide ventriculography (RNV) techniques in a prospective cohort study. METHODS AND RESULTS: In 58 consecutive CHF patients (mean age, 53 years; 39 patients with dilated cardiomyopathy; 48 men), upright symptom-limited bicycle ergometry was performed. During exercise, ventilatory and gas exchange data were recorded and peak VO(2) was calculated. RVEF was calculated by use of first-pass (FP) RNV with single and dual region of interest (ROI) acquisition and planar multigated acquisition (MUGA). Irrespective of the method used, RVEF showed no relevant correlation with the corresponding peak VO(2) value (r = 0.11 for FP single ROI, r = 0.06 for FP dual ROI, r = 0.16 for MUGA). Peak VO(2) or changes in peak VO(2) after 6 and 12 months of follow-up were not determined by RVEF measurements. CONCLUSION: In CHF patients no association was found between peak VO(2) at maximum exercise and RVEF at rest with different RNV techniques. Changes in exercise capacity are not reliably reflected by changes in RVEF measurements at rest.
Abstract: OBJECTIVE: Omega-3 polyunsaturated fatty acids (omega-3 PUFA) from fish oil slow atherosclerosis progression in coronary arteries, as we showed in a randomized double-blind placebo-controlled clinical trial. Embedded in this trial, the present study examined the influence of 2 years of dietary supplementation with 1.65 g omega-3 PUFA per day on progression of carotid atherosclerosis in 223 patients with coronary artery disease. METHODS: Coronary angiography, a comprehensive clinical examination, and intima-media thickness measurement by B-mode ultrasound of the carotid arteries (common, internal and bifurcation), were performed at the study start and study end. An expert panel visually evaluated the global change of carotid atherosclerosis on a semiquantitative scale. A second outcome measure was the change of overall mean maximum intima-media thickness. RESULTS: One hundred and seventy-one patients completed the study. In the global change score, 38% of the patients in the fish oil group and 35% in the placebo group showed progression. Global change was not different between intervention groups. Mean maximum intima-media thickness increased by 0.07+/-0.13 mm and 0.05+/-0.11 mm in the fish oil and placebo group, respectively (mean+/-S.D., P=0.24). No correlation was found between the change in carotid and coronary arteries. CONCLUSIONS: In this group of selected patients with documented coronary artery disease omega-3 PUFA given for 2 years did not demonstrate an effect on slowing progression of atherosclerosis in carotid arteries as measured by ultrasound.
Abstract: BACKGROUND: Intervention trials in postmenopausal women with coronary artery disease have failed to demonstrate beneficial effects of hormone replacement therapy (HRT) on the course of disease, potentially due to pro-inflammatory effects of conjugated equine estrogens. We characterized the effects of 48 weeks treatment with two estradiol-based HRT regimens on nonspecific (high sensitivity C-reactive protein [hs-CRP], blood sedimentation rate [BSR], fibrinogen) and specific endothelial markers (cell adhesion molecules: ICAM-1, VCAM-1, E-selectin). METHOD AND RESULTS: Postmenopausal women randomly received either 1 mg 17beta-estradiol daily plus 25 microg gestodene for the last 12 days of each 28 day cycle (=standard dose progestin; n=65), or gestodene added each third cycle only (=low dose progestin; n=65), or no HRT (n=73). Both HRT regimens reduced levels of ICAM-1 (-9%), VCAM-1 (-9%), E-selectin (-11%), fibrinogen (-12%), BSR (-5%). No effect was observed on hs-CRP levels in any group. In smokers, E-selectin remained unchanged whereas ICAM-1 and VCAM-1 were lowered. Subjects on antihypertensive or lipid lowering medication showed effects comparable to the whole cohort. Effects of low and standard dose progestin were not different. CONCLUSION: We conclude that a combination therapy with 1 mg 17beta-estradiol favourably affects the vascular inflammation processes as indicated by a neutral effect on hs-CRP and reduction of cell adhesion molecules.
Abstract: OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is considered a propagator of atherosclerosis and a key modulator of monocyte activity. Hormone replacement therapy (HRT) is currently being investigated as a means towards prevention of atherosclerosis. We aimed to assess (1) the range of circulating MCP-1 levels in postmenopausal women, (2) the correlation between MCP-1 and atherosclerotic burden, and (3) the effects of commencement and discontinuation of HRT on MCP-1 serum levels. METHODS: This clinical prospective trial investigated 51 postmenopausal women at increased risk for cardiovascular events who were randomized to receive either no HRT or 1 mg 17 beta-estradiol continuously plus sequential progestagen over 1 year. Intima-media thickness (IMT) of carotid and femoral arteries was measured by ultrasound. Serum levels of MCP-1 and cellular adhesion molecules were measured by ELISA. RESULTS: At baseline, MCP-1 levels and overall mean maximum IMT correlated (r=0.589; P<0.0001, Pearson's coefficient). MCP-1 levels in serum gradually decreased after 3, 6, and 12 months of HRT by 16.8 +/- 15.7% at 12 months (P<0.0001, MANOVA). Similarly, all cellular adhesion molecules decreased significantly by 6-12%. After 12 months, women decided whether to continue or discontinue treatment. At 18 months, in women discontinuing HRT (n=17), MCP-1 levels rose by 21 +/- 20% (P=0.003), but remained lowered in women continuing HRT. CONCLUSION: Our observations indicate that 17 beta-estradiol may have an antiatherosclerotic effect by reducing MCP-1 serum levels and cell adhesion molecules.
Abstract: OBJECTIVES: On the basis of epidemiological and experimental data, it has been supposed that hormone replacement therapy (HRT) inhibits atherosclerosis in postmenopausal women. This randomized controlled trial examined whether 1 mg 17beta-estradiol daily, combined cyclically with 0.025 mg gestodene in every month (HRT 1), or in every third month (HRT 2) slows the increase of intima-media thickness in femoral arteries compared with no HRT. METHODS: Healthy postmenopausal women (n=321) with an increased risk for future vascular disease as indicated by >1 mm of intima-media thickness in the carotid arteries were equally randomized to one of the three groups for 48 weeks. Ultrasound scans of femoral arteries were recorded at study start and study end, together with a thorough clinical examination and laboratory work-up. RESULTS: Complete scans were obtained in 260 of the 264 subjects who participated until study end. Mean maximum intima-media thickness of four femoral artery segments (common and superficial, both sides) was 0.93+/-0.37 mm (mean+/-S.D.) at study start. It increased by 0.02+/-0.05, 0.02+/-0.05, and 0.03+/-0.05 mm in the HRT 1, HRT 2 and no HRT groups, respectively (HRT 1 versus no HRT, HRT 2 versus no HRT; both P>0.2). Compared with no HRT, HRT significantly lowered follicle stimulating hormone, low-density lipoprotein cholesterol, and fibrinogen. CONCLUSIONS: In this 1-year trial, irrespective of the progestogen dose used, HRT with 1 mg 17 beta-estradiol did not inhibit progression of femoral artery atheroslerosis in postmenopausal women with subclinical vascular disease.
Abstract: -Postmenopausal hormone replacement therapy (HRT) is associated with low cardiovascular morbidity and mortality in epidemiological studies. Yet, no randomized trial has examined whether HRT is effective for prevention of coronary heart disease (CHD) in women with increased risk. The objective of this study was to determine whether HRT can slow progression of atherosclerosis, measured as intima-media thickness (IMT) in carotid arteries. Carotid IMT is an appropriate intermediate end point to investigate clinically relevant effects on atherogenesis. This randomized, controlled, observer-blind, clinical, single-center trial enrolled 321 healthy postmenopausal women with increased IMT in >/=1 segment of the carotid arteries. For a period of 48 weeks, subjects received either 1 mg/d 17ss-estradiol continuously plus 0.025 mg gestodene for 12 days every month (standard-progestin group), or 1 mg 17ss-estradiol plus 0.025 mg gestodene for 12 days every third month (low-progestin group), or no HRT. Maximum IMT in 6 carotid artery segments (common, bifurcation, and internal, both sides) was measured by B-mode ultrasound before and after intervention. HRT did not slow IMT progression in carotid arteries. Mean maximum IMT in the carotid arteries increased by 0.02+/-0.05 mm in the no HRT group and by 0.03+/-0.05 and 0.03+/-0.05 mm, respectively, in the HRT groups (P:>0.2). HRT significantly decreased LDL cholesterol, fibrinogen, and follicle-stimulating hormone. In conclusion, 1 year of HRT was not effective in slowing progression of subclinical atherosclerosis in postmenopausal women at increased risk.
Abstract: Coronary artery disease (CAD) is associated more closely with atherosclerosis in the popliteal than in the brachial artery. This case-control study aimed at clarifying whether endothelial dysfunction of patients with CAD can be detected non-invasively in the popliteal artery by means of ischemia-induced flow-mediated dilation (FMD) and cold pressor reaction (CPR), and how it compares with the brachial artery. We further investigated a new mode of evaluation of the CPR. Eleven cases with CAD were compared with 16 matched healthy controls. Popliteal and brachial arterial diameter was monitored by ultrasound for 20 min following ischemia and cold pressor. For CPR, the difference between maximum and minimum diameter was defined as maximum vasomotion. In the popliteal artery, maximum vasomotion and FMD were significantly smaller in cases than in controls, the difference being more pronounced than in the brachial artery, where only maximum vasomotion was significantly smaller. After exclusion of current smokers, only the difference in maximum vasomotion of both arteries remained significant. We conclude that maximum vasomotion may be more sensitive for detection of endothelial dysfunction than FMD. Endothelial dysfunction in patients with CAD is more pronounced in the popliteal artery than in the brachial artery.
Abstract: OBJECTIVES: It remains an unsolved issue whether hormone replacement therapy (HRT) lowers blood pressure. This randomized trial examined the effect of 17beta-oestradiol combined cyclically with gestodene on blood pressure of postmenopausal women who were not on antihypertensive medication. All subjects had an increased risk for adverse vascular events as indicated by intima-media thickness of carotid arteries and standard risk factors. DESIGN AND SETTING: Two hundred and twenty-six postmenopausal women were randomized to oral treatment for 48 weeks with 1 mg of 17beta-oestradiol per day continuously, plus 0.025 mg gestodene on days 17-28 of each 4-week cycle (HRT 1), or plus gestodene in each third cycle only (HRT 2), or no HRT. According to predefined criteria, four subjects in HRT 1, 12 in HRT 2 and 13 in no HRT who were started on antihypertensive medication were excluded from the analysis. Thirty subjects ended participation prematurely for other reasons. Resting blood pressure was measured at baseline and after 12, 22 and 48 weeks. RESULTS: During treatment diastolic blood pressure changed significantly in both HRT groups compared to no HRT, by -3.7 +/- 9.8 mmHg, -3.0 +/- 8.8 mmHg and 1.0 +/- 9.9 mmHg at week 48 in groups HRT 2, HRT 1 and no HRT, respectively (P = 0.008 for HRT 2 versus no HRT, P = 0.027 for HRT 1 versus no HRT). The higher the diastolic blood pressure was at beginning the greater was the decrease. The decrease of systolic blood pressure was not significantly different between groups. CONCLUSIONS: For postmenopausal women with high cardiovascular risk but without antihypertensive medication, long-term treatment with 17beta-oestradiol combined with gestodene lowers diastolic blood pressure.
Abstract: OBJECTIVES: The study objective was to clarify in a randomized, controlled, observer-blind trial whether hormone replacement therapy (HRT) improves elastic properties of the common carotid artery in women with signs of subclinical atherosclerosis, especially in subgroups with increased risk, and whether less progestin enhances the effect. BACKGROUND: Previous observational studies have yielded conflicting results on the influence of HRT on central arteries. Some studies reported improvement of distensibility by estrogen alone or in the subgroup of smokers. METHODS: A total of 321 postmenopausal women were randomized to 1 mg 17beta-estradiol plus 0.025 mg gestodene for 12 days every month (HRT 1), or 1 mg 17beta-estradiol plus 0.025 mg gestodene for 12 days every third month (HRT 2), or no-HRT, during 48 weeks. In 173 women, distensibility of the common carotid artery was determined before and after therapy by M-mode ultrasound and brachial blood pressure measurement. RESULTS: Change of distensibility was small and similar in the three treatment groups. In the subgroup of current smokers, HRT 2 (low progestin) increased distensibility by 32% (HRT 2: 8.2+/-11.7; HRT 1:0.6+/-6.0; no HRT: -1.8+/-6.8 x 10(-3)/kPa, p = 0.025 for no-HRT vs. HRT 2). In the subgroups with elevated blood pressure, high low density lipoprotein (LDL) cholesterol, or high age, no effect of HRT was detected. CONCLUSIONS: This randomized intervention study demonstrates that long-term HRT with estrogen and progestin does not substantially influence distensibility of central arteries. Yet, in currently smoking postmenopausal women, HRT with low progestin seems to improve distensibility; this merits further study in a specifically designed trial.
Abstract: Accelerated bone remodeling after the menopause is associated with increased bone loss that can be abolished using hormone replacement therapy (HRT). Biochemical markers of bone metabolism are known to correlate closely with changes in bone histomorphometry and osteodensitometry. Bone sialoprotein (BSP), a major constituent of bone matrix, is almost exclusively found in mineralized tissues and therefore considered a potential marker of bone metabolism. In 82 postmenopausal women, randomly allocated to either low-dose sequential HRT or no HRT, serum BSP was measured and compared with established specific biochemical markers of bone resorption [urinary deoxypyridinoline (DPD), pyridinoline (PYD) and amino-terminal telopeptide (NTx)] and markers of bone formation [serum osteocalcin (Oc) and bone-specific alkaline phosphatase (bALP)]. Longitudinal analysis showed a marked response of BSP levels following commencement of HRT, resulting in a 52% reduction after 12 months compared with initial values. The changes of BSP levels over time were at least as strong as in conventional markers of bone formation and resorption and paralleled their changes. A moderate to close correlation was found between BSP and both markers of bone resorption (r = 0.57 for NTx; r = 0.38 for DPD) and formation (r = 0.55 for Oc; r = 0.39 for bALP; p < 0.0001, respectively). Our data demonstrate a cause and effect relationship between commencement of HRT and a change in serum BSP. In conclusion, serum BSP circumvents some of the limitations of urinary measurements and appears valuable for the quantitative monitoring of the skeletal response to HRT in healthy postmenopausal women.
Abstract: Long-term dietary omega-3 fatty acids improve coronary endothelial function in CAD patients, heart transplant recipients and diabetics. This study assessed whether short term omega-3 fatty acids affect radial artery function in CAD patients. A high resolution A-mode echotracking device (NIUS 02) was used to measure continuously, radial artery internal diameter at rest, during flow mediated vasodilation (FMD), during cold pressure test (CPT), and after sublingual glyceryl trinitrate (GTN). We studied 18 male CAD patients in a randomized, double blind, placebo controlled design. Between pre- and post-intervention measurements 24 h apart, nine subjects received 18 g fish oil concentrate (6.4 g eicosapentaenoic acid and 3.9 g docosahexaenoic acid) and nine subjects 18 g placebo. In the placebo group correlation between both baseline diameters was 0.98; P < 0.001. Pre-intervention FMD was 7.5+/-5.6%, CPT mediated vasoconstriction was 3.8+/-2.5%, and GTN induced vasodilation was 15.7+/-9.8%. Vascular responses post-intervention showed no significant difference to pre intervention, there was no significant difference between both treatment groups. The radial artery does not seem to be an immediate target for vasodilatory actions of omega-3 fatty acids.
Abstract: Objective of the present study was to investigate the hemodynamic response to molsidomine in nitrate tolerance state. In 13 out of 16 patients (5 women, 11 men, 62 [53/71] years [median, 25%/75%-percentiles]) with chronic heart failure (NYHA stage II-III; median angiographic ejection fraction (EF) 55%) and coronary artery disease (stenosis of at least 75%) the development of tolerance under the continuous infusion of high doses of nitroglycerin (10 mg/h) was observed. Tolerance was defined as a benefit loss of at least 50% of the initial nitroglycerin effect with respect to the pulmonary capillary wedge pressure. Compared to the state of tolerance to nitroglycerin the infusion of 10 mg molsidomine over 15 minutes resulted in significant changes of the median values (25%/75%-percentiles) of mean right atrial pressure from 16 (12/21) to 9 (5/12) mmHg (p < 0.01), mean pulmonary artery pressure from 37 (30/40) to 24 (20/30) mmHg (p < 0.001), mean pulmonary capillary wedge pressure from 22 (18/25) to 15 (10/22) mmHg (p < 0.01) and cardiac output from 4.1 (3.5/4.7) to 5.2 (4.2/5.6) l/min (p < 0.01). This action of molsidomine corresponded to a complete overcoming (> 100%) of the benefit loss observed during the development of nitrate tolerance with respect to all above-mentioned hemodynamic parameters. Under parallel maintainance of nitroglycerin infusion (10 mg/h) these hemodynamic effects of molsidomine, i.e. at least 90% of the peak effect, lasted for 147 (130/182) minutes (median, 25%/75%-percentiles). Baseline values, i.e. a loss of at least 75% of the molsidomine effect, were only reached after 363 (319/412) minutes (median, 25%/75%-percentiles).(ABSTRACT TRUNCATED AT 250 WORDS)
