The impact of patient sex on the response to intramyocardial mesenchymal stem cell administration in patients with non-ischaemic dilated cardiomyopathy.

AIMS: Sex differences impact the occurrence, presentation, prognosis, and response to therapy in heart disease. Particularly, the phenotypic presentation of patients with non-ischaemic dilated cardiomyopathy (NIDCM) differs between men and women. However, whether the response to mesenchymal stem cell (MSC) therapy is influenced by sex remains unknown. We hypothesize that males and females with NIDCM respond similarly to MSC therapy. METHODS AND RESULTS: Male (n = 24) and female (n = 10) patients from the POSEIDON-DCM trial who received MSCs via transendocardial injections were evaluated over 12 months. Endothelial function was measured at baseline and 3 months post-transendocardial stem cell injection (TESI). At baseline, ejection fraction (EF) was lower (P = 0.004) and end-diastolic volume (EDV; P = 0.0002) and end-systolic volume (ESV; P = 0.0002) were higher in males vs. females. In contrast, baseline demographic characteristics, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-min walk test (6MWT) were similar between groups. EF improved in males by 6.2 units (P = 0.04) and in females by 8.6 units (P = 0.04; males vs. females, P = 0.57). EDV and ESV were unchanged over time. The MLHFQ score, New York Heart Association (NYHA) class, endothelial progenitor cell-colony forming units, and serum tumour necrosis factor alpha improved similarly in both groups. CONCLUSION: Despite major differences in phenotypic presentation of NIDCM in males and females, this study is the first of its kind to demonstrate that MSC therapy improves a variety of parameters in NIDCM irrespective of patient sex. These findings have important clinical and pathophysiologic implications regarding the impact of sex on responses to cell-based therapy for NIDCM.

The role of biomarkers in dilated cardiomyopathy: Assessment of clinical severity and reverse remodeling.

INTRODUCTION: Biomarkers in dilated cardiomyopathy (DCM) reflect various pathobiological processes, including neurohormonal activation, oxidative stress, matrix remodeling, myocyte injury and myocyte stretch. We assessed the role of biomarkers in clinical and echocardiographic parameters and in left ventricular (LV) reverse remodeling (LVRR). METHODS: In this prospective study of 50 DCM patients (28 men, aged 59±10 years) with LV ejection fraction (LVEF) <40%, LVRR was defined as an increase of >10 U in LVEF after optimal medical therapy. RESULTS: Baseline LVEF was 25.4±9.8% and LV end-diastolic diameter (LVEDD)/body surface area (BSA) was 34.2±4.5 mm/m2. LVRR occurred in 34% of patients within 17.6±15.6 months. No correlation was found between B-type natriuretic peptide (BNP), 25-hydroxyvitamin D (25(OH)D), CA-125, high-sensitivity C-reactive protein (hs-CRP), lipoprotein(a) [Lp(a)], noradrenaline, adrenaline, renin or aldosterone and LVRR. Patients in NYHA class III or IV, with pulmonary congestion or ankle edema, had higher CA-125, cystatin C, BNP and hs-CRP levels (p<0.05). CA-125 was correlated with BNP (r=0.61), hs-CRP (r=0.56) and uric acid (r=0.52) (all p=0.01). BNP correlated directly with LVEDD (r=0.49), LV volumes (r=0.51), pulmonary artery systolic pressure (PASP) (r=0.43) and E/e' (r=0.31), and was inversely correlated with LVEF (r=-0.50) and e' velocity (r=-0.32) (p<0.05). CA-125 was positively correlated with left atrial volume/BSA (r=0.46), E/A ratio (r=0.60) and PASP (r=0.49) (p<0.05). CONCLUSIONS: No correlation was found between biomarkers and LVRR, but CA-125, BNP and hs-CRP were predictors of clinical severity and congestion. BNP correlated with parameters of systolic and diastolic dysfunction, while CA-125 correlated with measures of diastolic dysfunction.

Echocardiographic assessment of right ventricular function in routine practice: Which parameters are useful to predict one-year outcome in advanced heart failure patients with dilated cardiomyopathy?

BACKGROUND: Right ventricular (RV) function has recently gained attention as a prognostic predictor of outcome even in patients who have left-sided heart failure. Since several conventional echocardiographic parameters of RV systolic function have been proposed, our aim was to determine if any of these parameters (tricuspid annular plane systolic excursion: TAPSE, tissue Doppler derived systolic tricuspid annular motion velocity: S', fractional area change: FAC) are associated with outcome in advanced heart failure patients with dilated cardiomyopathy (DCM). METHODS: We retrospectively enrolled 68 DCM patients, who were New York Heart Association (NYHA) Class III or IV and had a left ventricular (LV) ejection fraction <35%. All patients were undergoing evaluation for heart transplantation or management of heart failure. Primary outcomes were defined as LV assist device implantation or cardiac death within one year. RESULTS: Thirty-nine events occurred (5 deaths, 32 LV assist devices implanted). Univariate analysis showed that age, systolic blood pressure, heart rate, NYHA functional class IV, plasma brain natriuretic peptide concentration, intravenous inotrope use, left atrial volume index, and FAC were associated with outcome, whereas TAPSE and S' were not. Receiver-operating characteristic curve analysis showed that the optimal FAC cut-off value to identify patients with an event was <26.7% (area under the curve=0.74). The event-free rate determined by Kaplan-Meier analysis was significantly higher in patients with FAC≥26.7% than in those with FAC<26.7% (log-lank, p=0.0003). Moreover, the addition of FAC<26.7% improved the prognostic utility of a model containing clinical variables and conventional echocardiographic indexes. CONCLUSIONS: FAC may provide better prognostic information than TAPSE or S' in advanced heart failure patients with DCM.

Assessment of metabolic phenotypes in patients with non-ischemic dilated cardiomyopathy undergoing cardiac resynchronization therapy.

Studies of myocardial metabolism have reported that contractile performance at a given myocardial oxygen consumption (MVO2) can be lower when the heart is oxidizing fatty acids rather than glucose or lactate. The objective of this study is to assess the prognostic value of myocardial metabolic phenotypes in identifying non-responders among non-ischemic dilated cardiomyopathy (NIDCM) patients undergoing cardiac resynchronization therapy (CRT). Arterial and coronary sinus plasma concentrations of oxygen, glucose, lactate, pyruvate, free fatty acids (FFA), and 22 amino acids were obtained from 19 male and 2 female patients (mean age 56 ± 16) with NIDCM undergoing CRT. Metabolite fluxes/MVO2 and extraction fractions were calculated. Flux balance analysis (FBA) was performed with MetaFluxNet 1.8 on a metabolic network of the cardiac mitochondria (189 reactions, 230 metabolites) reconstructed from mitochondrial proteomic data (615 proteins) from human heart tissue. Non-responders based on left ventricular ejection fraction (LVEF) demonstrated a greater mean FFA extraction fraction (35% ± 17%) than responders [18 ± 10%, p = 0.0098, area under the estimated ROC curve (AUC) was 0.8238, S.E. 0.1115]. Calculated adenosine triphosphate (ATP)/MVO2 using FBA correlated with change in New York Heart Association (NYHA) class (rho = 0.63, p = 0.0298; AUC = 0.8381, S.E. 0.1316). Non-responders based on both LVEF and NYHA demonstrated a greater mean FFA uptake/MVO2 (0.115 ± 0.112) than responders (0.034 ± 0.030, p = 0.0171; AUC = 0.8593, S.E. 0.0965). Myocardial FFA flux and calculated maximal ATP synthesis flux using FBA may be helpful as biomarkers in identifying non-responders among NIDCM patients undergoing CRT.

Prognostic utility of B-type natriuretic peptide assessment in stable low-risk outpatients with nonischemic cardiomyopathy after decompensated heart failure.

OBJECTIVES: We investigated the clinical utility of B-type natriuretic peptide (BNP) assay in stable outpatients with nonischemic dilated cardiomyopathy (NICM) after decompensated heart failure (HF). BACKGROUND: Patients with NICM admitted for decompensated HF frequently experience sudden death or redecompensation after hospital discharge. The prognostic value of BNP during hospitalization has been demonstrated. However, clinical utility of BNP in stable outpatient setting has been poorly investigated. METHODS: Eighty-three NICM outpatients who were clinically stable in New York Heart Association functional class 1 to 2 for 6 months after discharge for decompensated HF were enrolled, and then followed for an additional 18 months. The main end point was first readmission for decompensated HF or death. B-type natriuretic peptide levels were measured at 3-month intervals from discharge to enrollment, and echocardiographic dimensions at discharge and enrollment. RESULTS: Mean discharge BNP level was 210 +/- 148 pg/ml. Twenty-eight patients were readmitted for decompensated HF or suddenly died at a median time of 11 months from the time of discharge. Among various variables including BNP measurements, clinical parameters and echocardiographic dimensions, a 6-month post-discharge BNP of >190 pg/ml was most closely associated with combined event in the Cox proportional hazards model (hazard ratio 2.29; 95% confidence interval 1.42 to 3.56; p = 0.0005), and had the best discriminatory power (area under the receiver operating characteristic curve 0.91, sensitivity 96%; specificity 76%). CONCLUSIONS: Even in stable low-risk outpatients with NICM at 6 months after hospital discharge for decompensated HF, BNP assessment predicts a long-term risk of redecompensation.

Plasma N-terminal protype-B natriuretic peptide levels in risk assessment of patients with mitral regurgitation secondary to ischemic and nonischemic dilated cardiomyopathy.

BACKGROUND: Functional mitral regurgitation (MR) is a factor affecting prognosis of patients with chronic left ventricular (LV) dysfunction. The aim of the study was to investigate whether the evaluation of plasma N-terminal protype-B natriuretic peptide (NT-proBNP) concentrations is useful for prognostic assessment of patients with functional MR due to either ischemic or nonischemic chronic LV dysfunction. METHODS: Echocardiograms were obtained in 207 patients with chronic LV dysfunction (ejection fraction or=0.7 cm raised MR grade to severe. Median follow-up duration was 29 months. RESULTS: The NT-proBNP levels increased significantly with MR severity. At multivariate analysis, NT-proBNP was an independent predictor of cardiac death (hazard ratio 2.17, CI 1.10-4.30, P = .026) and the most powerful predictor of cardiac death or heart failure-related hospitalization (hazard ratio 3.19, CI 1.89-5.37, P < .0001). A progressively worse outcome was apparent when patients were stratified by a graded increase in MR severity and by quartiles of NT-proBNP levels. Increased NT-proBNP concentrations and more-than-mild MR identified patients with the highest risk of cardiac mortality. CONCLUSION: Assessment of plasma NT-proBNP allows for stratifying patients with functional MR regardless of their degree of valvular incompetence. Even in case of only mild or moderate MR, but increased NT-proBNP, patients have to face poor outcome.

Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy.

Apelin is a recently discovered peptide ligand reported to be involved in the regulation of cardiovascular homeostasis. The exact role of apelin in the pathophysiology of congestive heart failure has remained obscure, and the reported circulating levels of apelin in patients with heart failure have been contradictory. To establish the role of apelin in the assessment of cardiac dysfunction we measured plasma apelin levels in 65 patients with congestive heart failure caused by idiopathic dilated cardiomyopathy (IDC) and 14 healthy volunteers by specific radioimmunoassay. IDC patients were carefully examined including echocardiography, both-sided cardiac catheterization and cardiopulmonary exercise test. In addition, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), N-terminal pro-atrial natriuretic peptide (NT-proANP), interleukin (IL)-6, tumor necrosis factor alpha (TNF-alpha), epinephrine and norepinephrine were determined. Plasma apelin levels were similar in IDC patients (median 26.5 pg/ml, range<3.40-97.6 pg/ml) and in control subjects (median 24.1 pg/ml, range 19.0-28.7 pg/ml; p=NS). Unlike the levels of NT-proBNP, IL-6, TNF-alpha, and norepinephrine, plasma apelin levels did not reflect the severity of heart failure. Our study demonstrates that although disturbed apelin-APJ signalling in heart may play a role in the pathophysiology of heart failure, circulating apelin levels cannot be applied in the clinical assessment of patients with chronic left ventricular dysfunction.

Prospective familial assessment in dilated cardiomyopathy: cardiac autoantibodies predict disease development in asymptomatic relatives.

BACKGROUND: In autoimmune disorders, circulating autoantibodies identify healthy relatives at risk years before clinical presentation. Healthy relatives of patients with dilated cardiomyopathy (DCM) who have echocardiographic changes, including left ventricular enlargement or depressed fractional shortening at baseline, have increased medium-term risk for DCM development. Approximately one third of relatives have serum anti-heart autoantibodies (AHAs) at baseline; we intended to assess their potential role in predicting DCM development. METHODS AND RESULTS: Baseline evaluation, including electrocardiography, echocardiography, and AHA, was performed in 592 asymptomatic relatives of 169 consecutive DCM patients (291 males and 301 females; mean age 36+/-16 years). Relatives were classified in accordance with published echocardiographic criteria; those who did not have DCM were followed up (median of 58 months). DCM among relatives was diagnosed by echocardiography at follow-up. Of the 592 individuals evaluated, 77% were assessed as normal, 4.4% as having DCM, and 19% as possibly affected on the basis of depressed fractional shortening without ventricular dilatation in 17 and left ventricular enlargement without systolic dysfunction in 94. Five-year follow-up of 311 relatives revealed that 26 had progressed (13 to DCM, 11 to left ventricular enlargement, and 2 to depressed fractional shortening). Relatives who developed DCM were more frequently AHA-positive than those who did not (69% versus 37%, P=0.02). Five-year probability of progression to DCM, among normal or possibly affected relatives, was higher in AHA-positive cases (P=0.03). By Cox regression, positive AHAs at baseline were independent predictors of progression (RR 2.26, CI 1 to 5.1, P=0.03). CONCLUSIONS: Among healthy relatives of DCM patients, AHAs are independent predictors of disease development within 5 years.

Dilated cardiomyopathy relieved as a result of beta-blocker therapy: a case report--key points in assessment of prognosis based on MIBG myocardial scintigraphy and BNP levels.

A 48-year-old male patient was admitted to our hospital with dyspnea accompanied by orthopnea. Chest x-rays showed a cardiothoracic ratio of 68% and pulmonary congestion. He was diagnosed with dilated cardiomyopathy. Beta-Blocker (carvedilol) therapy was initiated on Day 22 of the disease using a small initial dose. He was followed up based on BNP levels and MIBG scintigraphy. The H/M ratio and MIBG washout rate were 1.98 and 33.4%, respectively, on Day 20 and 2.15 and 28.1%, respectively, on Day 72. The patient was discharged on Day 72 when congestive heart failure improved. Relatively high BNP levels were observed for 1 month after starting treatment with a beta-blocker. Plasma BNP levels were still as high when his heart failure was improved. BNP is useful as a convenient indicator for the severity of cardiac diseases. MIBG scintigraphy may be used thereafter to evaluate the severity in greater detail and more precisely determine the prognosis.

Assessment of degree of oxidative stress and antioxidant concentrations in dogs with idiopathic dilated cardiomyopathy.

OBJECTIVE: To assess degree of oxidative stress and antioxidant concentrations in dogs with idiopathic dilated cardiomyopathy (IDCM). DESIGN: Prospective study. ANIMALS: 18 dogs with IDCM and 16 healthy control dogs. PROCEDURE: Concentrations of malondialdehyde (an indicator of oxidative stress); vitamins A, C, and E; glutathione peroxidase; and superoxide dismutase were measured. RESULTS: Glutathione peroxidase concentration was significantly increased in dogs with IDCM, compared with control dogs. Vitamin A and superoxide dismutase concentrations were not significantly different between groups. A negative correlation was found between disease severity and plasma vitamin E concentration. Disease severity was not correlated with concentrations of other antioxidants. Medications did not significantly affect oxidant or antioxidant concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: The change in glutathione peroxidase concentration and the correlation between vitamin E concentration and disease severity suggest that the oxidant-antioxidant system may play a role in development of IDCM.

[The cardiac changes in thalassemia major: their assessment by Doppler echocardiography]. / Alterazioni cardiache nella talassemia major: valutazione con ecocardiografia Doppler.

Dilated cardiomyopathy with impaired left ventricular function is the most common cause of death in patients (pts) with Thalassemia Major (TM) undergoing multiple transfusions. To assess the cardiac status in a young population with TM, 25 pts (mean age 15.8 +/- 5.7 years) and 25 controls (sex and age matched), underwent clinical, echocardiographic and Doppler evaluation. Thirteen pts who received a correct chelation therapy had serum Ferritin (F) below, and nine pts up to 1300 ng/ml. Three out of 9 pts with F > 1300 ng/ml were symptomatic for heart failure, and echocardiography showed a dilated cardiomyopathy. All pts with F < 1300 ng/ml had a normal systolic function. Mean left ventricular (LV) diastolic dimension and LV mass index were significantly increased in pts with TM versus controls (respectively: 37.2 +/- 7.9 mm vs 30.5 +/- 4.3 mm--p < 0.001; 78.6 +/- 16.7 g vs 65.2 +/- 19.4 g--p < 0.05). Moreover, LV end-diastolic dimension was significantly increased in patients with TM having normal systolic function versus controls (36.1 +/- 7.5 mm vs 30.5 +/- 4.3 mm). No difference was found between patients with TM and controls for wall thickness nor for Doppler diastolic indexes obtained from analysis of transmitral flow. Our study suggests that a correct chelation therapy may protect pts with TM from early development of a dilated cardiomyopathy. The first echocardiographic abnormality in pts still asymptomatic and with normal systolic function seems to be an increased end diastolic LV dimension. In our experience, left ventricular filling is not altered in asymptomatic patients.