Selective upregulation of endothelin converting enzyme-1a in the human failing heart

BACKGROUND: Increased plasma levels of endothelin-1 (ET-1) occur with congestive heart failure (CHF), but the components of the enzymatic activation of ET-1 in the myocardium remain to be defined. Accordingly, endothelin converting enzyme-1 (ECE-1) activity and expression in normal and failing heart were examined. METHODS AND RESULTS: Left ventricular (LV) tissue samples were obtained from patients undergoing heart transplantation because of dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) and from normal donor hearts. The gene expression of ET-1 precursor and ECE-1a was upregulated 4- and 3-fold, respectively, in the failing heart. ECE-1 activity (fmol/mg protein per hour) was augmented from 2,291+/-257 in normal tissue samples to 5,507+/-666 in DCM samples and to 7,435+/-682 in ICM samples (P < .05). Phosphoramidon and a specific ECE-1 inhibitor, FR901533, inhibited ECE-1 activity by over 90%. However, inhibitors of neutral endopeptidase (thiorphan) and matrix metalloproteases (batimistat) did not affect the conversion of big ET-1 to ET-1. CONCLUSIONS: This study showed that the biosynthetic pathway of ET-1 is activated in LV myocardium in the failing heart, and the myocardial processing of big ET-1 is highly specific for ECE-1.     

Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy

In myocardial membranes from hearts with dilated cardiomyopathy (DCM), there was a 37% increase of the Gi alpha-protein as measured by 32P-ADP-ribosylation of a approximately 40 kDa pertussis toxin substrate. Immunoblotting techniques also showed increased amounts of Gi alpha in DCM. In hearts with ischemic cardiomyopathy (ICM), Gi alpha was not altered compared with nonfailing myocardium (NF). Basal and Gpp(NH)p-stimulated adenylate cyclase activity was reduced in DCM but not in ICM. The number of beta-adrenoceptors was similarly reduced both in DCM and ICM compared with NF. Alterations of m-cholinoceptors or A1-adenosine receptors did not occur. Consistently, "indirect" negative inotropic effects of the m-cholinoceptor agonist carbachol and the A1-adenosine receptor agonist R-PIA were not different in ICM, DCM, and nonfailing myocardium. In ICM and DCM, there was a marked reduction of the positive inotropic responses to isoprenaline and milrinone. However, there was a further reduction in DCM compared with ICM. It is concluded that the increase of Gi alpha is accompanied by a reduction of basal and guanine-nucleotide-stimulated adenylate cyclase activity. Alterations of m-cholinoceptors and A1-adenosine receptors do not appear to be involved. The further decrease of the positive inotropic effects of isoprenaline and milrinone in DCM provides evidence that the increase of Gi alpha is functionally relevant in DCM but not ICM and hence might contribute to the reduced effects of endogenous catecholamines and exogenous cAMP-dependent positive inotropic agents in the former but not the latter condition.     

Comparison of benefits from cardiac resynchronization therapy in patients with ischemic cardiomyopathy versus idiopathic dilated cardiomyopathy

Cardiac resynchronization therapy (CRT) is a recently introduced therapeutic option for patients with severe heart failure and intraventricular conduction disturbances. However, it is estimated that 20% to 30% of patients may not respond to CRT. Patients with ischemic cardiomyopathy (IC) may respond less favorably to CRT compared with patients with idiopathic dilated cardiomyopathy (IDC). Accordingly, the beneficial effects of CRT were evaluated in 2 subsets of patients (IC and IDC). Seventy-four patients with end-stage heart failure, New York Heart Association (NYHA) class III or IV, left ventricular (LV) ejection fraction <35%, QRS >120ms, and left bundle branch block received a biventricular pacemaker. At baseline and 6 months after implantation these parameters were evaluated: NYHA class, Minnesota quality-of-life score, QRS duration, and 6-minute walking distance. LV ejection fraction and severity of mitral regurgitation were assessed before and 6 months after CRT using 2-dimensional echocardiography. Long-term follow-up and hospitalization rates were obtained up to 2 years. Of the 74 patients, 46% (n = 34) had IC and 54% (n = 40) IDC. At 6 months follow-up all clinical parameters, QRS duration, LV ejection fraction, and mitral regurgitation improved significantly in both groups. Long-term (2-year) follow-up showed a survival rate of 87.5% for patients with IDC and 88.3% for patients with IC. The percentages of responders to CRT (defined as an improvement in NYHA class >or=1 grade) were comparable in both groups (65% vs 71%). Therefore, the underlying etiology of heart failure (IC vs IDC) was not related to the response to CRT.     

Prognostic guides in patients with idiopathic or ischemic dilated cardiomyopathy assessed for cardiac transplantation

In an attempt to identify which parameters predict survival in advanced dilated cardiomyopathy, 232 patients presenting for assessment for cardiac transplantation were investigated and followed for 10 +/- 12 months (range 2 weeks to 5 years). Etiology of dilated cardiomyopathy included ischemic heart disease (33%), idiopathic (42%) and miscellaneous (25%). In each patient, 26 parameters were recorded. Whole group survival was 68% at 1 year, 56% at 2 years, 41% at 3 years and 25% at 4 years. On Cox multivariate regression analysis, 3 parameters predicted survival: New York Heart Association symptom class (p less than 0.0001), pulmonary capillary wedge pressure (p less than 0.008) and plasma atrial natriuretic factor level (p less than 0.002). On paired testing of actuarial survival curves, plasma noradrenaline also held predictive value (p less than 0.002), as did left ventricular ejection fraction less than or equal to 20% on radionuclide ventriculography (p = 0.007) and presence of greater than or equal to 4 beats of ventricular tachycardia on Holter monitoring (p = 0.007). Treatment with amiodarone did not appear to influence survival. Conventional determinants of prognosis in cardiomyopathy (symptom class, wedge pressure, nonsustained ventricular tachycardia and ejection fraction) do not alone always adequately differentiate survival in this group of high risk patients. More attention to plasma noradrenaline and to atrial natriuretic factor levels may give important additional information in the context of assessment of patients for transplantation.     

Antigens of the major histocompatibility system in ischemic heart disease and idiopathic dilated cardiomyopathy

BACKGROUND: Although dilated cardiomyopathy (DCM) is a disease of unknown and probably multifactorial etiology, a change in immune mechanisms is presumably significant, with many abnormalities in humoral and cellular responses having been reported. The heart thus becomes the target organ for an initial episode of myocardial damage that triggers an autoimmune response. HYPOTHESIS: The purpose of this study was to analyze the frequency of different human leukocyte antigens in patients with a diagnosis of well-advanced DCM and ischemic heart failure, comparing them with a control group of presumably healthy subjects. METHODS: The group with dilated cardiomyopathy consisted of 50 patients (7 women and 43 men), aged from 14 to 64 years. The group with ischemic heart disease included 76 patients (4 women and 72 men), with ages ranging from 34 to 64. The control group, consisting of 1,337 presumably healthy subjects from the Spanish Mediterranean area, was recruited based on paternity studies. RESULTS: Compared with the control group, we found in DCM a greater incidence of B15 (20 vs. 6%) and DQ3 (83 vs. 50%) antigens. In ischemic heart disease we found a lower incidence of A1 (3 vs. 22%), B8 (5 vs. 12%), and DQ2 (16 vs. 50%) in comparison with the control group. CONCLUSIONS: In the Spanish Mediterranean area, the presence of antigens B-15 and DQ3 would be associated with advanced DCM. The absence of antigens A1, B8, and DQ2 would be associated with the occurrence of severe ischemic heart disease.     

Mechanisms and immediate outcome of in-hospital cardiac arrest in patients with advanced heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

To differentiate patients with congestive heart failure who are more prone to develop malignant ventricular tachyarrhythmias or severe bradyarrhythmias as the terminal event, we retrospectively evaluated a group of 48 patients with advanced heart failure who experienced a monitored cardiac arrest during hospital stay. We found no significant differences with respect to several variables, apart from clinical status, which was worse in patients whose cardiac arrest was precipitated by severe bradycardia or electromechanical dissociation.     

Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy

OBJECTIVE: To study the mitochondrial respiratory chain enzyme activities in patients with idiopathic dilated cardiomyopathy (IDC). METHODS: Mitochondrial respiratory chain enzyme activities were assessed spectrophotometrically in left ventricular tissue of 17 patients with IDC undergoing cardiac transplantation, as well as in two groups of controls: a group of six patients suffering from ischemic dilated cardiomyopathy (IC) also undergoing cardiac transplantation, and a group of 17 organ donors considered normal from a cardiac point of view. Cytochrome b gene from three IDC patients whose complex III activity was particularly low and from three controls was also sequenced. RESULTS: We found that complex III enzymatic activity was lower not only in IDC but also in IC patients when compared with normal controls. When analysing cytochrome b gene we only found neutral polymorphisms previously described. CONCLUSIONS: In view of such results, we believe that the decrease of respiratory chain complex III activity found in some cases of IDC is a secondary phenomenon, and not due to a primary mitochondrial disease.     

Prognostic value of left atrial enlargement in patients with idiopathic dilated cardiomyopathy and ischemic cardiomyopathy

Previous studies have shown that abnormal mitral flow patterns and left atrial (LA) enlargement are independently associated with survival in patients with left ventricular (LV) dysfunction. However, it is not known whether these outcome indicators can provide different information in patients of various age groups. This study was designed to assess the prognostic value of the restrictive mitral flow pattern (RMFP) and increased LA size in patients with LV dysfunction (ejection fraction <45%) grouped into those < or = 70 years old (n = 102; mean age 61) and those >70 years old (n = 105; mean age 78). Echocardiographic and Doppler indexes were recorded in patients with LV systolic dysfunction due to dilated cardiomyopathy who were followed up for 22 plus minus 14 months. In patients >70 years, indexed LA size (>26 mm/m(2)) was the single best predictor of death (hazard ratio [HR] 3.0, p = 0.018) and emerged as the most important outcome variable of the combined end point (HR 2.2, p = 0.016) on multivariate analysis. In patients < or =70 years, RMFP, characterized by an early wave deceleration time <140 ms, was independently associated with cardiac death or heart failure hospitalization (HR 5.7, p = 0.0013). When demographics, clinical, echocardiographic, and Doppler measurements were analyzed in hierarchical order, indexed LA size yielded the most valuable contribution in predicting the combined end point in older patients (global chi-square from 11.5 to 18.7). RMFP was associated with the higher additional prognostic value in younger patients (global chi-square from 14.4 to 24.1). These data suggest that LA enlargement has an independent and additional prognostic value in elderly patients with LV dysfunction.     

Beta-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy.

BACKGROUND. We investigated the effects of bucindolol, a nonselective, non-ISA beta-blocker with mild-vasodilatory properties, in patients with congestive heart failure from ischemic dilated cardiomyopathy (ISCDC, n = 27) and compared the results with those in subjects with heart failure from idiopathic dilated cardiomyopathy (IDC, n = 22). METHODS AND RESULTS. Patients were randomized in a double-blind fashion to receive 12 weeks' treatment with either bucindolol or placebo, with randomization stratified for IDC or ISCDC. Invasive (right heart catheterization) and noninvasive (echo, MUGA, central venous norepinephrine, exercise treadmill studies, and symptom scores) tests of heart failure severity were determined at baseline and end of the study. For all subjects (ISCDC plus IDC), relative to placebo treatment, bucindolol-treated patients had significant improvement in ejection fraction, left ventricular size and filling pressure, stroke work index, symptom score, and central venous norepinephrine. However, most of these differences could be attributed to improvement in the IDC subgroup, as the only parameter with a statistically significant degree of improvement in the bucindolol-treated ISCDC subgroup was left ventricular size. CONCLUSIONS. We conclude that beta-blockade may produce quantitatively different degrees of response in different kinds of heart muscle disease.     

Efficacy of ivabradine in idiopathic dilated cardiomyopathy patients with chronic heart failure

BackgroundThe aim of this study was to investigate the effect of ivabradine on symptoms, quality of life, effort tolerance, and echocardiographic parameters in patients with idiopathic dilated cardiomyopathy presenting with New York Heart Association (NYHA) class III or IV heart failure (HF) symptoms.MethodsWe screened 167 patients hospitalized for NYHA class III or IV chronic HF symptoms and left ventricular (LV) ejection fraction <40%. Of these, 53 were randomly assigned to either guidelines-based medical therapy alone (23 patients, control group) or ivabradine as add-on therapy (30 patients) for 3 months with about 1 year follow up.ResultsAfter 3 months’ treatment, adding ivabradine significantly reduced the heart rate from 96 to 72 bpm (p < 0.0001 versus control group), with more improvement in echocardiographic LV dimensions, LV volumes, LV ejection fraction (p = 0.045), NYHA class symptoms (p = 0.004), exercise tolerance (p = 0.03), and quality of life (p = 0.02). The average number of hospitalizations for HF over a mean longer-term follow-up of 13.5 months was 1.0 ± 1.4 in the ivabradine group versus 2.1 ± 1.1 in the control group (p = 0.003). Heart rate reduction was significantly correlated with better exercise tolerance, quality of life, LV ejection fraction, and NYHA class, together with fewer HF hospitalizations. Multivariate analysis showed heart rate reduction to be a stronger predictor for better LV ejection fraction (p = 0.024) and decreased hospitalizations than ivabradine use.ConclusionAdding ivabradine to optimal medical treatment in HF patients improved symptoms, quality of life, effort tolerance, and echocardiographic parameters, and reduced hospitalization. This beneficial ivabradine effect is probably due to its heart rate–reducing properties.     

Timing of cardiac transplantation in idiopathic dilated cardiomyopathy

Seventy-nine patients with idiopathic dilated cardiomyopathy were assessed and followed up to evaluate 9 variables that might predict duration of survival after assessment for cardiac transplantation. Patients with ischemic heart disease, alcoholic and peripartum cardiomyopathy were excluded. There were 38 deaths (48%) during the 18-month (mean) follow-up. Patients underwent determination of left ventricular ejection fraction by radionuclide scan, echocardiography, cardiac catheterization and myocardial biopsy. Only left ventricular ejection fraction determined by radionuclide study correlated significantly with time to death in nonsurvivors (r = 0.38, p less than 0.05). Multivariant analysis and Cox multivariate regression analysis revealed that the single consistent determinant of prognosis was radionuclide-determined ejection fraction. It was an excellent predictor of survival to 3 months (p less than 0.0001) and a reasonable predictor of survival to 6 months (p less than 0.05). There was no variable that efficiently predicted survival for any period greater than 6 months. In 15 of 70 patients (21% of the entire group), clinical status and radionuclide ejection fraction improved after assessment but only one of these had an ejection fraction less than or equal to 0.10. No patient with a radionuclide ejection fraction greater than or equal to 0.20 died within 6 months of assessment. For those with ejection fraction between 0.11 and 0.19, survival after cardiac transplantation exceeded that of the natural history of their disease; this suggests that transplantation should be undertaken within 6 to 12 months of assessment. Left ventricular ejection fraction less than or equal to 0.10 predicts an extremely poor prognosis (6-month survival was 17%) and such patients should be transplanted with minimal delay.     

Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

Inflammatory cytokines may play a pathogenic role in the development of congestive heart failure (CHF). Elevated circulating levels of inflammatory cytokines have been reported in CHF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines are modulated by soluble cytokine receptors and cytokines with anti-inflammatory activities, and in the present study several of these interacting factors were examined simultaneously in 38 CHF patients with various degrees of heart failure and in 21 healthy controls. Patients with CHF had increased plasma concentrations of tumor necrosis factor (TNF)alpha, interleukin-6, soluble TNF receptors and the soluble interleukin-6 receptor, glycoprotein (gp)130. They also had elevated ratios of TNFalpha/soluble TNF receptors and interleukin-6/soluble gp130 as well as enhanced interleukin-6 bioactivity in serum, suggesting inflammatory net effects. In addition to raised circulating levels of inflammatory cytokines, CHF patients with severe heart failure also had abnormalities in the levels of anti-inflammatory cytokines, with decreased levels of transforming growth factor beta1 and inadequately raised interleukin-10 in relation to the elevated TNFalpha concentrations. This dysbalance between inflammatory and anti-inflammatory cytokines was also found in monocyte supernatants from CHF patients. The abnormalities in the cytokine network were most pronounced in patients with the most severe heart failure, and several of the immunologic parameters, in particular soluble gp130, were correlated with variables reflecting deranged hemodynamic status. The present study analyzing the complexity of the cytokine network in CHF, demonstrates profound disturbances in the levels of both inflammatory and anti-inflammatory mediators with a marked dysbalance favoring inflammatory effects.     

Usefulness of real-time three-dimensional echocardiography for reliable measurement of cardiac output in patients with ischemic or idiopathic dilated cardiomyopathy

The determination of stroke volume (SV) is a potentially important application of real-time 3-dimensional echocardiography (RT3DE). SV measurements by thermodilution were compared with values obtained using transthoracic RT3DE in a sequential cohort of patients who underwent assessment for potential cardiac transplantation. There was a strong correlation between echocardiographically derived SV and catheterization data (r = 0.95, n = 14). On average, RT3DE appeared to underestimate SV by 7.5 ml (SD = 5.8) or 17% (SD = 12%). A role for RT3DE in the measurement of SV in severe heart failure is suggested.     

Oscillatory hyperventilation in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy

Thirty-one subjects with chronic congestive heart failure (CHF) were separated into 3 groups according to ventilatory patterns during graded exercise: Group 1--oscillators (n = 6); group 2-intermediate oscillators (n = 14); and group 3--nonoscillators (n = 11). Group 1 patients showed cyclic fluctuations in minute ventilation (change of 30 to 40 liters/min) and arterial PO2 (change of 38.0 +/- 4.1 mm Hg) and PCO2 (change of 11 +/- 2.8 mm Hg). The nadir in arterial PO2 occurred at times when wasted ventilatory effort was maximal. The amplitude of ventilatory oscillations in group 1 patients increased in the transition from rest to light exercise and damped with heavy exercise. There was no evidence of alveolar hypoventilation at the nadirs of minute ventilation; arterial PCO2 was always 40 mm Hg or less. Substantial hyperventilation (ventilatory equivalent for CO2 twice normal) occurred with maximal minute ventilation in group 1 patients. Oscillatory hyperventilation correlated with severity of CHF. Maximal oxygen uptake was significantly lower in group 1 (11.7 +/- 1.1 ml/kg/min) than group 3 (17.9 +/- 1.8 ml/kg/min) (p less than 0.05). Oscillatory hyperventilation during exercise may accompany severe CHF and compounds the inadequate delivery of oxygen by the failing heart.     

T-lymphocyte subsets in patients with idiopathic dilated cardiomyopathy

T-cell subsets were measured in the peripheral blood of 33 patients with heart failure from idiopathic dilated cardiomyopathy, 22 patients with heart failure from other causes, and 33 normal controls. Mean T-suppressor cell percentage was 30% in normals, 21% in patients with idiopathic dilated cardiomyopathy whose duration of symptoms was less than 1 year (P = 0.0005), and 26% in those with symptoms for greater than 1 year (P = 0.05). Similarly, percentage of T-suppressor cells in the group with heart failure from causes other than idiopathic dilated cardiomyopathy was significantly lower (23%; P = 0.005) in those with short duration of symptoms. When both heart failure groups were combined those with symptoms for less than 1 year had significantly lower T-suppressor frequencies (22%) than those with symptoms for more than 1 year (P = 0.015). Multivariate analysis identified duration of symptoms and age as the only independent predictors of T-suppressor cell frequencies. Decreased percentage of T-suppressor cells in patients with idiopathic dilated cardiomyopathy may be an epiphenomenon related to duration of heart failure. This should be taken into account in assigning an etiologic mechanism for T-suppressor cells in idiopathic dilated cardiomyopathy.