Predictive value of wavelet decomposition of the signal-averaged electrocardiogram in idiopathic dilated cardiomyopathy.

BACKGROUND: Wavelet decomposition of the signal-averaged electrocardiogram has been proposed as a method of detecting small and transient irregularities hidden within the QRS complex and of overcoming some of the limitations of time domain analysis of the signal-averaged electrocardiogram. AIM: This study evaluated the potential utility of wavelet decomposition analysis in the risk stratification of patients with idiopathic dilated cardiomyopathy. METHODS AND RESULTS: Both wavelet decomposition and time domain analysis were applied to the signal-averaged electrocardiogram recordings of 82 patients with idiopathic dilated cardiomyopathy (mean age 43 +/- 14 years, 60 men) and 72 normal controls (mean age 44 +/- 15 years, 48 men). Three conventional time domain indices and four wavelet decomposition analysis parameters (QRS length, maximum count, surface area, and relative length) were derived from each recording using a Del Mar CEWS system and an in-house software package, respectively. The results showed that (1) more patients with idiopathic dilated cardiomyopathy than without had late potentials, and that the filtered QRS duration was significantly longer in patients than in controls (P<0.001). Similarly, abnormal wavelet decomposition analysis was more common in patients and wavelet decomposition measurements were significantly different between patients and controls (P<0.01); (2) conventional time domain analysis did not distinguish between clinically stable patients and patients who developed progressive heart failure, or between patients with and without arrhythmic events; (3) wavelet decomposition analysis identified patients who went on to develop progressive heart failure but failed to distinguish patients with arrhythmic events from those without; (4) survival analyses of a mean follow-up of 23 months showed that patients with late potentials tended to develop progressive heart failure more frequently than others (P=0.06). Patients with an abnormal wavelet decomposition result more frequently developed progressive heart failure than those with a normal wavelet decomposition result (P=0.027); (5) in a univariate analysis (Cox model), wavelet decomposition measurements but not time domain indices significantly correlated with the development of progressive heart failure (P=0.01). Multivariate analysis showed that only left ventricular end-diastolic dimension and peak oxygen consumption during exercise remained significant predictors of progressive heart failure. CONCLUSION: Wavelet decomposition analysis of the signal-averaged electrocardiogram is superior to conventional time domain analysis for identifying patients with idiopathic dilated cardiomyopathy at increased risk of clinical deterioration. Wavelet decomposition analysis, however, is unlikely to prospectively distinguish patients at a high risk of arrhythmic events in idiopathic dilated cardiomyopathy in its present form.     

Prognostic value of an abnormal signal-averaged electrocardiogram in patients with nonischemic dilated cardiomyopathy

The usefulness of an abnormal signal-averaged ECG (SAECG) for the risk stratification of patients with dilated cardiomyopathy was studied prospectively in 76 patients. Multiple analysis showed that an abnormal SAECG predicted cardiac mortality (p = 0.0046), sudden cardiac death, and the need for resuscitation (p = 0.003); however, it did not predict death from heart failure and heart transplantation.     

Elevated serum levels of soluble interleukin-2 receptor, neopterin and beta-2-microglobulin in idiopathic dilated cardiomyopathy: relation to disease severity and autoimmune pathogenesis

BACKGROUND: It has not been assessed whether high levels of soluble interleukin 2 receptor (sIL-2R), neopterin and beta-2 microglobulin in idiopathic dilated cardiomyopathy reflect heart failure severity and/or an active autoimmune process. The aim of this study was to relate serum levels of these markers to clinical and autoimmune features. METHODS: We studied 60 patients with idiopathic dilated cardiomyopathy, 67 controls with ischemic heart failure and 34 normals. RESULTS: Abnormal levels of sIL-2R, but not of neopterin and beta-2 microglobulin, were more frequent in idiopathic dilated cardiomyopathy than in ischemic patients (35% vs. 16%; P=0.02) or in normals (35% vs. 12%, P=0.01); mean sIL-2R levels were, however, similar in idiopathic dilated cardiomyopathy and ischemic heart failure (842+/-75 vs. 762+/-93 U/ml, P=NS). In idiopathic dilated cardiomyopathy abnormal levels of sIL-2R were associated with lower peak oxygen consumption (P=0.008), higher neopterin and HLA class II expression in the myocardium (P=0.02), but were unrelated to cardiac autoantibody status or titer. In addition, abnormal levels of neopterin were associated with adverse prognosis and higher beta-2 microglobulin; abnormal levels of beta-2 microglobulin with lower echocardiographic percent fractional shortening, higher sIL-2R and higher neopterin. CONCLUSIONS: There is no convincing evidence that abnormal sIL-2R, neopterin and/or beta-2 microglobulin are disease-specific markers of idiopathic dilated cardiomyopathy. The lack of association with cardiac autoantibodies suggests that these abnormalities are mainly related to heart failure severity rather than autoimmune pathogenesis. In keeping with this view, high levels of sIL-2R, neopterin and/or beta-2 microglobulin identified a subset of idiopathic dilated cardiomyopathy patients with advanced disease and poor prognosis.     

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.     

Increased ventricular sialylation in patients with heart failure secondary to ischemic heart disease

Background: Elevated serum sialic acids are associated with increased cardiovascular mortality, but sialic acid levels have not been studied in cardiac tissue. Methods: Myocardial samples were obtained at the time of transplantation from 23 patients (age 54 ± 12 years) with heart failure secondary to ischemic heart disease and 16 patients (age 51 ± 7 years) with idiopathic dilated cardiomyopathy (DCM). A control group comprised postmortem samples obtained from 14 patients (age 70 ± 5 years) who died of non-cardiovascular causes. Ventricular sialylation was quantitated using the sialic acid-specific lectins Maackia amurensis agglutinin (MAA) and Sambucus nigra agglutinin (SNA) using a chemiluminescence assay. Results are expressed as the percentage (± standard error of the mean) of the binding of lectin to a standardized control sample of human myocardium. Results: Ventricular sialylation recognized by MAA was 55 ± 7% in patients with heart failure secondary to ischemic heart disease compared with 26 ± 7% for DCM (p = 0.006) and 32 ±8% for controls (p = 0.04), and that recognized by SNA was 69 ± 7% in patients with heart failure secondary to ischemic heart disease compared with 42 ± 6% for DCM (p = 0.006) and 38 ± 7% for controls (p = 0.006). No significant difference in ventricular sialylation was observed between patients with DCM and controls. Conclusion: Myocardial levels of sialic acids are significantly increased in patients with heart failure secondary to ischemic heart disease compared with patients with idiopathic dilated cardiomyopathy and controls. Our findings are important in view of recent reports of an association between serum sialic acid concentration and cardiovascular mortality and require further investigation.     

Thallium scintigraphy for the prognosis of idiopathic dilated cardiomyopathy

OBJECTIVES: This study evaluated the significance of perfusion defects demonstrated by thallium-201 and age in the prognosis of patients with idiopathic dilated cardiomyopathy. METHODS: Seventy-four dilated cardiomyopathy patients underwent thallium scintigraphy as well as clinical and hemodynamic examination. RESULTS: Abnormal perfusion defects were present in 23 of 38 patients aged < 60 years (61%) and in 26 of 36 elderly patients aged > or = 60 years (72%; NS). Univariate analysis showed that such perfusion defects were a significant predictor of cardiac death only in patients aged < 60 years (p = 0.015). Stepwise discriminant analysis also revealed that perfusion defects were a significant predictor in patients aged < 60 years (Wilks' lambda 0.499, chi-square test 20.2, p = 0.003). Perfusion defects were not more important than the history of syncope or stroke in elderly dilated cardiomyopathy patients. Twenty-one patients died of disease-related causes during 58 +/- 43 months. The five-year survival rate was better in patients aged < 60 years without than in those with perfusion defects (100% vs 58.4%, respectively), but not affected in patients aged > or = 60 years (66.7% vs 62.2%). CONCLUSIONS: Thallium scintigraphy is valuable for the prognosis of patients with dilated cardiomyopathy aged < 60 years who are usually candidates for heart transplantation. Absence of thallium perfusion defects may indicate good long-term prognosis.     

Ischemic cardiomyopathy: endomyocardial biopsy and ventriculographic evaluation of patients with congestive heart failure, dilated cardiomyopathy and coronary artery disease.

OBJECTIVES. This study was designed to define clinical and pathophysiologic similarities and differences between patients with ischemic and idiopathic dilated cardiomyopathy. BACKGROUND. Significant coronary artery disease in patients with new onset congestive heart failure due to dilated cardiomyopathy has important prognostic and therapeutic implications. METHODS. Clinical, histologic, ventriculographic and hemodynamic features of patients with dilated cardiomyopathy who underwent coronary angiography were reviewed. RESULTS. Patients with ischemic cardiomyopathy (n = 21) compared with those with idiopathic cardiomyopathy (n = 40) had similar presenting symptoms, durations of illness, and coronary risk factor profiles, with the exception of a greater prevalence of cigarette smoking (71% vs. 39%, p = 0.028) and male gender (100% vs. 70%, p = 0.014). Endomyocardial biopsy specimens from patients with ischemic cardiomyopathy demonstrated a greater prevalence of replacement fibrosis (48% vs. 8%, p = 0.001) and a lesser degree of histologically assessed myocyte hypertrophy (mean grade 0.5 +/- 0.7 vs. 1.3 +/- 1.3, p = 0.015). Although ventriculographically determined regional dyskinesia was present in both groups, there was a higher prevalence of two or more adjacent segments in the ischemic cardiomyopathy group (50% vs. 10%, p = 0.03). This ischemic group had hemodynamic variables associated with a worse prognosis: higher pulmonary artery wedge pressure (23 +/- 10 vs. 15 +/- 9 mm Hg, p = 0.006) and lower cardiac index (2.0 +/- 0.5 vs. 2.3 +/- 0.5 liters/min per m2, p = 0.044). Also, in this group, patients had a mean of 2.6 +/- 0.7 diseased vessels; 15 (71%) of 21 patients had triple-vessel disease and 18 (86%) of 21 had at least one occluded or suboccluded artery. CONCLUSIONS. 1) Patients with ischemic and idiopathic cardiomyopathy may be clinically indistinguishable unless coronary angiography is performed. 2) A greater prevalence of replacement fibrosis and a lesser degree of myocardial hypertrophy in patients with ischemic cardiomyopathy may account for the greater extent of hemodynamic decompensation observed at presentation.     

Spectral Turbulence Versus Time-Domain Analysis of Signal-Averaged ECG Used for the Prediction of Different Arrhythmic Events in Survivors of Acute Myocardial Infarction

Spectral Turbulence SAECG After MI. Introduction : Spectral turbulence analysis of the signal-averaged ECG (SAECG) combines spectral analysis with statistical evaluation of spectrograms of individual parts of the QRS complex. It has been suggested that it may be superior to conventional time-domain analysis of the SAECG.
Methods and Results : This study compared the power of conventional time-domain (40 to 250Hz) and spectral turbulence analyses of SAECG for the prediction of cardiac death, ventricular tachycardia, sudden arrhythmic death, and arrhythmic events (ventricular tachycardia or fibrillation, and/or sudden arrhythmic death) after acute myocardial infarction in 603 patients. The population excluded patients with bundle branch block and other conduction abnormalities. During the first 2 years of follow-up, there were 40 cardiac deaths, 21 cases of ventricular tachycardia, 11 sudden arrhythmic deaths, and 29 arrhythmic events. The positive predictive accuracy of spectral turbulence analysis was significantly higher than time-domain analysis for cardiac death at most levels of sensitivity (e.g., 26% vs 20% at 40% sensitivity, P < 0.05). The positive predictive accuracies of the two techniques were not statistically different for the prediction of ventricular tachycardia. For the prediction of sudden arrhythmic death and arrhythmic events, the positive predictive accuracy of spectral turbulence was better than that of time-domain analysis only at the higher levels of sensitivity (9% vs 2%, P < 0.001 for sudden arrhythmic death at 60% sensitivity, and 14% vs 11%, P < 0.05 for arrhythmic events at 60% sensitivity).
Conclusions : Spectral turbulence analysis is essentially equivalent to time-domain analysis for the prediction of arrhythmic events after myocardial infarction. However, it performed significantly better than time-domain analysis for the prediction of cardiac death.     

Myocardial adenine nucleotides, glycogen, and Na, K-ATPase in patients with idiopathic dilated cardiomyopathy requiring mechanical circulatory support

Acute decompensation leading to progressive pump failure is a main cause of death in patients with congestive heart failure. To find possible metabolic defects associated with the onset of this fatal occurrence, we measured myocardial adenine nucleotides, glycogen, and Na,K-ATPase in patients with end-stage idiopathic dilated cardiomyopathy. The biopsy specimens were obtained from the right ventricle of beating hearts during implantation of a biventricular assistance device in 23 patients (group I) suffering from irreversible cardiogenic shock and during heart transplantation in 20 patients (group II) in compensated heart failure. Left ventricular ejection fraction (LVEF) was determined preoperatively by echocardiography. Left ventricular function in group I was more severely impaired than in group II (LVEF 16.8%+/-4.6% vs 22.1%+/-5.1 %; p <0.01). Myocardial adenosine triphosphate (ATP) in group I was significantly reduced in comparison with group II (119.4+/-10.2 vs 27.7+/-7.4 nmol/mg noncollagen protein; p <0.01). There was no difference in glycogen levels. Na,K-ATPase concentration in group I (n = 8) was lower than that of group II (n = 20) (425+/-80 vs 498+/-75 pmol/g wet weight; p <0.05). Linear regression analyses showed a significant correlation between adenosine triphosphate (ATP) and LVEF (r = 0.41, p <0.01) and between Na,K-ATPase and LVEF (r = 0.55, p <0.01). These results indicate that loss of myocardial ATP and Na,K-ATPase could partially contribute to the development of spontaneous deterioration of the chronically overloaded heart.     

Long-term prognostic value of time domain analysis of signal-averaged electrocardiography in idiopathic dilated cardiomyopathy

The aim of this study was to evaluate the long-term prognostic value of signal-averaged electrocardiography (SAECG) in idiopathic dilated cardiomyopathy (IDC). Time domain analysis of SAECG was assessed in 131 patients with angiographically confirmed IDC (age 52+/-12 years; 108 men; left ventricular ejection fraction 33+/-12%) using specific criteria in 44 patients with bundle branch block. Late potentials (LP) on SAECG were present in 27% of the patients. Patients with LP had a similar left ventricular ejection fraction and a similar left ventricular end-diastolic diameter than patients with a normal SAECG. With a follow-up of 54+/-41 months, 24 patients suffered cardiac death and 19 had major arrhythmic events (sudden death, resuscitated ventricular fibrillation, or sustained ventricular tachycardia). Patients with LP had an increased risk of all-cause cardiac death (RR 3.3, 95% confidence interval 1.5 to 7.5, p = 0.004) and of arrhythmic events (RR 7.2, 95% confidence interval 2.6 to 19.4, p = 0.0001). Using multivariate analysis, only LP on SAECG (p = 0.001), reduced SD of all normal-to-normal intervals (SDNN) (p = 0.002), increased pulmonary capillary wedge pressure (p = 0.005), and history of sustained ventricular tachyarrhythmia (p = 0.02) predicted cardiac death. A history of previous sustained ventricular tachyarrhythmia (p = 0.0001), reduced SDNN (p = 0.003), and LP on SAECG (p = 0.006) were the only independent predictors of major arrhythmic events. Results were not altered when considering separately patients with or without bundle branch block, or after exclusion of patients with a history of sustained ventricular tachyarrhythmia. This study is one of the first to suggest that LP on SAECG is an independent predictor of all-cause cardiac death and is of high interest for arrhythmia risk stratification in IDC.     

Influence of the infarct site on the identification of patients with ventricular tachycardia after myocardial infarction based on the time-domain and spectral turbulence analysis of the signal-averaged electrocardiogram

In a significant proportion of patients with sustained ventricular tachycardia (VT) following anterior myocardial infarction, the areas of slow conduction are activated early during cardiac depolarization. Therefore, they may not be detected by the standard time-domain analysis of the signal-averaged electrocardiogram (SAECG) which is limited to the terminal part of the QRS complex. Spectral turbulence analysis of the SAECG is a new frequency domain technique which examines the whole QRS complex and may improve identification of patients with sustained VT following anterior infarction. We compared the results of time-domain and spectral turbulence analyses of the SAECG in 53 postinfarction patients with sustained VT and in 53 age-, gender- and infarct site-matched patients without VT. The receiver operator characteristic curves have shown that the time-domain analysis resulted in better identification of patients with VT following inferior than following anterior infarction (e.g., at the sensitivity level of 90%, the corresponding values of specificity were 96 and 90%, respectively), whereas the spectral turbulence analysis performed better in the anterior site of infarction. When both time-domain and spectral turbulence analyses were combined, the accuracy of the SAECG for identification of patients with VT following anterior infarction improved, reaching a specificity of 97% at the sensitivity level of 90%. In conclusion (1) spectral turbulence analysis of the SAECG results in better identification of patients with VT following anterior than following inferior infarction, and (2) the combination of time-domain and spectral turbulence analyses of the SAECG may improve identification of patients with VT following anterior infarction.     

Heart transplantation in hypertrophic cardiomyopathy

Heart transplantation (HT) is the sole therapeutic option for selected patients with hypertrophic cardiomyopathy (HC) and refractory heart failure. However, the results of HT have not been systematically investigated in HC. We assessed the pathophysiologic profile of HT candidates and the outcome after transplantation in 307 patients with HC consecutively evaluated at our tertiary referral center from 1987 to 2005; follow-up was 9.9+8.2 years. Outcome of recipients with HC was compared with that of 141 patients who underwent transplantation for idiopathic dilated cardiomyopathy at our center over the same period. Of 21 patients with HC who entered the transplantation list, 20 had end-stage evolution with systolic dysfunction and 1 had an extremely small left ventricular cavity with impaired filling and recurrent cardiogenic shock during paroxysmal atrial fibrillation. Of 33 study patients with HC who showed end-stage evolution during follow-up, the 23 who were included on the waiting list or died from refractory heart failure (2 patients) were significantly younger than the 10 patients who remained clinically stable (37+/-14 vs 57+/-17 years, p=0.004). Of the 21 HT candidates, 18 underwent transplantation during follow-up. In heart transplant recipients, 7-year survival rate was 94% and not different from that of the 141 patients who received transplants for idiopathic dilated cardiomyopathy (p=0.66). In conclusion, long-term outcome after HT in patients with HC is favorable and similar to that of patients with idiopathic dilated cardiomyopathy. In patients with end-stage HC, young age is associated with more rapid progression to refractory heart failure.     

Cardiac transplantation in patients with hypertrophic cardiomyopathy

Cardiac transplantation is a treatment option for patients with hypertrophic cardiomyopathy (HC) who developed refractory heart failure and/or intractable arrhythmia. However, the pretransplant characteristics and post-transplant prognosis for patients with nondilated idiopathic HC has not yet fully elucidated. Therefore, we retrospectively reviewed 813 consecutive transplant recipients undergoing cardiac transplantation at Columbia University Medical Center from 1999 to 2010 and compared the clinical course of 41 patients with idiopathic HC with that of 373 patients with ischemic heart disease and 398 patients with other heart disease. The patients with HC were younger than those with ischemic heart disease (47.8 ± 14.0 vs 57.1 ± 9.4 years; p <0.0001). The proportion of patients undergoing ventricular assist devise surgery for bridge-to-transplant was lower in patients with HC than in those with ischemic heart disease or other heart disease (14.6% vs 31.1% vs 35.7%, all p <0.01). The post-transplant survival of those with HC was better than that for those with ischemic heart disease (90.1% vs 85.8% and 83.9% vs 67.1% at 1 and 5 years, respectively; p = 0.0359), although it was not significantly different from those with other heart disease. Proportional hazards analysis revealed that the subjects with HC had reduced post-transplant mortality (hazard ratio 0.4760, 95% confidential interval 0.1889 to 0.9762; p = 0.042) on univariate, but not multivariate, analysis. Most patients with HC had nondilated left ventricles (left ventricular end-diastolic dimension ≤ 55 mm; n = 27), and post-transplant survival did not differ from that for those with dilated left ventricles (left ventricular end-diastolic dimension >55 mm; n = 14). In conclusion, the post-transplant survival of those with HC did not differ from those of the subjects who underwent transplant for other non-HC indications.     

Prognostic value of heart rate variability for sudden death and major arrhythmic events in patients with idiopathic dilated cardiomyopathy

OBJECTIVE: This study was designed to evaluate the prognostic value of heart rate variability for sudden death, resuscitated ventricular fibrillation or sustained ventricular tachycardia in patients with idiopathic dilated cardiomyopathy. BACKGROUND: Previous studies have shown that heart rate variability could predict arrhythmic events and sudden death in postinfarction patients, but the prognostic value of heart rate variability for arrhythmic events or sudden death in patients with idiopathic dilated cardiomyopathy has not been established. METHODS: Time and frequency domain analysis of heart rate variability on 24-h electrocardiographic (ECG) recording was assessed in 116 patients with idiopathic dilated cardiomyopathy (91 men, aged 51+/-12 years, left ventricular ejection fraction 34+/-12%). RESULTS: Mean follow-up (+/-SD) was 53+/-39 months. Sixteen patients reached one of the defined study end-points (sudden death, resuscitated ventricular fibrillation or sustained ventricular tachycardia) during follow-up. Using multivariate analysis, only reduced standard deviation of all normal-to-normal intervals (SDNN) (p = 0.02) and ventricular tachycardia during 24-h ECG recording (p = 0.02) predicted sudden death and/or arrhythmic events. For SDNN, a cutoff level of 100 ms seemed the best for the risk stratification. CONCLUSIONS: Decrease in heart rate variability is an independent predictor of arrhythmic events and sudden death in idiopathic dilated cardiomyopathy, whether the mechanism of sudden death is ventricular tachyarrhythmia or not.     

Effect of bisoprolol on QT dispersion in patients with congestive heart failure--the etiology-dependent response

AIMS: To evaluate the effect of beta1-selective blocker bisoprolol on the QT and QTc dispersion in patients with chronic heart failure and to compare the responses to bisoprolol in patients with different etiologies. METHODS AND RESULTS: Eighty-one patients with heart failure secondary to ischemic heart disease (n=47) or idiopathic dilated cardiomyopathy (n=34) were stratified by etiology and then randomly assigned to the bisoprolol and control group (no tablet) on top of the conventional treatment. QT dispersion was calculated by subtracting the shortest QT from the longest QT, in absolute value (Qtmax-Qtmin). It was also corrected with Bazett's formula (QTc dispersion). After 6 weeks of treatment, QT and QTc dispersion were significantly decreased in the bisoprolol group (QT dispersion: 66.5+/-13.4 ms vs. 49.1+/-16.8 ms for ischemic heart disease (P<0.01); 67.5+/-12.4 ms vs. 59.4+/-14.4 ms for dilated cardiomyopathy (P<0.05); QTc dispersion: 78.3+/-15.2 ms vs. 53.3+/-18.1 ms for ischemic heart disease (P<0.01); 79.1+/-14.2 ms vs. 69.0+/-17.9 ms for dilated cardiomyopathy (P<0.05)), but there was no significant decrease of QT and QTc dispersion in the control group. Linear regression analysis showed that patients with ischemic heart disease tend to have lower 6-week QT dispersion than patients with dilated cardiomyopathy (coefficient beta=-0.283, P=0.009) after controlling for their baseline values in the bisoprolol group. CONCLUSION: These findings suggested that bisoprolol reduces QT and QTc dispersion in patients with chronic heart failure, but the etiology of heart failure affects the response of patients to bisoprolol.     

Association between the severity of heart failure and the susceptibility of myocytes to apoptosis in patients with idiopathic dilated cardiomyopathy

BACKGROUND: Bcl-2 proto-oncogene, an inhibitor of apoptosis and Bax proto-oncogene, an inducer of apoptosis play critical roles in the molecular circuit controlling apoptosis in cardiac muscle. The ratio of Bax to Bcl-2 proto-oncogene determines survival or death after an apoptotic stimulus. We speculated that susceptibility of myocytes to apoptosis determined as the Bax/Bcl-2 ratio might vary with the severity of heart failure. METHODS AND RESULTS: We studied immunohistochemically 108 endomyocardial biopsy specimens from 30 patients with idiopathic dilated cardiomyopathy (mild heart failure, n=14; moderate or severe heart failure, n=16) with the use of Bcl-2 and Bax monoclonal antibodies. The expression of each protein was determined semiquantitatively as the fraction of myocytes labeled with specific monoclonal antibodies using a digital morphometric analysis system. Patients with mild heart failure showed significantly increased Bax/Bcl-2 ratio than the patients with advanced heart failure (1.59+/-1.26 vs. 0.34+/-0.43, P=0.002). The expression of Bcl-2 was found to be independent of the severity of heart failure whereas the expression of Bax was significantly higher in patients with mild heart failure compared to the patients with moderate or severe heart failure (52.1+/-29.3 vs. 21.6+/-22.4%, P=0.005). Additionally, Bax/Bac-2 ratio was inversely correlated with the mitral E-interventricular septum distance, left ventricular end-systolic and end-diastolic diameter. CONCLUSION: The susceptibility of myocytes to apoptosis is significantly increased in the early phase of heart failure but it decreases with worsening of the disease due to depressed expression of Bax onco-protein. Increased myocyte susceptibility to apoptosis may have a role in the transition from mild heart failure to severe in patients with idiopathic dilated cardiomyopathy.     

Heart rate variability in dilated cardiomyopathy

Chronic heart failure is associated with excessive neurohormonal activation. Analysis of heart rate variability is considered a valid technique for assessment of the autonomic balance of the heart. Twenty symptomatic patients of dilated cardiomyopathy in NYHA class II-IV symptomatic status and as many normal controls were subjected to 24 hours Holter monitoring to assess the heart rate variability with both time domain and frequency domain analysis. Age of the patients ranged from 12 to 67 years (mean +/- SD 38.6 +/- 7 years), the male-female ratio was 4:1. The left ventricular ejection fraction of the patients was between 18-42 percent (mean +/- SD 30.2 +/- 9%) and all received diuretics, digoxin and angiotensin-converting enzyme inhibitors. Heart rate variability parameters measured included mean heart rate with standard deviation, hourly heart rate with SD and the mean of all normal RR intervals from the 24-hour recording. Time domain measures calculated were SD of all normal RR intervals, SD of 5 minute mean RR intervals and root mean square of difference of successive RR intervals. Using spectral plots, frequency domain subsets of low frequency and high frequency were analysed and expressed in normalised units. Total power was also measured. In the dilated cardiomyopathy patients, mean 24-hour heart rate in beats per minute was significantly higher in comparison to controls (82 +/- 13 vs 72 +/- 8; p < 0.001) whereas mean hourly heart rate with standard deviation (msec) was significantly lower (97 +/- 41 vs 232 +/- 25; p < 0.001), SD of all normal RR intervals (msec) was 85.5 +/- 26.3 vs 139.4 +/- 16.9 in controls (p < 0.001), SD of 5 minute mean RR intervals (msec) was also significantly less in patients in comparison to controls (75.8 +/- 39.6 vs 130.8 +/- 20.3; p < 0.001). However, although root mean square of difference of successive RR intervals (msec) was reduced in patients (30.1 +/- 9.3 vs 37.3 +/- 11.7; p < 0.05), the difference was non-significant. Low frequency power (0.05-0.15 Hz) (normalised units) was reduced in the dilated cardiomyopathy group (0.0721 +/- 0.003 vs 0.136 +/- 0.047 in the control group; p < 0.001). High frequency power (0.35-0.50 Hz) (normalised units) (0.08 +/- 0.05 in patients vs 0.09 +/- 0.02 in controls; p > 0.1) and total power frequency (0.02-0.50 Hz) (normalised units) (0.34 +/- 0.05 in patients vs 0.35 +/- 0.12 in controls; p > 0.1) was non-significantly different in the two groups. Regression analysis showed a significant decrease in SD of all normal RR intervals, SD of 5 minute mean RR intervals, low frequency, high frequency, total power and a non-significant decrease in root mean square of difference of successive RR intervals with a decrease in ejection fraction percent whereas there was a significant decrease in SD of all normal RR intervals, SD of 5 minute mean RR intervals, low frequency and total power and a less significant decrease in root mean square of difference of successive RR intervals and high frequency power with an increase in NYHA class. At 6 months duration, 6 patients were lost to follow-up, 3 patients were readmitted (2 for congestive cardiac failure, one of paroxysmal supraventricular tachycardia). One patient who was NYHA class IV at baseline was readmitted for congestive cardiac failure and showed much lower heart rate variability parameters compared to the average of the patients. We conclude that in symptomatic dilated cardiomyopathy patients, heart rate variability parameters are significantly reduced in comparison to control subjects.     

Angiotensin-converting enzyme gene deletion polymorphism modulation of onset of symptoms and survival rate of patients with heart failure

BACKGROUND: Angiotensin-converting enzyme is involved in the pathophysiology of heart failure. We hypothesized that clinical characteristics as well as survival rate in patients with heart failure of different etiologies may be modulated by functional variants DD, ID and II of the angiotensin-converting enzyme gene. METHODS: We studied 333 patients with heart failure, aged 43.3 +/- 10.5 years, 262 (78.7%) men and 71 (21.3%) women. Heart failure was ascribed to idiopathic dilated cardiomyopathy in 125 patients. Heart failure was caused by ischemic heart disease in 63 patients, Chagas' disease in 58, hypertensive heart disease in 41, alcoholic cardiomyopathy in 24, and was due to other etiologies in 22 patients. Statistical analysis was performed with the chi(2) test, Student's t-test, analysis of variance, Kaplan-Meier and Cox proportional hazards methods. RESULTS: The DD genotype was associated with increased systolic left ventricular diameter (p = 0.031). Earlier onset of symptoms was observed in patients with alcoholic cardiomyopathy and DD genotype (p = 0.033, codominant D) and in patients with hypertensive cardiomyopathy and DD genotype (p = 0.048, codominant D; p = 0.024, recessive D). Mortality was higher in patients older than 50 years with DD genotype (p = 0.007, codominant D; p = 0.002, recessive D). Variables independently associated with higher mortality in patients older than 50 years were age, diabetes mellitus, Chagas' disease etiology and DD genotype. CONCLUSIONS: These results add evidence for an association of the DD genotype of the angiotensin-converting enzyme gene with earlier onset of symptoms and decreased survival rate of selected patients with heart failure.     

Depressed low frequency power of heart rate variability as an independent predictor of sudden death in chronic heart failure.

AIMS: Identification of patients with chronic heart failure at risk for sudden death remains difficult. We sought to assess the prognostic value for all-cause and sudden death of time and frequency domain measures of heart rate variability in chronic heart failure. METHODS AND RESULTS: We prospectively enrolled 190 patients with chronic heart failure in sinus rhythm, mean age 61+/-12 years, 109 (57.4%) in NYHA class II and 81 (42.6%) in classes III or IV, mean cardiothoracic ratio 57.6+/-6.4% and mean left ventricular ejection fraction 28.2+/-8.8%, 85 (45%) with ischaemic and 105 (55%) with idiopathic dilated cardiomyopathy. Time and frequency domain measures of heart rate variability were obtained from 24 h Holter ECG recordings, spectral measures were averaged for calculation of daytime (1000h-1900h) and night-time (2300h-0600h) values. During follow-up (22+/-18 months), 55 patients died, 21 of them suddenly and two presented with a syncopal spontaneous sustained ventricular tachycardia. In multivariate analysis, independent predictors for all-cause mortality were: ischaemic heart disease, cardiothoracic ratio > or =60% and standard deviation of all normal RR intervals <67 ms (RR = 2.5, 95% CI 1.5-4.2). Independent predictors of sudden death were: ischaemic heart disease and daytime low frequency power <3.3 ln (ms(2)) (RR = 2.8, 95% CI 1.2-8.6). CONCLUSION: Depressed heart rate variability has independent prognostic value in patients with chronic heart failure; spectral analysis identifies an increased risk for sudden death in these patients.     

Circulating cytokines and complements in chronic heart failure.

Elevated levels of cytokines and complements have been reported in patients with advanced heart failure, but the exact clinical significance remains unclear. Therefore, assessments correlated with hemodynamic and clinical variables may provide important insight into the actions of cytokines and complements in chronic heart failure. The authors evaluated the clinical significance of cytokines and complements. The study included 60 subjects (50 men, 10 women); 34 had idiopathic dilated cardiomyopathy (DCM) and 26 had ischemic heart disease (IHD). Tumor necrosis factor alpha and interleukin-2 receptor concentrations in chronic heart failure were greater than in control subjects (20.0 +/- 0.4 vs 18.0 +/- 0.5 pg/mL, p<0.05 and 817.23 +/- 63.50 vs 642.75 +/- 27.31 pg/mL, p<0.05, respectively). There was no significant difference between DCM and IHD patients in circulating levels of the cytokines and the components complements (p=NS). Additionally, although functional classes III and IV heart failure patients showed a tendency to increase the levels of the cytokines and the component complements, these differences were not statistically significant (p=NS). Similarly, correlation analysis showed that the levels of the circulating cytokines and the component complements had independent value for mortality. These results suggest that humoral and cellular immunity abnormalities may play an important role in the pathogenesis of heart failure and dilated cardiomyopathy.