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Recently it could be demonstrated that systolic and diastolic blood pressure variability (BPV) as well as segmented Poincare plot analysis (SPPA) contribute to risk stratification in patients suffering from dilated cardiomyopathy (DCM). The aim of this study was to improve the risk stratification applying a multivariate technique including QT variability (QTV). We enrolled and significantly separated 56 low risk and 13 high risk DCM patients by nearly all applied BPV and QTV methods, but not with traditional heart rate variability analysis. The optimum set of two indices calculating the multivariate discriminate analysis (DA) included one BPV index calculated by symbolic dynamics method (DBP(Shannon)) and one index calculated from QTV (QTV(log)) achieving an area under the receiver operating characteristics curve (AUC) of 92%, sensitivity of 92.3% and specificity of 89.3%. Performing only electrocardiogram analysis, the optimum multivariate approach including indices from segmented Poincaré plot analysis and QTV still achieved a remarkable AUC of 88.3%. Increasing the number of indices for multivariate DA up to three, we achieved an AUC of 95.7%, sensitivity of 100% and specificity of 85.7% including one clinical, one BPV and one QTV index. Summarizing, we identified DCM patients with an increased risk of sudden cardiac death applying QTV analysis in a multivariate approach.

Background: The prognostic value of heart rate variability in patients with dilated cardiomyopathy (DCM) is limited and does not contribute to risk stratification although the dynamics of ventricular repolarization differs considerably between DCM patients and healthy subjects. Neither linear nor nonlinear methods of heart rate variability analysis could discriminate between patients at high and low risk for sudden cardiac death., Objective: The aim of this study was to analyze the suitability of the new developed segmented Poincaré plot analysis (SPPA) to enhance risk stratification in DCM., Methods: In contrast to the usual applied Poincaré plot analysis the SPPA retains nonlinear features from investigated beat-to-beat interval time series. Main features of SPPA are the rotation of cloud of points and their succeeded variability depended segmentation., Results: Significant row and column probabilities were calculated from the segments and led to discrimination (up to p<0.005) between low and high risk in DCM patients., Conclusion: For the first time an index from Poincaré plot analysis of heart rate variability was able to contribute to risk stratification in patients suffering from DCM.

Background: Dilated cardiomyopathy (DCM) has been suggested to be a consequence of a prior viral infection leading to a chronic inflammatory and immunological reaction that leads to a structural and functional deterioration of the heart. Nevertheless, the results of present studies are conflicting, regarding the natural course of heart diseases associated with detection of viral genome and inflammation. On the other hand, diabetes mellitus (DM) is the leading endocrine disorder worldwide and sufficient to induce a cardiomyopathy. It is not known whether DM contributes to the clinical picture of cardiomyopathy associated with the presence of viral genome or inflammatory cells in the myocardium. Therefore, the present study was undertaken to compare histological, immunohistochemical, biochemical, and functional data as well as the outcome of patients presenting with DCM and positive for DM with patients negative for DM to evaluate for a diabetic contribution in the course of the disease., Methods: A total of 216 patients were biopsied between January 1998 and April 2003. From 197 patients diagnosed as having DCM, we were able to complete data set regarding the presence of DM in 108 patients, 20 patients with and 88 patients without DM., Results: There was no significant difference regarding age, gender, body mass index, presence of viral genome and inflammatory cells in the myocardium, left ventricular function and diameter, and the degree of heart insufficiency. There was a significant difference of apoptotic cells in the myocardium of patients with DCM and DM compared to patients with DCM alone (1.7+/-1.9 vs. 0.2+/-0.4, p=0.028). During the follow-up of 16 months, left ventricular function improved in both groups significantly, but not between the groups. Death or transplantation-free survival was not significantly different., Conclusion: The different findings regarding the presence of apoptotic cells suggest a contribution of pathobiological pathways in the patients with DM to the underlying heart disease.

Elevated circulating levels of alpha- and beta-chemokines in heart failure have been reported. The objective of this study was to investigate the interrelation of chemotactic activity of serum and circulating chemokine levels in patients suffering from idiopathic dilated cardiomyopathy (IDCM). Chemokine serum levels (MCP-1, MIP1-alpha, RANTES, IL-8 and TNF-alpha) were determined in patients with IDCM (n = 10), patients with coronary artery disease with normal (CAD-1; n = 10) or depressed (CAD-2; n = 10) left ventricular function and healthy controls (n = 10). The chemotactic effect of sera obtained from these groups was measured using an in vitro chemotaxis assay. Sera obtained from IDCM (5475 +/- 681 cells) showed the highest chemotactic activity when compared to controls (1850 +/- 215 cells), CAD-1 (3325 +/- 275 cells) and CAD-2 (2800 +/- 275 cells, P < 0.05) associated with significantly higher circulating MCP-1 levels. Sera obtained from IDCM patients show a high chemotactic activity associated with significantly elevated circulating MCP-1.

Cardiomyocytes are known to be androgen targets. Changing systemic steroid levels are thought to be linked to various cardiac ailments, including dilated cardiomyopathy (DCM). The mode of action of gonadal steroid hormones on the human heart is unknown to date. In the present study, we used high-resolution immunocytochemistry on semithin sections (1 microm thick), IN SITU hybridization, and mass spectrometry to investigate the expression of androgen-binding protein (ABP) in human myocardial biopsies taken from male patients with DCM. We observed distinct cytoplasmic ABP immunoreactivity in a fraction of the myocytes. IN SITU hybridization with synthetic oligonucleotide probes revealed specific hybridization signals in these cells. A portion of the ABP-positive cells contained immunostaining for androgen receptor. With SELDI TOF mass spectrometry of affinity purified tissue extracts of human myocardium, we confirmed the presence of a 50 kDa protein similar to ABP. Our observations provide evidence of an intrinsic expression of ABP in human heart. ABP may be secreted from myocytes in a paracrine manner perhaps to influence the bioavailabity of gonadal steroids in myocardium.

Parameters of heart rate turbulence (HRT) and blood pressure turbulence (BPT) reflect the baroreflex mediated transient acceleration-deceleration response of the sinus node triggered by a premature ventricular complex (PVC) and are known to be useful risk markers in different cardiac diseases. However, the analyses of HRT and BPT are based on the prevalence of PVC. In this study the spontaneous HRT and BPT after most premature normal beats (MPNB) was investigated in comparison to HRT and BPT after PVC. ECG and blood pressure were recorded from 91 patients with dilated cardiomyopathy (DCM) and 45 healthy subjects (REF). In 69% of DCM and 33% of REF data sets PVCs were present. HRT and BPT were determined for all patients with PVC as well as in all patients triggered by MPNB. Univariate statistical analysis of the comparison between DCM and REF revealed similar results for HRT/BPT after PVC and MPNB. In conclusion, HRT and BPT triggered by PVC might be substituted by spontaneous HRT and BPT after MPNB. In contrast to the HRT and BPT after PVC, an increased number of data sets can be included in the analysis and may lead to an enhancement in risk stratification in different cardiac diseases.

The beat-to-beat variability of the diastolic blood pressure induces small variations in the afterload of the left ventricle. These variations influence myocardial contractility, and thus blood pressure amplitude. We assessed the interdependence of blood pressure and changes in the afterload. We continuously recorded blood pressure (duration 200 s, at rest) in 20 patients with dilated cardiomyopathy (ejection fraction 32 +/- 13%, left ventricular diameter 67 +/- 8 mm) and in 20 healthy volunteers. Interbeat intervals, diastolic pressures, systolic pressure amplitudes and mean slopes of systolic pressure amplitudes were measured. Correlation coefficients (r) were calculated to assess the interdependence of blood pressure amplitudes/mean systolic slopes and the preceding diastolic pressures/interbeat intervals, respectively. In healthy volunteers we found a strong interdependence between blood pressure amplitude and the preceding diastolic pressures (r = 0.62 +/- 0.21 and 0.47 +/- 0.22). Higher diastolic pressures were followed by higher blood pressure amplitudes, and by steeper slopes of the systolic peaks. In patients with dilated cardiomyopathy, such interdependence was significantly lower (r = 0.33 +/- 22 and r = 0.28 +/- 0.35), and in patients with severely reduced left ventricular function (ejection fraction < 32%) was only marginal (r = 0.23 +/- 0.27 and 0.21 +/- 0.44, respectively). The forces of the isovolumetric contraction necessary to initiate the ejection phase of the left ventricle depend on the afterload, i.e. on the diastolic pressure. The responses of amplitude and slope of the systolic blood pressure to small changes in the afterload make it possible to assess left ventricular contractility. The latter is impaired in dilated cardiomyopathy.

Background: Neurovegetative and haemodynamic changes impact on the regulation pattern of blood pressure and heart rate in patients with heart failure. We studied these patterns and their interactions in patients with idiopathic dilated cardiomyopathy (IDC) and in healthy subjects (REF)., Methods: We continually measured the heart rate and blood pressure (Portapres device) in twenty-five supine IDC patients (age: 51 +/- 13 y; left ventricular end-diastolic diameter 67 +/- 11 mm; ejection fraction 30 +/- 11%) and in twenty-seven REF (age: 50 +/- 11 y) Recording time was 30 minutes. The heart rate (HR) of each beat and the systolic blood pressure (SYS) of the subsequent beat were measured. Code numbers (symbols) were assigned to the beat-to-beat changes in HR and SYS (increase: 1; decrease: 0). The frequencies of the symbols sequences of three successive beats were counted. In this way we obtained a matrix consisting of eight (two to the power of three) HR and SYS combinations: 000, 100, 010, 001, 111, 110, 011 and 101. We then counted the frequencies of the different combinations of the symbol sequences in HR and SYS (2(3) x 2(3) = 64 combinations). The relative frequencies of symbol patterns appearing in HR, SYS and in the combined analysis of HR and SYS, were compared for IDC and REF using the T-test for independent samples., Results: Significant differences were seen between IDC and REF. The HR patterns 101 and 010 were more frequent in IDC than in REF patients (11.1 +/- 4.7 vs. 7.7 +/- 2.9%, p = 0.003, and 16.1 +/- 6.3 vs. 11.7 +/- 4.9%, p = 0.008). This finding was even more marked in the analysis of the SYS patterns 101 and 010 (11.0 +/- 7.4 vs. 8.2 +/- 2.9%, p < 0.001, and 11.6 +/- 7.4 vs. 5.4 +/- 2.7%, p < 0.001). Non-alternating patterns were more frequent in REF (e.g. 000HR & 111SYS: 4.6 +/- 3.3 vs. 2.9 +/- 2.4%, p = 0.03)., Conclusions: We demonstrated significant interaction of the regulation patterns of blood pressure and heart rate, as also their interactions in IDC. Opposed changes in HR and SYS mediated by the baroreflex, became superimposed by alternans phenomena in IDC. The pattern analysis of changes in HR and SYS detects these disturbances of neurovegetative short-term control.

We extracted and quantified high frequency intra-QRS signals in idiopathic dilated cardiomyopathy (IDC). In IDC the analysis of late potentials in the terminal QRS complex often fails in predicting clinical events because of intraventricular conduction abnormalities and the absence of a circumscribed arrhythmogenic substrate. Therefore, new approaches are required to assess the electrical state of the myocardium. We investigated 21 patients suffering from IDC with (n = 14) and without (n = 7) bundle branch block. High resolution 31 lead magnetocardiograms were filtered with a 67 point 4th order Savitzky-Golay filter. The difference of the measured and filtered signals was calculated (67-200 Hz). The spatio-temporal properties and the areas under the curves of the resulting high frequency intra-QRS signals (IQCs) were studied. We detected IQCs in all patients. The patients had individual patterns regarding the temporal and spatial properties of the IQCs during depolarisation. The IQCs predominantly appeared in the initial portion of the QRS. The ratios of the areas under the curves of the IQCs and the measured signals were linearly correlated to the left ventricular enddiastolic diameter (r = 0.71, significance 0.0012). In IDC the ventricular depolarization is accompanied by individual spatial and temporal patterns of high frequency intra-QRS signals. They can be studied non-invasively from body surface mapping data with the algorithm used in this study. This provides access to the assessment of the electrical status in patients with IDC.

In patients with idiopathic dilated cardiomyopathy, endothelium vasomotor function is disturbed. Increased oxidative stress and the consecutive formation of oxygen free radicals have been implicated as one possibility for this observation, suggesting that nitric oxide (NO) is inactivated by oxygen free radicals. We tested the hypothesis that the antioxidant, vitamin C, may improve endothelial function in idiopathic dilated cardiomyopathy. In 11 patients, the endothelium-dependent vasomotor response of the left anterior descending coronary artery to intracoronary acetylcholine (ACh) infusion (1/2 x 10(-6) mol/L, 1/4 x 10(-5) mol/L; respectively) was determined before and immediately after intravenous infusion of 3 g of vitamin C. Coronary cross-sectional diameter was obtained by quantitative coronary angiography, average peak velocity was measured by an intracoronary Doppler flow wire, and coronary blood flow (CBF) was calculated. Maximum cross-sectional diameter was determined after administration of nitroglycerin. Dose-dependent ACh showed a decrease in cross-sectional diameter (-5% to -7%, p <0.05) and an increase in average peak velocity (+16% to +25%, p <0.05); the CBF was unchanged (+1% to -2%, p = NS). After vitamin C infusion, the cross-sectional diameter increased in a dose-dependent manner from +11% to +15%, the average peak velocity increased from +20% to + 41% (p <0.05), and the CBF increased from +38% to + 82% (p <0.01, p <0.001, respectively). Thus, patients with idiopathic dilated cardiomyopathy had endothelial dysfunction, and administration of vitamin C reversed endothelium-dependent dysfunction.

Myocarditis is a common cardiological disease. New molecular biological and immunohistological methods have confirmed the persistence of viral infection and chronic myocardial inflammation in a considerable number of patients. A causal link between viral myocarditis and the development of dilated cardiomyopathy has been recognized. This has prognostic implications and helps for the decision of a specific immunosuppressive, immunomodulatory and antiviral therapy.

Unlabelled: In chronic heart failure, elevated plasma norepinephrine (NE) levels and a disparity between the neuronal release and the effective reuptake of NE lead to an increased concentration of NE in the presynaptic cleft, causing a downregulation of the myocardial beta-adrenoceptors. The clinical and prognostic effectiveness of beta-blocker therapy has been shown in patients with chronic heart failure in several large trials. The purpose of this study was to investigate the effect of long-term beta-blocker therapy on the cardiac adrenergic nervous system as assessed by the myocardial uptake of 123I-metaiodobenzylguanidine (MIBG), an analog of NE, in idiopathic dilated cardiomyopathy (IDC)., Methods: In 10 patients with IDC and stable chronic heart failure the myocardial MIBG uptake was measured at baseline and at 1 y (median, 11.5 mo) after treatment with beta-blockers (metoprolol, n = 5; bisoprolol, n = 1; and carvedilol, n = 4) in addition to standard medication. In parallel with the changes in MIBG uptake, the New York Heart Association functional class, the left ventricular ejection fraction (LVEF), and the left ventricular end-diastolic diameter (LVEDD) were documented before and after 1 y of therapy with beta-blockers., Results: During the 1-y follow-up, a significant increase in myocardial 123I-MIBG uptake (P = 0.005) in parallel with an improved LVEF (P = 0.005) and a reduced LVEDD (P = 0.019) was found. A trend toward an improvement of the New York Heart Association functional class under the beta-blocker therapy (P = 0.139) was also found., Conclusion: Assessment of the myocardial 123I-MIBG uptake is a useful noninvasive tool for evaluating changes in cardiac sympathetic nerve activity under medical therapy. Long-term treatment with beta-blockers in IDC causes a recovery of the cardiac adrenergic nervous system concomitantly with a clinical and hemodynamic improvement.

High numbers of inflammatory cells are found in a subgroup of patients with idiopathic dilated cardiomyopathy (IDCM). We hypothesized that the extent of inflammation is linked to myocardial TNF-alpha expression in human IDCM. Fourteen patients who consecutively underwent endomyocardial biopsy (EMB) were stratified into two groups-a group with low and a group with high myocardial inflammatory index (MII)-based on immunohistochemical analysis of cellular infiltration and HLA I and II expression. Myocardial TNF-alpha messenger RNA (mRNA) expression was determined by reverse transcriptase polymerase chain reaction, TNF-alpha protein was localized by immunohistochemistry and TNF-alpha serum levels were measured by EIA. IDCM patients with a high MII (n=6) showed a 1. 9-fold higher TNF-alpha mRNA expression when compared to IDCM patients with low MII (n=8, P=0.020). TNF-alpha protein was detected at perinuclear regions of cardiac myocytes and the endothelium. TNF-alpha serum levels were 3.0 (0.55) pg/ml in patients with high MII compared to 1.35 (0.20) pg/ml in patients with low MII (P=0.017). According to immunolocalization cardiac myocytes and the endothelium seem to be the major source of TNF-alpha production. Whether the elevated systemic level of TNF-alpha found in patients with high MII are elaborated by the myocardium or are produced by other tissues representing a general immune activation is not clear., (Copyright 2000 Academic Press.)

Background: Enteroviruses were detected in up to 50% in myocardium of patients with myocarditis and dilated cardiomyopathy, the latter being considered as a result of a prior subclinical myocarditis. A wide range of other infectious agents are being discussed as pathogens, often only based on reports of single cases. Adenovirus genome was recently identified in a significant number in the myocardium of paediatric patients with myocarditis. However, data on the role of adenoviruses for the aetiopathogenesis of myocarditis in adult patients is missing so far. Therefore, we studied the prevalence of adenoviral and enteroviral genome in myocardium of adults with myocarditis and dilated cardiomyopathy., Methods: 15 patients were diagnosed at baseline with myocarditis, 16 patients with dilated cardiomyopathy according to clinical and histological criteria. Endomyocardial biopsies of these patients and 8 control patients with non-infectious heart diseases were evaluated by polymerase chain reactions for enterovirus and adenovirus genome., Results: Enteroviral genome was detected in 27.3% patients with myocarditis or dilated cardiomyopathy, whereas adenoviral genome was not identified in any patient. Samples from control subjects systematically yielded negative results., Conclusions: From our data, it seems doubtful that adenoviruses are major pathogens of myocarditis or DCM, whereas enterovirus genome was identified in a significant number of patients with both diseases.

We investigated the prevalence of hepatitis C virus in patients with dilated cardiomyopathy (DCM) and myocarditis in comparison to a control group of patients suffering from noninflammatory cardiac diseases such as aortic stenosis. In contrast to the results of previous studies on small numbers of patients, no significant difference in the prevalence of hepatitis C infections was observed. Our data suggest that HCV is not an important causal agent for myocarditis and DCM.

The main feature of idiopathic dilated cardiomyopathy is the dilation and impaired contractility of the left ventricle or both ventricles. The clinical picture with forward and backward failure is based on the pump impairment of the left ventricle. However, the clinical presentation of patients with dilated cardiomyopathy is indistinguishable from any other secondary form of heart failure. The symptoms of myocarditis are also often determined by the degree of left ventricular dysfunction and--apart from perimyocarditis-associated precordial discomfort--therefore also often indistinguishable from dilated cardiomyopathy. The differentiation of dilated cardiomyopathy from other myocardial diseases by noninvasive methods is insufficient. Without invasive tests about 1/3 of the patients will be diagnosed incorrectly. Therefore, invasive diagnostics including coronary angiography are necessary to differentiate dilated cardiomyopathy from other diseases, especially coronary artery disease. Standard laboratory findings and cytokine serum concentrations (e.g. TNF-alpha) are not suitable to differentiate dilated cardiomyopathy and myocarditis and endomyocardial biopsy is indicated. Endomyocardial biopsies have to undergo evaluation by standard histology and immunohistology, and should be tested for the persistence of infectious agents. According to cardiac catheterization and evaluation of the endomyocardial biopsy idiopathic left ventricular dysfunction can be further stratified using the criterion of a myocardial virus persistence and the presence/absence of inflammatory infiltrates. Idiopathic dilated cardiomyopathy (approximately 70 to 75%), virus-associated dilated cardiomyopathy (approximately 20 to 25%), myocarditis (approximately 7%) and autoimmune myocarditis (approximately 3%) are the 4 possible resulting forms of idiopathic left ventricular dysfunction. Beside conventional medical therapy there are new therapeutic concepts e.g. using interferon for enterovirus-positive patients and immunosuppression for autoimmune, virus-negative patients with a cellular infiltrate.

Objective: To investigate plasma tumor necrosis factor (TNF)alpha, tumor necrosis factor alpha soluble receptor I, interleukin-1beta and neopterin concentrations as markers of monocyte activation in patients with heart failure., Study Design: The group consisted of patients with heart failure due to dilated cardiomyopathy (n=19) and coronary artery disease (n=11). Patients without cardiac failure served as controls (n=10)., Results: TNFalpha concentrations were elevated only in heart failure patients with coronary artery disease (2.9+/-0.3 pg/ml versus 1.7+/-0.3 pg/ml; P<0.05). When the patients were grouped according to acute and chronic failure, TNFalpha concentrations were significantly elevated in acute failure (3.1+/-0.4 pg/ml, n=6 versus 1.7+/-0.2 pg/ml, n=8; P<0.05). TNFalpha concentrations were elevated in patients with coronary artery disease and chronic heart failure compared to coronary artery disease patients without failure (2.0+/-0.4 pg/ml, n=6 versus 1.8+/-0.3 pg/ml, n=7; P<0.05). A higher proportion of patients with myocardial insufficiency showed increased lipopolysaccharide-inducible TNFalpha concentrations (10/30 versus 0/9, P<0.05)., Conclusions: TNFalpha is elevated in patients with acute cardiac decompensation. Among patients with chronic heart failure only those with coronary artery disease exhibit increased levels. Cytokine concentrations are similar in heart failure due to dilated cardiomyopathy and coronary artery disease. Monocytes of patients suffering from cardiac insufficiency show an increased sensitivity towards stimuli such as lipopolysaccharides.

Background: Evidence is arising that calcium antagonists in idiopathic dilated cardiomyopathy (IDC) may have beneficial effects on virus-induced cardiopathology, alcohol toxicity, micro-circulatory disorders, and impaired calcium cycling, all possibly involved in the pathogenesis of the disease. Thus, the effect of adjunct diltiazem (60 to 90 mg TID) on standard treatment was investigated., Methods and Results: The Diltiazem in Dilated Cardiomyopathy (DiDi) trial was a randomized, double-blind, placebo-controlled, multicenter trial of 186 patients (92 receiving diltiazem, 94 receiving placebo) with IDC diagnosed by coronary angiography, catheterization of the left side of the heart, and a left ventricular ejection fraction of < 0.50 (mean, 0.34 +/- 0.11). The effect of adjunct diltiazem treatment on transplant listing-free survival, hemodynamics, exercise capacity, and subjective status was investigated. During the 24-month study period, 33 patients dropped out of the study; 153 patients finished the study protocol. Twenty-seven patients died or had a listing for heart transplantation: 16 in the placebo group and 11 in the diltiazem group. The transplant listing-free survival rate was 85% for diltiazem and 80% for placebo recipients (P = .444). After 24 months, only diltiazem significantly increased cardiac index at rest (P = .01) and under a workload (P = .02), systolic and diastolic pressures (P = .003 and P = .004), stroke volume index (P = .003), and stroke work index (P = .000) and decreased both pulmonary artery pressure under workload (P = .007) and heart rate (P = .001). Diltiazem also increased exercise capacity (P = .002) and subjective well-being (P = .01). Adverse reactions were minor and evenly distributed in both groups, except for an increase in the PQ interval in the diltiazem group., Conclusions: In patients with IDC, the adjunct therapy of diltiazem improves cardiac function, exercise capacity, and subjective status without deleterious effects on transplant listing-free survival.

The assessment of left ventricular diastolic function by Doppler echocardiography shows both a nonrestrictive and restrictive type of filling in idiopathic dilated cardiomyopathy. These different filling patterns are related to the symptoms of cardiac failure and the prognosis. It remains to be established whether changes of Doppler parameters during follow-up procedures were of clinical relevance. Doppler echocardiography of left ventricular filling was done in 45 patients with idiopathic dilated cardiomyopathy at the time of their diagnosis and repeatedly during a follow-up study of 38 +/- 19 months. The deceleration time of early filling, the maximum early and atrial Doppler velocities and their ratios, as well as echocardiographic parameters of cardiac dimensions and systolic function, were measured. During the follow-up period, seven patients died and four patients underwent heart transplantation because of progressive heart failure. The deceleration time was shorter in patients who died or had to undergo heart transplantation as compared with survivors (119 +/- 43 ms vs 188 +/- 63 ms; P < .005). There was no difference in changes of clinical symptoms in survivors and nonsurvivors. The systolic function improved only in survivors. The difference in deceleration time remained significant between both groups, and it also remained a prognostic discriminator. Peak early velocity increased in nonsurvivors (from 0.66 +/- 0.20 m/s to 0.95 +/- 0.21 m/s; P < .01), while it remained constant in survivors (0.65 +/- 0.17 m/s and 0.67 +/- 0.25 m/s). The peak early/atrial velocity ratio varied widely in either group during the follow-up study, its changes were closely related to the concomitant changes of clinical symptoms (r = .59; P < .005) with a decrease of the peak early/atrial velocity ratio in patients with clinical improvement and an increase of the peak early/atrial velocity ratio in those without clinical improvement. The Doppler echocardiographic deceleration time discriminated between survivors and nonsurvivors in idiopathic dilated cardiomyopathy at the time of the initial diagnostic procedure, and this difference was persistent during the follow-up study. The serial evaluation of patients with idiopathic dilated cardiomyopathy showed a close association of changes in diastolic filling with changes in clinical symptoms.

Seventy-seven consecutive patients with dilated cardiomyopathy underwent left ventricular endomyocardial biopsy. In 20 biopsies (26%) enteroviral RNA was detected by in-situ hybridization. After an average observation period of more than 2 years only one patient had died in the enterovirus positive (ev+) group compared with 11 deaths and four heart transplantations in the enterovirus negative (ev-) group. After a mean follow-up of 16 +/- 9 months haemodynamic evaluation of the surviving ev+ patients showed significantly better results with respect to left ventricular ejection fraction and left ventricular end-diastolic diameter. The four ev+ patients with haemodynamic deterioration were given interferon-alpha, 3 million units subcutaneously every other day for six months. No severe side effects were seen and all four patients improved according to their haemodynamic and clinical parameters. In two of the four patients enteroviral RNA was not detectable in a subsequent biopsy.

Objectives: Endomyocardial biopsy samples from patients with idiopathic dilated cardiomyopathy were screened for the presence of enterovirus genome. Patients with enterovirus-positive samples were further studied with regard to disease course, histologic variables and response to interferon-alpha treatment., Background: Studies of patients with idiopathic dilated cardiomyopathy have reported widely divergent clinical outcomes, suggesting that there is no unique underlying pathogenetic mechanism., Methods: Five left ventricular endomyocardial biopsy samples were screened for the presence of the enterovirus genome by an established in situ hybridization technique in combination with a histologic, histomorphometric and immunohistologic workup. The course of the disease was then prospectively followed for up to 50 months. Virus-positive patients whose condition deteriorated were treated with interferon-alpha., Results: Of 77 patients, 20 (26%) had enterovirus-positive and 57 (74%) enterovirus-negative biopsy samples. During a mean follow-up period of 25.8 +/- 13.7 months, 1 patient in the enterovirus-positive group and 11 in the enterovirus-negative group died. Four patients in the enterovirus-negative group underwent heart transplantation (p < 0.05). The surviving 19 enterovirus-positive patients had a decrease in mean left ventricular end-diastolic diameter from 66 to 61 mm (p < 0.05) and a mean increase in left ventricular ejection fraction from 0.35 to 0.43 (p < 0.05). In contrast, enterovirus-negative patients had no significant change in end-diastolic diameter or left ventricular ejection fraction. Four patients in the enterovirus-positive group whose condition deteriorated were treated with a 6-month course of subcutaneous interferon-alpha (3 x 10(6) U every second day). This treatment induced hemodynamic improvement in all four patients and eliminated the persistent enteroviral infection in two., Conclusions: Enterovirus-positive patients have a better heart transplantation-free survival rate and hemodynamic course, with fewer histologic changes, than do enterovirus-negative patients. In addition, enterovirus-positive patients respond favorably to interferon-alpha treatment. These observations indicate that myocardial enteroviral infection with associated left ventricular dysfunction is a distinct disease entity with a benign course.

The relation of left ventricular (LV) diastolic filling with the clinical outcome in patients with idiopathic dilated cardiomyopathy (IDC) was examined. LV diastolic filling was assessed by Doppler echocardiography in 57 patients with IDC at the time that the diagnosis was established by angiocardiography. Patients were followed for 29 +/- 16 months. Fifteen patients died: 12 due to progressive congestive heart failure and 3 suddenly. Four other patients underwent cardiac transplantation because of progressive heart failure (1-year survival 86%). Patients who died of congestive heart failure or underwent cardiac transplantation had a steep increase and decrease in the early filling phase as compared with survivors; the peak early Doppler velocity was higher (0.84 +/- 0.16 vs 0.65 +/- 0.21 m/s; p < 0.005), and the deceleration time of the early velocity peak was shorter (117 +/- 26 vs 188 +/- 62 ms; p < 0.001) than in survivors. Surviving patients and those who died suddenly showed similar patterns of LV filling. Deceleration time and peak early Doppler velocity were the strongest predictors of survival as compared with systolic function and clinical status in a Cox proportional-hazards analysis. Patients with a shortened deceleration time (< or = 140 ms) had a significantly reduced 2-year survival rate of 52% (confidence interval 34 to 71%) as compared with those with a longer deceleration time (94%; confidence interval 89 to 98%) (p < 0.001). Evidence was presented for a relation between LV filling and survival in patients with IDC.

In idiopathic dilated cardiomyopathy (IDC), an impaired left ventricular filling as assessed by the Doppler echocardiographic mitral flow pattern is closely related to the severity of congestive heart failure. This study examined the relation of left ventricular filling and the clinical course of the disease in patients with a recent diagnostic procedure and initiation of medical therapy (group 1, n = 15) as compared with patients in a chronic stage of the disease (group 2, n = 24) with the diagnosis established > 1 year before. All patients had to be in sinus rhythm to facilitate the Doppler echocardiographic evaluation of left ventricular filling. The clinical status was assessed by the New York Heart Association classification and a heart failure score at baseline and after a period of 12 +/- 7 months. At baseline the ratio of the peak early/atrial Doppler velocities (VE/VA) was shifted toward the early diastole in group 1 as compared to group 2 (1.84 +/- 1.02 vs 1.12 +/- 0.55; p < 0.05). Symptoms of heart failure were more severe in group 1. During follow-up, VE/VA tended to decrease in group 1 from 1.84 +/- 1.02 to 1.35 +/- 1.03 (p = 0.07) and remained unchanged in group 2 (1.12 +/- 0.55 and 1.34 +/- 1.23; not significant). In a subgroup of 10 patients who underwent repeat right heart catheterization, the decrease of VE/VA coincided with a decrease of the pulmonary capillary wedge pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with heart failure are known to demonstrate periodic respiration (PR) during sleep. The factors causing PR are not well known. We therefore studied 20 patients (aged 18-66 years) with idiopathic dilated cardiomyopathy. Full-night polysomnography and evaluation of respiration and transcutaneous oxygen saturation were performed. Hypercapnic ventilatory response (HCVR) was evaluated during daytime. The patients showed PR for 25 +/- 26% (mean +/- standard deviation) of total sleep time. During PR, oxygen desaturated 7.1 +/- 4.6%. Sleep was impaired. HCVR was normal. Oxygen desaturation during PR was predicted by HCVR (r = 0.47, P < 0.05) and left atrial diameter (r = 0.60, P < 0.05). The time period of PR expressed as a fraction of total sleep time was correlated with HCVR (r = 0.45, P < 0.05) and left atrial diameter (r = 0.51, P < 0.05). In conclusion, PR with oxygen desaturation, arousals, and impaired sleep was observed in stable heart failure. HCVR and left heart dimensions were related to PR. These findings confirm the concept of a feedback loop describing respiratory control in PR.

The myocardial uptake of indium-111 antimyosin indicates the presence of ongoing myocyte damage. To evaluate the role of this finding in patients with idiopathic dilated cardiomyopathy (IDC), 36 patients were studied by planar and SPECT antimyosin imaging. The diagnosis of IDC was based on coronary angiography and left ventricular endomyocardial biopsy. The antimyosin scan was evaluated qualitatively from SPECT images and assessed quantitatively by a count density index (CDI) which measured the tracer activity over the heart relative to the lung and sternal region (normal value less than 1.20). Group 1 consisted of 13 patients (36%) with an increased myocardial antimyosin uptake, while 23 patients had a normal antimyosin scan (group 2). Clinical data, pulmonary artery pressures, gated blood pool ejection fraction and histomorphometry of endomyocardial biopsies were similar in both groups. During a follow-up of 21 +/- 12 months there were two cardiac deaths in group 1 and 10 deaths in group 2 (P = 0.12). The 2-year survival rate was 81% and 59%, respectively. During follow-up, there was no significant change in haemodynamic parameters in either group, but there was a slight improvement in functional NYHA class in group 1 (P < 0.05). No association was found between the presence of myocardial enterovirus infection, determined in 17 patients by in situ hybridization and the antimyosin scan (P = 0.5 g). Myocardial antimyosin uptake was found in a high percentage of patients with IDC, indicating ongoing myocyte damage. This finding was not related to any clinical, haemodynamic, morphological parameter, or enterovirus infection. Myocyte damage is a distinct feature in a subgroup of patients with IDC unrelated to any known causes of myocellular destruction. This subgroup showed a trend towards a more favourable clinical outcome.

Doppler echocardiography and radionuclide angiography were shown to provide valuable tools with comparable functional parameters for the noninvasive assessment of left ventricular (LV) diastolic function in patients with coronary artery disease or LV hypertrophy. In order to examine the influence of an impaired systolic function on both methods, we studied LV filling simultaneously by Doppler echocardiography and radionuclide angiography in 47 patients with idiopathic dilated cardiomyopathy and stable sinus rhythm. The Doppler echocardiographic peak velocities (VE, VA) and radionuclide angiographic peak filling rates (PFRFF, PFRA) normalized to either left ventricular enddiastolic volume or stroke volume were measured and systolic function was assessed by obtaining the ejection fraction (EF) with the radionuclide angiography. Patients were divided into two groups with moderately (group 1: EF > or = 35%) or severely impaired (group 2: EF < 35%) systolic function. In group 2 the PFRFF (1.8 +/- 0.5 vs. 3.3 +/- 0.8 SV/s; p < 0.01) and PFRA (1.2 +/- 0.6 vs. 2.5 +/- 1.0 SV/s; p < 0.01) were both lower than in group 1, as was the Doppler echocardiographic VA (0.44 +/- 0.20 vs. 0.63 +/- 0.17 m/s; p < 0.01). However, VE was increased with reduced systolic function (0.75 +/- 0.20 vs. 0.53 +/- 0.16 m/s; p < 0.01). No relation was found between PFRFF and VE and only a weak relation between the atrial filling parameters of Doppler echocardiography and radionuclide angiography. The peak filling rates were closely correlated with the systolic function (PFRFF:r = 0.86; p < 0.001) and were reduced with an impaired systolic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Many physicians assume that a reliable diagnosis of idiopathic dilated cardiomyopathy can be made by noninvasive methods, mainly echocardiography. On the other hand, use of endomyocardial biopsy in those patients who have undergone left heart catheterization and who demonstrate left ventricular dysfunction of unknown origin is increasing. Therefore the purpose of this study was to investigate the yield of that diagnostic strategy in patients with the tentative diagnosis of idiopathic dilated cardiomyopathy. Between 1980 and 1988, 3.2% of our 15,442 patients were diagnosed as having idiopathic dilated cardiomyopathy on the basis of left heart catheterizations and coronary angiograms. Idiopathic dilated cardiomyopathy was diagnosed in 444 patients on the basis of clinical data and results of noninvasive tests before catheterization, but in only 295 of these cases was the diagnosis confirmed by means of coronary angiography and left heart catheterization (predictive value of noninvasive tests is 66%). The remaining 34% of patients demonstrated extensive coronary artery disease (13%), significant valvular heart disease (11%), and other or no heart disease (10%). The diagnostic sensitivity of noninvasive tools (patient history, ECG, stress test, echocardiography) was only 59%. Left heart catheterization can easily be combined with endomyocardial biopsy. With the use of histologic techniques, specific heart muscle diseases were detectable in 3.5% of 209 patients, but in only 1% could therapeutic consequences be determined. Thus coronary angiography and left heart catheterization are mandatory for the correct diagnosis of idiopathic dilated cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Diastolic ventricular function was assessed by Doppler echocardiography in 50 patients with idiopathic dilated cardiomyopathy (DCM) and sinus rhythm. The patients were subdivided into two groups with either a moderately reduced ejection fraction (less than 32%; group 1, n = 25) or a severely reduced ejection fraction (less than 32%; group 2, n = 25), the latter having an unfavorable prognosis. The degree of heart failure according to the NYHA classification was more pronounced in group 2 (p less than 0.05). Mean pulmonary capillary wedge pressure (PCm) was also higher in group 2 (gr. 1:9.8 +/- 5.5 vs. gr. 2: 16.2 +/- 8.9; p less than 0.02), and the morphological parameters obtained by conventional M-mode echocardiography showed increased left ventricular volumes and mass in both groups with DCM, as compared with a control group (n = 16); there was a reduced volume/mass ratio in group 2. The parameters of systolic function derived from M-mode and Doppler echocardiography were reduced in patients with DCM, but were more pronounced in group 2. Doppler parameters of diastolic ventricular filling were differently affected in both groups with DCM. In group 1 there was a reduced contribution of the early diastolic phase to ventricular filling (FE/FA) (contr.: 2.29 +/- 0.99 vs gr. 1: 1.40 +/- 0.45; p less than 0.05) and a reduced early peak Doppler velocity, indicating an impaired ventricular relaxation. In group 2, as compared with controls and group 1, there was an increased ratio of early/late diastolic peak velocities (VE/VA) (contr.: 1.49 +/- 0.54 vs gr. 2: 2.32 +/- 1.37; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The etiology of idiopathic dilated cardiomyopathy (DCM) is yet unknown; this study aimed at further differentiation of the disease by means of enzyme histochemistry. Endomyocardial biopsies from the left ventricle of 40 DCM patients and 5 control specimens had enzymes examined histochemically and semiquantitatively and analyzed according to staining intensities of nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR), succinate dehydrogenase, cytochrome c oxidase, lactate dehydrogenase and acid phosphatase (aPh). In DCM, the NADH-TR activity was elevated as compared to controls, indicating impaired mitochondrial oxidative phosphorylation. However, a concrete relation of enzyme histochemical intensity to anamnestic, hemodynamic or histomorphometric data could not be determined, except for the fact that the intensity of the lysosomal enzyme aPh was elevated in DCM patients with a relatively high left ventricular ejection fraction. The results demonstrate an interindependence of structural, hemodynamic and historical parameters as well as enzyme concentrations in DCM. Thus, a pathological change in the enzyme concentrations tested here cannot be responsible for the functional myocardial impairment in DCM.

The defects underlying the impairment of systolic pump function in human dilated cardiomyopathy (DCM) are not known. We isolated mitochondrial particles from 10 hearts of transplant recipients with DCM and from nine normal hearts not used for transplantation. Yield was similar in both groups (2.77 vs 2.81 mg mitochondrial protein per gram heart). Cytochrome content (difference spectrophotometry) was found reduced in DCM mitochondria, e.g. cytochrome c was 0.295 +/- 0.06 in the DCM group and 0.371 +/- 0.04 mumol g-1 in the control group (P less than 0.05). Enzymatic activity of the cytochrome-containing complexes III (3.77 +/- 0.82 vs 4.95 +/- 1.15 mumol min-1.mg-1) and IV (2.63 +/- 0.96 vs 3.65 +/- 0.6 mumol min-1.mg-1) of the respiratory chain was reduced in the DCM group (P less than 0.05). Complex IV, the cytochrome c oxidase, in the DCM group showed impaired activity also in whole heart homogenates (0.173 +/- 0.04 vs 0.258 +/- 0.8 mumol min-1.mg-1). Subunit composition of the cytochrome c oxidase on sodium dodecyl sulphate-gel electrophoresis did not differ between DCM and normal hearts. Activity of complexes II and V of the respiratory chain, not containing cytochromes, was unchanged in DCM mitochondria compared with the control group. The present data show a decrease in cytochrome content and in cytochrome-dependent enzyme activity in human dilated cardiomyopathy. Further studies are necessary to clarify whether these findings are specific for dilated cardiomyopathy or whether they are epiphenomena of failing hearts.

There is increasing evidence that sarcolemmal disorders in idiopathic dilated cardiomyopathy (IDC), due either to viral infection, catecholamine excess, ethanol intoxication, microcirculatory disorders, or autoimmune responses, induce enhanced Ca2+ inflow. This may lead to mitochondrial Ca2+ accumulation and activation of phospholipase and proteases, resulting in left ventricular dysfunction. The acute beneficial hemodynamic response to diltiazem in IDC patients, in comparison to other calcium blockers, enabled us to perform an open trial investigating the effects of chronic diltiazem (60-90 mg t.i.d.) in patients with IDC. The results of this trial suggested that adjunctive diltiazem in IDC had beneficial effects on mortality, hemodynamics, and symptoms. Thus a multicenter, double-blind, placebo-controlled trial was initiated.

To prove the use of Doppler-echocardiography in the determination of cardiac output during supine bicycle exercise, 14 patients suffering from dilatative cardiomyopathy were studied. Cardiac output was simultaneously determined by Doppler-echocardiography and with radionuclide ventriculography. In some cases, cardiac output was additionally measured using the thermodilution technique. In 12 patients (success rate 86%) flow velocity signals from the ascending aorta could be recorded with sufficient quality. Both methods were closely correlated, the r-value was 0.91 and the standard error of estimate was found to be 2.09 l/min. Mean deviation was 1.50 l/min (0.09-5.45 l/min) or 13% (1%-64%) respectively. For changes in cardiac output with exercise, the correlation was r = 0.88 with a mean deviation of 69% (2%-453%). The coefficient of variation for exercise measurements was 19% and did not differ from the resting value of 20%. Comparing the mean values of the whole group, no differences between the two methods could be found at rest, during exercise or for changes from rest to maximal exercise. Using the suprasternal approach, aortic flow velocities can be assessed by Doppler-echocardiography during exercise. Gross estimation of cardiac output during exercise seems possible; judgement of changes in cardiac output in individual cases appears to be uncertain.

There is increasing evidence that chronic enhanced exogenous or endogenous catecholamine stimulation in patients with dilated cardiomyopathy may worsen hemodynamic status and prognosis. The cause of this deterioration may lie in myocellular calcium accumulation and microcirculatory disorders. In a prospective study, the calcium channel antagonist diltiazem was given to 22 patients with dilated cardiomyopathy (60 to 90 mg three times daily) in addition to conventional therapy of digitalis, diuretics and vasodilators. Twenty-five patients received the conventional therapy and served as historical controls. Eight additional patients who were not originally included in this control group received adjunctive diltiazem treatment after initially receiving conventional therapy alone. The three patient groups were similar in all hemodynamic and anamnestic features. Only patients with reduced myofibrillar volume fraction on myocardial biopsy were included in the trial, because they could be expected to show hemodynamic deterioration. The mean survival time was 29 months in the control group, whereas no patient in the diltiazem group died over a mean follow-up period of 15.4 months (p less than 0.001). Mean left ventricular ejection fraction increased from 0.34 to 0.44 (p less than 0.001) and New York Heart Association functional class improved significantly in the diltiazem group and during the diltiazem period in the crossover patients, but deteriorated in the control group. The results suggest that adjunctive diltiazem treatment in dilated cardiomyopathy has beneficial effects on mortality, hemodynamics and symptoms.

There is increasing evidence that chronic enhanced exogenic or endogenic catecholamine stimulation in patients with dilated cardiomyopathy may worsen hemodynamics and prognosis. The cause of this may lie in myocellular calcium accumulation and microcirculatory disorders. In a prospective study the calcium antagonist diltiazem was given to 22 patients with dilated cardiomyopathy (60-90 mg t.i.d.) in addition to conventional therapy of digitalis, diuretics, and vasodilators. Twenty-five patients received the conventional therapy and served as historical controls. Eight additional patients who were not originally included in the 25 controls changed over from conventional therapy to adjunctive diltiazem treatment. The patient groups compared were similar in all hemodynamic and anamnestic features. Further, only patients with reduced myofibril volume fraction in the myocardial biopsy were included in the trial, since hemodynamic deterioration could be expected in them. The mean survival rate was 29 months in the controls, while within a mean of 15.4 months no patient died in the diltiazem group (p less than 0.001). Mean left ventricular ejection fraction increased from 0.34 to 0.44 (p less than 0.001) and the New York Heart Association classification was significantly improved in the diltiazem group and during the diltiazem period in the crossovers, but deteriorated in the controls. Therefore, the results suggest that adjunctive diltiazem treatment in dilated cardiomyopathy has beneficial effects on letality, hemodynamics, and symptoms.

Human hearts with dilated cardiomyopathy (DCM) exhibit a hypertrophy of the myocytes; consequently, the intercapillary distance increases, which may impede the diffusionable metabolic supply. Therefore in the following study the microcirculation of living human hearts with DCM, excised during cardiac transplantation, was investigated. The hearts were reperfused with a FITC-stained salt-solution, this allowed the precise detection of all plasma perfused capillaries. Thus, functional capillary density, capillary distribution and its effect on oxygen supply could be determined. In eight human hearts, the average functional capillary density amounted to 1245 +/- 345 capillaries/mm2, while 50% of the tissue was within 12 micron from the nearest capillary. However, a small portion of the tissue (1%) might become anoxic under the assumption of a simple oxygen diffusion model. The results favor the view that capillary density is low in human DCM and tissue is at the border of hypoxia.

The hemodynamic courses of 56 patients with congestive cardiomyopathy (CCM) were investigated. Fourteen patients died within 24 months after diagnosis. The hemodynamic courses of the remaining 42 patients were investigated in subsequent examinations by determination of left ventricular ejection fraction (LVEF), mean pulmonary arterial pressure at maximal workload, and peak systolic pressure/end-systolic volume index. During the study interval of 32.2 +/- 20.0 months the conditions of 20 patients (48%) deteriorated, according to their hemodynamic status, and at least five of these died of terminal heart failure. Surprisingly, the conditions of 22 patients (52%) improved or stabilized. One of these died of leukemia. Seven patients in the latter group with initial LVEFs of 0.30 or less experienced an average increase from 0.22 to 0.51. Retrospectively consideration of age, alcohol intake, exercise capacity, and hemodynamic status were not helpful in predicting the course of the disease. In 38 patients endomyocardial biopsy samples could be obtained at the time of diagnosis. Reduced myofibril volume fraction (less than 60%) had prognostic significance for both hemodynamic deterioration and death (sensitivity 23/24 = 96%), while 14 of 15 patients whose conditions improved or stabilized had a myofibril volume fraction of 60% or more (specificity 14/15 or 93%, p less than .002). A relationship between hemodynamic status and the myofibril volume fraction could not be found. Individual patients with CCM differ significantly with respect to course of the disease. A distinct separation of the patients by means of morphologic criteria is possible. This makes it more likely that the pathogenesis of the disease is not unique.

In order to assess the occurrence and clinical significance of abnormal electrograms in idiopathic dilated cardiomyopathy, endocardial electrode mapping during sinus rhythm and programmed ventricular stimulation were performed in 52 patients with or without clinical ventricular tachycardia. Abnormal endocardial electrograms were recorded in 77% of the patients and were diffusely distributed over the entire left ventricular endocardium. No relation could be established between the occurrence of late potentials or fractionations and clinical or induced arrhythmias. Endomyocardial biopsy samples were taken from 20 patients and showed that reduced myofibril volume fraction was related to the occurrence of abnormal endocardial electrograms. Neither induced arrhythmias nor the presence of late potentials or fractionations identified patients who died of sudden cardiac death during the mean (SD) follow up of 33 (11) months. Thus abnormal endocardial electrograms recorded during sinus rhythm in idiopathic dilated cardiomyopathy may only be interpreted as being a sign of damage to the myocardial cells.

High doses of verapamil, diltiazem or nifedipin were administered to three groups of eight patients each, with severely abnormal left-ventricular (LV) function (mean ejection fraction 0.29). Various haemodynamic measurements were made immediately before and 30 minutes after drug administration: LV ejection fraction, ratio of peak systolic pressure to endsystolic volume index, stroke index, pulmonary capillary closing pressure, and maximal diastolic filling rate. None of these were reduced. In fact, ejection fraction rose by a mean of 0.05, stroke index by a mean of 5 ml/m2, while p.c. closing pressure and contractility did not alter significantly. Verapamil and diltiazem reduced the pressure X rate product (an important determinant of oxygen consumption); nifedipine reduced total systemic resistance. It is concluded that verapamil and diltiazem can be used with advantage in cases of unstable angina, if there are severe abnormalities of LV function; they are to be preferred to beta-blockers in this situation. Nifedipin is the calcium antagonist of choice in hypertension and abnormal LV function.