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Background: Risk stratification for ventricular arrhythmias (VA) and sudden death in nonischemic dilated cardiomyopathy (DCM) remains suboptimal., Objectives: The goal of this study was to provide an improved risk stratification algorithm for VA and sudden death in DCM., Methods: This was a retrospective cohort study of consecutive patients with DCM who underwent cardiac magnetic resonance with late gadolinium enhancement (LGE) at 2 tertiary referral centers. The combined arrhythmic endpoint included appropriate implantable cardioverter-defibrillator therapies, sustained ventricular tachycardia, resuscitated cardiac arrest, and sudden death., Results: In 1,165 patients with a median follow-up of 36 months, LGE was an independent and strong predictor of the arrhythmic endpoint (hazard ratio: 9.7; p < 0.001). This association was consistent across all strata of left ventricular ejection fraction (LVEF). Epicardial LGE, transmural LGE, and combined septal and free-wall LGE were all associated with heightened risk. A simple algorithm combining LGE and 3 LVEF strata (i.e., ≤20%, 21% to 35%, >35%) was significantly superior to LVEF with the 35% cutoff (Harrell's C statistic: 0.8 vs. 0.69; area under the curve: 0.82 vs. 0.7; p < 0.001) and reclassified the arrhythmic risk of 34% of patients with DCM. LGE-negative patients with LVEF 21% to 35% had low risk (annual event rate 0.7%), whereas those with high-risk LGE distributions and LVEF >35% had significantly higher risk (annual event rate 3%; p = 0.007)., Conclusions: In a large cohort of patients with DCM, LGE was found to be a significant, consistent, and strong predictor of VA or sudden death. Specific high-risk LGE distributions were identified. A new clinical algorithm integrating LGE and LVEF significantly improved the risk stratification for VA and sudden death, with relevant implications for implantable cardioverter-defibrillator allocation., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood., Objectives: The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients., Methods: A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF)., Results: A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction., Conclusions: Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to establish the incidence of and risk factors for sudden cardiac death (SCD) in pediatric dilated cardiomyopathy (DCM)., Background: The incidence of SCD in children with DCM is unknown. The ability to predict patients at high risk of SCD will help to define who may benefit most from implantable cardioverter-defibrillators., Methods: The cohort was 1,803 children in the PCMR (Pediatric Cardiomyopathy Registry) with a diagnosis of DCM from 1990 to 2009. Cumulative incidence competing-risks event rates were estimated. We achieved risk stratification using Classification and Regression Tree methodology., Results: The 5-year incidence rates were 29% for heart transplantation, 12.1% non-SCD, 4.0% death from unknown cause, and 2.4% for SCD. Of 280 deaths, 35 were SCD, and the cause was unknown for 56. The 5-year incidence rate for SCD incorporating a subset of the unknown deaths is 3%. Patients receiving antiarrhythmic medication were at higher risk of SCD (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.3, p = 0.025). A risk stratification model based on most recent echocardiographic values had 86% sensitivity and 57% specificity. Thirty of 35 SCDs occurred in patients who met all these criteria: left ventricular (LV) end-systolic dimension z-score >2.6, age at diagnosis younger than 14.3 years, and the LV posterior wall thickness to end-diastolic dimension ratio <0.14. Sex, ethnicity, cause of DCM, and family history were not associated with SCD., Conclusions: The 5-year incidence rate of SCD in children with DCM is 3%. A risk stratification rule (86% sensitivity) included age at diagnosis younger than 14.3 years, LV dilation, and LV posterior wall thinning. Patients who consistently meet these criteria should be considered for implantable cardioverter-defibrillator placement., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

To varying extents, women with pre-existing cardiomyopathies have a limited cardiovascular reserve. The hemodynamic challenges of pregnancy, labor, and delivery pose unique risks to this group of patients, which can result in clinical decompensation with overt heart failure, arrhythmias, and rarely, maternal death. A multidisciplinary team approach and a controlled delivery are crucial to adequate management of patients with underlying heart disease. Pre-conception planning and risk assessment are essential, and proper counseling should be offered to expectant mothers with regard to both the risks that pregnancy poses and the implications for future offspring. In this article, we will review the hemodynamic stressors that pregnancy places upon women with pre-existing cardiomyopathies and risk assessment and discuss what evidence exists with regard to the management of 2 forms of cardiomyopathy during pregnancy, labor, and delivery: dilated and hypertrophic cardiomyopathy., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to identify the remodeling parameters cardiomyocyte (CM) damage or death, hypertrophy, and fibrosis that may be linked to outcomes in patients with advanced heart failure (HF) in an effort to understand the pathogenic mechanisms of HF that may support newer therapeutic modalities., Background: There are controversial results on the influence of fibrosis, CM hypertrophy, and apoptosis on outcomes in patients with HF; other modalities of cell damage have been poorly investigated., Methods: In endomyocardial biopsy specimens from 100 patients with idiopathic dilated cardiomyopathy and advanced HF, CM diameter and the extent of fibrosis were determined by morphometry. The proportion of CMs with evidence of apoptosis, autophagic vacuolization (AuV), and oncosis was investigated by immunohistochemical methods and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling. Those parameters were correlated with mortality in 3 years of follow-up by univariate analysis and with multivariate models incorporating the clinical variables more relevant to the prediction of outcomes., Results: CM AuV occurred in 28 patients (0.013 ± 0.012%) and oncosis in 41 (0.109 ± 0.139%). Nineteen patients showed both markers. Apoptotic CM nuclei were observed in 3 patients. In univariate analysis, CM diameter and AuV, either alone or associated with oncosis, were predictors of mortality. In multivariate analysis, CM diameter (hazard ratio: 1.37; 95% confidence interval: 1.12 to 1.68; p = 0.002) and simultaneous presence in the same endomyocardial biopsy specimen of AuV and oncosis (hazard ratio: 2.82; 95% confidence interval: 1.12 to 7.13; p = 0.028) were independent predictors of mortality., Conclusions: CM hypertrophy and AuV, especially in association with oncosis, are predictors of outcome in patients with idiopathic dilated cardiomyopathy and severe HF., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study was designed to test the effects of n-3 polyunsaturated fatty acids (PUFAs) on left ventricular (LV) systolic function in chronic heart failure (HF) due to nonischemic dilated cardiomyopathy (NICM)., Background: One hundred thirty-three patients with NICM and minimal symptoms on standard therapy were randomized to 2 g of n-3 PUFAs or placebo. LV function and functional capacity were assessed prospectively by echocardiography and cardiopulmonary exercise testing at baseline and at 12 months after randomization., Methods: Patients with chronic HF due to NICM and minimal symptoms while receiving evidence-based therapy were enrolled. LV function and functional capacity were assessed prospectively by echocardiography, cardiopulmonary exercise test, and New York Heart Association functional class at baseline and at 12 months after randomization to either 2 g of n-3 PUFAs or placebo., Results: At 12 months after randomization, the n-3 PUFAs group and the placebo group differed significantly (p <0.001) in regard to: 1) LV ejection fraction (increased by 10.4% and decreased by 5.0%, respectively); 2) peak VO(2) (increased by 6.2% and decreased by 4.5%, respectively); 3) exercise duration (increased by 7.5% and decreased by 4.8%, respectively); and 4) mean New York Heart Association functional class (decreased from 1.88 ± 0.33 to 1.61 ± 0.49 and increased from 1.83 ± 0.38 to 2.14 ± 0.65, respectively). The hospitalization rates for HF were 6% in the n-3 PUFAs and 30% in the placebo group (p = 0.0002)., Conclusions: In patients with NICM and minimal symptoms in response to evidence-based medical therapy, n-3 PUFAs treatment increases LV systolic function and functional capacity and may reduce hospitalizations for HF. Given these promising results, larger studies are in order to confirm our findings., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine whether T-wave alternans (TWA) induced by anger in a laboratory setting predicts future ventricular arrhythmias in patients with implantable cardioverter-defibrillators (ICDs)., Background: Anger can precipitate spontaneous ventricular tachycardia/ventricular fibrillation and induce TWA. Whether anger-induced TWA predicts future arrhythmias is unknown., Methods: Sixty-two patients with ICDs underwent ambulatory electrocardiography during a mental stress protocol, 3 months after the ICD was implanted. T-wave alternans was analyzed using time-domain methods. After a > or =1 year follow-up, ICD stored data was reviewed to determine incidence of ICD-terminated ventricular tachycardia/ventricular fibrillation., Results: Patients with ICD-terminated arrhythmias during follow-up (n = 10) had higher TWA induced by anger, 13.2 microV (interquartile range [IQR] 9.3 to 16 microV), compared with those patients without future ventricular arrhythmias, 9.3 microV (IQR 7.5 to 11.5 microV, p < 0.01). Patients in the highest quartile of anger-induced TWA (>11.9 microV, n = 15) were more likely to experience arrhythmias by 1 year than those in the lower quartiles (33% vs. 4%) and during extended follow-up (40% vs. 9%, p < 0.01 for both). In multivariable regression controlling for ejection fraction, prior clinical arrhythmia, and wide QRS, anger-induced TWA remained a significant predictor of arrhythmia, with likelihood in the top quartile 10.8 times that of other patients (95% confidence interval: 1.6 to 113, p < 0.05)., Conclusions: Anger-induced TWA predicts future ventricular arrhythmias in patients with ICDs, suggesting that emotion-induced repolarization instability may be 1 mechanism linking stress and sudden death. Whether there is a clinical role for anger-induced TWA testing requires further study.

Objectives: This study sought to evaluate whether increased left ventricular (LV) adenylyl cyclase VI (AC(VI)) expression, at a time when severe congestive heart failure (CHF) was present, would increase function of the actively failing heart., Background: Increased LV AC(VI) content markedly reduces mortality and increases LV function after acute myocardial infarction (MI) in mice. However, the effects of increased cardiac AC(VI) content in the setting of severe heart failure caused by ischemic cardiomyopathy are unknown., Methods: Mice with cardiac-directed and regulated expression of AC(VI) underwent coronary artery ligation to induce severe CHF 5 weeks later. AC(VI) expression was then activated in 1 group (AC-On) but not the other (AC-Off). Multiple measures of LV systolic and diastolic function were obtained 5 weeks later, and LV samples were assessed for alterations in calcium and beta-adrenergic receptor signaling, apoptosis, and cardiac troponin I phosphorylation., Results: The LV systolic and diastolic function was increased 5 weeks after activation of AC(VI) expression. Improved LV function was associated with normalization of cardiac troponin I phosphorylation and reduced apoptosis., Conclusions: Activation of cardiac AC(VI) expression in mice with ischemic cardiomyopathy and severe CHF improves function of the failing heart.

Objectives: We studied the prognostic implications of midwall fibrosis in dilated cardiomyopathy (DCM) in a prospective longitudinal study., Background: Risk stratification of patients with nonischemic DCM in the era of device implantation is problematic. Approximately 30% of patients with DCM have midwall fibrosis as detected by late gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR), which may increase susceptibility to arrhythmia and progression of heart failure., Methods: Consecutive DCM patients (n = 101) with the presence or absence of midwall fibrosis were followed up prospectively for 658 +/- 355 days for events., Results: Midwall fibrosis was present in 35% of patients and was associated with a higher rate of the predefined primary combined end point of all-cause death and hospitalization for a cardiovascular event (hazard ratio 3.4, p = 0.01). Multivariate analysis showed midwall fibrosis as the sole significant predictor of death or hospitalization. However, there was no significant difference in all-cause mortality between the 2 groups. Midwall fibrosis also predicted secondary outcome measures of sudden cardiac death (SCD) or ventricular tachycardia (VT) (hazard ratio 5.2, p = 0.03). Midwall fibrosis remained predictive of SCD/VT after correction for baseline differences in left ventricular ejection fraction between the 2 groups., Conclusions: In DCM, midwall fibrosis determined by CMR is a predictor of the combined end point of all-cause mortality and cardiovascular hospitalization, which is independent of ventricular remodeling. In addition, midwall fibrosis by CMR predicts SCD/VT. This suggests a potential role for CMR in the risk stratification of patients with DCM, which may have value in determining the need for device therapy.

Objectives: We sought to determine whether the presentation and prognosis of children with complete atrioventricular block (CAVB) were related to maternal antibody status., Background: Comparative studies related to the presence or absence of maternal antibodies anti-SSB/La and anti-SSA/Ro are lacking in children with isolated complete CAVB., Methods: From 1980 to 2004, we screened for maternal antibodies in 111 children <15 years old with CAVB. According to the presence (Ab+) or absence (Ab-) of antibodies, 2 groups of patients were retrospectively compared., Results: The study group included 56 Ab+ and 55 Ab- patients with equal gender distribution. A total of 96% Ab+ patients were diagnosed in utero or within the first month, compared with 24% Ab- patients. Progression from incomplete to complete block was shown in 23 Ab- and 2 Ab+ patients. Echocardiography showed normal heart structures in Ab- patients, but 8 Ab+ patients had ostium secundum or ductus arteriosus. Pacemaker implantation was performed in 105 patients, and age at implantation was younger in the Ab+ group. At follow-up (age 9.7 +/- 6 years), all Ab- patients were alive with normal left ventricular function; dilated cardiomyopathy was diagnosed at diagnosis or during follow-up in 16 Ab+ patients, and 6 of 16 have died., Conclusions: Patients with antibody-mediated CAVB were diagnosed and underwent pacing earlier in life and had a more severe prognosis than Ab- patients because of a high risk of dilated cardiomyopathy. The absence of antibody suggests a different pathologic mechanism than autoimmunity, and the term congenital may be not appropriate in these cases.

Objectives: We sought to evaluate whether statins were associated with a survival benefit and significant attenuation in life-threatening arrhythmias in patients with nonischemic dilated cardiomyopathy., Background: Statins are associated with a reduction in appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with coronary artery disease and improved clinical status in nonischemic dilated cardiomyopathy., Methods: The effect of statin use on time to death or resuscitated cardiac arrest and time to arrhythmic sudden death was evaluated in 458 patients enrolled in the DEFINITE (DEFIbrillators in Non-Ischemic cardiomyopathy Treatment Evaluation) study. The effect of statin use on time to first appropriate shock was analyzed only in the 229 patients who were randomized to ICD therapy., Results: The unadjusted hazard ratio (HR) for death among patients on versus those not on statin therapy was 0.22 (95% confidence interval [CI] 0.09 to 0.55; p = 0.001). When controlled for statin effects, ICD therapy was associated with improved survival (HR 0.61; 95% CI 0.38 to 0.99; p = 0.04). There was one arrhythmic sudden death in the 110 patients receiving statin therapy (0.9%) versus 18 of 348 patients not receiving statins (5.2%; p = 0.04). The unadjusted HR for arrhythmic sudden death among patients on versus those not on statin therapy was 0.16 (95% CI 0.022 to 1.21; p = 0.08). The HR for appropriate shocks among patients on versus those not on statin therapy was 0.78 (95% CI 0.34 to 1.82) after adjustment for baseline differences in the two groups., Conclusions: Statin use in the DEFINITE study was associated with a 78% reduction in mortality. This reduction was caused, in part, by a reduction in arrhythmic sudden death. These findings should be confirmed in a prospective, randomized clinical trial.

Objectives: This study sought to compare tissue Doppler imaging (TDI) with velocity-encoded (VE) magnetic resonance imaging (MRI) for left ventricular (LV) dyssynchrony assessment., Background: Cardiac resynchronization therapy (CRT) is proposed for patients with heart failure, depressed LV function, and a wide QRS complex. Selection is based mainly on electrocardiogram criteria, but recent data suggest that intraventricular dyssynchrony may be preferred for selection. An LV dyssynchrony can adequately be assessed with TDI, but this has not been compared directly with other imaging modalities. A VE MRI potentially allows direct myocardial wall motion measurements similar to TDI., Methods: Twenty patients with heart failure, systolic LV dysfunction, and a wide QRS complex were included, as well as 10 normal individuals with normal QRS duration and LV function. The TDI and VE MRI data were acquired to study intraventricular dyssynchrony., Results: Left ventricular dyssynchrony was not observed in normal individuals (mean dyssynchrony -2 +/- 15 ms on TDI; mean -5 +/- 17 ms on MRI, p = NS). In patients, mean LV dyssynchrony was 55 +/- 37 ms on TDI; 49 +/- 38 ms on MRI (p = NS). Good correlation between both modalities was observed (linear regression TDI = 0.99 x MRI - 5, n = 30, r = 0.98, p < 0.01). The MRI showed a small, nonsignificant underestimation of 5 +/- 8 ms compared with TDI. Agreement between MRI and TDI for classification according to severity of LV dyssynchrony (minimal, intermediate, and extensive) was excellent (kappa +/- SE = 0.96 +/- 0.07, p < 0.01) with 95% of patients classified identical., Conclusions: Both MRI and TDI yield comparable information on LV dyssynchrony; MRI is useful in the selection of patients for CRT.

Objectives: The relation between the occurrence of pacing-induced mechanical alternans and prognosis in patients with mild-to-moderate idiopathic dilated cardiomyopathy (IDCM) in sinus rhythm was investigated prospectively. The myocardial expression of genes for Ca2+-handling proteins in such patients was also examined., Background: Mechanical alternans occurs in some patients with severe heart failure, but the relation between the occurrence of mechanical alternans and prognosis in patients with IDCM has remained unknown., Methods: Left ventricular (LV) pressure was measured during atrial pacing, and LV endomyocardial biopsy specimens were collected in 36 IDCM patients and 8 controls. Idiopathic dilated cardiomyopathy patients were divided into two groups consisting of 22 individuals who did not develop mechanical alternans at heart rates up to 140 beats/min (group A) and of 14 individuals who did (group B). The patients were followed up for a mean of 3.7 years., Results: There was no significant difference in LV ejection fraction or the plasma concentration of brain natriuretic peptide between groups A and B. The myocardial abundance of ryanodine receptor 2 messenger ribonucleic acid (mRNA) was significantly lower in groups A and B than in controls, whereas that of sarcoplasmic reticulum Ca2+-ATPase mRNA was significantly lower in group B than in group A or controls. Stepwise multivariate analysis identified pacing-induced mechanical alternans as the strongest predictor of cardiac events. Event-free survival in group A was significantly greater than that in group B., Conclusions: The occurrence of pacing-induced mechanical alternans is a potentially useful indicator of poor prognosis in patients with mild-to-moderate IDCM in sinus rhythm.

Objectives: To compare the incidence of diastolic and systolic asynchrony, assessed by tissue Doppler imaging (TDI), in patients with congestive heart failure (CHF) and severe left ventricular (LV) dysfunction, and to assess TDI changes induced by cardiac resynchronization therapy (CRT)., Background: Thirty percent of CRT candidates are nonresponders. Besides QRS width, the presence of echographic systolic asynchrony has been used to identify future responders. Little is known about diastolic asynchrony and its change after CRT., Methods: Tissue Doppler imaging was performed in 116 CHF patients (LV ejection fraction 26 +/- 8%). Systolic and diastolic asynchrony was calculated using TDI recordings of right ventricular and LV walls., Results: The CHF group consisted of 116 patients. Diastolic asynchrony was more frequent than systolic, concerning both intraventricular (58% vs. 47%; p = 0.0004) and interventricular (72 vs. 45%; p < 0.0001) asynchrony. Systolic and diastolic asynchrony were both present in 41% patients, but one-third had isolated diastolic asynchrony. Although diastolic delays increased with QRS duration, 42% patients with narrow QRS presented with diastolic asynchrony. Conversely, 27% patients with large QRS had no diastolic asynchrony. Forty-two patients underwent CRT. Incidence of systolic intraventricular asynchrony decreased from 71% to 33% after CRT (p < 0.0001), but diastolic asynchrony decreased only from 81% to 55% (p < 0.0002). Cardiac resynchronization therapy induced new diastolic asynchrony in eight patients., Conclusions: Diastolic asynchrony is weakly correlated with QRS duration, is more frequent than systolic asynchrony, and may be observed alone. Diastolic asynchrony is less improved by CRT than systolic. Persistent diastolic asynchrony may explain some cases of lack of improvement after CRT despite good systolic resynchronization.

Objectives: We hypothesized that some aspects of left ventricular assist device (LVAD) reverse remodeling could be independent of hemodynamic factors and would primarily depend upon normalization of neurohormonal milieu., Background: The relative contributions of LVAD-induced hemodynamic unloading (provided to the left ventricle [LV]) and normalized neurohormonal milieu (provided to LV and right ventricle [RV]) to reverse remodeling are not understood., Methods: Structural and functional characteristics were measured from hearts of 65 medically managed transplant patients (MED), 30 patients supported with an LVAD, and 5 nonfailing donor hearts not suitable for transplantation., Results: Compared with MED patients, diastolic pulmonary pressures trended lower (p < 0.01) and cardiac output higher (p < 0.001) in LVAD patients; V(30) (ex vivo ventricular volume yielding 30 mm Hg, an index of ventricular size) in LVAD patients was decreased in the LV (p < 0.05) but did not change significantly in RV. The LVAD support improved force generation in response to beta-adrenergic stimulation in isolated LV (increase in developed force from 6.3 +/- 0.6 to 18.5 +/- 4.4 mN/m(2), p < 0.01) and RV (increase in developed force, from 10.9 +/- 2.0 to 20.5 +/- 3.1 mN/m(2), p < 0.05) trabeculae. The LVAD patients had higher myocardial beta-adrenergic receptor density in LV (p < 0.01) and RV (p < 0.01). Protein kinase A (PKA) hyperphosphorylation of the ryanodine receptor 2 (RyR2)/calcium release channel was significantly reduced by LVAD in both RV and LV (p < 0.01)., Conclusions: Improved beta-adrenergic responsiveness, normalization of the RyR2 PKA phosphorylation, and increased beta-adrenergic receptor density in LV and RV after LVAD support suggest a primary role of neurohormonal environment in determining reverse remodeling of the beta-adrenergic pathway.

Objectives: This study evaluated the causes of syncope and the significance and differences in left ventricular (LV) dysfunction, coronary disease, and idiopathic dilated cardiomyopathy (DCM)., Background: Risk stratification of and indications for an automated defibrillator could differ according to the cause of LV dysfunction., Methods: Electrophysiologic study, including atrial and ventricular programmed stimulation, was performed in 119 patients with coronary disease (group I) and 61 patients with DCM (group II) with an left ventricular ejection fraction (LVEF) <40% and syncope. Patients were followed from one to six years (mean 4 +/- 2 years)., Results: Sustained monomorphic ventricular tachycardia (VT) was induced in 44 group I patients (37%) and 13 group II patients (21%); ventricular flutter (>270 beats/min) or ventricular fibrillation (VF) was induced in 24 group I patients (19%) and 9 group II patients (15%); and various other arrhythmias were identified. Syncope remained unexplained in 34 group I patients (30%) and 16 group II patients (27%). Prognosis depended on the heart disease: VT or VF induction was a predictive factor of mortality in coronary disease and identified a group with high cardiac mortality (46%), compared with patients with a negative study, who had a lower mortality (6%; p < 0.001) than in other studies. Cardiac mortality was only correlated with LVEF in DCM., Conclusions: Various causes could explain syncope in 70% of patients with coronary disease and DCM, but differences were noted: VT was frequent in coronary disease with a bad prognosis, and ischemia could explain syncope; in DCM, different causes such as atrial tachycardia could be responsible for syncope, but the prognosis only depended on LVEF.

Objectives: The purpose of this study was to evaluate the occurrence, locations, and relationship of ventricular tachycardia (VT) to low-voltage areas in dilated cardiomyopathy (DCM)., Background: The substrate causing monomorphic VT after infarction is characterized by regions of low-voltage (<1.5 mV) scar on electroanatomic maps. The substrate causing VT associated with DCM is less well defined., Methods: A total of 28 patients were studied with endocardial (26 patients) and epicardial (8 patients) electroanatomic mapping. The VT circuits were defined by entrainment or pace mapping., Results: Ventricular tachycardia was due to focal VT in 5, bundle-branch re-entry in 2, and myocardial re-entry in 22 patients (both focal and re-entry VTs in 1 patient). All patients with myocardial re-entry had endocardial (20 of 20 patients) and/or epicardial (7 of 7 patients mapped) scar. Most (63%) endocardial scars were adjacent to a valve annulus. Of the 19 VT circuit isthmuses identified, 12 were associated with an endocardial scar and 7 with an epicardial scar. All myocardial re-entrant VTs were abolished in 12 of 22 patients, and inducible VT was modified in 4 patients. During follow-up of 334 +/- 280 days, 54% of patients with myocardial re-entry were free of VT despite frequent episodes before ablation., Conclusions: The VTs in DCM are most commonly the result of myocardial re-entry associated with scar. Scars are often adjacent to a valve annulus, deep in the endocardium, and can be greater in extent on the epicardium than on the endocardium. The use of epicardial mapping and radiofrequency is likely to improve success.

Objectives: We investigated the integrity of dystrophin in left ventricle (LV) and right ventricle (RV) of patients with end-stage heart failure due to ischemic cardiomyopathy (IHD) or dilated cardiomyopathy (DCM), and compared the efficacy of pulsatile or continuous flow assist devices on dystrophin reverse remodeling., Background: Recently we demonstrated that the amino (N)-terminus of dystrophin is preferentially disrupted in failing LV myocardium irrespective the underlying etiology, and that this defect is reversed by mechanical unloading using left ventricular assist device (LVAD) therapy., Methods: Myocardial samples were obtained from seven normal controls, seven failing hearts (either DCM or IHD), and 14 failing-heart patients who underwent placement of either pulsatile (7 patients) or continuous flow (7 patients) LVADs for progressive refractory HF. The expression and integrity of dystrophin in these samples were determined by immunohistochemistry using antibodies against the N-terminal and carboxyl (C)-terminal domains., Results: Immunohistochemical staining identified disruption of the N-terminal dystrophin in both LVs and RVs of all seven failing-heart patients, whereas the C-terminus was normal. Furthermore, this disruption was reversed in 12 of the 14 patients after LVAD therapy using either pulsatile or continuous devices; the degree of the reverse remodeling was similar in both ventricles, although greater recovery was noted in patients treated with pulsatile flow devices., Conclusions: Integrity of the N-terminus of dystrophin is a useful indicator of both LV and RV function. In addition to improving LV hemodynamics, LVAD therapy results in amelioration of the myocardial structure of the right cardiac chamber.

Objectives: The purpose of this study was to analyze cardiac tissue and blood for viral genomes using polymerase chain reaction (PCR) to define the common viral etiologies of myocarditis by age group., Background: Enteroviruses are considered the most common cause of myocarditis at all ages. Diagnosis relies on viral cultures, serology, and cardiac histology, which lack sensitivity, as well as PCR. However, in many cases enteroviruses are not detected., Methods: Cardiac samples were obtained for PCR analysis from patients with myocarditis (n = 624) and dilated cardiomyopathy (DCM) (n = 149). Patients were analyzed by age group, including neonates (n = 116), infants (n = 191), toddlers (n = 87), children (n = 110), adolescents (n = 92), and adults (n = 177). After nucleic acids had been extracted from an endomyocardial biopsy, an explant, or autopsy samples, PCR and reverse transcription PCR were performed to detect the genomic sequences of enterovirus, adenovirus, cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), parvovirus, respiratory syncytial virus (RSV), and influenza A virus., Results: Viral genome was amplified (adenovirus = 142, enterovirus = 85, CMV = 18, parvovirus = 6, influenza A = 5, HSV = 5, EBV = 3, RSV = 1) from 239 (38%) of the 624 samples from myocarditis patients, including 26 patient samples in which dual infection was found. Virus was detected in 30 (20%) of 149 DCM patient samples; only adenovirus (n = 18) and enterovirus (n = 12) were detected., Conclusions: Polymerase chain reaction identified adenovirus as the most common virus in the myocardium of children and adults with myocarditis and DCM. Although enteroviruses are also found in these patients, they appear to be a less common cause of myocarditis than adenovirus.

Objectives: This study was designed to evaluate the ability of microvolt-level T-wave alternans (MTWA) to identify prospectively patients with idiopathic dilated cardiomyopathy (DCM) at risk of ventricular tachyarrhythmic events and to compare its predictive accuracy with that of conventional risk stratifiers., Background: Patients with DCM are at increased risk of sudden death from ventricular tachyarrhythmias. At present, there are no established methods of assessing this risk., Methods: A total of 137 patients with DCM underwent risk stratification through assessment of MTWA, left ventricular ejection fraction, baroreflex sensitivity (BRS), heart rate variability, presence of nonsustained ventricular tachycardia (VT), signal-averaged electrocardiogram, and presence of intraventricular conduction defect. The study end point was either sudden death, resuscitated ventricular fibrillation, or documented hemodynamically unstable VT., Results: During an average follow-up of 14 +/- 6 months, MTWA and BRS were significant univariate predictors of ventricular tachyarrhythmic events (p < 0.035 and p < 0.015, respectively). Multivariate Cox regression analysis revealed that only MTWA was a significant predictor., Conclusions: Microvolt-level T-wave alternans is a powerful independent predictor of ventricular tachyarrhythmic events in patients with DCM.

Objectives: The purpose of this multicenter randomized trial was to compare total mortality during therapy with amiodarone or an implantable cardioverter-defibrillator (ICD) in patients with nonischemic dilated cardiomyopathy (NIDCM) and nonsustained ventricular tachycardia (NSVT)., Background: Whether an ICD reduces mortality more than amiodarone in patients with NIDCM and NSVT is unknown., Methods: One hundred three patients with NIDCM, left ventricular ejection fraction < or =0.35, and asymptomatic NSVT were randomized to receive either amiodarone or an ICD. The primary end point was total mortality. Secondary end points included arrhythmia-free survival, quality of life, and costs., Results: The study was stopped when the prospective stopping rule for futility was reached. The percent of patients surviving at one year (90% vs. 96%) and three years (88% vs. 87%) in the amiodarone and ICD groups, respectively, were not statistically different (p = 0.8). Quality of life was also similar with each therapy (p = NS). There was a trend with amiodarone, as compared to the ICD, towards improved arrhythmia-free survival (p = 0.1) and lower costs during the first year of therapy ($8,879 US dollars vs. $22,039 US dollars, p = 0.1)., Conclusions: Mortality and quality of life in patients with NIDCM and NSVT treated with amiodarone or an ICD are not statistically different. There is a trend towards a more beneficial cost profile and improved arrhythmia-free survival with amiodarone therapy.

Objectives: We studied the acute effects of cardiac resynchronization therapy (CRT) on functional mitral regurgitation in heart failure (HF) patients with left bundle branch block (LBBB)., Background: Both an decrease [corrected] in left ventricular (LV) closing force and mitral valve tethering have been implicated as mechanisms for functional mitral regurgitation (FMR) in dilated hearts. We hypothesized that an increase in LV closing force achieved by CRT could act to reduce FMR., Methods: Twenty-four HF patients with LBBB and FMR were studied after implantation of a biventricular CRT system. Acute changes in FMR severity between intrinsic conduction (OFF) and CRT were quantified according to the proximal isovelocity surface area method by measuring the effective regurgitant orifice area (EROA). Results were compared with the changes in estimated maximal rate of left ventricular systolic pressure rise (LV+dP/dt(max)) and transmitral pressure gradients (TMP), both measured by Doppler echocardiography., Results: Cardiac resynchronization therapy was associated with a significant reduction in FMR severity. Effective regurgitant orifice area decreased from 25 +/- 19 mm(2) (OFF) to 13 +/- 8 mm(2) (CRT). The change in EROA was directly related to the increase in LV+dP/dt(max) (r = -0.83, p < 0.0001). Compared with OFF, TMP increased more rapidly during CRT, and a higher maximal TMP was observed (OFF 73 +/- 24 mm Hg vs. CRT 85 +/- 26 mm Hg, p < 0.01)., Conclusions: Functional mitral regurgitation is reduced by CRT in patients with HF and LBBB. This effect is directly related to the increased closing force (LV+dP/dt(max)). The results support the hypothesis that an increase in TMP, mediated by a rise in LV+dP/dt(max) due to more coordinated LV contraction, may facilitate effective mitral valve closure.

Objectives: We explored whether there are gender differences in cardiac remodeling and whether etiology influences organ and cellular remodeling in advanced heart failure (HF)., Background: Several studies have shown a survival benefit for women compared to men with symptomatic HF. This observation may be related to gender differences in cardiac remodeling., Methods: We studied hearts from 100 patients (72 men and 28 women) receiving cardiac transplantation at our institution. Cardiac morphology was assessed with echocardiography and direct measurement of cardiac mass. Cardiac myocyte volume, length, width, cross-sectional area, and contraction were measured using previously validated techniques., Results: Among 50 patients with idiopathic cardiomyopathy (CM), we observed no gender-based differences in cardiac or cellular remodeling. In contrast, among 50 patients with ischemic cardiomyopathy (ICM), the heart weight index was significantly greater in men, and there was a strong trend toward an increased left ventricular (LV) mass index as well. These gender differences in cardiac and LV mass were paralleled by marked gender differences in myocyte volume, such that average myocyte volume was 36% greater in men than in women, in association with a 14% increase in resting cell length., Conclusions: Our studies demonstrate a multilevel gender difference in post-infarction remodeling, with women exhibiting reduced hypertrophy. Our studies further demonstrate that gender differences in cardiac remodeling in ICM are largely related to fundamental differences in cellular remodeling rather than simply differences in infarct size or expansion. Distinctions observed between ischemic and idiopathic CM suggest that gender may influence local myocardial responses to injury.

Objectives: We sought to separate the effects of associated left bundle branch block (LBBB) and coronary artery disease (CAD) on peak cardiac output (CO) during dobutamine stress in patients with dilated cardiomyopathy (DCM)., Background: The mechanisms limiting CO during stress in patients with DCM are unclear. Both LBBB and CAD may do so by prolonging the total isovolumic time (t-IVT)., Methods: A total of 59 patients with DCM-34 with CAD (20 normal activation [NA], 14 LBBB) and 25 without CAD (15 NA, 10 LBBB)-were studied. The total IVT (s/min; calculated as: 60 - [total ejection time + total filling time] ) and CO were measured by Doppler echocardiography., Results: At rest, t-IVT was 8 s/min longer with LBBB (p < 0.001), was unaffected by CAD, and did not correlate with rest CO. During stress, CO correlated with t-IVT (r = -0.73, p < 0.001) in all four patient groups. In the absence of CAD, t-IVT became shortened (NA by 7 +/- 3 s/min; LBBB by 9 +/- 4 s/min) and correlated with a fall in the QRS duration (NA: r = 0.87; LBBB: r = 0.91), and CO increased with stress (NA by 4.7 +/- 2.7 l/min; LBBB by 4.0 +/- 2.3 l/min; all p < 0.001). With CAD, t-IVT did not shorten normally with stress. Instead, t-IVT was 5.6 s/min longer and CO was 3.3 l/min lower than in those without CAD (both p < 0.001), and t-IVT did not correlate with the QRS duration., Conclusions: In patients with DCM, t-IVT during pharmacologic stress depends on changes in ventricular activation induced by LBBB or CAD and is, by itself, a major determinant of peak CO during stress.

Objectives: We sought to test the hypothesis that autoantibodies (Abs) produced against sarcolemmal Na-K-ATPase play a role in the development of ventricular tachycardia (VT) and cardiac sudden death in patients with dilated cardiomyopathy (DCM)., Background: Autoimmunity is one of the mechanisms of pathogenesis of DCM as well as virus infection and genetic predisposition., Methods: One hundred patients with DCM and age-matched control subjects (CTL) were screened for Abs produced against Na-K-ATPase by using enzyme-linked immunosorbent assay., Results: Abs were detected in 26 DCM and 2 CTL patients. Na-K-ATPase activity in the presence of patient IgG was lower in DCM with Abs than without Abs, but there was no difference between two groups in CTL. Western blots showed that Abs recognized the alpha subunit of Na-K-ATPase, and 3H-ouabain bindings in the presence of patient IgG showed that dissociation constant was higher in DCM with Abs than without Abs. No difference existed between subjects with regard to age, gender, New York Heart Association functional class, cardiac function, or neurohormone levels, except for plasma norepinephrine, which was higher in patients with Abs than without Abs. VTs were more common in patients with Abs than without Abs, and multiple logistic regression analysis demonstrated that the presence of Abs, but not plasma norepinephrine, was an independent predictor for the occurrence of VT. Cardiac sudden death was independently predicted by the presence of Abs, as well as poor systolic function., Conclusion: We conclude that there are Abs produced against sarcolemmal Na-K-ATPase in patients with DCM and that Abs could be responsible for the electrical instability in some cases.

Objectives: We investigated the prevalence of lamin A/C (LMNA) gene defects in familial and sporadic dilated cardiomyopathies (DCM) associated with atrioventricular block (AVB) or increased serum creatine-phosphokinase (sCPK), and the corresponding changes in myocardial and protein expression., Background: It has been reported that familial DCM, associated with conduction disturbances or variable myopathies, is causally linked to LMNA gene defects., Methods: The LMNA gene and myocardial ultrastructural and immunochemical changes were analyzed in 73 cases of DCM (49 pure, 15 with AVB [seven familial, eight sporadic], 9 with increased sCPK), four cases of familial AVB and 19 non-DCM heart diseases. The normal controls included eight heart donor biopsies for tissue studies and 107 subjects for LMNA gene studies., Results: Five novel LMNA mutations (K97E, E111X, R190W, E317K, four base pair insertion at 1,713 cDNA) were identified in five cases of familial autosomal dominant DCM with AVB (5/15: 33%). The LMNA expression of the myocyte nuclei was reduced or absent. Western blot protein analyses of three hearts with different mutations showed an additional 30-kDa band, suggesting a degrading effect of mutated on wild-type protein. Focal disruptions, bleb formation and nuclear pore clustering were documented by electron microscopy of the myocyte nuclear membranes. None of these changes and no mutations were found in the nine patients with DCM and increased sCPK or in the disease and normal controls., Conclusions: The LMNA gene mutations account for 33% of the DCMs with AVB, all familial autosomal dominant. Increased sCPK in patients with DCM without AVB is not a useful predictor of LMNA mutation.

Objectives: This study investigated the incidence of appropriate implantable cardioverter defibrillator (ICD) interventions for ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients with idiopathic dilated cardiomyopathy (IDC) and nonsustained VT in the presence of a left ventricular ejection fraction below 30%, versus in patients with syncope and patients with a history of VT or VF., Background: To date, only limited information is available about the prophylactic use of ICDs in patients with IDC., Methods: From January 1993 to July 2000, 101 patients with IDC underwent implantation of ICDs with electrogram storage capability at our institution. Patients were placed into one of three groups according to their clinical presentation: asymptomatic or mildly symptomatic nonsustained VT in the presence of a left ventricular ejection fraction < or = 30% (49 patients, prophylactic group), unexplained syncope or near syncope (26 patients, syncope group) and a history of sustained VT or VF (26 patients, VT/VF group)., Results: During 36 +/- 22 months follow-up, 18 of 49 patients (37%) in the prophylactic group received appropriate shocks for VT or VF, compared with 8 of 26 patients (31%) in the syncope group and with 9 of 26 patients (35%) of the VT/VF group. Multivariate Cox analysis of baseline clinical variables identified left ventricular ejection fraction, atrial fibrillation and a history of sustained VT or VF as predictors for appropriate ICD interventions during follow-up., Conclusions: Patients with IDC and prophylactic ICD implantation for nonsustained VT in the presence of a left ventricular ejection fraction < or = 30% had an incidence of appropriate ICD interventions similar to that of patients with a history of syncope or sustained VT or VF. These findings indicate that ICDs may have a role in not only secondary but also primary prevention of sudden death in IDC.

Objectives: The study evaluated the relationship between plasma cardiotrophin-1 (CT-1) concentration and left ventricular (LV) mass in dilated cardiomyopathy (DCM) patients with congestive heart failure (CHF)., Background: Cardiotrophin-1 is a newly identified member of the interleukin-6 (IL-6) family of cytokines and one of the endogenous ligands for gp130 signaling pathways in the heart, and it has potent hypertrophic and survival effects on cardiac myocytes. However, the clinical significance of CT-1 is poorly understood., Methods: We measured the plasma CT-1 level in 51 consecutive patients with DCM. Patients were classified into two groups: small LV mass index group and large LV mass index group, based on the median level of LV mass index., Results: The plasma CT-1 level was increased in DCM patients with the severity of CHF and was significantly higher in the large LV mass group than in the small LV mass group, despite the absence of a difference in LV ejection fraction between the two groups. In addition, there was a significant positive correlation between the plasma CT-1 level and the LV mass index (r = 0.627, p < 0.0001). According to stepwise multivariate analyses among hemodynamic and neurohumoral factors, a high plasma CT-1 level showed an independent and significant positive relationship with a large LV mass index in patients with DCM., Conclusions: These results indicate that the plasma CT-1 level is increased in patients with DCM and is significantly correlated with the LV mass index, suggesting that CT-1 plays an important role in structural LV remodeling in patients with DCM.

Objectives: This retrospective study was undertaken to provide data on occurrence, significance and therapy of ventricular tachyarrhythmia (VT) clusters (VTCs) in patients with dilated cardiomyopathy (DCM) and implantable cardioverter defibrillators (ICDs)., Background: Data on the clinical significance of VTCs are lacking in patients with DCM and ICDs., Methods: Baseline characteristics of 106 consecutive patients with DCM and ICDs were prospectively collected, and chart reviews and episode data retrospectively analyzed. A VTC was defined as > or =3 sustained VTs/24 h., Results: During a mean follow-up of 33+/-23 months, 73 patients (68.9%) had recurrent VT or ventricular fibrillation (VF), 43 patients (40.6%) suffered only single VTs and 30 patients (28.3%) experienced 52 clusters of VTs. Actuarial survival free of VT or VF was 44.6%, 33.0% and 26.5%, and survival free of VTC was 77.3%, 72.2% and 67.1% after one, two and three years, respectively. Independent predictors of VT clusters were heart failure before ICD implantation (p = 0.033), presenting monomorphic VT (p = 0.044), EF <0.40 (p = 0.014) and inducible mVT, especially with right bundle branch block and superior axis configuration (p<0.001). Survival free of recurrent VTCs was 50.8%, 38.1% and 19.0% after one, two and three years, respectively. Once a VTC had occurred, only 56.7%, 46.4%, 30.9% and 15.5% of patients survived and were not transplanted after one, two, three and four years, respectively. Survival was even more reduced if a VTC was associated with cardiac decompensation: 65.6% and 21.9% after one and two years, respectively., Conclusions: Despite antiarrhythmic intervention, clusters of VTs occur and recur frequently in patients with DCM. They signify impaired survival, especially if they are associated with cardiac decompensation, and may be a harbinger of progressive myocardial deterioration rather than a primarily arrhythmic problem. The benefit of ICD therapy may therefore be low in these patients.

Objectives: This study was designed to determine the stage of myocardial dysfunction at which an upregulation of the Na+/Ca2+ exchanger (EXCH) transcription takes place., Background: Because EXCH is an important regulator of intracellular calcium homeostasis, alterations in EXCH expression may occur before the onset of end-stage heart failure (HF) to maintain normal intracellular Ca2+ concentrations. We analyzed whether the EXCH transcription level is correlated to the degree of myocardial dysfunction and whether it can be a suitable molecular marker to define the transition to myocardial decompensation early on., Methods: By quantitative polymerase chain reaction technique, the level of EXCH transcription was analyzed in myocardial biopsies from 40 patients with various degrees of myocardial dysfunction due to valvular heart disease (VHD; n = 22) or dilated cardiomyopathy (DCM; n = 18). Additionally, biopsies from 7 individuals with excluded heart disease and explanted heart tissue from 13 patients with end-stage HF were investigated., Results: The level of EXCH transcription of controls (2.6 +/- 1.2 attomoles [amol]/ng total RNA) did not differ from that of patients with DCM (2.3 +/- 1.5 amol/ng) or VHD (2.1 +/- 1.5 amol/ng). No alteration in the EXCH transcription was found in VHD and DCM patients with respect to the severity of myocardial dysfunction. However, patients with end-stage HF showed a four-fold increase in EXCH transcription, amounting to 8.9 +/- 1.9 amol/ng (p < 0.05)., Conclusions: The upregulation in EXCH transcription either occurs very late in human heart failure or is a phenomenon of heart transplantation in end-stage HF. Consequently, myocardial EXCH transcription cannot be used as a marker for early myocardial decompensation.

Objective: To measure ventricular contractile synchrony in patients with dilated cardiomyopathy (DCM) and to evaluate the effects of biventricular pacing on contractile synchrony and ejection fraction., Background: Dilated cardiomyopathy is characterized by abnormal ventricular activation and contraction. Biventricular pacing may promote a more coordinated ventricular contraction pattern in these patients. We hypothesized that biventricular pacing would improve synchrony of right ventricular and left ventricular (RV/LV) contraction, resulting in improved ventricular ejection fraction., Methods: Thirteen patients with DCM and intraventricular conduction delay underwent multiple gated equilibrium blood pool scintigraphy. Phase image analysis was applied to the scintigraphic data and mean phase angles computed for the RV and LV. Phase measures of interventricular (RV/LV) synchrony were computed in sinus rhythm and during atrial sensed biventricular pacing (BiV)., Results: The degree of interventricular dyssynchrony present in normal sinus rhythm correlated with LV ejection fraction (r = -0.69, p < 0.01). During BiV, interventricular contractile synchrony improved overall from 27.5 +/- 23.1 degrees to 14.1 +/- 13 degrees (p = 0.01). The degree of interventricular dyssynchrony present in sinus rhythm correlated with the magnitude of improvement in synchrony during BiV (r = 0.83, p < 0.001). Left ventricular ejection fraction increased in all thirteen patients during BiV, from 17.2 +/- 7.9% to 22.5 +/- 8.3% (p < 0.0001) and correlated significantly with improvement in RV/LV synchrony during BiV (r = 0.86, p < 0.001)., Conclusions: Dilated cardiomyopathy with intraventricular conduction delay is associated with significant interventricular dyssynchrony. Improvements in interventricular synchrony during biventricular pacing correlate with acute improvements in LV ejection fraction.

Objectives: The aim of this study was to clarify the clinical significance and the determinant of microvolt-level T-wave alternans (TWA) in patients with dilated cardiomyopathy (DCM)., Background: The prevention of sudden death in patients with DCM remains the therapeutic target. T-wave alternans has been proposed as a powerful tool for identification of patients at high risk for ventricular arrhythmias and sudden death in coronary artery disease., Methods: In 58 DCM patients, TWA was measured during bicycle exercise testing using a CH 2000 system (Cambridge Heart, Bedford, Massachusetts). The New York Heart Association class, signal-averaged electrocardiogram, QT dispersion, left ventricular end-diastolic diameter (LVDd) and percent fractional shortening detected by echocardiogram and the grade of the ventricular arrhythmia were obtained in all patients., Results: T-wave alternans was positive in 23 patients (TWA+ group), negative in 25 (TWA- group) and indeterminate in 10. Univariate analysis showed that the percentage of patients with ventricular tachycardia (VT) and the LVDd in the TWA+ group was significantly higher than those in the TWA- group (61% vs. 8%, p < 0.001 and 65 +/- 11 mm vs. 58 +/- 8 mm, p < 0.05, respectively). The sensitivity, specificity and predictive accuracy of TWA for VT were 88%, 72% and 77%, respectively. Multivariate analysis showed that the presence of VT was a major independent determinant of TWA in patients with DCM (p = 0.003)., Conclusions: T-wave alternans was closely related to VT in patients with DCM. T-wave alternans is a useful noninvasive test for identifying high risk patients with DCM who have VT.

Objectives: The purpose of this study was to determine the outcome of patients with nonischemic dilated cardiomyopathy, unexplained syncope and a negative electrophysiology test who are treated with an implantable defibrillator., Background: Patients with nonischemic cardiomyopathy and unexplained syncope may be at high risk for sudden cardiac death, and they are sometimes treated with an implantable defibrillator., Methods: This study prospectively determined the outcome of 14 consecutive patients who had a nonischemic cardiomyopathy, unexplained syncope and a negative electrophysiology test and who underwent defibrillator implantation (Syncope Group). Nineteen consecutive patients with a nonischemic cardiomyopathy and a cardiac arrest who were treated with a defibrillator (Arrest Group) served as a control group., Results: Seven of 14 patients (50%) in the Syncope Group received appropriate shocks for ventricular arrhythmias during a mean follow-up of 24+/-13 months, compared with 8 of 19 patients (42%) in the Arrest Group during a mean follow-up of 45+/-40 months (p = 0.1). The mean duration from device implantation until the first appropriate shock was 32+/-7 months (95% confidence interval [CI], 18 to 45 months) in the Syncope Group compared to 72+/-12 months (95% CI, 48 to 96 months) in the Arrest Group (p = 0.1). Among patients who received appropriate shocks, the mean time from defibrillator implantation to the first appropriate shock was 10+/-14 months in the Syncope Group, compared with 48+/-47 months in the Arrest Group (p = 0.06). Recurrent syncope was always associated with ventricular tachyarrhythmias., Conclusions: The high incidence of appropriate defibrillator shocks and the association of recurrent syncope with ventricular arrhythmias support the treatment of patients with nonischemic cardiomyopathy, unexplained syncope and a negative electrophysiology test with an implantable defibrillator.

Objectives: The purpose of this study was to analyze whether long-term treatment with the nonselective beta-adrenergic blocking agent carvedilol may have beneficial effects in patients with dilated cardiomyopathy (DCM), who are poor responders in terms of left ventricular (LV) function and exercise tolerance to chronic treatment with the selective beta-blocker metoprolol., Background: Although metoprolol has been proven to be beneficial in the majority of patients with heart failure, a subset of the remaining patients shows long-term survival without satisfactory clinical improvement., Methods: Thirty consecutive DCM patients with persistent LV dysfunction (ejection fraction < or =40%) and reduced exercise tolerance (peak oxygen consumption <25 ml/kg/min) despite chronic (>1 year) tailored treatment with metoprolol and angiotensin-converting enzyme inhibitors were enrolled in a 12-month, open-label, parallel trial and were randomized either to continue on metoprolol (n = 16, mean dosage 142+/-44 mg/day) or to cross over to maximum tolerated dosage of carvedilol (n = 14, mean dosage 74+/-23 mg/day)., Results: At 12 months, patients on carvedilol, compared with those continuing on metoprolol, showed a decrease in LV dimensions (end-diastolic volume -8+/-7 vs. +7+/-6 ml/m2, p = 0.053; end-systolic volume -7+/-5 vs. +6+/-4 ml/m2, p = 0.047), an improvement in LV ejection fraction (+7+/-3% vs. -1+/-2%, p = 0.045), a reduction in ventricular ectopic beats (-12+/-9 vs. +62+/-50 n/h, p = 0.05) and couplets (-0.5+/-0.4 vs. +1.5+/-0.6 n/h, p = 0.048), no significant benefit on symptoms and quality of life and a negative effect on peak oxygen consumption (-0.6+/-0.6 vs. +1.3+/-0.5 ml/kg/min, p = 0.03)., Conclusions: In DCM patients who were poor responders to chronic metoprolol, carvedilol treatment was associated with favorable effects on LV systolic function and remodeling as well as on ventricular arrhythmias, whereas it had a negative effect on peak oxygen consumption.

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.

Objectives: We used the Doppler proximal flow convergence technique as a physiologic tool to explore the effects of the time courses of mitral annular area and transmitral pressure on dynamic changes in regurgitant orifice area., Background: In functional mitral regurgitation (MR), regurgitant flow rate and orifice area display a unique pattern, with peaks in early and late systole and a midsystolic decrease. Phasic changes in both mitral annular area and the transmitral pressure acting to close the leaflets, which equals left ventricular-left atrial pressure, have been proposed to explain this dynamic pattern., Methods: In 30 patients with functional MR, regurgitant orifice area was obtained as flow (from M-mode proximal flow convergence traces) divided by orifice velocity (v) from the continuous wave Doppler trace of MR, transmitral pressure as 4v(2), and mitral annular area from two apical diameters., Results: All patients had midsystolic decreases in regurgitant orifice area that mirrored increases in transmitral pressure, while mitral annular area changed more gradually. By stepwise multiple regression analysis, both mitral annular area and transmitral pressure significantly affected regurgitant orifice area; however, transmitral pressure made a stronger contribution (r2 = 0.441) than mitral annular area (added r2 = 0.008). Similarly, the rate of change of regurgitant orifice area more strongly related to that of transmitral pressure (r2 = 0.638) than to that of mitral annular area (added r2 = 0.003). A similar regurgitant orifice area time course was observed in four patients with fixed mitral annuli due to Carpentier ring insertion., Conclusions: In summary, the time course and rate of change of regurgitant orifice area in patients with functional MR are predominantly determined by dynamic changes in the transmitral pressure acting to close the valve. Thus, although mitral annular area helps determine the potential for MR, transmitral pressure appears important in driving the leaflets toward closure, and would be of value to consider in interventions aimed at reducing the severity of MR.

Objectives: We sought to assess the clinical significance of peak negative myocardial velocity gradient (MVG) in early diastole as a noninvasive indicator of left ventricular (LV) diastolic function., Background: Peak systolic MVG has been shown useful for the quantitative assessment of regional wall motion abnormalities, but limited data exist regarding the diastolic MVG as an indicator of LV diastolic function., Methods: Peak negative MVG was obtained from M-mode tissue Doppler imaging (TDI) in 43 subjects with or without impairment of systolic and diastolic performance: 12 normal subjects, 12 patients with hypertensive heart disease (HHD) with normal systolic performance and 19 patients with dilated cardiomyopathy (DCM), and was compared with standard Doppler transmitral flow velocity indices. In a subgroup of 30 patients, effects of preload increase on these indices were assessed by performing passive leg lifting. In an additional 11 patients with congestive heart failure at the initial examination, the measurements were repeated after 26+/-16 days of volume-reducing therapy., Results: Peak negative MVG was significantly depressed both in HHD (-3.9+/-1.3/s, p < 0.01 vs. normal=-7.7+/-1.5/s) and DCM (-4.4+/-1.4/s, p < 0.01 vs. normal). In contrast, transmitral flow indices failed to distinguish DCM from normal due to the pseudonormalization. Transmitral flow velocity indices were significantly altered (peak early/late diastolic filling velocity [E/A]=1.1+/-0.5 to 1.5+/-0.7, p < 0.01; E deceleration time=181+/-41 to 153+/-38 ms, p < 0.01), while peak negative MVG remained unchanged (-5.3+/-2.2 to -5.3+/-2.0/s, NS) by leg lifting. Volume-reducing therapy resulted in the apparent worsening of the transmitral flow velocity pattern toward abnormal relaxation, as opposed to peak negative MVG, which improved by the therapy (p < 0.05)., Conclusions: Peak negative MVG derived from TDI may be a noninvasive indicator of LV diastolic function that is less affected by preload alterations than the transmitral flow velocity indices, and thereby could be used for the follow-up of patients with nonischemic LV dysfunction presenting congestive heart failure.