Dilated cardiomyopathy (DC) is the final common pathway of different pathogenetic processes and presents a significant prognostic heterogeneity, possibly related to its etiologic variety. The characterization and long-term prognosis of postmyocarditic dilated cardiomyopathy (PM-DC) remain unknown. This study assesses the clinical-instrumental evolution and long-term prognosis of a large cohort of patients with PM-DC. We analyzed 175 patients affected with DC consecutively enrolled from 1993 to 2008 with endomyocardial biopsy (EMB) data available. PM-DC was defined in the presence of borderline myocarditis at EMB or persistent left ventricular dysfunction 1 year after diagnosis of active myocarditis at EMB. Other patients were defined as affected by idiopathic dilated cardiomyopathy (IDC). Analysis of follow-up evaluations was performed at 24, 60, and 120 months. We found 72 PM-DC of 175 enrolled patients (41%). Compared with IDC, patients with PM-DC were more frequently females and less frequently presented a familial history of DC. No other baseline significant differences were found. During the long-term follow-up (median 154, first to third interquartile range 78 to 220 months), patients with PM-DC showed a trend toward slower disease progression. Globally, 18 patients with PM-DC (25%) versus 49 with IDC (48%) experienced death/heart transplantation (p = 0.045). The prognostic advantage for patients with PM-DC became significant beyond 40 months of follow-up. At multivariable time-dependent Cox analysis, PM-DC was confirmed to have a global independent protective role (hazard ratio 0.53, 95% confidence interval 0.28 to 0.97, p = 0.04). In conclusion, PM-DC is characterized by better long-term prognosis compared with IDC. An exhaustive etiologic characterization appears relevant in the prognostic assessment of DC.
Dilated cardiomyopathy (DC) is a myocardial disease phenotypically characterized by left ventricular (LV) dilation and systolic dysfunction, which represents the final common pathway of different pathogenetic processes. In particular, although a significant portion of DC cases presents a familial clustering and a probable genetic origin, remaining sporadic cases are mostly ascribable to de novo mutations or to the evolution of a myocardial inflammatory process (postmyocarditic dilated cardiomyopathy [PM-DC]). In contrast, in common practice, cases in which a specific origin is not recognized are usually indicated as idiopathic dilated cardiomyopathy (IDC). Besides these considerations, prognosis of DC markedly improved in the last decades, mostly as a consequence of evidence-based pharmacologic and nonpharmacologic interventions. However, although most patients affected by DC currently show a favorable long-term survival, usually associated with LV reverse remodeling (LVRR), some of them are still projected through a severe outcome. This prognostic heterogeneity is possibly related to the etiologic variety of this disease. Previous articles reported a similar outcome of PM-DC compared with other forms of DC, however, referring to small populations, not treated according to current evidence-based recommendations, and importantly with a relatively short-term follow-up with respect to the life perspective of patients affected by DC. The aim of the present study was to assess the clinical-instrumental evolution and long-term prognosis of a large cohort of PM-DC.
Methods
Study population included all patients affected by DC consecutively enrolled from 1993 to 2008 in the Trieste Heart Muscle Disease Registry with endomyocardial biopsy (EMB) data available to assess the cause of the disease.
The diagnosis of DC was determined according to the World Health Organization criteria. Patients presenting with significant coronary artery disease (stenosis >50% of a major coronary artery), history of severe systemic hypertension (>160/100 mm Hg), alcohol intake over 100 g/day, severe organic valve diseases, congenital heart diseases, ongoing active myocarditis, persistent high-rate supraventricular arrhythmias in the 6 months before enrollment, autoimmune, and advanced systemic diseases affecting short-term prognosis were excluded.
PM-DC was defined
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in the presence of borderline myocarditis at EMB according to Dallas criteria in patients with diagnosis of DC, with at least a multifocal interstitial staining at immunohistochemical analysis or
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in the presence of persistent LV dysfunction 1 year after the diagnosis of active myocarditis at EMB according to Dallas criteria despite specific therapy added to standard optimal treatment.
Patients without evidence of inflammation on EMB were considered as affected by IDC. The familial history was systematically investigated and all familial DC cases fulfilled the published criteria.
All patients were extensively evaluated at baseline and during regular long-term follow-up. After enrollment, if not contraindicated, all patients received ACE inhibitors/angiotensin receptor blockers and β blockers titrated to the highest tolerated dose. Implanted cardioverter defibrillators were systematically provided for primary prevention since 1998 in patients with DC considered at high risk for sudden cardiac death (i.e., persistent LV dysfunction with LV ejection fraction [LVEF] ≤35% and New York Heart Association classes II to III on chronic optimal medical treatment). Since 2005, cardiac resynchronization therapy was provided when appropriate.
The primary study outcome measurement was a composite of death and heart transplantation (HT).
The institutional ethical board approved the study, and the informed consent was obtained under the institutional review board policies of hospital administration. Information regarding the status and outcome of patients lost to follow-up were obtained by telephone interview to patients, relatives, general practitioners, or by the registers of death of the municipalities of residence.
EMB was performed in patients who presented with (1) recent onset of heart failure (HF) (within 6 months from enrollment), (2) severe LV dysfunction (LVEF <40%), and/or (3) idiopathic major ventricular arrhythmias (sustained ventricular tachycardias/ventricular flutter or fibrillation, aborted sudden death). Details on the collection and preparation of bioptic samples for histopathologic and immunohistochemical analysis are described in the Supplementary Material .
Echocardiographic assessment consisted in comprehensive M-mode, 2-dimensional, and Doppler studies. Details on echocardiographic assessment and measures are provided in the Supplementary Material .
LVRR was defined according to literature by the combined presence of an increase of LVEF of at least 10 points (or a follow-up LVEF ≥50% in patients with LVEF 45% to 49% at enrollment) associated with a decrease in indexed LV end-diastolic diameter of at least 10% or a follow-up indexed LV end-diastolic diameter ≤33 mm/m 2 .
Statistical Analyses
Summary statistics of clinical and instrumental variables at enrollment were expressed as mean and SD, median and interquartile range (IQR), or counts and percentage, as appropriate. Cross-sectional comparisons at baseline and subsequent follow-up between groups were made by the ANOVA test on continuous variables, using the Brown-Forsythe statistic when the assumption of equal variances did not hold, or the Mann-Whitney test when necessary. The chi-square or Fisher’s exact test was calculated for discrete variables. Repeated measures between baseline and follow-up visits were evaluated by means of the paired t test for continuous Gaussian distributed parameters or the Wilcoxon test as appropriate. For binary variables, the McNemar test was calculated; moreover, mixed-effects generalized linear models were estimated to evaluate globally the time-effect. Univariable Cox regression models were fitted to find factors associated with the primary outcome, both at baseline and at subsequent follow-up, using a landmark approach (i.e., starting each time at the follow-up date ). The proportional hazard assumption of the univariable Cox model with PM-DC was tested using the Grambsch and Therneau test. To fully exploit the available longitudinal values of many clinical and instrumental parameters, a multivariable time-dependent Cox regression model was estimated to evaluate predictors of outcome, using both parameters fixed at baseline and time-dependent covariates: variables included in the model were selected from the univariable results taking also into account their clinical relevance and degree of correlation in sake of parsimony. The IBM SPSS Statistics for Windows, Version 19.0., IBM Corp., Armonk, New York, software and the R statistical package, version 3.0.2, were used for the analysis.
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