Acute Hemodynamic Response to Cardiac Resynchronization in Dilated Cardiomyopathy: Effect on Late Mitral Regurgitation.

BACKGROUND: Functional mitral regurgitation (FMR) is associated with reduced survival in dilated cardiomyopathy (DCM). Cardiac resynchronization therapy (CRT) can improve FMR. We sought to identify the predictors of FMR improvement after CRT in DCM. METHODS: From January 2003 to December 2013, 430 DCM patients consecutively enrolled were retrospectively analyzed. Inclusion criteria were successful CRT implantation in the presence of conventional indications (i.e., left bundle branch block, left ventricular ejection fraction ≤35%, New York Heart Association functional class ≥II) and moderate-to-severe FMR at the time of procedure. Early echocardiographic evaluation after CRT implantation (median 2.5 days) has been performed in each patient. Improvement in FMR (absent/mild) at midterm (7 months; interquartile range 4-10) was considered as the primary study end point. RESULTS: A total of 44 patients (10% of the overall cohort) were included. A significant reduction in FMR severity was observed in 21 patients (48%) at midterm after CRT (median time 7 months). No preimplantation variables predicted FMR evolution, but FMR improvement at midterm was strongly predicted by an acute favorable hemodynamic response (persistence/development of normal right ventricular function and 10-mm Hg decrease or normalization [≤35 mm Hg] of systolic pulmonary artery pressure) at postimplantation echocardiography (odds ratio: 13.7; 95% confidence interval: 1.27-42.8; P = 0.016). FMR improvement at midterm was stable during follow-up and was associated with superior long-term transplant-free survival (P = 0.022). CONCLUSIONS: Stable FMR improvement frequently occurs after CRT implantation in DCM and is associated with improved transplant-free survival. Echocardiographic evaluation of acute hemodynamic response to CRT is helpful to early identification of the favorable FMR evolution.

Transient versus persistent improved ejection fraction in non-ischaemic dilated cardiomyopathy.

AIMS: The recent definition of heart failure with improved ejection fraction outlined the importance of the longitudinal assessment of left ventricular ejection fraction (LVEF). However, long-term progression and outcomes of this subgroup are poorly explored. We sought to assess the LVEF trajectories and their correlations with outcome in non-ischaemic dilated cardiomyopathy (NICM) with improved ejection fraction (impEF). METHODS AND RESULTS: Consecutive NICM patients with baseline LVEF ≤40% enrolled in the Trieste Heart Muscle Disease Registry with ≥1 LVEF assessment after baseline were included. ImpEF was defined as a baseline LVEF ≤40%, and second evaluation showing both a ≥10% point increase from baseline LVEF and LVEF >40%. Transient impEF was defined by the documentation of recurrent LVEF ≤40% during follow-up. The primary endpoint was a composite of all-cause death, heart transplantation and left ventricular assist device (D/HT/LVAD). Among 800 patients, 460 (57%) had impEF (median time to improvement 13 months). Transient impEF was observed in 189 patients (41% of the overall impEF group) and was associated with higher risk of D/HT/LVAD compared with persistent impEF at multivariable analysis (hazard ratio 2.54; 95% confidence interval 1.60-4.04). The association of declining LVEF with the risk of D/HT/LVAD was non-linear, with a steep increase up to 8% points reduction, then remaining stable. CONCLUSIONS: In NICM, a 57% rate of impEF was observed. However, recurrent decline in LVEF was observed in ≈40% of impEF patients and it was associated with an increased risk of D/HT/LVAD.

Longitudinal Arrhythmic Risk Assessment Based on Ejection Fraction in Patients with Recent-Onset Nonischemic Dilated Cardiomyopathy.

BACKGROUND: Practice guidelines suggest the use of implantable cardioverter-defibrillators in patients with left ventricular ejection fractions (LVEF) ≤ 35% despite 3 to 6 months of guideline-directed medical therapy (GDMT). It remains unclear whether this strategy is appropriate for patients with dilated cardiomyopathy (DCM), who can experience reverse ventricular remodeling for up to 24 months after the initiation of GDMT. The aim of this study was to assess the longitudinal dynamic relationship between LVEF ≤ 35% and arrhythmic risk in patients with recent-onset nonischemic DCM on GDMT. METHODS: A retrospective analysis was conducted among patients with recent-onset DCM (≤6 months) and recent initiation of GDMT (≤3 months) consecutively enrolled in a longitudinal registry. Risk for major ventricular arrhythmic events or sudden cardiac death was assessed in relationship to LVEF ≤ 35% at enrollment and 6 and 24 months after initiation of GDMT. RESULTS: Five hundred forty-four patients met the inclusion criteria. LVEF ≤ 35% identified patients with increased risk for major ventricular arrhythmic events or sudden cardiac death starting from 24 months after initiation of GDMT (hazard ratio, 2.126; 95% CI, 1.065-4.245; P = .03). However, LVEF ≤ 35% at presentation or 6 months after enrollment did not have prognostic significance. Sixty-seven percent of 131 patients with LVEF ≤ 35% at 6 months after initiation of GDMT had improved LVEFs (to >35%) by 24 months. This late LVEF improvement correlated with lower arrhythmic risk (P = .012) and was preceded by a reduction of LV dimensions in the first 6 months of GDMT. CONCLUSIONS: In patients with DCM, the present findings suggest that risk stratification for major ventricular arrhythmic events or sudden cardiac death on the basis of LVEF ≤ 35% is effective after 2 years of GDMT, but not after 6 months. In selected patients with DCM, it would be appropriate to wait 24 months before primary prevention ICD implantation.

Prevalence and Evolution of Right Ventricular Dysfunction Among Different Genetic Backgrounds in Dilated Cardiomyopathy.

BACKGROUND: Titin (TTN)-related dilated cardiomyopathy (DCM) has a higher likelihood of left ventricular reverse remodelling compared with other genetic etiologies. No data regarding the evolution of right ventricular dysfunction (RVD) according to genetic background are available. METHODS: Consecutive 104 DCM patients with confirmed pathogenic genetic variants (51 TTN-related DCM; 53 other genetic DCM) and a control group of 139 patients with negative genetic testing and available follow-up data at 12-24 months were analysed. RVD was defined as a right ventricular fractional area change (RVFAC) < 35%. The main study end point was the comparison of the evolution of RVD and the change of RVFAC throughout the follow-up according to etiology. A composite of all-cause mortality and heart transplantation was included as outcome measure. RESULTS: At enrollment, RVD was present in 29.1% of genetically positive DCM without differences between genetic cohorts. At 14 months follow-up, 5.9% of TTN-related DCM patients vs 35.8% of other genetic DCM patients had residual RVD after treatment (P < 0.001). Accordingly, RVFAC significantly improved in the TTN-related DCM cohort and remained stably impaired in other genetic DCM patients. However, the evolution of RVD was similar between TTN-related DCM and patients without a genetic mutation. After adjusting for RVD at follow-up, no differences in the outcome measure were seen in the study cohorts. CONCLUSIONS: The evolution of RVD in DCM is heterogeneous in different genetic backgrounds. TTN-related DCM is associated with a higher chance of RVD recovery compared with other genetic etiologies.

Sex Differences in the Long-term Prognosis of Dilated Cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) represents a specific phenotype of heart failure. Sex differences in the long-term prognosis of patients with DCM are unknown. The aim of this study is to investigate the long-term prognostic role of gender in a large cohort of patients with DCM. METHODS: A total of 1113 patients with DCM were prospectively enrolled. To investigate the impact of sex, a propensity score-matching analysis was performed on a sample of 586 patients. Univariable and multivariable Cox models and competing-risk analyses were estimated on both cohorts for the following outcome measures: (1) all-cause mortality/heart transplantation (HTx)/ventricular assist device (VAD); (2) cardiovascular mortality/HTx/VAD; and (3) sudden cardiac death or malignant ventricular arrhythmias. RESULTS: Women were older than men (50 ± 15 years vs 47 ± 15 years, respectively, P = 0.004) and more frequently had moderate to severe left ventricular dilation (P < 0.001) and left bundle branch block (P = 0.019). At multivariable analyses, male sex was independently associated with all considered outcome measures in the total cohort. At propensity score-matching analysis, over a median follow-up of 126 months (interquartile range, 62-201), 96 men (33%) vs 66 women (22%) experienced all-cause mortality/HTx/VAD (P = 0.03), 95 men (32%) vs 57 women (20%) experienced cardiovascular mortality/HTx/VAD (P = 0.025), and 46 men (16%) vs 28 women (10%) experienced sudden cardiac death/malignant ventricular arrhythmias (P = 0.07). CONCLUSION: The long-term outcomes of women affected by DCM are more favourable than those of men, and sex emerged as an important independent factor, particularly for cardiovascular outcomes.

Sex-Specific Prognostic Implications in Dilated Cardiomyopathy After Left Ventricular Reverse Remodeling.

BACKGROUND: Women affected by Dilated Cardiomyopathy (DCM) experience better outcomes compared to men. Whether a more pronounced Left Ventricular Reverse Remodelling (LVRR) might explain this is still unknown. AIM: We investigated the relationship between LVRR and sex and its long-term outcomes. METHODS: A cohort of 605 DCM patients with available follow-up data was consecutively enrolled. LVRR was defined, at 24-month follow-up evaluation, as an increase in left ventricular ejection fraction (LVEF) ≥ 10% or a LVEF > 50% and a decrease ≥ 10% in indexed left ventricular end-diastolic diameter (LVEDDi) or an LVEDDi ≤ 33 mm/m2. Outcome measures were a composite of all-cause mortality/heart transplantation (HTx) or ventricular assist device (VAD) and a composite of Sudden Cardiac Death (SCD) or Major Ventricular Arrhythmias (MVA). RESULTS: 181 patients (30%) experienced LVRR. The cumulative incidence of LVRR at 24-months evaluation was comparable between sexes (33% vs. 29%; p = 0.26). During a median follow-up of 149 months, women experiencing LVRR had the lowest rate of main outcome measure (global p = 0.03) with a 71% relative risk reduction compared to men with LVRR, without significant difference between women without LVRR and males. A trend towards the same results was found regarding SCD/MVA (global p = 0.06). Applying a multi-state model, male sex emerged as an independent adverse prognostic factor even after LVRR completion. CONCLUSIONS: Although the rate of LVRR was comparable between sexes, females experiencing LVRR showed the best outcomes in the long term follow up compared to males and females without LVRR. Further studies are advocated to explain this difference in outcomes between sexes.

Risk of sudden cardiac death in New York Heart Association class I patients with dilated cardiomyopathy: A competing risk analysis.

AIMS: Primary prevention implantable cardioverter defibrillator (ICD) is not generally recommended in New York Heart Association (NYHA) I class patients with dilated cardiomyopathy (DCM). This study sought to assess the competing risk of sudden cardiac death (SCD) in DCM patients with left ventricular ejection fraction (EF) ≤35% and NYHA I class. METHODS: A total of 272 DCM patients with EF ≤35% and NYHA class I-III after ≥3 months of guideline-directed medical therapy were included. The risk of SCD and SCD/malignant ventricular arrhythmias (MVA) was assessed in NYHA I vs. NYHA II and NYHA III groups by competing risk analysis. RESULTS: NYHA I patients were younger, had higher EF and smaller left atrium, were less likely receiving mineral corticoid receptor antagonists. The cumulative incidence of SCD (p = 0.92) and SCD/MVA (p = 0.42) did not differ between NYHA I vs NYHA II-III classes. NYHA class did not influence the association between ICD and SCD risk (p for interaction = 0.125). CONCLUSIONS: In this cohort of DCMs, patients with EF ≤35% and NYHA I class were exposed to a risk of SCD and life-threatening arrhythmias not different from NYHA II-III. Therefore, inclusion of asymptomatic patients with DCM and systolic dysfunction should be strongly considered in future randomized studies on primary prevention ICD.

Contemporary survival trends and aetiological characterization in non-ischaemic dilated cardiomyopathy.

AIM: Contemporary survival trends in dilated cardiomyopathy (DCM) are largely unknown. The aim of this study is to investigate clinical descriptors, survival trends and the prognostic impact of aetiological characterization in DCM patients. METHODS AND RESULTS: Dilated cardiomyopathy patients were consecutively enrolled and divided into four groups according to the period of enrolment (1978-1984; 1985-1994; 1995-2004; and 2005-2015). A subset of patients with DCM of specific aetiology, enrolled from 2005 to 2015, was also analysed. Over a mean follow-up of 12 ± 8 years, 1284 DCM patients (52 in the 1978-1984 group, 326 in the 1985-1994 group, 379 in the 1995-2004 group, and 527 in the 2005-2015 group) were evaluated. Despite older age (mean age 51 ± 15, 43 ± 15, 45 ± 14, and 52 ± 15 years for the 1978-1984, 1985-1994, 1995-2004, and 2005-2015 groups, respectively; P < 0.001), most of the baseline clinical characteristics improved in the 2005-2015 group, suggesting a less advanced disease stage at diagnosis. Similarly, at competing risk analysis, the annual incidence of all outcome parameters progressively decreased over time (global P < 0.001). At multivariable analysis, the last period of enrolment emerged as independently associated with a reduction in all-cause mortality/heart transplantation (HTx)/ventricular assist device (VAD) implantation (1.46 events/100 patients/year), cardiovascular death/HTx/VAD implantation (0.82 events/100 patients/year) and sudden cardiac death (0.15 events/100 patients/year). Lastly, in 287 patients with DCM of specific aetiology, patients with environmental, toxic, or removable factors appeared to have different phenotypes and prognosis compared to those with genetic, post-myocarditis, or idiopathic DCM (P < 0.001). CONCLUSIONS: Contemporary survival trends in DCM significantly improved, mainly due to a reduction of cardiovascular events. Appropriate aetiological characterization might help in prognostication of DCM patients.

[Diagnostic work-up and clinical management of cardiomyopathies: the operative protocol from the Cardiothoracovascular Department of Trieste, Italy]. / Inquadramento e gestione delle cardiomiopatie: il protocollo della Cardiologia di Trieste.

Cardiomyopathies are primary myocardial disorders, genetically determined, with clinical onset between the third and the fifth decade of life. They represent the main causes of sudden cardiac death and heart failure in the youth. The more common myocardial diseases in clinical practice are dilated cardiomyopathy, arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy. Next generation sequencing techniques, recently available for genetics researches, together with the diffusion of advanced imaging techniques, permitted in the last years a deeper knowledge of these pathologies. Nevertheless, diagnosis, etiology and several aspects of patients' clinical management remain complex and controversial. This review paper aims to propose some operative flow-charts, derived from scientific evidences and the internal protocol of the Cardiothoracovascular Department of Trieste Hospital, Italian referral Center for cardiomyopathies and heart failure, with more than 30 years of experience in diagnosis and management of patients who suffer from primary myocardial disorders.

Dilated Cardiomyopathy With Mid-Range Ejection Fraction at Diagnosis: Characterization and Natural History.

Background Limited data are available on mid-range ejection fraction (mrEF) patients with dilated cardiomyopathy. We sought to define the characteristics, evolution, and long-term prognosis of dilated cardiomyopathy patients with mrEF at diagnosis. Methods and Results We analyzed all dilated cardiomyopathy patients consecutively evaluated in the Trieste Heart Muscle Disease Registry from 1988 to 2013. mrEF and reduced ejection fraction (rEF) were defined as baseline left ventricular (LV) ejection fraction values between 40% and 49% and <40%, respectively. All-cause mortality or heart transplantation, sudden cardiac death, or major ventricular arrhythmias were considered as outcome measures. Worsening LV ejection fraction (reduction to <40%) during follow-up was also considered to identify possible predictors of adverse remodeling. Among 812 enrolled patients, 175 (22%) presented with mrEF at presentation. At baseline, as compared with the rEF group, mrEF patients had lower rates of moderate-severe mitral regurgitation and restrictive LV filling pattern. During a median follow-up period of 120 (60-204) months, the mrEF group presented a lower rate of death/heart transplantation (9% versus 36%, P<0.001) and sudden cardiac death or major ventricular arrhythmias (4.5% versus 15%, P<0.001) than rEF patients. Moreover, 29 out of 175 mrEF patients (17%) evolved to rEF. Restrictive LV filling pattern emerged as the strongest predictor of rEF development following multivariable analysis. Conclusions mrEF identified a consistent subgroup of dilated cardiomyopathy patients diagnosed in an earlier stage with subsequent apparent better long-term evolution. However, 17% of these patients evolved into rEF despite the use of medical therapy. A baseline restrictive LV filling pattern was independently associated with subsequent evolution to rEF.

Arrhythmic risk stratification in patients with dilated cardiomyopathy and intermediate left ventricular dysfunction.

AIMS: Arrhythmic risk stratification is a challenging issue in patients with dilated cardiomyopathy (DCM), particularly when left ventricular ejection fraction (LVEF) is more than 35%. We studied the prevalence and predictors of sudden cardiac death or malignant ventricular arrhythmias (SCD/MVAs) in DCM patients categorized at low arrhythmic risk because of intermediate left ventricular dysfunction under optimal medical treatment (OMT). METHODS: DCM patients considered at low arrhythmic risk (LVEF >35% and New York Heart Association class I-III after 6 ±â€Š3 months of OMT) were analysed. An arrhythmogenic profile was defined as the presence of at least one among a history of syncope, nonsustained ventricular tachycardia, at least 1000 premature ventricular contractions/24 h, at least 50 ventricular couplets/24 h at Holter ECG monitoring. SCD/MVAs was considered as the study end-point. RESULTS: During a median follow-up of 152 months (interquartile range 100-234), 30 out of 360 (8.3%) patients at low arrhythmic risk (LVEF 47 ±â€Š7%) experienced the study end-point [14 (3.9%) SCD and 16 (4.4%) MVA]. Compared with survivors, patients who experienced SCD/MVAs had more frequently an arrhythmogenic profile and a larger left atrium. Their LVEF at the last available evaluation before the arrhythmic event was 36 ±â€Š12%. At multivariable analysis, left atrial end-systolic area [hazard ratio 1.107; 95% confidence interval (95% CI) 1.039-1.179, P = 0.002 for 1 mm increase] and arrhythmogenic profile (hazard ratio 3.667; 95% CI 1.762-7.632, P = 0.001) emerged as predictors of SCD/MVAs during follow-up. CONCLUSION: A consistent quota of DCM patients with intermediate left ventricular dysfunction receiving OMT experienced SCD/MVA during follow-up. Left atrial dilatation and arrhythmogenic pattern were associated with a higher risk of SCD/MVA.

Left bundle branch block in dilated cardiomyopathy with intermediate left ventricular dysfunction: Clinical phenotyping and outcome correlates.

BACKGROUND: Left bundle branch block (LBBB) negatively affects prognosis in heart failure patients with a reduced left ventricular ejection fraction (LVEF). Less is known about the prognostic role of LBBB in dilated cardiomyopathy (DCM) with intermediate LVEF (between 36% and 50%). We sought to assess the role of LBBB in optimally treated DCM patients with mildly to moderately reduced LVEF and to determine the possible variables associated with subsequent LVEF reduction. METHODS: We retrospectively analyzed DCM patients with LVEF >35% after 3-to-9 months of optimal medical treatment (OMT) consecutively evaluated from 1990 to 2010. All-cause mortality or heart transplantation (D/HTx) and sudden cardiac death (SCD) or major ventricular arrhythmias (MVA) were considered as outcome measures. LVEF deterioration during follow-up was also considered. RESULTS: Among 280 (49%) patients that met the study criteria, 76 had LBBB (27%). During a mean follow-up of 151 months, the rates of D/HTx and SCD/MVA were similar between LBBB and not LBBB patients (p value = 0.52 and p = 0.39, respectively). Twenty-six out of 76 (34%) patients with LBBB experienced LVEF deterioration below 36%. The persistence of moderate-severe mitral regurgitation (MR), left atrial end-systolic area index and LV end-diastolic volume index emerged as independent predictors of LVEF deterioration and were associated with an increased risk of D/HTx during follow-up. CONCLUSIONS: LBBB does not affect mortality in DCM patients with intermediate LVEF after OMT. However, among these patients those with persistent significant MR, left atrial and LV remodeling carries a higher risk of LVEF deterioration during follow-up.

Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy.

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.

Usefulness of Addition of Magnetic Resonance Imaging to Echocardiographic Imaging to Predict Left Ventricular Reverse Remodeling in Patients With Nonischemic Cardiomyopathy.

Defining short-term prognosis in nonischemic cardiomyopathy (NICM) is challenging in clinical practice. Although left ventricular reverse remodeling (LVRR) is a key prognostic marker in NICM there are few parameters able to predict it. We investigated whether a complete structural and functional cardiac magnetic resonance imaging (cMRI) evaluation was incremental to the classic clinical-echocardiographic approach in predicting LVRR in a large cohort of NICM patients receiving evidence-based treatment. Patients with a recent diagnosis of NICM (<3 months) who underwent complete clinical, echocardiographic and cMRI assessment were consecutively enrolled from 2008 to 2016. LVRR was defined as an increase in ≥10 points or normalization of left ventricular ejection fraction, associated with a ≥10% reduction or normalization of left ventricular end-diastolic diameter at midterm (median time 20 months) echocardiographic follow-up. Among 80 NICM patients included in the study, LVRR was observed in 43 (54%). At multivariate analysis, the clinical-echocardiographic evaluation failed to identify independent predictors of LVRR. However, absence of late gadolinium enhancement (odds ratio [OR] 9.07; confidence interval [CI] 2.7 to 13.1; p value 0.0003), left ventricular mass (OR 1.018; CI 1.001 to 1.036; p value 0.045) and peak circumferential strain (OR 1.213; CI 1.011 to 1.470; p value 0.049) assessed by cMRI were independently associated with LVRR. A model for LVRR prediction based on cMRI and clinical-echocardiographic parameters performed significantly better than the clinical-echocardiographic model alone (area under curve 0.84 vs 0.72; p value 0.023). In conclusion, an integrated imaging approach with the addition of a structural and functional cMRI study to the standard-of-care evaluation improves the prediction of LVRR in a large cohort of patients with recently diagnosed NICM receiving evidence-based treatment.

Insights into mildly dilated cardiomyopathy: temporal evolution and long-term prognosis.

AIMS: Mildly dilated cardiomyopathy (MDCM) has been proposed as a subtype of dilated cardiomyopathy (DCM) characterized by systolic dysfunction in the absence of significant LV dilatation. Few data on the characteristics and outcomes of MDCM patients are available. We sought to assess the main features and the long-term natural history of MDCM. METHODS AND RESULTS: From 1988 to 2010 we analysed all DCM patients consecutively evaluated at our Institution. MDCM was defined as LVEF <45% and LV end-diastolic volume index (LVEDVI) ≤70 mL/m2 in women and ≤89 mL/m2 in men. Among a total population of 638 patients, 226 (35%) fulfilled the criteria for MDCM. Compared with the other patients, they presented features of a less advanced disease and an overall long-term lower rate of all-cause mortality/heart transplantation (D/HTx; total events = 209; 144 deaths, 65 HTx): D/HTx at 10 years 15% in MDCM vs. 30% in DCM (P < 0.001). However, throughout the follow-up, 55 MDCM patients (24%) evolved to DCM by increasing LVEDVI, consistently worsening their long-term prognosis. Among persistent MDCM patients, a restrictive filling pattern [hazard ratio (HR) 5.30; 95% confidence interval (CI) 2.34-12.01, P < 0.001] and non-sustained ventricular tachycardia (HR 2.21; 95% CI 1.003-5.11, P = 0.047), but not LVEF, were independently associated with D/HTx at multivariate analysis [time-dependent receiver operating characteristic (ROC) curve: area under the curve (AUC) 0.80, 95% CI 0.65-0.94, P = 0.003]. CONCLUSIONS: MDCM identifies a consistent subgroup of DCMs diagnosed in an earlier stage and presenting an apparent better evolution. However, some MDCMs evolve into DCM despite medical therapy, whereas persistent MDCMs with non-sustained ventricular arrhythmias and restrictive filling pattern are characterized by a very poor outcome.

Comparison of Patient Characteristics and Course of Hypertensive Hypokinetic Cardiomyopathy Versus Idiopathic Dilated Cardiomyopathy.

Hypertensive hypokinetic cardiomyopathy (HHC) is defined by left ventricular (LV) systolic dysfunction with a history of systemic hypertension as the only possible cause. Although commonly encountered in clinical practice, its characterization and differences with true idiopathic dilated cardiomyopathy (IDC) are lacking. The aim of this study was to characterize the clinical instrumental features and the natural history of HHC. We analyzed the data of 4,191 patients referred to our center for newly diagnosed LV systolic dysfunction from 2005 to 2010. Of them, 310 presented idiopathic LV systolic dysfunction (LV ejection fraction <50%): 136 (44%) had a history of systemic hypertension and were defined HHC. The remaining 174 patients were considered IDC. Compared with patients with IDC, those with HHC were older (63 ± 11 vs 47 ± 14 years, p <0.001), with worse comorbidity profile, higher blood pressure, and increased LV mass. During follow-up, patients with HHC showed earlier and higher proportion of LV reverse remodeling (46% vs 21% at 6 months' follow-up). Moreover, they had a better long-term survival free from cardiovascular death/ventricular assist device/heart transplant/malignant ventricular arrhythmias (5.1 vs 12.6 in HHC and IDC, p = 0.03). Indeed, their mortality was mainly driven by noncardiovascular causes (at 10 years 9.6% vs 1.7% in HHC and IDC, p <0.001). In conclusion, HHC has a high prevalence among patients with "idiopathic" LV dysfunction. The natural history of patients with HHC is characterized by a rapid response to optimal therapy for heart failure, a favorable cardiovascular outcome, and a relevant incidence of noncardiovascular events.

Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy.

OBJECTIVE: To explore the genetic landscape of a well selected dilated cardiomyopathy (DCM) cohort, assessing the possible relation between different genotypes and left ventricular reverse remodelling (LVRR). METHODS: A cohort of 152 patients with DCM from the Heart Muscle Disease Registry of Trieste has been studied by next-generation sequencing (NGS). Patients were grouped into different 'gene-clusters' with functionally homogeneous genetic backgrounds. LVRR was defined by left ventricular ejection fraction normalisation or increase ≥10% associated with normalisation in indexed left ventricular end-diastolic diameter or relative decrease ≥10% at 24 months follow-up. RESULTS: A pathogenic disease-related gene variant was identified in 57% of patients: 28 (18%) TTN; 7 (5%) LMNA; 16 (11%) structural cytoskeleton Z-disk genes; 9 (6%) desmosomal genes; 18 (12%) motor sarcomeric genes and 9 (6%) other genes. Baseline clinical features were similar throughout the different genotypes. A significant relationship was found between gene cluster subgroups and LVRR, with a lower rate of LVRR in structural cytoskeleton Z-disk gene mutation carriers (1/16 patients, 6%, p<0.05 vs the other subgroups). Of note, structural cytoskeleton Z-disk gene rare variants were independently and inversely associated with LVRR when adjusted for clinical predictors of LVRR (OR 0.065; 95% CI 0.008 to 0.535, p=0.011). CONCLUSIONS: NGS confirmed a high genetic diagnostic yield in DCM. A specific 'gene-clusters' classification based on functional similarities in different genes might be helpful in the clinical management of genetically determined DCM. In this study, structural cytoskeleton Z-disk gene rare variants were independently associated with a lower rate of LVRR at follow-up.

Characterization and Long-Term Prognosis of Postmyocarditic Dilated Cardiomyopathy Compared With Idiopathic Dilated Cardiomyopathy.

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.

Natural History of Dilated Cardiomyopathy in Children.

BACKGROUND: The long-term progression of idiopathic dilated cardiomyopathy (DCM) in pediatric patients compared with adult patients has not been previously characterized. In this study, we compared outcome and long-term progression of pediatric and adult DCM populations. METHODS AND RESULTS: Between 1988 and 2014, 927 DCM patients were consecutively enrolled. The pediatric population (aged <18 years at enrollment) included 47 participants (5.1%). At presentation, the pediatric population compared with adult patients had a significantly increased occurrence of familial forms (P=0.03), shorter duration of heart failure (P=0.04), lower systolic blood pressure (P=0.01), decreased presence of left bundle-branch block (P=0.001), and increased left ventricular ejection fraction (P=0.03). Despite these baseline differences, long-term longitudinal trends of New York Heart Association class III to IV, left ventricular dimensions, left ventricular ejection fraction, and restrictive filling pattern were similar between the 2 populations. Regarding survival analysis, because of the size difference between the 2 populations, we compared the pediatric population with a sample of adult patients randomly matched using the above-mentioned baseline differences in a 3:1 ratio (141 adult versus 47 pediatric patients). During a median follow-up of 110 months, survival free from heart transplantation was significantly lower among pediatric patients compared with adults (P<0.001). Furthermore, pediatric age (ie, <18 years) was found to be associated with an increasing risk of both death from pump failure and life-threatening arrhythmias. CONCLUSIONS: Despite the pediatric DCM population having higher baseline left ventricular ejection fraction and similar long-term echocardiographic progression compared with the adult DCM population, the pediatric DCM patients had worse cardiovascular prognosis.

Early right ventricular response to cardiac resynchronization therapy: impact on clinical outcomes.

AIMS: Right ventricular (RV) dysfunction has been associated with a worse outcome in heart failure patients undergoing CRT. However, evidence on the RV response to CRT is controversial and there are no data regarding the early effects of CRT on RV function (RVF). We sought to investigate whether a CRT device favourably influences the RVF acutely after implantation, impacting on long-term outcomes. METHODS AND RESULTS: Patients who successfully underwent CRT device implantation from January 2005 to January 2014 were retrospectively analysed. RV dysfunction was defined by an RV fractional area change <35%. Post-procedural echocardiographic evaluation was performed at a median time of 2 days (interquartile range 1-6 days). The primary endpoint was a composite of all-cause mortality and urgent heart transplantation. A total of 194 patients with available pre- and post-procedural RVF assessment were included. Sixty-two (32%) presented an impaired RVF before the procedure. Of them, 32% showed prompt normalization of RVF following CRT. This occurred in parallel with a large improvement in pulmonary arterial pressure, mitral regurgitation, E/E' ratio, and diastolic function. Pre-implantation independent predictors of early RVF normalization were LBBB (P = 0.034) and higher systolic blood pressure (P = 0.026). Improvement in RVF was independently associated with a better long-term prognosis at multivariable analysis [hazard ratio 0.124; 95% confidence interval 0.016-0.966, P = 0.04). CONCLUSIONS: Acute normalization of RVF can be observed after CRT along with haemodynamic improvement, and therefore can be used as an independent predictor of transplant-free survival.