Ventricular Arrhythmias and Sudden Death in Nonischemic Dilated Cardiomyopathy: Matter of Sex or Scar?

BACKGROUND: To evaluate the association between sex and ventricular arrhythmias (VA) or sudden death (SD) in nonischemic dilated cardiomyopathy, including analysis of potential confounders. METHODS AND RESULTS: Retrospective cohort study of consecutive patients with DCM referred for cardiac magnetic resonance at 2 tertiary hospitals. The primary combined end point encompassed sustained VA, appropriate implantable cardioverter defibrillator therapies, resuscitated cardiac arrest, and SD. We included 1165 patients with median follow-up of 36 months (interquartile range 20-58 months). The majority of patients (66%) were males. Males and females had similar left ventricular ejection fraction, but the prevalence of late gadolinium enhancement (LGE) at cardiac magnetic resonance was significantly higher among males (48% vs 30%, P < .001). Males had higher cumulative incidence of the primary end point (8% vs 4%, P = .02), and male sex was a significant predictor of the primary end point at univariate analysis (hazard ratio 1.93, P = .02). However, LGE had a major confounding effect in the association between sex and the primary outcome: the hazard ratio of male sex adjusted for LGE was 1.29 (P = .37). LGE+ females had significantly higher cumulative incidence of the primary end point than LGE- males (13% vs 1.8%, P < .001). CONCLUSIONS: In patients with DCM, the prevalence of LGE is significantly higher among males, implying a major confounding effect in the association between male sex and VA or SD. LGE+ females have significantly higher risk than LGE- males. These data do not support the inclusion of sex into risk stratification algorithms for VA or SD in DCM.

Predictive value of a comprehensive atrial assessment with cardiac magnetic resonance in non-ischemic cardiomyopathy: keep it simple.

Cardiac magnetic resonance (CMR) can provide a multi-parametric evaluation of left atrial (LA) size and function. A complete CMR-based LA assessment might improve the risk stratification of patients with non-ischemic dilated cardiomyopathy (DCM). We performed a comprehensive CMR-based evaluation of LA size and function, in order to assess the prognostic impact of specific LA parameters in DCM. Secondary analysis of a prospective registry (UHSM-CMR study, NCT02326324) including 648 consecutive patients with DCM and CMR evaluation of LA area and LA length. Of these, 456 had complete LA assessment covering reservoir, conduit and booster pump function and including LA reservoir strain evaluated with feature tracking. The heart failure (HF) endpoint included HF hospitalizations, HF death and heart transplant. The arrhythmic endpoint included ventricular arrhythmias (VA) (sustained or treated by implantable defibrillator) and sudden death (SD). At median follow-up of 23 months, 34 patients reached the HF endpoint; in a multivariable model including NYHA class and LVEF, LA length had incremental predictive value. LA length ≥ 69 mm was the best cut-off to predict HF events (adjusted HR 2.3, p = 0.03). Among the 456 patients with comprehensive LA assessment, only LA length was independently associated with the HF endpoint after adjusting for LVEF and NYHA class. By contrast, no LA parameter independently predicted the arrhythmic risk. In DCM patients, LA length is an independent predictor of HF events, showing stronger association than other more complex parameters of LA function. No atrial parameter predicts the risk of VA and SD.

Growth differentiation factor-15 in patients with or at risk of heart failure but before first hospitalisation.

OBJECTIVE: Identification of patients at risk of adverse outcome from heart failure (HF) at an early stage is a priority. Growth differentiation factor (GDF)-15 has emerged as a potentially useful biomarker. This study sought to identify determinants of circulating GDF-15 and evaluate its prognostic value, in patients at risk of HF or with HF but before first hospitalisation. METHODS: Prospective, longitudinal cohort study of 2166 consecutive patients in stage A-C HF undergoing cardiovascular magnetic resonance and measurement of GDF-15. Multivariable linear regression investigated determinants of GDF-15. Cox proportional hazards modelling, Net Reclassification Improvement and decision curve analysis examined its incremental prognostic value. Primary outcome was a composite of first hospitalisation for HF or all-cause mortality. Median follow-up was 1093 (939-1231) days. RESULTS: Major determinants of GDF-15 were age, diabetes and N-terminal pro-B-type natriuretic peptide, although despite extensive phenotyping, only around half of the variability of GDF-15 could be explained (R2 0.51). Log-transformed GDF-15 was the strongest predictor of outcome (HR 2.12, 95% CI 1.71 to 2.63) and resulted in a risk prediction model with higher predictive accuracy (continuous Net Reclassification Improvement 0.26; 95% CI 0.13 to 0.39) and with greater clinical net benefit across the entire range of threshold probabilities. CONCLUSION: In patients at risk of HF, or with HF but before first hospitalisation, GDF-15 provides unique information and is highly predictive of hospitalisation for HF or all-cause mortality, leading to more accurate risk stratification that can improve clinical decision making. TRIAL REGISTRATION NUMBER: NCT02326324.

Prognostic impact of late gadolinium enhancement at the right ventricular insertion points in non-ischaemic dilated cardiomyopathy.

AIMS: To evaluate the baseline characteristics and the prognostic implications associated with late gadolinium enhancement limited to the right ventricular insertion points (IP-LGE) or present at both the right ventricular insertion points and the left ventricle (IP&LV-LGE) in non-ischaemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: This is a retrospective observational multicentre cohort study including 1165 consecutive patients with DCM evaluated by cardiac magnetic resonance. The primary endpoint included appropriate defibrillator therapies, sustained ventricular tachycardia, resuscitated cardiac arrest, or sudden death. The secondary outcome encompassed heart failure hospitalizations, heart transplant, left ventricular assist device implantation, and end-stage heart failure death. IP-LGE was found in 72 patients (6%), who had clinical characteristics closer to LGE- than to LGE+ patients. During follow-up (median 36 months), none of the IP-LGE patients experienced the primary endpoint. The cumulative incidence of the primary endpoint was similar between IP-LGE and LGE- patients (P = 1), while IP-LGE had significantly lower cumulative incidence when compared with LGE+ patients (P < 0.001). When compared with IP-LGE patients, the cumulative incidence of the secondary endpoint was similar in LGE- cases (P = 0.86) but tended to be higher in LGE+ patients (P = 0.06). Both clinical characteristics and outcomes were similar between IP&LV-LGE patients and the rest of LGE+ cases. CONCLUSIONS: In a large cohort of DCM patients, IP-LGE was associated with similar outcome when compared with LGE- patients and with significant lower risk of ventricular arrhythmias and sudden death when compared with LGE+ cases. Patients with IP&LV-LGE had clinical characteristics and outcomes similar to the rest of LGE+ cases.

Improved Risk Stratification for Ventricular Arrhythmias and Sudden Death in Patients With Nonischemic Dilated Cardiomyopathy.

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.

Towards cardiac MRI based risk stratification in idiopathic dilated cardiomyopathy.

Sudden cardiac death (SCD) secondary to arrhythmia remains a risk in those with dilated cardiomyopathy (DCM), an implantable cardiac defibrillator (ICD) is an effective strategy to prevent SCD. Current guidelines recommend selection for ICD based on ejection fraction (EF) less than 35%, however, most SCD occurs in those with EF>35%. Although meta-analysis has demonstrated a survival benefit for primary prevention ICD in DCM, no randomised trial has shown a significant reduction in overall mortality including the most recent 'Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heat Failure on Mortality' study. Clearly, a more sophisticated selection strategy is required. Cardiac MRI (CMR) is an ideal non-invasive imaging technique which allows calculation of EF as well as tissue characterisation with gadolinium contrast, parametric mapping and feature tracking. Late gadolinium enhancement detects mid-wall fibrosis in approximately 30% of those with DCM, three meta-analyses have demonstrated an association between fibrosis in DCM and SCD, and those without fibrosis are at low risk of SCD. T1 mapping and extracellular volume (ECV) calculation are methods of demonstrating diffuse fibrosis in the myocardium. Raised ECV and native T1 have been associated with worse outcomes but the relationship to SCD has not been well studied. Undoubtedly, more research is required but CMR has several tools which offer incremental value above EF to improve risk stratification and consequent outcomes and resource utilisation in those with DCM.