ONISCHEMIC DILATED CARDIomyopathy is a common heart muscle disease with a prevalence of at least 1 in 2500 adults. 1 It is characterized by left ventricular cavity enlargement and impaired contractility in the absence of significant coronary artery disease. 1 The condition is associated with significant morbidity and mortality due to progressive heart failure (HF) and sudden cardiac death (SCD). 2 Despite For editorial comment see p 929.

The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) provides new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5,267 individuals across the spectrum of cardiac physiology, and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms, and demonstrate that these data, coupled with TTNtv position, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause for DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses we provide evidence for a length-dependent, dominant negative mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.

Midwall fibrosis was an independent predictor of mortality in patients with moderate and severe aortic stenosis. It has incremental prognostic value to ejection fraction and may provide a useful method of risk stratification.

Dilated cardiomyopathy (DCM) is best understood as the final common response of myocardium to diverse genetic and environmental insults. A rigorous work-up can exclude alternative causes of left ventricular (LV) dilation and dysfunction, identify etiologies that may respond to specific treatments, and guide family screening. A significant proportion of DCM cases have an underlying genetic or inflammatory basis. Measurement of LV size and ejection fraction remain central to diagnosis, risk stratification, and treatment, but other aspects of cardiac remodeling inform prognosis and carry therapeutic implications. Assessment of myocardial fibrosis predicts both risk of sudden cardiac death and likelihood of LV functional recovery, and has significant potential to guide patient selection for cardioverter-defibrillator implantation. Detailed mitral valve assessment is likely to assume increasing importance with the emergence of percutaneous interventions for functional mitral regurgitation. Detection of pre-clinical DCM could substantially reduce morbidity and mortality by allowing early instigation of cardioprotective therapy.

CMR is a valuable adjunct to conventional investigations in a diagnostically challenging and important group of patients with troponin-positive chest pain and unobstructed coronary arteries.

Background-Cardiovascular magnetic resonance is the gold-standard technique for the assessment of ventricular function.Although left ventricular volumes and ejection fraction are strong predictors of outcome in dilated cardiomyopathy (DCM), there are limited data regarding the prognostic significance of right ventricular (RV) systolic dysfunction (RVSD). We investigated whether cardiovascular magnetic resonance assessment of RV function has prognostic value in DCM. Methods and Results-We prospectively studied 250 consecutive DCM patients with the use of cardiovascular magnetic resonance. RVSD, defined by RV ejection fraction ≤45%, was present in 86 (34%) patients. During a median follow-up period of 6.8 years, there were 52 deaths, and 7 patients underwent cardiac transplantation. Received March 10, 2013; accepted July 30, 2013. From the Royal Brompton Hospital, London, United Kingdom (A.G., T.F.I., A.J., F.A., K.G., N.A.I., S.R., J.K., T.D.H.B., K.M., E.L., M.R., R.W., T.C.P., R.S., J.-P.C., S.A.C., M.R.C., R.G.A., D.J.P., S.K.P.); Ealing Hospital, London, United Kingdom (R.G.A.); National Heart & Lung Institute, Imperial College, London, United Kingdom (T.F.I., K.G., R.S., J.-.P.C., S.A.C., M.R.C., D.J.P., S.K.P.); and National Heart Centre Singapore, Singapore (S.A.C.).The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl

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In DCM, the presence of septal LGE is associated with a large increase in the risk of death and SCD events, even when the extent is small. SCD risk is greatest with concomitant septal and free-wall LGE. The incremental value of LGE extent beyond small amounts and LGE pattern is limited.