Complex roads from genotype to phenotype in dilated cardiomyopathy: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

Abstract

Dilated cardiomyopathy (DCM) frequently affects relatively young, economically, and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance-malignancy of the mutated gene-but also on epigenetics, age, toxic factors, pregnancy, and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN), or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.

Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology

“…Early fibrosis in cardiomyopathies is regarded as a malicious event as the need for cardiac repair usually is minimal. Clearly, the events triggering fibrosis in cardiomyopathies are very heterogeneous, and encompass events such as cell death, metabolic derangements, neurohormonal activation, and direct toxic effects of mutated proteins …”

Genetic Basis of Myocarditis: Myth or Reality?

“…The term, however, does not specify the type of inflammation, the nature of inflammatory cells, and the cause. In clinical practice, the diagnosis of myocarditis implies that the observed phenotype is attributable to the inflammation of the myocardium or that the myocardial inflammation constitutes a "comorbidity" or "complication" of preexisting known heart disease, even of a noninflammatory nature [2].…”

“…"Mendelian" myocarditis is rare, and the available information is based on single case reports and small clinical series. Disease genes are either immunity genes or non-immunity genes whose defects cause heritable cardiomyopathies [2] and may eventually predispose to myocarditis.…”

Lamin missense mutations—the spectrum of phenotype variability is increasing

“…Should we be scrutinizing the myocardial fitness landscape of these mutation‐positive disease ‘escapers’ more rigorously to understand the workings of pleiotropy? This takes us naturally onto the evolving paradigm in heart muscle disease, which regards phenotype as dependent not only on the malignancy of the mutated gene and defect, but also on epigenetics, age, toxic factors, pregnancy, gender, inflammation, and a raft of stochastic processes and acquired diseases in operation throughout the life course …”

“…fibroblasts from mutated patients) 15 and in vivo pathologic studies (endomyocardial biopsy, or heart samples from hearts excised at transplantation) 16 can provide morpho-functional evidence of damage caused by the mutation (Figure 1). When myocardial samples are unavailable, fibroblasts derived from skin biopsies of mutation carriers are an easy alternative source of cells that can be used to measure the transcripts of the mutated gene 14 (qRT-PCR), mutated and non-mutated protein expression (Western blotting), presence and distribution of the mutated lamin in cell nuclei (immunohistochemistry), and quantitative amount of the mutated lamin using protein mass spectrometry. In the larger family with LMNA-p.Arg216Cys mutation (more favourable phenotype) reported by Al-Saaidi et al, 2 mutated patients expressed less mutant lamin compared to wild-type protein (30:70 mut/wt), whilst carriers of LMNA-p.Arg471Cys and LMNA-p.Arg471His mutations (more adverse phenotypes) expressed considerably more mutant lamin relative to wild-type (50:50 mut/wt).…”