Dilated cardiomyopathy: second hits knock-down the heart

Abstract

Dilated cardiomyopathy (DCM) is commonly defined as the presence of left ventricular (LV) or biventricular dilatation and global or regional systolic dysfunction unexplained solely by abnormal loading conditions (e.g. hypertension or primary valve disease) or significant coronary artery disease sufficient to cause ventricular remodelling.1 The prevalence is estimated to ∼1 in 250 people, and annual incidence of DCM at 5–8 per 100 000 patients. Causes are considered as being either genetic (primary DCM) or acquired (secondary DCM) such as chemotherapy, ethyl abuses, myocarditis, tachy-arrhythmias, or auto-immune diseases. The clinical presentation and outcome of DCM, however, is strongly determined by the common co-existence of both genetic and the above-acquired factors, disease modifiers (such as pregnancy), or co-morbidities (diabetes, hypertension, endocrinopathies, and renal, hepatic or (micro)-vascular disease).1,2 Genetic and acquired hits both knock-down the heart. Severity of cardiac dysfunction and related outcome of DCM thus depends on the presence of a second genetic or acquired hit. In line, between 5% and 15% of all patients with so-called acquired -including ischaemic, myocarditis, chemotherapy-induced, tachy-arrhythmia, or alcohol abuses- triggered DCM harbour a likely pathogenic (LP) or pathogenic (P) gene variant (i.e. gene mutation), mainly within the TTN gene among other DCM genes.1 The penetrance -development of clinical manifestation- of P/LP variants depends on these ‘second hits’, either direct causal acquired factors, or disease modifiers and co-morbidities.2 Vice-versa the identification of an acquired cause does not exclude a second genetic hit. By extension in ischaemic heart disease, if cardiac dysfunction exceeds what would be expected based on the coronary artery disease and the extent of infarct scar, one may also consider a second genetic hit as recently suggested.3 In brief, the diagnostic work-up and treatment of any cardiomyopathy should always consider both genetic and acquired factors, requiring a multidisciplinary approach including geneticists, cardiologists, immunologists, and pathologists, among others. The second hit paradigm also applies to the newly defined phenotype, non-dilated left ventricular cardiomyopathy (NDLVC). This second hit paradigm -a combination of genetics and acquired causes- also applies to other imaging phenotypes of non-ischaemic cardiomyopathies, including the newly defined NDLVC.1 NDLVC is characterized/defined by either (i) the presence of non-ischaemic LV scarring or fatty replacement regardless of the presence of global or regional wall motion abnormalities, or (ii) isolated global LV hypokinesia without scarring.1 LV hypokinesis without dilation (also isolated LV dysfunction), isolated LV dilatation and/or scarring with normal ejection fraction, or atrial/ventricular tachy-arrhythmias are often the initial or only presenting morpho-functional phenotype of a genetic/acquired/idiopathic cardiomyopathy. In line, the prevalence of LP/P gene variants and their prognostic impact did not differ in isolated LV dysfunction compared with DCM in a first single-centre study.4 Atrial disease/arrhythmias as second hits or part of the (cardio)myopathy? Left bundle branch block, frequent ventricular extrasystoles, and atrial tachy-arrhythmias are known detrimental outcome factors and possible second hits in DCM/NDLVC.1 Atrial disease -dilatation or strain abnormalities at cardiac imaging- are among the strongest predictors of worse outcomes in DCM/NDLVC, overruling LV ejection fraction or dilation.5 Atrial disease may result from direct injury caused by genetic factors, as suggested by a 5%–10% prevalence of TTN variants in early onset atrial fibrillation (below the age of 30 years).6 It may also reflect increased filling pressure in the LV, with the atrium being an early sensor of LV disease. Overall, atrial disease seems to be a clear second hit for -besides being a victim of- LV disease and its treatment might help to improve cardiac function. Still, besides the ‘mediaeval’ practice of causing wounds and scars to reduce the arrhythmogenic burden along with atrial fibrillation, effective molecular therapy to stop the progression of atrial disease is still lacking. Polygenic risk score (PRS): the genetic fingerprint that predisposes the heart. An important proportion of DCM and NDLVC has a complex non-monogenic architecture, attributable to the effect of multiple variants in cardiac and non-cardiac genes. A PRS implicates the sum of common genetic variants -each carrying a small risk- associated with LV structure and function, contributing to the risk of DCM/NDLVC.7,8 For example, isolated LV dilatation may reflect the extreme phenotypic boundary of such PRS, where the sum of these common genetic variants -not being LP/P as single variants- determines the end-systolic volume. A PRS may also increase the risk of developing a DCM phenotype, as revealed for TTNtv carriers.8 Therefore, an unfavourable genetic background -polygenic risk- may influence the expression of an LP/P variant (or even an acquired cause), and act as a second hit.7,8 Future studies should investigate the relative contributions of common variants -explore other immune-, metabolic, and fibrosis related gene variants- along with monogenic and acquired causes.8 The MOGES (Morphology, Organ involvement, Genetic, Etiology, Stage) classification, endorsed by the World Heart Federation tries to cover the complexity of DCM.9,10 This classification including morpho-functional classification, extra-cardiac organ involvement, genes, other aetiologies, and symptoms also reflects the second hit paradigm. Although it remains difficult to practically implement in daily practice, the MOGES classification gives a much better holistic view than the morpho-functional or single-cause description. An updated version including recent knowledge and trying to increase its clinical applicability is required. In conclusion, the diagnostic work-up of a DCM or NDLVC should always include genetic and acquired causes as second hits and aggravators of functional phenotype and its related outcome. Gene–acquired interactions likely account for a large portion of the ‘missing heritability’ or ‘dark matter’ of gene-elusive cardiomyopathies, where a further refinement of the polygenic risk as a second hit in acquired/secondary DCM/NDLVC is urgently required. The clinical presentation and outcome of DCM or NDLVC are determined by the common co-existence of both genetic -mono and polygenic risk- and acquired factors (such as toxins, viruses, and auto-immune diseases), disease modifiers (such as pregnancy), or co-morbidities (diabetes, hypertension, endocrinopathies, and renal, hepatic or (micro)-vascular disease). S.H. receives personal fees for independent scientific advice on early development in the field of heart failure from AstraZeneca, Ribocure, and CSL Behring, and receives research support from AstraZeneca and CSL Behring for preclinical research in the field of heart failure. J.V. has nothing to disclose.

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