Cardiac arrhythmias are a major cause of clinical deterioration and demise in patients with dilated cardiomyopathy (DCM). In line with this, current International guide-lines recommend prophylactic intervention with implantable cardioverter-defibrillators (ICD) in patients with heart failure and left ventricular ejection fraction <35%.
Whilst data from longitudinal studies show a 44% decline in sudden cardiac death over the past two decades, a recent clinical trial (Defibrillator Implantation in Patients with Non ischemic Systolic Heart Failure, [DANISH]) showed lack of mortality benefit from ICD implantation in DCM as a primary prevention strategy with a notable complication rate (3.6–4.9%).
Risk stratification criteria devised to date have focussed on non-invasive parameters including clinical history, ventricular size and function, electrocardiogram (ECG) characteristics such as QRS fragmentation and T-wave alternans, late gadolinium enhancement on cardiac magnetic resonance imaging, and autonomic nervous system activity.
These parameters have had only modest success in predicting sudden cardiac death in patients with non- ischaemic DCM and have limited clinical utility. A notable omission from these criteria is consideration of the cause of DCM. Ventricular (and atrial) arrhythmias may arise as a non-specific consequence of DCM in association with secondary structural and electrical chamber remodelling. However, cardiac arrhythmias can also be primary manifestations of the disease process itself. A better under- standing of the aetiology of DCM may provide a means for personalising risk stratification.
Genetic variation has an important role in the pathogenesis of dilated cardiomyopathy and long lists of putative disease genes have been compiled. Disease-causing gene variants can be identified in 25%–40% of families with DCM and in 10%–25% of sporadic DCM cases but, because of the high costs and the relatively low yield, clinical genetic testing has not been part of routine patient care.
An exception to this has been the subset of patients with DCM and conduction-system abnormalities, in whom screening of the LMNA and SCN5A genes is recommended in clinical practice guidelines. In recent years, there has been emerging evidence that a number of genes in addition to LMNA and SCN5A have significant arrhythmic phenotypes.
Recognition of these arrhythmic genotypes is paramount, as variant carriers may require aggressive early intervention.
Data from literature search aimed to investigate cardiac phenotypes associated with DCM-causing genetic variants identified 11 genes in which both DCM and ventricular arrhythmias had been reported in multiple families+/-sporadic cases.
These genes encode proteins involved in diverse aspects of cardiomyocyte structure and function with no clear common pathogenetic mechanism. Classification of these genes based on phenotype alone was challenging, as most fell in a diagnostic grey zone between DCM and arrhythmogenic right ventricular cardiomyopathy (ARVC), a disorder characterised by fibro- fatty infiltration of the right ventricle and early arrhythmias. An alternative classification based on genotype would be equally problematic, as these genes have each been associated with multiple different phenotypes. A caveat to both classification methods is the variable level of evidence for disease causation, with many of these associations relying on reports of predicted-pathogenic variants in single cases.
Arrhythmogenic right ventricular cardiomyopathy is most frequently caused by desmosomal gene variants that result in altered cell-cell coupling, inflammation and fibrosis with eventual chamber dilatation and dysfunction. Approximately 75% of patients with ARVC have bi-ventricular involvement and left-dominant forms are not uncommon.
Genes such as DSP, DSG2, and DSC2, fall into this category. Another subset of arrhythmic genes, including TMEM43, PLN, and DES, encode non-desmosomal proteins and have also been associated with ARVC, DCM, or overlap syndromes, all of which are frequently complicated by malignant ventricular arrhythmias.
Interestingly, TMEM43 and PLN variants are relatively uncommon but have been seen as founder mutations in specific populations. DES variants are associated with a range of cardiac and skeletal myopathies, including ARVC, DCM, and restrictive cardiomyopathy, with disease phenotypes often including cardiac conduction abnormalities, ventricular arrhythmias and sudden cardiac death.
A third subset of genes primarily cause arrhythmic forms of DCM, with some reported associations with ARVC. While some of these genes, such as LMNA and SCN5A, are widely known for their arrhythmic phenotypes, the arrhythmic potential of other, more recently-reported DCM disease genes, particularly RBM20 and FLNC, is less well recognised.
Peters S, et al. Arrhythmic Genotypes in Familial Dilated Cardiomyopathy: Implications for Genetic Testing and Clinical Management. Heart, Lung and Circulation (2018), https://doi.org/10.1016/j.hlc.2018.09.010
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.
Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Europace 2015;17:1601–87.
Shen L, Jhund PS, Petrie MC, Claggett BL, Barlera S, Cleland JG, et al. Declining risk of sudden death in heart failure. N Engl J Med 2017;377:41– 51.