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Department of Cardiology, Royal Melbourne Hospital, Melbourne, Vic, AustraliaDepartment of Medicine, University of Melbourne, Melbourne, Vic, Australia
Department of Cardiology, Westmead Hospital, Westmead Applied Research Centre, Sydney, NSW, AustraliaSydney Medical School, University of Sydney, Sydney, NSW, Australia
Department of Cardiology, Royal Melbourne Hospital, Melbourne, Vic, AustraliaDepartment of Medicine, University of Melbourne, Melbourne, Vic, Australia
Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, NSW, AustraliaSt. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, AustraliaCardiology Department, St. Vincent’s Hospital, Sydney, NSW, Australia
Cardiac arrhythmias are frequently seen in patients with dilated cardiomyopathy (DCM) and can precipitate heart failure and death. In patients with non-ischaemic DCM, evidence for the benefit of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death has recently been questioned. Algorithms devised to identify high-risk individuals who might benefit most from ICD implantation have focussed on clinical criteria with little attention paid to the underlying aetiology of DCM. Malignant ventricular arrhythmias often occur as a nonspecific consequence of DCM but can also be a primary manifestation of disease in heritable forms of DCM and may precede DCM onset. We undertook a literature search and identified 11 genes that have been associated with DCM and ventricular arrhythmias in multiple kindreds. Many of these genes fall into a diagnostic grey zone between left-dominant arrhythmogenic right ventricular cardiomyopathy and arrhythmic DCM. Genes associated predominantly with arrhythmic DCM included LMNA and SCN5A, as well as the more recently-reported DCM disease genes, RBM20, FLNC, and TTN. Recognition of arrhythmic DCM genotypes is important, as this may impact on clinical management. In particular, prophylactic ICD implantation and early referral for heart transplantation may be indicated in genotype-positive individuals. Collectively, these findings argue in favour of including genetic testing in standard-of-care management of familial DCM. Further studies in genotyped patient cohorts are required to establish the long-term health and economic benefits of this strategy.
Cardiac arrhythmias are a major cause of clinical deterioration and demise in patients with dilated cardiomyopathy (DCM). In keeping with this, current international guidelines recommend prophylactic intervention with implantable cardioverter-defibrillators (ICD) in patients with heart failure and left ventricular ejection fraction <35% [
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.
]. The risk-benefit ratio of routine ICD implantation has recently been questioned. Whilst data from longitudinal studies show a 44% decline in sudden cardiac death over the past two decades [
], a recent clinical trial (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality, [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%) [
]. Potential reasons for lack of survival benefit may be inappropriate selection in non-arrhythmogenic DCM genotypes and exclusion of genetic DCM where malignant ventricular arrhythmias occur in individuals with only mild or moderate reductions in ejection fraction [
Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study.
]. Collectively, these findings have prompted review of indications for ICD use, particularly in the setting of non-ischaemic heart failure, and have highlighted the need to identify subsets of high-risk patients who might derive the greatest benefit from ICD implantation for the primary prevention of sudden cardiac death [
Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study.
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 [
Late gadolinium enhancement in cardiac magnetic resonance predicts adverse cardiac outcomes in nonischemic cardiomyopathy: a systematic review and meta-analysis.
]. 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 understanding of the aetiology of DCM may provide a means for personalising risk stratification.
Genetic variation has an important role in the pathogenesis of DCM and long lists of putative disease genes have been compiled [
]. 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. In this article, we will provide an overview of current knowledge of cardiac arrhythmias in genotyped individuals with familial or sporadic DCM, and the implications for genetic testing and clinical management.
Spectrum of Arrhythmic Phenotypes Associated With Dilated Cardiomyopathy Disease Genes
We undertook a literature search to investigate cardiac phenotypes associated with DCM-causing genetic variants and identified 11 genes in which both DCM and ventricular arrhythmias had been reported in multiple families ± sporadic cases (Table 1). 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 fibrofatty infiltration of the right ventricle and early arrhythmias (Figure 1). An alternative classification based on genotype would be equally problematic, as these genes have each been associated with multiple different phenotypes (Table 1). 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.
Table 1Spectrum of phenotypes and other disorders associated with arrhythmic cardiomyopathy genes.
Gene
Protein
Protein Function
AA
CCD
VA
SCD
Other disorders
LMNA
Lamin A/C
Nuclear lamina component
Y
Y
Y
Y
ARVC, CMT, HGP, LVNC, MAD, MD, PL, RD
SCN5A
Nav1.5
Cardiac sodium channel α-subunit
Y
Y
Y
Y
AF, ARVC, AS, BrS, IVF, CCD, LQTS, SIDS, SSS
FLNC
Filamin C
Z-disc and cytoskeletal actin cross-linking protein
ARVC, HCM, MM, RCM
RBM20
RNA binding motif protein 20
Splicing regulation
Y
Y
Y
Y
ARVC
TTN
Titin
Sarcomere protein
Y
Y
Y
ARVC, HCM, LVNC, MD, RCM, SkM
DES
Desmin
Cytoskeletal intermediate filament protein
Y
Y
Y
ARVC, HCM, MD, MM, RCM, SPS
PLN
Phospholamban
Sarcoplasmic reticulum; inhibits Ca2+-ATPase
Y
Y
ARVC, HCM
TMEM43
Transmembrane protein 43
Nuclear envelope protein; interacts with lamin A and emerin.
Y
ARVC, MD
DSP
Desmoplakin
Desmosomal component; links intermediate filaments to desmosomal plaques
Figure 1Phenotype overlap between arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). There is a diagnostic grey zone between left-dominant forms of ARVC and arrhythmic forms of DCM.
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 (Figure 2). 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 [
Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.
] (Figure 2). 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 (Figure 2). 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. Characteristics of these arrhythmic DCM disease genes are highlighted below.
Figure 2Genes associated with a high propensity for dilated cardiomyopathy (DCM) and ventricular arrhythmias. These arrhythmic genes included desmosomal genes that predominantly cause arrhythmogenic right ventricular cardiomyopathy (ARVC), non-desmosomal genes associated with ARVC, DCM or both, and genes that predominantly cause DCM.
] and are now recognised to be one of the most common causes of familial DCM, accounting for ∼5% cases. Pathogenic LMNA variants have a distinctive phenotype in which conduction-system abnormalities or atrial fibrillation may precede the onset of DCM by several decades [
]. Longitudinal studies have demonstrated that LMNA variant carriers typically have an aggressive clinical course as a result of progressive heart failure or malignant ventricular arrhythmias [
]. Factors proposed to predict adverse outcomes include male sex, loss-of function variants (frameshift insertion/deletions, splice site loss), a left ventricular ejection fraction <45% or increased left ventricular end-diastolic diameter, and the presence of non-sustained ventricular tachycardia [
]. Studies in murine models have shown that lamin A/C deficiency results in altered nuclear morphology and abnormal nuclear-cytoskeletal connections that may impair the mechanical stability of cardiomyocytes [
]. The hearts of human LMNA variant carriers are often notable for the presence of marked fibrosis, which may contribute to the high propensity for ventricular arrhythmias [
]. A key clinical feature of LMNA-related heart disease is the proclivity for malignant ventricular arrhythmias that precede ventricular dilation and dysfunction. As such, these patients will classically be ineligible for ICD implantation for sudden death based on left ventricular ejection fraction alone, unless a genetic diagnosis is made. This underscores the need for vigilance for phenotypic recognition and early genetic testing [
SCN5A encodes the cardiac sodium channel, Nav1.5, and like LMNA, pathogenic variants in this gene have been associated with DCM, conduction-system abnormalities and atrial and ventricular arrhythmias [
]. The vast majority of reported pathogenic variants have been missense variants, with a predilection for location in the S3 and S4 transmembrane domain, implicating disruption of voltage-sensing mechanisms [
]. Dilated cardiomyopathy-associated SCN5A variants have been shown to have loss-of-function or gain-of-function effects on cardiac sodium channel activity [
]. There has been debate about whether contractile impairment is a consequence of atrial or ventricular ectopy/tachyarrhythmias or a primary phenotypic feature. However, the severity of DCM may be disproportionate to the arrhythmic burden, suggesting that it is a bona fide disease manifestation. Mechanisms other than direct modulation of channel activity may be involved, including down-regulation of Nav1.5 expression, channel mislocalisation due to altered cytoskeletal anchoring, or altered intracellular pH and Ca2+ homeostasis [
RNA binding motif protein 20 (RBM20) is a component of the RNA splicing machinery and is involved in regulation of constitutive and alternative splicing. Pathogenic RBM20 variants have been associated with a particularly aggressive phenotype, with early onset severe DCM and a high likelihood of heart transplantation, ventricular arrhythmias and premature death [
]. Most of the DCM-associated RBM20 variants have been missense variants, with many of these located in a mutational hotspot in the arginine-serine (RS)-rich domain [
]. However, RBM20 contributes to the post-translational modification of at least 30 cardiac genes, and loss-of-function RBM20 variants are now appreciated to have a broad spectrum of effects that impact on diverse aspects of sarcomere structure and function [
]. Changes in expression of genes involved in Ca2+ handling and increased spontaneous Ca2+ release from the sarcoplasmic reticulum are thought to be important determinants of arrhythmogenesis in variant carriers.
FLNC
Filamin C is an actin-binding cytoskeletal protein that is located at Z-discs and costameres in cardiac and skeletal muscle. It is thought to contribute significantly to the structural stability of muscle cells and to mechanical stress sensing and signal transduction. Variants in the FLNC gene can result in the formation of intracellular protein aggregates and myofibrillar myopathies and have been identified in patients with hypertrophic cardiomyopathy and restrictive cardiomyopathy [
]. In 2016, two groups of investigators reported that truncating variants in the FLNC gene resulted in a highly arrhythmic form of DCM that was characterised by severe early-onset ventricular dysfunction and a high prevalence of atrial arrhythmias, ventricular ectopy, ventricular tachycardia and sudden death [
]. Cardiac tissue from variant carriers showed reduced FLNC RNA and protein expression suggesting a loss-of-function effect. This was confirmed by studies in zebrafish embryos, with morpholino-mediated knockdown of filamin C resulting in dysmorphic or dilated cardiac chambers, pericardial oedema, and premature death [
]. Myocardial histological studies in the zebrafish embryos showed abnormal cardiomyocyte ultrastructure, with altered sarcomere alignment and irregular or absent Z-discs. In filamin C-deficient human hearts, protein aggregates are generally absent but marked ventricular fibrosis has been observed, and this may contribute to the high arrhythmia propensity [
]. In a very recent study, a subset of patients with DCM due to truncating FLNC variants were shown to have epicardial fibrofatty infiltration of the left ventricle, as well as dilation and interstitial fibrosis of the right ventricle [
Truncating variants in the TTN gene (TTNtv) have been identified in 15–20% of patients with DCM and have been proposed to be the most common genetic cause of DCM [
]. However, since these variants are also present in up to 3% of the general population, their clinical significance has been questioned. Studies in zebrafish models suggest that TTNtv can be sufficient alone to cause DCM [
]. There is increasing evidence, however, that the phenotypic manifestations of TTNtv are likely to be modified by additional genetic and acquired factors, such as alcohol and pregnancy [
]. Although it has been suggested in some studies that TTNtv carriers have a high risk of ventricular arrhythmias, data from other studies suggest that overall outcomes, including heart failure progression and malignant ventricular arrhythmias, are milder than those observed in patients with high-impact variants in other genes such as LMNA and RBM20 [
Taking a careful clinical history, including a family history of at least three generations, is the essential first step in diagnosing arrhythmic forms of familial DCM. A high index of suspicion is needed, and a spectrum of clinical presentations amongst different family members may be potentially relevant, including DCM, other cardiomyopathy types, conduction-system abnormalities, atrial and ventricular arrhythmias, congenital heart defects, skeletal myopathy, and sudden unexplained death. Probands and family members need to be evaluated with physical examination, echocardiography, and 24-hour ECG. In patients with suspected arrhythmic DCM, cardiac magnetic resonance imaging is useful to delineate left and right ventricular size and function, and for assessment of the presence and extent of ventricular fibrosis. Additional investigation with electrophysiological studies should be undertaken according to standard clinical indications. Measurement of serum creatine kinase levels is often helpful, even in the absence of overt symptoms and signs of skeletal myopathy, and may help to prioritise potential causative genetic variants. In all affected individuals, causes of DCM other than familial disease need to be excluded. Distinctive phenotypic patterns within families may give clues to specific genetic aetiologies, such as DCM + conduction abnormalities (LMNA, SCN5A), and DCM + conduction abnormalities + raised creatine kinase levels (LMNA, DES).
Genetic Testing
Unlike many other disorders, genetic testing in DCM cases is not performed to establish a diagnosis but rather, to find the underlying genetic aetiology. To date, the main benefit of genetic testing has been to enable cascade predictive testing of asymptomatic family members and this has been used to guide clinical follow-up strategies. Historically, the overall cost-efficacy and treatment impact of genetic testing in DCM was considered relatively modest, and this resulted in a class II recommendation (“may be useful”) in international guidelines [
]. With advances in next-generation sequencing technologies, human genome sequencing has become more available and affordable, and its value needs to be revisited. Efforts to revise genetic testing guidelines by authoritative bodies such as the Heart Failure Society of North America are both timely and warranted [
]. Recognition of families with arrhythmic DCM genotypes is particularly important in the light of accumulating evidence that this information can directly impact on clinical management. To this end, genetic testing should be considered in any newly-diagnosed patients with familial DCM, especially if there is a suspicion of arrhythmic events in the index case or in family members.
Implications of Genetic Diagnosis for Family Management
Heart failure and arrhythmias in affected family members are generally treated using pharmacological, device therapy, and heart transplantation in accordance with standard clinical guidelines [
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.
]. In decisions regarding invasive ablation procedures for patients with atrial or ventricular arrhythmias, the impact of a genetically-determined cardiomyopathic substrate on procedural success and recurrence rates needs to be considered.
There are emerging data to suggest that genetic information may allow gene-targeted and more personalised therapeutic strategies. For example, it has been recommended that carriers of pathogenic LMNA variants should receive ICDs rather than pacemakers, and undergo early heart transplantation [
]. Similar aggressive approaches may be warranted in carriers of other highly arrhythmic gene variants. Although treatments to date have mainly provided symptomatic relief, gene-specific therapies that are directed against primary pathogenetic mechanisms are increasingly being explored. An example of this is the p.R222Q SCN5A variant that has been associated with arrhythmic DCM [
Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LDB3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.
Rapid and effective response of the R222A SCN5A to quinidine treatment in a patient with Purkinje-related ventricular arrhythmia and familial dilated cardiomyopathy: a case report.
]. Although treatment with drugs that have sodium channel blocking properties is generally contraindicated for the treatment of ventricular arrhythmias in patients with heart failure [
], we and others have found that drugs such as flecainide, amiodarone, and quinidine have been remarkably effective in p.R222Q SCN5A carriers, resulting in a spectacular reduction of arrhythmia burden and improved left ventricular function [
Rapid and effective response of the R222A SCN5A to quinidine treatment in a patient with Purkinje-related ventricular arrhythmia and familial dilated cardiomyopathy: a case report.
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.
]. Several biologically-targeted drug therapies have shown promising results in animal models of LMNA deficiency, and pilot human studies have been performed or are currently underway [
Unaffected genotype-positive family members require baseline clinical evaluation and periodic surveillance to detect symptoms and signs of declining cardiac function and/or arrhythmia onset. In the absence of clinical trial data, the efficacy of pre-emptive intervention is unknown. Future studies in large cohorts of genotyped individuals are clearly needed in order to address important questions such as who, when, and how to treat asymptomatic variant carriers in order to attenuate or prevent disease onset.
In all family members, attention should be given to treatment of co-morbidities and lifestyle factors that may exacerbate the disease phenotype. In recent years, exercise has been shown to accelerate disease progression in patients with ARVC [
Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers.
], but the impact of exercise on arrhythmic forms of DCM is unknown. Interestingly, regular moderate exercise was shown to be beneficial in a murine model of lamin A/C-deficient DCM [
]. Family members should also receive genetic counselling and psychosocial issues need to be addressed. Genetic testing and ongoing family management is ideally performed in the setting of a multidisciplinary clinic.
Further comparative studies in genotyped patient cohorts are required to better define the range of genotypes that give rise to arrhythmic forms of familial DCM, and to document natural history and outcomes. Such studies will only be possible in the first instance, if genetic testing of DCM families is more widely adopted. Genetic testing holds the key to a better understanding of molecular underpinnings of arrhythmic DCM and the development of gene-targeted therapies. Mechanistic and intervention studies in experimental models and genotyped human cohorts are needed.
In conclusion, there are emerging data that a subset of DCM disease genes is associated with a highly arrhythmic phenotype. Genetic testing has an important role in identifying variant carriers and should be undertaken promptly when arrhythmic forms of DCM are suspected. Individuals with deleterious variants arrhythmic DCM genes, especially LMNA, SCN5A, RBM20, FLNC, need aggressive early intervention.
Conflicts of Interest
None.
Acknowledgements
Dr Peters is supported by an Australian Postgraduate Award from the University of Melbourne. Dr Fatkin is supported by the National Health and Medical Research Council of Australia (NHMRC), Victor Chang Cardiac Research Institute, Estate of the Late RT Hall, Simon Lee Foundation, and the St Vincent’s Clinic Foundation. Dr. Kumar is supported by a NHMRC Career Development Fellowship. Dr Kalman is supported by a NHMRC Practitioner Fellowship.
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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.
Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study.
Late gadolinium enhancement in cardiac magnetic resonance predicts adverse cardiac outcomes in nonischemic cardiomyopathy: a systematic review and meta-analysis.
Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.
Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LDB3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.
Rapid and effective response of the R222A SCN5A to quinidine treatment in a patient with Purkinje-related ventricular arrhythmia and familial dilated cardiomyopathy: a case report.
Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers.
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