Arrhythmias as Presentation of Genetic Cardiomyopathy

Abstract

There is increasing evidence regarding the prevalence of genetic cardiomyopathies, for which arrhythmias may be the first presentation. Ventricular and atrial arrhythmias presenting in the absence of known myocardial disease are often labelled as idiopathic, or lone. While ventricular arrhythmias are well-recognized as presentation for arrhythmogenic cardiomyopathy in the right ventricle, the scope of arrhythmogenic cardiomyopathy has broadened to include those with dominant left ventricular involvement, usually with a phenotype of dilated cardiomyopathy. In addition, careful evaluation for genetic cardiomyopathy is also warranted for patients presenting with frequent premature ventricular contractions, conduction system disease, and early onset atrial fibrillation, in which most detected genes are in the cardiomyopathy panels. Sudden death can occur early in the course of these genetic cardiomyopathies, for which risk is not adequately tracked by left ventricular ejection fraction. Only a few of the cardiomyopathy genotypes implicated in early sudden death are recognized in current indications for implantable cardioverter defibrillators which otherwise rely upon a left ventricular ejection fraction ≤0.35 in dilated cardiomyopathy. The genetic diagnoses impact other aspects of clinical management such as exercise prescription and pharmacological therapy of arrhythmias, and new therapies are coming into clinical investigation for specific genetic cardiomyopathies. The expansion of available genetic information and implications raises new challenges for genetic counseling, particularly with the family member who has no evidence of a cardiomyopathy phenotype and may face a potentially negative impact of a genetic diagnosis. Discussions of risk for both probands and relatives need to be tailored to their numeric literacy during shared decision-making. For patients presenting with arrhythmias or cardiomyopathy, extension of genetic testing and its implications will enable cascade screening, intervention to change the trajectory for specific genotype-phenotype profiles, and enable further development and evaluation of emerging targeted therapies.

Keywords: atrial fibrillation; dilated cardiomyopathy; heart failure; phenotype; premature ventricular complexes.

Figure 1.

Cardiac magnetic resonance (CMR) images of genetic CM showing typical patterns of late gadolinium enhancement (LGE). A. 39M with family history of arrhythmogenic right ventricular cardiomyopathy with pathogenic PKP2 variant. CMR showed normal function of the left ventricle (LV) and right ventricle (RV), with LGE of the anterior RV free wall (arrows) but no LGE in the LV. B. 21F pathogenic DSP mutation and family history of dilated cardiomyopathy, ventricular arrhythmias, and sudden death. CMR showed normal LVEF 0.58 with sub-epicardial LGE of the inferior LV wall, extending into the septum without separate RV involvement. C. 45M with atrial fibrillation and family history of dilated cardiomyopathy, CMR showed a ring-like pattern of intramural LGE in the LV. Genetic testing revealed a pathogenic LMNA variant.

Figure 2.

Panel A presents the genes often included on comprehensive commercial panels for cardiomyopathy and arrhythmia genes, showing the overlap of genes most commonly implicated in both. Panel B presents the results from sequencing 1,293 participants with early-onset AF defined as AF diagnosed before age 65. According to the genes listed in Panel A, 43% of disease-associated variants occurred in genes commonly included on cardiomyopathy panels, 14% in genes on arrhythmia panels, and 43% in genes included on both panels. CM = cardiomyopathy, Arr = arrythmia, AR = autosomal recessive

Figure 3.

Examples of selected cardiomyopathy genes commonly associated with atrial or ventricular arrhythmias or conduction disease. The common genes coding for titin and the sarcomeric proteins are associated with a large number of variants, many of which are implicated in atrial fibrillation, but a minority of which are associated with ventricular arrhythmias, and conduction disease is rare. Variants recognized in less common genes such as LMNA and FLNC are more consistently associated with ventricular arrhythmias and sudden cardiac death. Variants in genes for desmosomal proteins, phospholamban, and filamin-C can be associated with both RV and LV involvement. ACM= general term for arrhythmogenic cardiomyopathy, ACM-RV = arrhythmogenic cardiomyopathy with dominant RV involvement; ACM-LV= arrhythmogenic cardiomyopathy with dominant LV involvement, DCM = dilated cardiomyopathy, HCM = hypertrophic cardiomyopathy. (Illustration credit: Ben Smith).

Figure 4.

Examples of 12-lead electrocardiograms (ECG) from 2 patients with arrhythmogenic cardiomyopathies Panels A and B are from a 53-year-old man with ACM-RV. Panel A shows SMVT with atrio-ventricular dissociation. V1 has a left bundle branch block-type configuration and the frontal plane is directed superiorly, consistent with a VT origin in the inferior RV. Panel B shows sinus rhythm ECG findings typical for RV disease with T-wave inversion in leads V1–V6 and inferiorly, and a slurred and prolonged terminal s-wave in V2. Panel C is from a 77-year old man with a long history of PVCs that had been considered benign in the absence of either known disease or concerning family history. The most frequent PVC (PVC1) has a right bundle branch configuration in V1 with dominant R waves across the precordium and inferiorly directed frontal plan axis, consistent with an origin in the periaortic LV. Panel D in the same patient shows the tracing during ventricular tachycardia, taken by paramedics after he presented with syncope. Genetic testing revealed a pathogenic TTN mutation. ACM-RV=arrhythmogenic right ventricular dysplasia, LV= left ventricle, RV=right ventricle, SMVT = sustained monomorphic ventricular tachycardia

Figure 5.

Arrhythmias at the time of presentation for 689 patients with dilated cardiomyopathy in relation to the presence or absence of family history and identified pathogenic variants on genetic testing. At Arr = atrial arrhythmias, AV = atrioventricular, LBBB = left bundle branch block, NSVT = non-sustained ventricular tachycardia. Figure drawn from published data from the Maastricht Cardiomyopathy Registry, with permission from Verdonschot and Hunner.