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MINI-FOCUS ISSUE ON CARDIOMYOPATHIES AND GENETIC COUNSELING

EDITORIAL COMMENT

The Ever-Expanding Landscapeof Cardiomyopathies

Babken Asatryan, MD, PHD,a Frank I. Marcus, MDb

T he second half of the 20th century saw theemergence of a disease entity, referred to ascardiomyopathies: a group of myocardial dis-

eases associated with a risk of heart failure and sud-den death. The curiosity and dedication of manyminds to uncover this collection of conditions led tosignificant progress in the recognition of the clinicaland pathological features of cardiomyopathies.Initially, this was manifest as a predominantly post-mortem diagnosis. Subsequently, the clinical recogni-tion of the cardiomyopathies has evolved over time.In 1990, the first myopathic disease due to a pointmutation in the b-myosin heavy chain gene was iden-tified in a French-Canadian family with hypertrophiccardiomyopathy (HCM) (1,2). This finding initiated anew era of cardiomyopathy research, extending thecare from individual patients to entire families.

With the advent of next-generation geneticsequencing and multimodality cardiac imaging, thephenotype spectrum and genetic architecture of the 3main cardiomyopathies, dilated cardiomyopathy(DCM), HCM, and arrhythmogenic right ventricularcardiomyopathy (ARVC) (Figure 1), are increasinglyrecognized and clinically relevant genotype-phenotype-risk associations have become evident.Patients with DCM, characterized by idiopathic left

ISSN 2666-0849

From the aDepartment of Cardiology, Inselspital, Bern University

Hospital, University of Bern, Bern, Switzerland; and the bSarver Heart

Center, University of Arizona, Tucson, Arizona. The authors have re-

ported that they have no relationships relevant to the contents of this

paper to disclose.

The authors attest they are in compliance with human studies commit-

tees and animal welfare regulations of the authors’ institutions and Food

and Drug Administration guidelines, or patient consent where appro-

priate. For more information, visit the JACC: Case Reports author

instructions page.

ventricular or biventricular dysfunction and dilata-tion often present in the third to fifth decade of lifewith mild symptoms (3,4). Patients with DCMfrequently have ventricular arrhythmias and 30% diesuddenly (5). Although ventricular arrhythmias weretraditionally thought to occur at a later stage of thedisease in DCM with symptomatic heart failure,recent evidence has indicated that certain geneticforms are significantly arrhythmogenic even duringthe early course of the disease (6–8). Beyond thewidely recognized lamin A/C (LMNA), mutations ingenes encoding filamin C (FLNC), desmoplakin(DSP), phospholamban (PLN), and RNA bindingmotif protein 20 (RBM20) have been associated witha substantial risk of life-threatening ventricular ar-rhythmias despite only mild ventricular dysfunction(8–11). Mutations in the titin gene (TTN), the mostprevalent genetic substrate of DCM, are associatedwith a high incidence of ventricular arrhythmiasand particular susceptibility to environmentalstressors, such as viral infection, immune response,and toxic exposure (12). Genetic risk stratificationhelps in decision-making for the need of implant-able cardioverter-defibrillator therapy. However,present knowledge of the genetic background ex-plains only approximately 30% to 35% of DCMcases, hindering the precision care of many patientsand families (13).

HCM often has a silent course. Nevertheless, asizeable proportion of patients present with angina,dyspnea, palpitations, syncope, or sudden cardiacdeath (SCD). In hypertrophic obstructive cardiomy-opathy, nearly 70% of all deaths are sudden (14).Mutations in the b-myosin heavy chain gene, MYH7,result in an earlier and more severe phenotype thanother HCM forms (15). Patients with sarcomeric genemutations are diagnosed at a younger age and have a

https://doi.org/10.1016/j.jaccas.2020.02.006

FIGURE 1 The Clinical and Genetic Characteristics of Hypertrophic, Dilated, and Arrhythmogenic Cardiomyopathies

*In the presence of family history of HCM, left ventricular wall thickness of $13 mm is diagnostic for HCM. CCB ¼ calcium channel blocker; CMR ¼ cardiac magnetic

resonance imaging; CRT-P/D ¼ cardiac resynchronization therapy pacemaker/ defibrillator; CT ¼ computed tomography; DHP ¼ dihydropyridine;

ECG ¼ electrocardiogram; EMB ¼ endomyocardial biopsy; FHx ¼ family history; HCM ¼ hypertrophic cardiomyopathy; HF ¼ heart failure; HOCM ¼ hypertrophic

obstructive cardiomyopathy; ICD ¼ implantable cardioverter-defibrillator; LGE ¼ late gadolinium enhancement; LV ¼ left ventricle; LVEF ¼ left ventricular ejection

fraction; LVH ¼ left ventricular hypertrophy; LVOTO ¼ left ventricular outflow tract obstruction; NSVT ¼ nonsustained ventricular tachycardia; PVC ¼ premature

ventricular contraction; RVEF ¼ right ventricular ejection fraction; SAECG ¼ single averaged electrocardiogram; SCA ¼ sudden cardiac arrest; SCD ¼ sudden cardiac

death; TWI ¼ T-wave inversion; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.

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higher rate of familial SCD (16,17). The risk stratifica-tion in patients with HCM is based on a predictionmodel, which quantifies the risk of life-threateningarrhythmias during the following 5 years based onclinical variables (18). However, precision treatmentof patients with HCM is only in its early days. Drugsthat alter the myofilament calcium sensitivity andcalcium homeostasis such as blebbistatin, diltiazem,and ranolazine, modifiers of myocardial energeticsubstrates, inhibitors of mitogen-activated proteinkinase and mammalian target of rapamycin path-ways, as well as genome editing and gene transfertechnologies are currently under investigation andmay enable precision therapy for treatment of HCM inthe near future.

ARVC is genetic heart disease with a progressivecourse and a risk of SCD. In the advanced stages, it ischaracterized histopathologically by necrosis andfibrofatty replacement of the right ventricularmyocardium, which may lead to progressive heartfailure and increased susceptibility to SCD (19).However, ARVC may be manifest with life-threatening ventricular arrhythmias before thedevelopment of clinical structural heart disease (19).Due to its variable phenotype, there is no single goldstandard for the diagnosis of ARVC. Therefore, theTask Force diagnostic criteria were proposed in 1994,and then revised in 2010 to improve the sensitivitybut maintaining diagnostic specificity (19). During thepast decade, ARVC has been increasingly recognizedas a biventricular disease with involvement of the leftventricle to a lesser extent. Also, left-dominant formsof disease have been reported. These observationshave resulted in a broader term, arrhythmogeniccardiomyopathy, to reflect the spectrum of arrhyth-mogenic cardiomyopathies (20). Recently, a predic-tion model has been proposed to stratify the risk oflife-threatening arrhythmias in patients with ARVC,and tailor the therapy according to an individual pa-tient’s needs (21).

Most cardiomyopathies are not rare and are oftenseen by cardiologists, molecular geneticists, and pa-thologists. Because the phenotype in cardiomyopa-thies appears to be influenced by a variety of geneticand environmental factors, it is not uncommon to befaced with both a diagnostic and challenging thera-peutic situation in patients with cardiomyopathies.The ultimate need for improved care of patientsmandates the reporting of such rare experiences incase reports or case series to enable the transfer ofknowledge between clinical specialists.

For the purpose of promoting the understanding,recognition, and precision management ofpatients with cardiomyopathies, JACC: Case Reportslaunched this issue on inherited cardiomyopathies.Carreras-Mora et al. (22) describe a case of cardiogenicshock caused by right ventricular Takotsubo syn-drome. The authors emphasize the importance ofrecognizing this rare condition because patients withshock might benefit more from phosphodiesterase-3inhibitors than treatment with dobutamine, whichcan exacerbate the condition. Binder et al. (23)describe a new mutation in the FHL1 gene, whichsegregated with a phenotype of HCM, neuromusculardisease, and/or SCD, and underscore the implicationsof FHL1 screening in patients and families with HCM.Gi et al. (24) report a large atrial myxoma in a patientwith apical HCM. Concomitant occurrence of myxomaand HCM is characterized in LEOPARD syndrome, arare multiple congenital anomaly predominantly

affecting the skin, face, and heart. The authors haveexcluded LEOPARD syndrome because of the absenceof extracardiac manifestations. Based on this patientand the previous 6 reports of atrial myxoma in pa-tients with HCM, the authors raise the hypothesis thatthere may be a link between the 2 conditions,particularly based on the shared pathogenetic acti-vation of RAS/MASK pathway in LEOPARD syndromeand HCM, and the fact that RAS is the most commononcogene in humans. Ali et al. (25) describe a case of apatient with hypertrophic obstructive cardiomyopa-thy and accompanying aortic valve stenosis. In thispatient, percutaneous coronary intervention in theproximal left-anterior descending coronary artery,associated with occlusion of the first septal coronaryartery, resulted in substantial reduction in the leftventricular outflow tract gradient and improvementin the left ventricular function. These observationsillustrate the expanding spectrum of cardiomyopa-thies. The evolving knowledge of the genetics,mechanisms of disease, and determinants of pheno-type in cardiomyopathies will result in better riskstratification and improve the outcome in patientswith cardiomyopathy.

ADDRESS FOR CORRESPONDENCE: Dr. BabkenAsatryan, Department of Cardiology, Inselspital, BernUniversity Hospital, Freiburgstrasse 10, 3010 Bern,Switzerland. E-mail: babken.asatryan@insel.ch.

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KEY WORDS arrhythmia, cardiomyopathy,genetics, precision medicine, sudden cardiac death