Arrhythmogenic cardiomyopathy: forms and clinical overview

Article written and reviewed by Dr Luca Moretti

Arrhythmogenic cardiomyopathy is a disease of the heart muscle in which loss of cardiomyocytes and their replacement by scar create a substrate capable of generating ventricular arrhythmias even before pump function becomes severely impaired. Its defining feature is therefore not a particular cardiac shape but the combination of nonischemic scar, electrical instability and progressive myocardial disease.

The modern term encompasses a broader spectrum than historical arrhythmogenic right ventricular dysplasia. In some people, dilation, wall-motion abnormalities and arrhythmias originating from the right ventricle predominate; in others, subepicardial left ventricular fibrosis dominates, while a third trajectory involves both ventricles. Thinking in terms of a phenotypic spectrum prevents an exclusive focus on the right ventricle from delaying recognition of left-sided forms.

Many forms are inherited and arise from variants that alter desmosomes or other structures required for mechanical and electrical continuity of the myocardium. The presence of a causal variant, however, does not deterministically predict age, severity or disease distribution because penetrance and expressivity depend on gene, sex, age, exercise and other modifiers. Intrafamilial variability is therefore a biological property rather than a contradiction of the genetic diagnosis.

Palpitations, syncope, ventricular tachycardia or cardiac arrest may be the first manifestation, but some patients are identified during family screening and have no symptoms. Chest pain with troponin elevation may mimic myocarditis, particularly in certain left-dominant desmosomal cardiomyopathies. This clinical heterogeneity requires integrating electrical findings, imaging, tissue and pedigree rather than relying on a single finding.

When arrhythmogenic cardiomyopathy is suspected, the distribution between the right and left ventricles is defined together with the electrical burden because two hearts with similar global function may have different risks and causes. A useful diagnosis therefore specifies phenotype, degree of certainty, genotype, scar and arrhythmias while keeping demonstrated data separate from still-provisional inferences.

A spectrum with different distributions

The right-dominant form retains a central historical and clinical role. arrhythmogenic right ventricular cardiomyopathy combines regional wall-motion abnormalities, right ventricular dilation or dysfunction, anterior electrocardiographic signs and arrhythmias often showing left bundle branch block morphology. None of these elements has sufficient specificity in isolation.

In the right ventricle, the thin wall, complex geometry and proximity to the sternum make imaging technically demanding. Normal variants, volume overload, congenital heart disease and athletic remodeling can mimic dilation or irregularity. Diagnosis therefore requires regional and quantitative abnormalities interpreted by experienced operators rather than generic descriptions such as mildly enlarged right ventricle.

Left-dominant arrhythmogenic cardiomyopathy may present with preserved global function despite extensive subepicardial or mid-wall scar. Inferolateral T-wave inversion, low limb-lead voltages, arrhythmias with right bundle branch block morphology and ring-like late gadolinium enhancement are clues, but they acquire meaning only within a coherent assessment.

A nonischemic left ventricular scar does not automatically equal arrhythmogenic cardiomyopathy. Myocarditis, sarcoidosis, muscular dystrophies, laminopathies and other cardiomyopathies can produce overlapping distributions; an irrelevant genetic variant can also become false confirmation if the gene lacks demonstrated disease validity. The etiologic context distinguishes a useful category from a label applied to CMR alone.

The 2023 ESC classification describes nondilated left ventricular cardiomyopathy as a nondilated left ventricle with nonischemic scar or fatty replacement, or with isolated global hypokinesia. This phenotype may include ALVC, a genetic form that is not strictly arrhythmogenic, or an acquired etiology: NDLVC describes what is observed, whereas ALVC requires the overall criteria to support an arrhythmogenic nature. This overlap without synonymy allows both classifications to be used without confusing their purposes and family implications.

Biventricular arrhythmogenic cardiomyopathy is not merely a terminal stage of the right-sided form. In some genotypes, both ventricles are involved early, with left ventricular scar and right ventricular functional abnormalities progressing at different rates. Defining the distribution contributes to prognosis, differential diagnosis and selection of surveillance tools.

The right-sided, left-sided and biventricular categories describe the predominant phenotype at a specific time, not biologically impermeable compartments. A patient may change classification during follow-up when imaging recognizes new involvement of the opposite ventricle. This phenotypic mobility makes it necessary to preserve serial images and measurements so that the first definition does not become permanent by inertia.

Desmoplakin cardiomyopathy clearly illustrates the limitations of the older nomenclature. DSP variants often produce left-sided or biventricular disease, subepicardial scar, inflammatory episodes and arrhythmias disproportionate to ejection fraction, creating a profile distinct from classic PKP2-associated ARVC.

From the cell junction to scar

Desmosomes distribute forces among cardiomyocytes and participate in complexes that interact with adherens junctions, ion channels and intracellular signaling. Their disruption does not simply cause a mechanical defect: it alters intercellular organization, conduction and the response to stress. The intercalated disc should therefore be understood as an integrated platform in which structure and electrical function cannot be separated.

Repeated stress promotes detachment, injury or death of cells in vulnerable tissue. Repair replaces functioning myocardium with fibrosis and, particularly in classic right-sided disease, adipose tissue; scar slows propagation and creates corridors for reentry circuits. This scar progression explains why monomorphic arrhythmias may recur after technically successful ablation.

Inflammation may accompany cell death and is clinically prominent in some genotypes. Episodes with pain, troponin elevation and transient CMR abnormalities may precede stable scar, but they do not by themselves prove viral infection or automatically justify immunosuppression. A hot phase requires a differential diagnosis including myocarditis, acute coronary syndrome and sarcoidosis while keeping open the possibility of genetic disease.

High-intensity endurance exercise increases wall stress, volume load and adrenergic stimulation, conditions that are particularly demanding for myocardium with vulnerable cell adhesion. Cohorts of desmosomal variant carriers have associated greater exposure with earlier penetrance, arrhythmias and heart failure. This dose-intensity effect does not, however, justify treating every movement as dangerous: moderate activity and general health require individualized exercise prescription.

PKP2 is the gene most frequently implicated in classic ARVC, whereas DSP, DSG2, DSC2 and JUP complete the desmosomal group with established evidence. ClinGen reassessment assigns definitive evidence for ARVC to TMEM43 and moderate evidence to PLN and DES; numerous other genes historically included in panels instead have limited or refuted associations. Gene-disease validity protects against overdiagnosis caused by rare but noncausal variants.

Most nonsyndromic forms follow autosomal dominant inheritance with incomplete, age-dependent penetrance. Recessive forms such as Naxos disease combine cardiomyopathy with cutaneous signs and woolly hair, whereas biallelic variants can modify severity. The inheritance pattern must be reconstructed case by case and cannot be inferred solely from the presence of several affected relatives.

Navigating phenotypes and diagnostic systems

Diagnosis arises from convergence of structural, electrical and familial information, but the system to apply depends on the phenotype being classified. The 2010 Task Force Criteria were built for classic ARVC; the 2020 Padua criteria and the 2023 European Task Force criteria, published in the 2024 issue, extend analysis to the left ventricle and biventricular forms. The scope of application prevents mechanically transferring a rule designed for right-sided disease to left ventricular scar.

In the 2010 system, major and minor findings belong to six domains: morphofunctional abnormalities, histology, repolarization, depolarization or conduction, arrhythmias, and family history or genetics. Combinations from different categories determine definite, borderline and possible levels so that redundant findings of the same type are not added as independent evidence. Imaging must combine a regional right ventricular abnormality with quantitative measurements, whereas ECG findings and arrhythmic morphology gain meaning in context. The 2010 criteria do not include LGE and therefore remain better suited to classic ARVC than to phenotypes with left ventricular scar.

Padua 2020 retains six categories but creates parallel assessment of the two ventricles, requiring at least one morphofunctional or structural criterion from the involved chamber. Introduction of LGE makes it possible to recognize right, left and biventricular scar and distinguish phenotypic distribution before establishing the degree of certainty. To diagnose isolated ALVC in the absence of right ventricular morphofunctional or structural criteria, this system required qualifying left ventricular scar and a pathogenic or likely pathogenic variant causally associated with ACM. The Padua genetic requirement cannot be satisfied by a VUS.

The 2023 ETF criteria, appearing in the 2024 volume, refine Padua by grading the extent and specificity of left ventricular scar, excluding focal, patchy or junctional patterns that are not diagnostic and reducing the weight of isolated right ventricular LGE. They also remove isolated regional left ventricular hypokinesia because it is too nonspecific and redefine some electrical and arrhythmic signs. In the genetic domain, a pathogenic variant has major weight, a likely pathogenic variant minor weight and a VUS contributes nothing; however, genotype is no longer a mandatory gate for clinical recognition of ALVC. Subsequent etiologic attribution distinguishes genetic forms, familial forms without an identified variant, idiopathic forms and acquired forms without confusing diagnostic certainty with prognosis.

The ETF consensus remains a proposed framework requiring further external validation rather than a gold standard capable of eliminating clinical judgment. Compatible scar must be distinguished from myocarditis, sarcoidosis, ischemia, muscular dystrophies and other cardiomyopathies; on the right side, volume or pressure overload, congenital heart disease, athlete’s heart and idiopathic outflow-tract tachycardia must be excluded. A positive differential diagnosis seeks evidence specific to alternatives rather than relegating them to nominal phenocopies.

How phenotype modifies risk and daily life

The meaning of risk markers changes with disease distribution. In classic ARVC, right ventricular dysfunction, extent of T-wave inversion, syncope, nonsustained tachycardia and premature ventricular contraction burden contribute to specific prognostic models; in left-sided forms, particularly DSP-associated disease, scar extent and episodes of myocardial injury may matter even with preserved ejection fraction. Phenotype-specific stratification avoids automatically transferring tools built for right-sided disease to the left ventricle.

The ARVC calculator estimates the risk of a first sustained ventricular arrhythmia in people with a definite diagnosis according to the 2010 criteria and no previous major event. It provides a probability, not a mandatory implantation threshold. The defibrillator decision integrates model limitations, the type of event being prevented, age, genotype, preferences and cumulative complications.

An ICD terminates ventricular tachycardia or fibrillation but does not prevent scar formation, heart failure or all arrhythmias. In young patients, infections, malfunctions, inappropriate shocks and generator replacements accumulate over decades. The net benefit is highly favorable for secondary prevention and requires greater individualization when implantation is preventive.

Right ventricular function may deteriorate slowly and manifest as reduced exercise capacity, edema, ascites or hepatic congestion; left ventricular dysfunction adds risk of heart failure and thromboembolism. Frequent arrhythmias may in turn worsen hemodynamics. This combined risk therefore includes sudden death and heart failure, different targets requiring different tools.

The recommendation to avoid competitive sports or intense endurance activity in clinically manifest disease does not mean imposing sedentary behavior. An exercise prescription evaluates diagnosis, gene, arrhythmias, function, device status and previous exposure, then defines intensity, mode and stopping signals. Agreed physical activity preserves metabolic and psychological benefits without ignoring the role of mechanical stress.

Pregnancy, occupation, driving and device selection raise questions that cannot be resolved by the diagnosis alone. Hemodynamic tolerance of pregnancy is often good in stable disease, but arrhythmias and function require planning; driving restrictions depend on syncope, therapies and regulations. Contextual counseling translates risk into decisions compatible with real life.

Common principles, different decisions across phenotypes

Beta-blockers attenuate adrenergic stimulation and may reduce symptoms or arrhythmic burden in selected patients, whereas sotalol or amiodarone are considered for recurrences in specific settings. When individual risk supports ICD implantation, drug therapy is not considered equivalent protection. Rhythm treatment depends on the type of tachycardia, predominant substrate and expected adverse effects rather than the ACM label alone.

Ablation is useful for recurrent tachycardias or device shocks and often requires an epicardial approach because the ARVC substrate develops from the outer surface inward. It reduces arrhythmic burden but does not guarantee cure because disease may extend beyond treated areas. The expected clinical result is a lower recurrence frequency, not definitive elimination of sudden-death risk.

When left ventricular dysfunction develops, prognosis-modifying treatments for heart failure with reduced ejection fraction are applied and adapted to blood pressure, renal function and rhythm. In right-dominant disease, diuretics and preload management require caution because excessive volume reduction can compromise output. Ventricular physiology guides therapy more than the general label of heart failure.

A patient with refractory arrhythmias or advanced heart failure may be a candidate for transplantation, sometimes before left ventricular dilation appears extreme. Previous epicardial ablations, adhesions and right ventricular function influence the surgical strategy. Advanced evaluation should begin before irreversible congestion, cachexia or end-organ damage develops.

First-degree relatives require history, ECG, rhythm monitoring and imaging according to age, gene and family history. A normal initial evaluation does not exclude future expression because penetrance increases particularly from adolescence into adulthood. Longitudinal screening is therefore more informative than a single assessment performed at the wrong time.

If a pathogenic or likely pathogenic variant is demonstrated in the proband, cascade testing identifies carrier relatives who require surveillance and generally allows noncarriers to leave disease-specific follow-up. A variant of uncertain significance should not instead be used for predictive diagnosis. Genetic counseling clarifies the difference among informative, negative and indeterminate results.

Follow-up reassesses symptoms, syncope, physical activity, ECG, arrhythmic burden, function and scar. Intervals and methods change according to phase, gene and previous events, whereas device data are useful but do not replace imaging and clinical review. Dynamic reassessment recognizes that risk and phenotype change, allowing therapy to be modified before a clinical event.

From the phenotypic map to the clinical pathway

Assessment begins by determining whether the dominant problem is a threatening arrhythmia, heart failure or an episode of active myocardial injury. Stabilization precedes nonurgent investigations, but ECGs before and after the event, tachycardia tracings, troponin values and acute imaging should be preserved. Documentation at presentation may contain information that disappears after resolution.

Family history is extended across at least three generations and includes sudden deaths, drownings, unexplained accidents, refractory epilepsy, transplantation and early pacemaker implantation. Certificates and medical records from relatives reduce recall and classification errors. A verified pedigree guides genetic testing and may transform a borderline finding into a coherent picture without replacing clinical criteria.

ECG, echocardiography and Holter monitoring form the foundation, whereas CMR characterizes both ventricles and tissue. Exercise testing, CT, PET, coronary angiography or biopsy answer selected questions and do not constitute a mandatory panel. The hierarchy of tests avoids both omissions and accumulation of incidental findings that confuse pretest probability.

The diagnostic conclusion should specify phenotype, degree of certainty, genetic variant if present, arrhythmic burden, function and scar burden. Simply stating arrhythmogenic cardiomyopathy conceals the information that determines risk and family implications. A multidimensional definition makes decisions understandable and allows the clinical picture to be compared at subsequent assessments.

An effective pathway coordinates cardiomyopathy cardiology, electrophysiology, imaging, genetics and sports medicine, involving advanced heart failure care when needed. Decisions about ICD therapy, ablation, activity and screening are not independent because each modifies interpretation of the others. Integrated care transforms a rare and fragmented disease into a trajectory that can be monitored.

An outflow-tract morphology tachycardia in an apparently normal heart does not have the same meaning as multiple morphologies associated with scar and family history. In the first scenario, an idiopathic focus is common and often curable; in the second, multiplicity suggests a diffuse substrate requiring characterization. Pretest probability prevents the absolute number of premature ventricular contractions from erasing more specific information about their origin.

Even a CMR report described as suggestive should be reconsidered in the context of the original images. Small right ventricular wall irregularities, epicardial fat or equivocal LGE can receive excessive weight in a report already influenced by clinical suspicion, whereas a subtle left ventricular scar may be overlooked. Expert review is particularly valuable before communicating an inherited diagnosis or implanting a device.

Evaluation for sarcoidosis or myocarditis becomes a priority when atrioventricular block, extracardiac uptake, rapid arrhythmias, fever or active myocardial injury appear. An inflammatory process and a genetic predisposition can also coexist, so finding a variant does not automatically close the differential diagnosis. Concurrent causality keeps specific therapies available without denying family implications.

Risk communication distinguishes the possibility of a sustained arrhythmia from the probability of sudden death and from heart failure risk. An appropriate ICD therapy demonstrates that the device treated a programmed rhythm but not always that the event would have been lethal. The semantics of outcomes are necessary for informed implantation decisions and correct interpretation of prognostic studies.

The written plan lists permitted activities, management of palpitations and syncope, emergency contacts, medications and surveillance of relatives. For patients with an ICD it also includes device identification and what to do after a shock. Event preparedness reduces delay and fear without turning every premature beat or heart-rate variation into an emergency.

Transitions between centers, pediatric and adult care, or pregnancy are moments when history and the rationale for decisions may be lost. An updated summary with tachycardia tracings, classified variants and key images preserves continuity. Clinical memory is part of safety in a rare, progressive disease that depends on longitudinal interpretation.

Arrhythmogenic cardiomyopathy ultimately shows why phenotype-based and genotype-based medicine must remain connected. Visible scar is not sufficient to explain cause, and a genetic variant alone does not predict an individual’s destiny. Keeping substrate, trigger and trajectory together makes it possible to prevent arrhythmia, preserve function and recognize disease early within the family.