ARVC: Refining Diagnostic Criteria and Risk Stratification

Arrhythmogenic right ventricular cardiomyopathy has evolved from a rare autopsy curiosity into a well-recognised clinical entity. Once labelled as dysplasia of the right ventricular myocardium, it is now understood as a heritable desmosomal disease in which fibrofatty replacement creates the substrate for ventricular arrhythmias, heart failure, and sudden cardiac death. Because it can mimic benign ectopy or idiopathic ventricular tachycardia, clinicians in Sydney, Melbourne, and Perth are increasingly attuned to features that distinguish it from phenocopies.

The past two decades have moved the field from descriptive pathology to mechanism-based care. Molecular genetics has revealed that pathogenic variants in desmosomal genes—most often plakophilin-2—drive disease expression, while cardiac imaging detects structural change long before overt dysfunction develops. Modern risk stratification combines electrical, structural, genetic, and demographic information to guide defibrillator implantation, exercise prescription, and family screening. Australian cardiologists have contributed meaningfully through the Australian Genetic Heart Disease Registry at Sydney's Centenary Institute, shaping local and international thinking.

This review synthesises contemporary diagnostic standards, highlights practical challenges, and explores how risk models inform therapeutic choices. Particular attention is paid to areas where international guidelines diverge from local practice under the Therapeutic Goods Administration framework and Medicare funding rules, recognising that Australian cardiologists balance evidence-based recommendations against resource realities in regional services.

Molecular and Pathophysiological Foundations

ARVC is fundamentally a disease of the intercalated disc. Desmosomal proteins—including desmoplakin, plakoglobin, plakophilin-2, desmoglein-2, and desmocollin-2—maintain tissue integrity under mechanical stress. Pathogenic variants destabilise these junctions, particularly in the thin-walled right ventricle, where wall stress is high and reserve limited. Over time, myocyte loss triggers inflammation and fibrofatty replacement, slowing conduction and predisposing to re-entrant ventricular tachycardia.

Beyond classical genetics, modifiers influence phenotype dramatically. Exercise is the most potent acquired modifier: endurance athletes, including those in Australian Rules football or surf lifesaving, develop earlier and more severe disease than sedentary relatives. Male carriers present a decade earlier on average. Researchers at the Baker Heart and Diabetes Institute in Melbourne have contributed important genotype-phenotype data informing Australian clinical counselling.

Inflammation represents an increasingly recognised layer. "Hot phases," with chest pain and troponin release, often reflect acute myocyte death within diseased segments rather than viral myocarditis, although distinguishing the two remains challenging in younger patients presenting to emergency departments across Brisbane and Adelaide. Cardiac MRI with tissue characterisation, combined with genetic testing, has dramatically reduced misdiagnosis.

The 2010 Revised Task Force Criteria in Practice

The 2010 Revised Task Force Criteria remain the diagnostic backbone, structured around six categories: depolarisation and repolarisation ECG abnormalities, ventricular arrhythmias, structural features by imaging, tissue characterisation, family history, and genetics. Major and minor criteria are weighted, with definite diagnosis requiring two major, or one major plus two minor, or four minor criteria from distinct categories. Though developed internationally, the criteria perform well in Australian cohorts.

In everyday practice, the criteria present challenges. Signal-averaged ECG has largely fallen out of routine use, supplanted by high-resolution 12-lead analysis and ambulatory monitoring. T-wave inversion beyond V1, the classic repolarisation hallmark, must be interpreted cautiously in patients under 14, where juvenile patterns overlap. Local experience at Royal Adelaide Hospital's arrhythmia service has shown that incorporating right ventricular activation delay improves sensitivity without sacrificing specificity.

Genetic testing deserves special emphasis. A pathogenic variant classified as definite or strong contributes a major criterion; a borderline variant counts as minor. Variant interpretation requires collaboration with clinical geneticists, and Australia offers ready access through Medicare-funded familial cascade testing for first-degree relatives. Negative genetic testing does not exclude disease, particularly in probands without family history.

Imaging the Right Ventricle

Cardiac MRI is the reference standard for non-invasive tissue characterisation, providing cine assessment of function and late gadolinium enhancement to identify fibrofatty scar. Quantitative criteria from the 2010 document—reduced right ventricular ejection fraction, regional akinesia, dyskinesia, or aneurysm—remain valid, though the right ventricular ejection fraction threshold may sit closer to 45 percent. Australian centres, including St Vincent's Hospital in Sydney, routinely provide dedicated ARVC protocols exceeding the 2010 minimum dataset.

Echocardiography retains a frontline role because of accessibility and Medicare rebate availability. Speckle-tracking-derived right ventricular longitudinal strain detects subclinical dysfunction before ejection fraction falls. Three-dimensional echocardiography improves volumetric assessment. However, distinguishing ARVC from idiopathic right ventricular outflow tract tachycardia, pulmonary hypertension, or athletic remodelling remains challenging, requiring integration with arrhythmia phenotype and family data.

Cardiac CT has emerged as an alternative for patients with implantable devices, where MRI is contraindicated. CT-derived fibrosis imaging using delayed enhancement protocols now approaches MRI accuracy in experienced hands. Right ventricular angiography has largely been supplanted by cross-sectional imaging but retains utility in selected electrophysiology studies, particularly when anatomical detail of the tricuspid annulus is required.

Risk Stratification Models and Predictors of Arrhythmic Events

Risk stratification in ARVC is non-trivial because annual event rates vary widely and individual trajectories can shift. The most consistent predictors of ventricular arrhythmia include prior cardiac arrest, sustained ventricular tachycardia, extensive right ventricular dysfunction, left ventricular involvement, and arrhythmic syncope. Spontaneous ventricular tachycardia burden on ambulatory monitoring and inducibility on electrophysiology study offer additional information, though the predictive value of non-inducibility is modest.

A landmark development is the ARVC risk calculator, derived from a multinational cohort and validated across several populations, including Australian patients. The model incorporates age, sex, cardiac arrest history, recent syncope, non-sustained ventricular tachycardia, right ventricular ejection fraction, and ventricular premature beat count on Holter. It provides a 5-year arrhythmic risk estimate framing primary prevention defibrillator decisions.

Genetic information increasingly refines risk assessment. Patients with multiple desmosomal variants or compound heterozygosity carry higher arrhythmic risk. Variants in desmoplakin, with greater-than-expected left ventricular involvement in this subgroup, have prompted calls for dedicated imaging surveillance. Sex-specific thresholds have also been proposed, with male sex conferring roughly two-fold higher arrhythmic risk in early adulthood.

Family Screening and Cascade Genetic Testing

Once a proband is identified, systematic family evaluation becomes a clinical priority. First-degree relatives should undergo clinical evaluation, including 12-lead ECG, signal-averaged ECG, ambulatory monitoring, and cardiac imaging. Genetic testing, where a pathogenic variant has been identified in the proband, enables predictive testing in relatives, with negative results reliably excluding disease in those carrying the family variant. The Australian Genetic Heart Disease Registry has shown that cascade screening identifies affected relatives in roughly a third of families. Readers seeking a deeper dive into related inherited arrhythmia topics may wish to explore journal collections curated by the editorial team.

Counselling before and after genetic testing is essential. Pre-test counselling explores implications for insurance, employment, sport participation, and reproduction. In Australia, life insurance underwriting is permitted to consider genetic information, a regulatory feature that differs from several European systems. Post-test counselling guides lifestyle modification and surveillance planning for variant-positive, phenotype-negative relatives.

Children present a nuanced situation. Phenotypic expression is uncommon before puberty, but pathogenic variant carriers warrant ongoing surveillance because penetrance rises sharply in adolescence. Australian paediatric cardiology services, supported by the National Heart Foundation of Australia, recommend baseline evaluation in late childhood, with follow-up determined by sex and family history. Decisions about competitive sport restriction should be individualised, balancing risk against the psychosocial benefits of athletic participation.

Exercise Restriction and Lifestyle Modification

Endurance exercise accelerates disease onset and progression in genotype-positive individuals, whether or not overt phenotype is present. Animal models and human cohort studies have shown that high-intensity endurance activity increases penetrance, arrhythmic events, and heart failure. Restricting competitive and high-intensity endurance exercise is therefore a Class I recommendation in most contemporary guidelines. Australian sporting culture, with its emphasis on surf lifesaving, marathon running, and Australian Rules football, creates a particular need for clear, culturally informed advice.

Activity restriction does not mean inactivity. Moderate recreational activity, including walking, light cycling, and resistance training at modest loads, appears safe. The challenge lies in defining safe thresholds, which differ by genotype, sex, and phenotype. Some centres offer cardiopulmonary exercise testing with arrhythmia surveillance to identify safe upper limits, an approach pioneered in part by services at the Royal Melbourne Hospital. Patients are advised to wear heart rate monitors during exercise and avoid dehydration, particularly during Australia's hot summer months when electrolyte shifts may provoke ectopy.

Ongoing surveillance during exercise restriction matters because reductions in training volume alter cardiac remodelling and may unmask underlying dysfunction. Imaging and Holter monitoring should be repeated at least annually in genotype-positive, phenotype-positive individuals, and less frequently—but still regularly—in genotype-positive, phenotype-negative relatives. Counselling about warning symptoms should be reinforced at every visit.

Therapeutic Interventions and Long-Term Management

The implantable cardioverter-defibrillator remains the only proven therapy for preventing sudden cardiac death in ARVC. Decision-making balances arrhythmic risk against procedural complications, including lead failure, infection, and inappropriate shocks. Primary prevention defibrillators suit high-risk patients identified through validated calculators, while secondary prevention is recommended for survivors of cardiac arrest or sustained ventricular tachycardia. Australian data, drawn largely from device registries at major tertiary centres, mirror international experience.

Antiarrhythmic therapy, particularly beta-blockade, plays a complementary role. It reduces symptomatic ventricular ectopy and may decrease ICD shocks during adrenergic surges. Sotalol and amiodarone remain options for recurrent ventricular tachycardia, though long-term amiodarone use is constrained by extracardiac toxicity. Catheter ablation offers an adjunctive strategy for drug-refractory ventricular tachycardia, with endocardial and epicardial approaches increasingly combined. Acute success rates exceed 80 percent, though recurrence rates remain substantial over five years.

Heart failure management follows standard guidelines when left ventricular involvement emerges. Standard pharmacotherapy—beta-blockers, ACE inhibitors, mineralocorticoid antagonists—is initiated as needed. Cardiac transplantation is reserved for end-stage disease, with Australian outcomes comparable to international benchmarks. Adjunctive neuromodulatory strategies are attracting attention across the broader arrhythmia landscape, and interested readers can review vagal stimulation evidence for complementary insights. Long-term follow-up through specialised clinics optimises quality of life for affected individuals and families.

Clinicians, researchers, and trainees across Australia and the wider Asia-Pacific region are invited to submit their original research, reviews, and case series to the Journal of Arrhythmia, where themed collections and open-access dissemination ensure broad reach. Sharing clinical experience, registry data, and translational discoveries accelerates the iterative refinement of diagnostic criteria and risk models. Engagement with the journal's educational resources supports the multidisciplinary collaboration that patients and families affected by arrhythmogenic right ventricular cardiomyopathy deserve.