2019 HRS Expert Consensus Statement on Evaluation, Risk Stratification, and Management of Arrhythmogenic Cardiomyopathy

Authors, Journal, Affiliations, Type, DOI

• Chair: Jeffrey A. Towbin; Vice-Chair: William J. McKenna
• 30 expert writing committee members; 12 co-endorsing societies (ACC, AHA, ASE, APHRS, EHRA, HFSA, ISHLT, JHRS, LAHRS, NSGC, PACES, SOBRAC)
• Journal: Heart Rhythm, Vol 16, No 11, November 2019
• Type: Expert consensus statement / practice guideline
• DOI: 10.1016/j.hrthm.2019.05.007

Overview

This international expert consensus statement redefines arrhythmogenic cardiomyopathy (ACM) as an arrhythmia-presenting myocardial disorder not explained by ischemic, hypertensive, or valvular disease. It encompasses a broad spectrum including ARVC, ALVC, amyloidosis, sarcoidosis, Chagas disease, and LVNC. The document provides comprehensive guidance on genetics, diagnosis (Task Force Criteria), cascade family screening, ICD risk stratification, antiarrhythmic therapy, catheter ablation, exercise restrictions, and disease mechanisms spanning desmosomal, ion channel, cytoskeletal, sarcomeric, and mitochondrial pathways. Mean consensus across all recommendations was 94%, with recommendations graded by ACC/AHA COR/LOE system.

Keywords

Arrhythmogenic cardiomyopathy; ARVC; ALVC; Cascade family screening; Catheter ablation; Diagnosis; Disease mechanisms; Exercise restriction; Genetic testing; ICD decisions; LVNC; Risk stratification; Treatment.

Key Takeaways

Section 1–2: ACM Definition and Spectrum

• ACM is defined by arrhythmia as a clinical presentation (conduction disease, AF, RV/LV ventricular arrhythmia) in the absence of ischemic, hypertensive, or valvular disease. If arrhythmia is absent, the patient does not have ACM.
• ACM includes ARVC (RV-predominant, desmosomal), ALVC (LV-predominant, associated with DSP, LMNA, PLN, FLNC, SCN5A), biventricular forms, and acquired causes (amyloidosis, sarcoidosis, Chagas, myocarditis).
• The "final common pathway" hypothesis holds that ACM subtypes converge on dysfunction of the intercalated disc — specifically desmosome dysfunction in ARVC, with overlap into ion channel and cytoskeletal pathways in ALVC.
• ARVC overlaps phenotypically with DCM; the key distinguishing feature is arrhythmia as the early/dominant presentation rather than heart failure.
• Autosomal dominant inheritance predominates; ARVC is considered a "desmosomopathy." Recessive forms (Naxos disease [JUP], Carvajal syndrome [DSP]) have cardiocutaneous phenotypes.

Section 3.1–3.3: Diagnosis

• Diagnosis of ACM requires high clinical suspicion. The diagnosis of ARVC should be considered in: exercise-related palpitations/syncope; cardiac arrest survivors; and individuals with >500 PVCs/24h or LBBB morphology VT without other heart disease.
• Initial evaluation: clinical history, physical exam, 3-generation family history, 12-lead ECG, 2D echo, ambulatory ECG, CMR.
• A normal ECG is reported in up to 12% of ARVC patients; ECG changes are dynamic and progressive.

Section 3.4: ECG Features in ARVC

• T-wave inversion (TWI): Major criterion when present in V1–V3 in patients >14 years (absence of complete RBBB). Prevalence 19–67% across cohorts.
• Epsilon wave: Reproducible low-amplitude deflection between end of QRS and T onset in V1–V3; reflects delayed RV conduction. Prevalence 0.9–25%; low sensitivity/specificity; dependent on ECG filter settings.
• Prolonged TAD: Terminal activation duration ≥55 ms from S-wave nadir to end of QRS in V1–V3 (without CRBBB) — aids differentiation from RVOT-VT; confirmed in 30/42 ARVC vs 1/27 RVOT-VT patients.
• ECG abnormalities in other ACMs (ALVC): TWI in I, aVL, V4–V6; generalized low voltage (PLN, desmosomal); conduction disease (LMNA); minor repolarization changes only (FLNC).

Section 3.5: Cardiac Imaging

• CMR is the gold standard: includes RVEF ≤40% and RVEDV/BSA ≥110 mL/m² (male) or ≥100 mL/m² (female) as major criteria.
• LGE on CMR is typically subepicardial or mid-wall in LV; may be the sole imaging abnormality in DSP disease with LV arrhythmia and normal ECG.
• 2010 Task Force Criteria do not define diagnostic criteria for LV involvement; LV dominant disease is underdiagnosed.

Section 3.7: Endomyocardial Biopsy

• Biopsy is rarely used for initial ARVC diagnosis due to: invasiveness, low sensitivity (patchy involvement, sampling error), and risk of RV free wall perforation. Septal biopsy is generally not helpful. Most useful for identifying sarcoidosis or myocarditis.

Section 3.8: Genetic Testing

• COR I, LOE C-EO: Genetic testing of all established ACM-susceptibility genes is recommended for individuals with a clinical or necropsy diagnosis of ACM.
• Variants classified per ACMG system: Class 5 (pathogenic, >95%), Class 4 (likely pathogenic, >90%), Class 3 (VUS, 10–90%), Class 2 (likely benign, <10%), Class 1 (benign, <5%).
• Class 4/5 variants are actionable; Class 3 (VUS) should be deemed non-actionable.
• Core gene panel (minimum set): PKP2, DSP, DSG2, DSC2, JUP, LMNA, PLN, SCN5A, TMEM43, FLNC, RBM20, DES, BAG3, NKX2-5, LDB3.
• Multiple pathogenic variants (~3–6% of patients) are associated with earlier disease onset (<20 vs. 35 years) and higher lifetime arrhythmia risk.
• Genotype-phenotype highlights:
  • LMNA: AF + conduction disease precede cardiomyopathy by decades; risk factors for malignant VT: NSVT, LVEF <45%, male sex, nonmissense variants (≥2 factors → ICD)
  • PLN (R14del): Low-voltage ECG, LVEF <45%, NSVT → high-risk for malignant arrhythmia and end-stage HF
  • TMEM43 (p.S358L): Male predominance, LV enlargement in 43%; ICD survival benefit confirmed
  • DSP: Spectrum from cardiocutaneous syndromes to isolated ALVC; LGE present even without LV dysfunction

Section 3.9: Cascade Family Screening

• COR I, LOE C-EO: 3-generation family history required, obtained by genetic counselor.
• COR I, LOE B-NR: First-degree relatives should undergo clinical evaluation every 1–3 years starting at age 10–12 years.
• COR I, LOE B-NR: Evaluation includes 12-lead ECG, ambulatory ECG, and cardiac imaging.
• Gene-negative relatives (confirmed pathogenic family variant) may be released from regular screening (COR IIb, LOE C-EO) but should be educated to return if symptoms develop.
• Disease expression onset is highest in the 3rd–4th decade; almost exclusively seen in probands under age 14. ECG changes typically precede structural changes.

Section 3.10: ICD Risk Stratification

• COR I, LOE B-NR: ICD recommended for: (1) cardiac arrest with VT/VF; (2) hemodynamically intolerated sustained VT.
• COR IIa, LOE B-NR: ICD reasonable for: syncope suspected due to VA; hemodynamically tolerated sustained VT in ARVC; ≥3 major or 2 major + 2 minor ARVC risk factors.
  • Major risk factors: NSVT, VT inducibility at EPS, LVEF ≤49%
  • Minor risk factors: male sex, >1000 PVCs/24h, RV dysfunction (per Task Force major criteria), proband status, ≥2 desmosomal variants
• COR I, LOE B-R: ICD recommended for LVEF ≤35% + NYHA class II–III + expected meaningful survival >1 year.
• Gene-specific ICD thresholds:
  • LMNA: ICD if ≥2 of: NSVT, LVEF <45%, male sex (COR IIa, LOE B-NR)
  • PLN: ICD if LVEF <45% or NSVT (COR IIa, LOE B-NR)
  • FLNC: ICD if LVEF <45% (COR IIa, LOE C-LD)
  • LMNA with pacing indication: ICD with pacing capabilities (COR IIa, LOE C-LD)

Section 3.11: Management

• LV failure (ALVC/HFrEF): Follows standard AHA/ACC/ESC guideline-directed medical therapy — ACE inhibitors/ARBs, beta-blockers, aldosterone antagonists, sacubitril/valsartan, ivabradine.
• RV failure (ARVC): Evidence more limited; ACE inhibitors/ARBs, beta-blockers, aldosterone antagonists, diuretics reasonable (COR IIa, LOE C-EO); isosorbide dinitrate for preload reduction may be considered (COR IIb).
• Anticoagulation (COR I, LOE B-NR): Required in the presence of AF, intracavitary thrombosis, or venous/systemic thromboembolism.
• Antiarrhythmic drugs:
  • Beta-blockers: recommended for inappropriate ICD therapies (COR I); reasonable without ICD (COR IIa)
  • Amiodarone (LOE B-NR) or sotalol (LOE C-LD): reasonable for symptom control or ICD shock reduction (COR IIb)
  • Flecainide + beta-blocker: reasonable for refractory VA with preserved biventricular function and ICD (COR IIb, LOE C-LD)
• Catheter ablation:
  • COR IIa for recurrent sustained VT after amiodarone failure/intolerance
  • Combined endocardial + epicardial approach required for ARVC (60–80% long-term success)
  • Not curative; does not prevent SCD or reduce mortality in ARVC
  • VT ablation in LMNA cardiomyopathy has poor outcomes (high recurrence, progression to end-stage HF)

Section 3.12: Exercise Restriction

• COR III: Harm, LOE B-NR: Individuals with ARVC should NOT participate in competitive or frequent high-intensity endurance exercise.
• COR I, LOE B-NR: Clinicians should counsel phenotype-negative, genotype-positive individuals that competitive/high-intensity endurance exercise increases likelihood of developing ARVC and ventricular arrhythmias.
• Evidence for dose-dependent relationship: exercise intensity (METs) and duration independently predict ARVC penetrance, structural dysfunction (RV and LV), and ventricular arrhythmia events.
• Athletes who reduced exercise after presentation had better arrhythmic outcomes than those who continued.
• Only athletes (not recreational exercisers) progressed to transplantation or Class C HF in key series.
• Vigorous-intensity exercise defined as ≥6 METs; competitive exercise = organized sport with regular competition and systematic intense training.
• Limited data for other ACMs (PLN, LMNA, FLNC); exercise restriction is less definitively established.

Section 4: Disease Mechanisms

• The intercalated disc (ID) has three main structures: gap junctions (GJs), adherens junctions (AJs), and desmosomes. These form an integrated functional unit (area composita) with ion channels.
• Desmosomes: PKP2 (most common ARVC gene) → reduced Nav1.5 and Cx43 at ID → conduction slowing + arrhythmia. DSP connects desmosomes to desmin; DSG2/DSC2 form the intercellular bridge; JUP (plakoglobin) mediates IF attachment.
• Ion channels (SCN5A): Pathogenic SCN5A variants cause arrhythmogenic DCM and LVNC (≈2% of ACM). Nav1.5 co-precipitates with PKP2 and N-cadherin — primary desmosomal defects can secondarily impair sodium current.
• Cytoskeleton: Filamin-C (FLNC) links costamere to Z-disc; truncating variants cause myofibrillar myopathy + ACM with SCD risk. ZASP/LDB3 stabilizes Z-disc via α-actinin; variants impair Nav1.5 function. Desmin (DES) connects desmosomes to IFs — variants cause skeletal myopathy + ACM.
• Sarcomere: Troponin T variants can cause cardiac arrest despite minimal LV hypertrophy; troponin I → RCM phenotype with AF.
• Mitochondrial: Kearns-Sayre syndrome causes ACM via mitochondrial dysfunction; histiocytoid (oncocytic) cardiomyopathy is an extreme form.
• Wnt/β-catenin: PKP2 dysfunction releases β-catenin from the desmosome, activating Wnt signaling → adipogenesis and fibrosis in RV → the molecular basis of fibrofatty replacement.

Key Concepts Mentioned

• concepts/Arrhythmogenic-Cardiomyopathy — umbrella framework redefined in this document
• concepts/ARVC-Task-Force-Criteria — diagnostic system for ARVC
• concepts/Final-Common-Pathway — unifying pathogenetic hypothesis
• concepts/Exercise-Restriction-in-ARVC — dose-dependent exercise-penetrance relationship
• concepts/Desmosome — primary structural pathology in ARVC
• concepts/Cascade-Family-Screening — systematic family evaluation framework
• concepts/Sudden-Cardiac-Death — key outcome; ARVC accounts for up to 20% of SCD in young
• concepts/Ion-Channel-Mutations — SCN5A overlap with ACM
• concepts/Cardiac-Action-Potential — disrupted by desmosomal dysfunction via Nav1.5

Key Entities Mentioned

• entities/ARVC — best-characterized ACM; desmosomal disease
• entities/ALVC — LV-predominant ACM; less-defined diagnostic criteria
• entities/PKP2 — most common ARVC gene; plakophilin-2
• entities/DSP — desmoplakin; causes both ARVC and ALVC; cardiocutaneous syndromes
• entities/LMNA — lamin A/C; causes progressive conduction disease + ALVC
• entities/PLN — phospholamban; R14del founder variant; high HF/SCD risk
• entities/FLNC — filamin-C; truncating variants → ALVC + myofibrillar myopathy
• entities/SCN5A — sodium channel; arrhythmogenic DCM/LVNC; functional link to desmosome
• entities/Brugada-Syndrome — differential diagnosis; loss-of-function SCN5A overlap
• entities/KCNQ1 — discussed in context of TRPM4 and potassium channel defects in ACM
• entities/KCNH2 — SQTS/LQTS gene; potassium channel overlap with ACM phenotypes

Limitations of the Document

• Diagnostic criteria for ALVC do not yet exist; phenotypic overlap with DCM creates diagnostic ambiguity.
• Exercise restriction data are largely retrospective and almost exclusively from PKP2 carriers; applicability to other desmosomal and nondesmosomal ACMs is not established.
• The 2010 Task Force Criteria were developed for ARVC and have not been validated against other ACMs with overlapping phenotypes (sarcoidosis, myocarditis).
• EPS predictive value for VT/VF in ARVC is poor (PPV 35%, NPV 70%); its role in risk stratification is limited.
• Catheter ablation does not prevent SCD or reduce mortality in ARVC — it is palliative only.
• VUS (class 3) variants are common and non-actionable; reclassification over time is critical but currently inconsistent across laboratories.

Wiki Pages Updated

• wiki/sources/acm-hrs-2019.md (created)
• wiki/concepts/Arrhythmogenic-Cardiomyopathy.md (created)
• wiki/concepts/ARVC-Task-Force-Criteria.md (created)
• wiki/concepts/Final-Common-Pathway.md (created)
• wiki/concepts/Exercise-Restriction-in-ARVC.md (created)
• wiki/concepts/Desmosome.md (created)
• wiki/concepts/Cascade-Family-Screening.md (created)
• wiki/entities/ARVC.md (updated)
• wiki/entities/ALVC.md (created)
• wiki/entities/PKP2.md (created)
• wiki/entities/DSP.md (created)
• wiki/entities/LMNA.md (created)
• wiki/entities/PLN.md (created)
• wiki/entities/FLNC.md (created)
• wiki/entities/SCN5A.md (updated)
• wiki/index.md (updated)
• wiki/log.md (updated)