#cardiomyopathy #genetics #sudden-cardiac-death #heart-failure

Dilated Cardiomyopathy (DCM)

Details

Dilated cardiomyopathy (DCM) is defined as LV dilatation and global or regional systolic dysfunction not explained solely by abnormal loading conditions (hypertension, valve disease, congenital heart disease) or coronary artery disease. Prevalence in adults is 0.036–0.400%. DCM is the leading indication for cardiac transplantation. Pharmacological management follows standard heart failure guidelines; ICD decisions are increasingly genotype-informed.

Key Facts

Diagnosis

LV dilatation + systolic dysfunction (regional or global). Right ventricular involvement may be present but is not required. (sources/esc-cmp-2023)
"Isolated left ventricular dilatation" with normal EF does not fulfill DCM criteria but may represent early DCM. (sources/esc-cmp-2023)
Non-genetic causes include: viral myocarditis, autoimmune, toxic (alcohol, anthracyclines, trastuzumab), metabolic, peripartum, and tachycardia-induced CMP. (sources/esc-cmp-2023)
CMR is recommended at baseline; key CMR findings — lateral wall epicardial LGE suggests dystrophinopathy; subepicardial/midwall LGE at basal septum ± inferolateral extension suggests sarcoidosis; apical transmural LGE suggests Chagas disease. (sources/esc-cmp-2023)
NT-proBNP/BNP and high-sensitivity troponin T carry diagnostic, prognostic, and therapeutic monitoring value. (sources/esc-cmp-2023)

Genetics

Genetic yield: ~30% of DCM patients carry a monogenic cause. (sources/esc-cmp-2023)
Most common genes: TTN (truncating variants, ~25% familial / ~18% sporadic), LMNA, RBM20, MYH7, SCN5A, and others.
ClinGen Gene-Disease Validity for DCM (2026-05-09): Definitive DCM genes: TTN, LMNA, MYH7, SCN5A, DES, FLNC, BAG3, RBM20, TNNC1, TNNT2. Strong DCM genes: TNNI3 (both AD and AR), VCL, CAMK2D. Moderate: TPM1, BAG5 (AR). Limited: CSRP3, DSG2, SGCD, CDH2, MYH6, ANKRD1. Disputed: PKP2 (disputing 05/30/2025) — a major ARVC gene that does NOT have confirmed DCM causation by ClinGen. MYBPC3 has only limited DCM evidence (03/04/2026) despite being the #1 HCM gene. See concepts/ClinGen-Gene-Disease-Validity and sources/clingen-summary-2026-05-09. (sources/clingen-summary-2026-05-09, rating: high)
Key genotype–phenotype associations:
- LMNA LMNA: conduction disease/AF precede cardiomyopathy; highest malignant VA risk; specific ICD risk calculator (lmna-risk-vta.fr).
- RBM20 : severe phenotype, biventricular involvement.
- SCN5A SCN5A: overlap with channelopathy phenotype. First linked to DCM in 2004 (D1275N mutation). >20 SCN5A mutations now associated; >90% missense. Age-dependent penetrance. Conduction defects (AV block, bundle branch block) precede DCM onset by 15–20 years — a key diagnostic clue in unexplained IDCM. Arrhythmias in >90% of cases (AF, SSS, PVCs, VT). Three pathomechanisms proposed: (1) direct structural disruption of intercalated disc/cytoskeletal interactions or cation-leak-induced Ca²⁺ overload; (2) conduction-defect-mediated dyssynchrony → DCM; (3) long-lasting arrhythmia → tachycardia-induced CMP (reversible in MEPPC/R222Q). Standard HF therapy + avoid sodium channel blockers; paradoxical Na-channel blocker use (hydroquinidine/flecainide) in selected patients with high PVC burden, no significant conduction defects, and no CMR fibrosis. (sources/scn5a-jaccep-2018, rating: high)
- MYBPC3: second highest frequency of disease-causing mutations in European multi-centre DCM cohort (38/294, 13%; Haas et al. 2014). Both missense and truncating mutations; phenotypic overlap with HCM and LVNC. The South Asian 25-bp intron 32 deletion (4% population prevalence, 6.99x HF risk) also produces DCM and restrictive CMP in addition to HCM. (sources/mybpc3-gene-2015, rating: medium)
- TTN TTN: most common; peripartum CMP association (10% carry TTNtv). Higher rate of LV reverse remodeling (up to 70%) but also higher risk of atrial and ventricular tachyarrhythmias. (sources/esc-cmp-2023, sources/HF-ESC-2021)
TTNtv associated with alcoholic CMP (13.5% prevalence) and cancer therapy-induced CMP. (sources/esc-cmp-2023)
"Second hit theory": genetic predisposition + environmental trigger (alcohol, pregnancy, chemotherapy) drives phenotypic expression. (sources/esc-cmp-2023)

GWAS and Polygenic Risk

Inverse HCM-DCM risk loci (Tadros et al.): Several GWAS loci at MYBPC3, ALPK3, and FHOD3 show opposing effect directions for HCM vs. DCM — the same SNP allele that increases HCM susceptibility has the opposite allele increasing DCM susceptibility. This biologically confirms that HCM (sarcomere stiffness/hypercontractility) and DCM (sarcomere insufficiency/hypocontractility) represent opposite poles of a shared contractility-gene axis. Therapeutic implication: mavacamten (reduces myosin cross-bridge engagement; approved for HCM) and omecamtiv mecarbil (increases myosin cross-bridge formation; in development for DCM) pharmacologically target opposing ends of this same axis. See entities/HCM and concepts/GWAS-Cardiac-Genetics. (sources/gwas-arrhythmias-cmp-genes-2025, rating: high)
Jurgens 2024 DCM PRS — multi-ancestry validation: Multi-ancestry GWAS + MTAG-derived PRS validated in three populations: OR 1.73 (European), 1.61 (African), and 1.34 (Admixed-American) per SD increase in PRS for DCM case status. This is the most ancestry-diverse cardiac PRS validation for any cardiomyopathy to date and demonstrates that DCM polygenic risk architecture generalises across ancestries better than most cardiac GWAS. (sources/gwas-arrhythmias-cmp-genes-2025)
BAG3 p.C151R common variant modifier: A common low-frequency BAG3 variant (p.C151R) is associated with DCM risk with an effect size larger than typical GWAS SNPs — occupying the intermediate spectrum between common and rare variants. Operates as a modifier in addition to, and independent of, rare TTN/LMNA pathogenic variants. (sources/gwas-arrhythmias-cmp-genes-2025)

Mitochondrial DCM

Several nuclear-encoded and mtDNA-encoded mitochondrial gene variants cause DCM; not included in standard DCM panels — a negative panel does not exclude a mitochondrial cause. (sources/mitochondrial-cv-aha-2025, rating: very high)
Key nuclear-encoded mitochondrial genes causing DCM:
- TAFAZZIN (Barth syndrome, X-linked): DCM + hypertrabeculation + LQT + WPW; often presents in infancy; may stabilise by age 5–6; mean life expectancy 40 y
- DNAJC19 (DCMA syndrome, AR): DCM + ataxia + LQT; most deaths by 15 months
- TWNK/C10orf2 (mtDNA depletion, AD): DCM, SCD, PVCs
- MGME1 (mtDNA depletion, AR): DCM
- OXPHOS complex deficiencies (complex I, III, IV; >30 nuclear genes, AR): DCM in the context of multisystem disease (Leigh syndrome phenotype)
DCM may arise secondarily after mitochondrial HCM progresses to systolic dysfunction. (sources/mitochondrial-cv-aha-2025)
WGS is recommended as first-line for suspected mitochondrial DCM; clinical clues include maternal inheritance, multisystemic features, elevated serum lactate, hearing loss, or diabetes. (sources/mitochondrial-cv-aha-2025)
See concepts/Mitochondrial-Cardiomyopathy and concepts/Heteroplasmy for full detail.

Management

Pharmacological treatment follows ESC 2021 HF Guidelines: four-pillar therapy — ACEi/ARNI + beta-blocker + MRA + SGLT2 inhibitors (dapagliflozin or empagliflozin; Class I regardless of diabetes status). SGLT2i reduces CV death and worsening HF. (sources/esc-cmp-2023, sources/HF-ESC-2021)
ESC 2021 minimum genetic panel for DCM/HNDC (Class I for all patients): TTN, LMNA, MYH7 (MHC), TNNT, troponin-C, MYPC, RBM20, PLN, SCN5a, BAG3, actin alpha cardiac muscle, nexilin, tropomyosin-1, vinculin. Additional large panels may be considered for clear familial history or structural phenotype, by preference combined with family segregation analysis. (sources/HF-ESC-2021)
TRED-HF: Withdrawal of medical therapy in non-ischaemic DCM achieving partial/complete LVEF recovery (>40%) led to relapse in 44% within 6 months, with early LV remodelling changes even in non-relapsers — supports long-term continuation of medical therapy even after EF normalisation. (sources/HF-ESC-2021)
Anticoagulation and rate/rhythm control for AF as per standard guidelines.
ICD primary prevention: LVEF ≤35% after ≥3 months of OMT (as per HF guidelines, Class I/IIa, Level A).
Genotype-guided ICD thresholds: ICD should be considered in LMNA, PLN, FLNC, RBM20, DES, TMEM43 variants even with LVEF >35% in the presence of additional risk factors (NSVT, syncope, LGE, male sex). (sources/esc-cmp-2023)
Cardiac transplantation and LVAD for end-stage HF refractory to medical therapy. (sources/esc-cmp-2023)
IV iron supplementation (ESC 2023 update): In HFrEF (and HFmrEF) with iron deficiency (transferrin saturation <20% OR serum ferritin <100 μg/L):
- To improve symptoms and QoL: Class I, Level A (upgraded from Class IIa in 2021 ESC HF guidelines). (sources/HF-update-ESC-2023)
- Ferric carboxymaltose or ferric derisomaltose to reduce HF hospitalization risk: Class IIa, Level A. (sources/HF-update-ESC-2023)
Post-discharge strategy (STRONG-HF, ESC 2023): Intensive oral HF therapy up-titration pre-discharge + close follow-up visits (congestion, BP, HR, NT-proBNP, K+, eGFR) in first 6 weeks after HF hospitalization — Class I, Level B to reduce HF rehospitalization or death. (sources/HF-update-ESC-2023)

SCD Prevention

SCD risk varies substantially by genotype; LMNA, FLNC, and RBM20 carry the highest risk.
Gene-specific risk calculators: LMNA risk-VTA calculator; PLN p.Arg14del risk calculator. (sources/esc-cmp-2023)
ICD for secondary prevention (cardiac arrest, haemodynamically compromised sustained VT): Class I. (sources/esc-cmp-2023)

VA Risk Predictors — Meta-Analysis Data (Sammani 2020)

Annual event rate of sustained VA in non-ischaemic DCM: 4.5% (55 studies, 11,451 patients). (sources/VA-DCM-Sammani-2020)
Pooled hazard ratios for sustained VA:
- LGE presence: HR 5.55 [4.02–7.67] — strongest single predictor (sources/VA-DCM-Sammani-2020)
- Prior sustained VA: HR 4.15 [1.32–13.02] (sources/VA-DCM-Sammani-2020)
- Hypertension: HR 1.95 [1.26–3.00] (sources/VA-DCM-Sammani-2020)
- LVEF per 10% decrease (echo only): HR 1.45 [1.19–1.78] — significant; but non-significant when CMR and echo are pooled (sources/VA-DCM-Sammani-2020)
- LV dilatation (LVEDV or LVESV per 10 mL/m²): HR 1.10 — small but significant (sources/VA-DCM-Sammani-2020)
- Younger age (per 10-year increase): HR 0.82 [0.74–1.00] — protective (sources/VA-DCM-Sammani-2020)
Non-pooled signals: nsVT (9/14 studies significant), TWA (HR 6.5), PLN/LMNA/FLNC mutations. (sources/VA-DCM-Sammani-2020)
LVEF categorical cutoffs (<30%, <35%) non-significant in pooled analysis; LVEF alone is insufficient for risk stratification. (sources/VA-DCM-Sammani-2020)
See concepts/VA-Risk-Stratification-DCM for full detail.

TTNtv-DCM — Molecular Pathomechanisms

TTNtv are the most common genetic cause of DCM (15–25% of DCM cohorts). Also most common genetic predisposition in peripartum, alcoholic, and anthracycline-induced CMP. (sources/TTN-CVResearch-2022, rating: high)
Location-dependent risk: A-band TTNtv → OR 49.8 for DCM (prevalence 10.74% vs. control 0.24%). Central I-band TTNtv in low-PSI exons → OR 1.5 (near-population risk). Risk is proportional to the percentage of cardiac transcripts that include the truncated exon. (sources/TTN-CVResearch-2022, rating: high)
Triple pathomechanism (Fomin et al., Sci Transl Med 2021):
1. Titin haploinsufficiency (lifelong): reduced wt-titin protein content → fewer sarcomeres per unit area → chronic contractile deficiency.
2. Truncated protein toxicity (late-onset): tr-titin proteins stably expressed in adult TTNtv-DCM hearts (up to 50% of total titin pool); sequestered in cytoplasmic aggregates (not incorporated into sarcomeres). Higher tr-titin content correlates with younger age at transplantation.
3. PQC deregulation (progressive): UPS overwhelmed and downregulated (including reduced MuRF1); increased autophagy as partial compensation. Nonsense-mediated decay of TTNtv mRNA is NOT a prominent feature in adult hearts. (sources/TTN-CVResearch-2022, rating: high)
Therapeutic proof-of-concept: In TTNtv hiPSC-CMs: UPS inhibition increased wt-titin and improved contractility (despite raised tr-titin). CRISPR/Cas9 correction of TTNtv fully normalized wt-titin, eliminated tr-titin, and restored contractility — strongest proof-of-concept for gene correction in TTNtv-DCM. (sources/TTN-CVResearch-2022, rating: high)

HFSA 2018 — Genetic Testing Yield and Gene-Specific Guidance

Overall genetic yield in DCM: ~10–40% in familial DCM; ~10–25% in isolated (non-familial) DCM (sources/genetic-cmp-jcf-2018 — very high)
TTN truncating variants (TTNtv) are the most common genetic finding (10–20% of DCM). Interpretation is challenging: TTNtv frequency in the general population, non-segregating cases, and population-level LV function decrements suggest some TTNtv may function as risk alleles rather than fully penetrant pathogenic variants (sources/genetic-cmp-jcf-2018 — very high)
LMNA is the second most common DCM cause (~5.5%); gene-specific early ICD consideration before LVEF <35% (Guideline 9 of HFSA 2018) (sources/genetic-cmp-jcf-2018 — very high)
BAG3 (chaperone regulator) and RBM20 (RNA splicing) each account for ~2% of DCM and represent novel molecular mechanisms; adding TTN and BAG3 to DCM panels increases yield by >10% (sources/genetic-cmp-jcf-2018 — very high)
For peripartum cardiomyopathy: rare variants in DCM genes are found; TTNtv rates are similar to the DCM population — a genetic evaluation should be considered (sources/genetic-cmp-jcf-2018 — very high)
Genetic testing in mothers of Duchenne/Becker muscular dystrophy patients is important: carrier females may develop DCM in the 3rd–5th decade (sources/genetic-cmp-jcf-2018 — very high)
Multigene panel testing is the standard of care for DCM; all HCM and ARVC genes should be included in DCM panels owing to gene/phenotype overlap (sources/genetic-cmp-jcf-2018 — very high)

EHJ 2024 — EOAF Genetic Yield Comparable to Non-Familial DCM

Diagnostic yield in EOAF (~10%) matches non-familial DCM: The genetic yield of broad cardiomyopathy/arrhythmia panel testing in EOAF patients is ~10% — comparable to the ~10% yield in non-familial (sporadic) DCM. By contrast, familial DCM yields ~50% and mean DCM yield averages ~19%. This parallel supports a Class IB-equivalent justification for genetic testing in EOAF, yet ESC guidelines currently carry only a Class IIb (ACC/AHA) recommendation for AF <45 years — while DCM carries a Class IB recommendation. (sources/genetic-eoaf-ehj-2024, rating: high)
Cardiomyopathy genes dominate the EOAF P/LP landscape: In the largest EOAF genetic study (Yoneda et al., n=1293), DCM-associated genes accounted for 7.2% of all EOAF patients, HCM genes 3.3%, and ARVC genes 2.9% of EOAF patients — reinforcing the DCM–EOAF genetic overlap and the rationale for including DCM genes in any EOAF panel. (sources/genetic-eoaf-ehj-2024)

Lancet 2023 Seminar — Molecular Pathomechanisms and Future Therapy

Gene-Specific Molecular Mechanisms

DSP (Desmoplakin): Truncating LP/P variants disrupt intercalated junctions and Na/Ca channel handling. Plakoglobin is released from the desmosome complex → dislocates to cytosol and nucleus → downregulates canonical Wnt/β-catenin pathway → adipogenesis, fibrogenesis, and myocyte apoptosis. CMR: inferior sub-epicardial LGE pattern. Approximately 30% of DSP-related ACM presents with chest pain, troponin release, and ECG changes mimicking acute myocarditis. (sources/DCM-Lancet-2023, rating: very high)
FLNC (Filamin-C): Truncating LP/P variants saturate the ubiquitin-proteasome and autophagy pathways → impair Z-disc proteostasis → separation of FLNC from Z-discs → myofibril disintegration. (sources/DCM-Lancet-2023, rating: very high)
PLN (Phospholamban): PLN LP/P variants impair calcium handling; PLN protein aggregation is an early manifestation preceding cardiac dysfunction and fibrosis (confirmed in R14del zebrafish and mice models). Unfolded protein response is activated in PLN-R14del hiPSC-CMs. PLN-R14del-DCM is prone to treatment-resistant HF and arrhythmias. (sources/DCM-Lancet-2023, rating: very high)
BAG3: BAG3 protein maintains sarcomere integrity, autophagy, apoptosis, and mitochondrial function. Haploinsufficiency → disrupted Z-discs + enhanced apoptosis sensitivity in cardiac and skeletal myocytes + disrupted HSP70-mediated autophagy + impaired sarcomeric protein turnover → reduced myofilament maximal force-generating capacity. High penetrance in patients >40 years. (sources/DCM-Lancet-2023, rating: very high)
Sarcomere genes generally (MYH7, TPM1, TNNT2): Sarcomere haploinsufficiency → increased metabolic demand + shift toward glucose utilisation + oxidative and mitochondrial stress → hypertrophic cardiomyocyte growth + eccentric cardiac remodelling. (sources/DCM-Lancet-2023, rating: very high)

REALM-DCM — LMNA Pathway Therapy Failure

Phase 3, placebo-controlled REALM-DCM trial tested p38α-MAPK inhibitor (PF-07265803/ARRY-371797) in symptomatic LMNA-DCM — showed no benefit. Highlights the complexity of LMNA pathophysiology: LMNA controls nuclear function in cardiomyocytes, fibroblasts, endothelial, and inflammatory cells simultaneously; cardiac transcriptomes show enrichment of both cardiomyocyte survival transcripts and reactive fibrosis transcripts. Single-pathway inhibition is insufficient. (sources/DCM-Lancet-2023, rating: very high)

Peripartum Cardiomyopathy

Defined as cardiomyopathy in last month of pregnancy or within 5 months of delivery, without another cause. Risk factors: African ancestry, multiparity, pre-eclampsia/hypertensive disorders of pregnancy, advanced maternal age.
Pathophysiology: "multiple hits" — insufficient vascular/metabolic cardiac adaptation + rapid hormonal fluctuations (prolactin, oestrogen, progesterone, FGF-21) + genetic predisposition (TTNtv in ~10%) + acquired triggers (pre-eclampsia, autoimmune, myocarditis).
Outcomes range from complete recovery to transplantation. Genetic counselling and TTNtv testing recommended. (sources/DCM-Lancet-2023, rating: very high)

Sport and Exercise Thresholds

Low-to-moderate intensity recreational exercise: integral part of DCM management.
Contraindications for high-intensity exercise and competitive sports (shared decision-making required): LVEF <45%; unexplained syncope; extensive cardiac fibrosis at CMR or biopsy; high-risk genotype (LMNA, FLNC); frequent VT on Holter or exercise testing. (sources/DCM-Lancet-2023, rating: very high)

AHA/ACC 2025 Sports Statement — DCM-Specific Guidance

Genotype+/phenotype-: Competitive sports participation reasonable. (sources/competitive-sports-aha-2025, rating: very high)
Clinical DCM: Competitive sports participation reasonable to consider after comprehensive expert SDM; effect of vigorous exercise on DCM progression and SCA risk is unknown. (sources/competitive-sports-aha-2025)
LMNA variants: Close surveillance warranted — preliminary evidence suggests higher cumulative lifetime exercise exposure is associated with lower LVEF in LMNA-DCM. Exercise restriction should be individualized for LMNA carriers; competitive sports participation requires particular caution and longitudinal surveillance. (sources/competitive-sports-aha-2025)
EF <40% or symptomatic DCM: Higher risk — athletes should be explicitly informed of elevated risk before choosing to continue competitive sports. (sources/competitive-sports-aha-2025)
ICD should NOT be implanted solely to enable competitive sports participation. (sources/competitive-sports-aha-2025)
See concepts/Sports-Cardiology-SDM for full SDM framework.

Gene Therapy Pipeline

AAV9-LAMP2B (Danon disease, NCT03882437): Phase 1 single-dose IV gene replacement therapy; preliminary results show efficacy without prohibitive toxicity — first proof-of-concept for AAV gene therapy in a monogenic cardiomyopathy. (sources/DCM-Lancet-2023, rating: very high)
PLN antisense oligonucleotides (ASO): In PLN-R14del mice, PLN-ASO prevented PLN protein aggregation, reduced cardiac dysfunction, and improved survival rate. (sources/DCM-Lancet-2023, rating: very high)
CRISPR-Cas9: Can overcome frameshift variants and restore gene product functionality. Currently in phase 3 for sickle cell disease ex vivo (NCT05329649); in vivo cardiac application awaits cardiac-specific delivery and minimal off-target effects. (sources/DCM-Lancet-2023, rating: very high)
When to initiate gene therapy — balancing benefit vs. risk of adjunctive therapies — remains an open question.

AHA 2022 — Genetic Testing and HFimpEF in DCM Context

Genetic testing (COR 2a, LOE B-NR): Referral for genetic counseling and testing is reasonable in select patients with nonischemic cardiomyopathy to identify conditions guiding treatment for patients and family members. (sources/HF-AHA-2022, rating: very high)
Genetic testing COR 1: First-degree relatives of patients with genetic/inherited cardiomyopathy should have genetic screening and counseling. (sources/HF-AHA-2022, rating: very high)
ICD for high-risk genotypes (COR 2a): LMNA/C, desmosomal proteins, phospholamban, and FLNC — ICD consideration even with LVEF >35% or <3 months GDMT. (sources/HF-AHA-2022, rating: very high)
HFimpEF — continue GDMT (COR 1, LOE B-R): Even when LVEF normalises, withdrawal of GDMT in non-ischaemic DCM leads to 40% relapse within 6 months. Only 50% of patients can successfully withdraw treatment. Aligns with TRED-HF findings already cited from ESC sources. (sources/HF-AHA-2022, rating: very high)
Four-pillar AHA 2022 GDMT for DCM/HFrEF: ARNi/ACEi/ARB (COR 1A) + beta-blocker (COR 1A) + MRA (COR 1A) + SGLT2i (COR 1A). Consistent with ESC 2021; AHA 2022 also provides explicit NNTs and relative risk reductions (Table 15). (sources/HF-AHA-2022, rating: very high)

ESC 2022 — HNDCM Phenotype and Multi-Risk-Factor ICD Threshold

HNDCM (Hypokinetic Non-dilated Cardiomyopathy): New phenotype formalized in ESC 2022 — wall motion abnormalities without LV dilatation meeting classic DCM criteria. Managed identically to DCM for VA/SCD purposes. (sources/VA-SCD-ESC-2022)
Genetic testing (Class I): LMNA, PLN, RBM20, FLNC in DCM/HNDCM with AV conduction delay <50 years OR family history of DCM/HNDCM or SCD <50 years. (sources/VA-SCD-ESC-2022)
Genetic testing for risk stratification (Class IIa): Consider in apparently sporadic DCM/HNDCM at young age or with features of inherited aetiology. (sources/VA-SCD-ESC-2022)
Multi-risk-factor ICD threshold (Class IIa): ICD in DCM/HNDCM with LVEF <50% AND ≥2 risk factors: syncope, LGE on CMR, inducible SMVT at PES, pathogenic mutations in LMNA, PLN, FLNC, or RBM20. (sources/VA-SCD-ESC-2022)
Standard ICD threshold (Class IIa, downgraded from Class I): DCM/HNDCM + NYHA II–III + LVEF ≤35% after ≥3 months OMT. (sources/VA-SCD-ESC-2022)
Haemodynamically tolerated SMVT in DCM/HNDCM: ICD Class IIa. (sources/VA-SCD-ESC-2022)
LMNA mutation carriers: Competitive sports and high-intensity exercise NOT recommended: Class III. (sources/VA-SCD-ESC-2022)
Family screening: First-degree relatives of DCM/HNDCM patient should have ECG + echocardiogram if index patient diagnosed <50 years or has suggestive inherited features, or family history of DCM/HNDCM or premature unexpected SD: Class I. (sources/VA-SCD-ESC-2022)

Contradictions / Open Questions

Dual Class IIa ICD thresholds within ESC 2022 itself: Two simultaneous Class IIa indications with meaningfully different LVEF cutoffs — the standard threshold (LVEF ≤35%, NYHA II–III, ≥3 months OMT) and the multi-risk-factor threshold (LVEF <50% + ≥2 risk factors including high-risk genotype). A patient with LVEF 40% and an LMNA mutation could be a Class IIa candidate under either threshold with no guidance on which applies. (sources/VA-SCD-ESC-2022)
ESC 2022 vs. ESC CMP 2023 on ICD threshold for high-risk genotypes: ESC CMP 2023 recommends ICD for LMNA, FLNC, RBM20, DES, TMEM43 carriers with LVEF >35% and additional risk factors (broadly), citing the genotype-specific risk calculators. ESC VA 2022 uses the multi-risk-factor LVEF <50% + ≥2 factors framework specifically. The two guidelines overlap but do not use identical criteria for the same patient population. (sources/VA-SCD-ESC-2022, sources/esc-cmp-2023)
Standard DCM ICD threshold downgraded from Class I to Class IIa between 2015 and 2022 ESC guidelines, reflecting uncertainty from the DANISH trial showing no all-cause mortality benefit of ICD in DCM — yet Class I for CAD + same LVEF/NYHA criteria was maintained. The distinction remains controversial. (sources/VA-SCD-ESC-2022)
PKP2 disputed for DCM by ClinGen (05/30/2025): PKP2 is definitively established as the primary ARVC gene but ClinGen's GCEP disputes its role in causing isolated DCM (disputing classification 05/30/2025). Clinicians receiving "PKP2-positive, DCM" reports should consider whether the underlying phenotype is actually ARVC/ALVC rather than true DCM. MYBPC3, despite being the most common HCM gene, has only "limited" evidence for DCM — caution warranted when interpreting MYBPC3 variants in DCM patients. (sources/clingen-summary-2026-05-09, rating: high)
New DCM-definitive genes (ClinGen 2026): DES, FLNC, TNNC1, TNNT2, and CAMK2D (strong) have been upgraded to definitive or strong DCM evidence in recent ClinGen curations (2025–2026), expanding the actionable DCM gene list beyond the traditional TTN/LMNA/RBM20/MYH7/SCN5A core. Importantly, TNNI3 now has strong evidence for both autosomal dominant AND autosomal recessive DCM. (sources/clingen-summary-2026-05-09, rating: high)

Connections

Related to entities/Heart-Failure
Related to entities/TTN
Related to entities/LMNA
Related to entities/FLNC
Related to entities/PLN
Related to entities/NDLVC
Related to concepts/Phenotypic-Approach-to-Cardiomyopathy
Related to concepts/Late-Gadolinium-Enhancement
Related to concepts/Sudden-Cardiac-Death
Related to concepts/Cascade-Family-Screening
Related to concepts/VA-Risk-Stratification-DCM
Related to sources/HF-ESC-2021
Related to sources/HF-AHA-2022
Related to concepts/Genetic-Testing-in-Cardiomyopathy
Related to sources/genetic-cmp-jcf-2018
Related to sources/genetic-eoaf-ehj-2024
Related to sources/TTN-CVResearch-2022
Related to concepts/Titin-Isoform-Switch
Related to concepts/Titin-PTMs
Related to sources/DCM-Lancet-2023
Related to concepts/Sports-Cardiology-SDM
Related to sources/competitive-sports-aha-2025
Related to concepts/Mitochondrial-Cardiomyopathy
Related to entities/MYBPC3
Related to sources/mybpc3-gene-2015
Related to concepts/Heteroplasmy
Related to sources/mitochondrial-cv-aha-2025
Related to sources/scn5a-jaccep-2018
Related to concepts/MEPPC
Related to concepts/GWAS-Cardiac-Genetics
Related to concepts/Polygenic-Risk-Score
Related to sources/gwas-arrhythmias-cmp-genes-2025
Related to concepts/ClinGen-Gene-Disease-Validity
Related to sources/clingen-summary-2026-05-09