Dilated cardiomyopathy: causes, mechanisms, and current and future treatment approaches

Authors, Journal, Affiliations, Type, DOI

• Authors: Stephane Heymans, Neal K Lakdawala, Carsten Tschöpe, Karin Klingel
• Journal: Lancet 2023; 402: 998–1011
• Affiliations: Department of Cardiology, Cardiovascular Research Institute Maastricht & KU Leuven (Heymans); Cardiovascular Medicine, Brigham and Women's Hospital / Harvard Medical School (Lakdawala); Department of Cardiology, German Heart Center of the Charité / Berlin Institute of Health (Tschöpe); Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen (Klingel)
• Type: Seminar / Review Article
• DOI: Not provided in source file

Overview

This 2023 Lancet Seminar provides a comprehensive multidimensional update on DCM, covering epidemiology, genetic and acquired causes, pathophysiology, diagnosis, and treatment. The central conceptual contribution is the second hit paradigm: genetic predisposition (LP/P gene variants) alone rarely causes DCM — an environmental trigger (myocarditis, alcohol, pregnancy, chemotherapy) is typically required to unmask the phenotype. The paper catalogues 12 definitive and 7 moderate-evidence DCM genes with their gene-specific clinical profiles, outlines CMR tissue characterisation patterns per genotype, and charts future precision medicine directions including AAV gene replacement, CRISPR-Cas9 editing, and ASO/siRNA silencing. Key trials discussed include TRED-HF, DANISH, and REALM-DCM.

Keywords

Dilated cardiomyopathy, genetic cardiomyopathy, myocarditis, titin, lamin A/C, endomyocardial biopsy, cardiac magnetic resonance, gene therapy, heart failure with reduced ejection fraction, precision medicine

Key Takeaways

Epidemiology

• Annual incidence ~5–8 per 100,000; likely underestimated due to incomplete ascertainment
• Affects ~1 in 250 people overall; accounts for up to 40% of HFrEF clinical trial populations and is a leading indication for cardiac transplantation
• Sex modulates prevalence and phenotype: LMNA higher penetrance in men; DSP variants potentially more penetrant in women
• DCM accounts for ~60% of childhood cardiomyopathies; diagnosis in infancy is most common in tertiary centres
• MOGES classification (Morpho-function, extra-cardiac Organ involvement, Genetic inheritance, Etiologies, Stage) recommended to capture full complexity

Genetic Causes and Pathophysiology

• DCM is familial in 30–40% of cases; typically autosomal dominant, though X-linked, autosomal recessive, and mitochondrial patterns occur (especially paediatric)
• Monogenic, polygenic, and multifactorial (including environmental) architectures all recognised
• ~25–40% of familial DCM and 10–20% of sporadic DCM have an identifiable monogenic cause
• More than 50 genes associated with DCM; 12 definitive causative genes established:

• Seven moderate-evidence genes: TPM1, VCL, NEXN, MYBPC3 (mainly HCM), and others
• Second hit paradigm (Figure 1): TTNtv present in ~0.5% of the general population; most do not develop DCM without a second genetic or environmental trigger. TTNtv also found in ~10% of presumed alcoholic, toxic, or peripartum CMP — these "acquired" causes do not exclude underlying genetic susceptibility

Molecular Pathomechanisms by Gene

• TTNtv: Titin is the largest protein; TTNtv → reduced full-length TTN (haploinsufficiency) + truncated TTN protein (poison-peptide) → impaired myofibrillogenesis and sarcomere function → metabolic shift toward glucose utilisation + increased oxidative stress + eccentric remodelling. Less cardiac hypertrophy than other genetic forms.
• LMNA: Highly penetrant; conduction disease and VA often precede ventricular remodelling. Controls nuclear function in cardiomyocytes, fibroblasts, endothelial, and inflammatory cells → complex pathophysiology. REALM-DCM trial failed: p38α-MAPK inhibitor (PF-07265803) showed no benefit in symptomatic LMNA-DCM — highlighting the complexity of LMNA pathways
• DSP: Disrupts intercalated junctions + Na/Ca channel handling; plakoglobin released from desmosome → cytosol → nucleus → downregulation of Wnt/β-catenin pathway → adipogenesis, fibrogenesis, myocyte apoptosis
• FLNC: Truncating variants → saturation of ubiquitin-proteasome and autophagy pathways → impaired Z-disc proteostasis → myofibril disintegration
• PLN: Calcium handling impairment; PLN protein aggregation precedes cardiac dysfunction and fibrosis; unfolded protein response in R14del hiPSC-CMs
• BAG3: Haploinsufficiency → disrupted Z-discs, enhanced apoptosis sensitivity, disrupted HSP70-mediated autophagy, impaired sarcomeric protein turnover

Acquired Causes and Disease Modifiers

Myocarditis

• Most relevant acquired cause of DCM; histological types: lymphocytic (virus/bacteria/protozoa/fungi), eosinophilic, granulomatous, giant cell
• Main cardiotropic viruses: enteroviruses, parvovirus B19 (B19V), HHV-6, EBV, CMV (immunocompromised)
• SARS-CoV-2 may trigger myocarditis through cytokine-mediated cardiotoxicity or autoimmune response; rare anti-IL-1RA antibody-associated myocarditis post-mRNA vaccination in young men
• ~20% of myocarditis patients develop DCM at 1 year (uncertain due to diagnostic difficulty)
• Genetic dilated cardiomyopathy (especially DSP and TTN variants) increases risk for cardiac inflammation — biopsy-proven myocarditis can be present in genetic DCM in both adults and children

Toxins

• Anthracyclines: doxorubicin causes cardiomyocyte death via ROS/DNA damage/mitochondrial dysfunction + innate immune activation
• Immune checkpoint inhibitors (CTLA-4, PD-1/PD-L1, LAG-3 blockade): disinhibited T-cell attack on cardiac antigens → potentially fatal myocarditis in 1–2% of patients; requires high-dose prednisolone ± alemtuzumab/abatacept
• Alcohol: direct toxic effect mediated by oxidative stress, apoptosis, innate immune/neurohumoral upregulation; fibrosis, iron deposition, epicardial fat; abstinence may allow systolic dysfunction reversal
• Methamphetamines/cocaine: chronic sympathetic overactivation + endothelial dysfunction + ROS; damage less reversible than alcohol

Peripartum Cardiomyopathy

• Defined as cardiomyopathy in the last month of pregnancy or within 5 months of delivery, without another cause
• Risk factors: African ancestry, multiparity, hypertensive disorders of pregnancy (pre-eclampsia), increased maternal age
• Pathophysiology: insufficient vascular/metabolic cardiac adaptation + hormonal fluctuations (prolactin, oestrogen, progesterone, FGF-21) + genetic susceptibility (mainly TTNtv ~10%) + acquired triggers (pre-eclampsia, autoimmune, myocarditis)
• Outcomes highly variable (complete recovery to transplantation); genetic counselling and TTNtv testing recommended

Diagnosis

Clinical and ECG

• Diagnostic tests: clinical history, laboratory tests, ECG, cardiac imaging
• Diagnosis can be expanded to patients with systolic dysfunction without LV dilation (expanding definition); early presentations may be limited to conduction disease or arrhythmias
• Familial DCM: ≥2 first- or second-degree relatives with DCM, or first-degree relative with autopsy-proven DCM + sudden death <50 years
• Gene-specific ECG patterns: sinus bradycardia/AV block/AF → LMNA; lateral T-wave inversions/low QRS voltage/frequent VPBs → DSP, FLNC, PLN
• Ambulatory ECG monitoring recommended in high arrhythmogenic risk genes (LMNA, TTN, RBM20, FLNC, DSP)

Imaging

• Echocardiography: anatomical + functional; 3D echo increasingly used; LVEF remains strongest prognostic predictor
• LVEF ≤35% threshold for primary prevention ICD, but challenged by DANISH trial
• Global longitudinal strain (GLS) provides incremental prognostic value over LVEF; reduced GLS in sarcomere variants even with normal LVEF
• CMR recommended as part of initial DCM evaluation:
  • Gold standard for biventricular volumes, systolic function, and tissue characterisation
  • LGE patterns are gene-specific:
    • TTNtv-DCM: no distinguishable LGE pattern
    • LMNA-DCM: mid-myocardial LGE at basal septum
    • DSP-DCM: inferior sub-epicardial LGE
  • LGE presence/extent: independent predictor of outcomes, SCD, and lack of reverse remodelling, incremental over LVEF
  • T1/T2 mapping + LGE required if myocarditis suspected
  • Left atrial conduit strain: independent prognostic predictor, superior to LVEF and LA volume, incremental to LGE
• PET/CT: alternative to CMR for cardiac inflammation; full-body PET-CT for suspected sarcoidosis

Genetic Testing

• Recommended for all patients with DCM regardless of family history (professional societies endorse this)
• If resource-limited: clinical risk score (family history + low QRS amplitude + skeletal myopathy + absence of hypertension/LBBB) helps identify highest-yield patients
• Next-generation sequencing covering all exons/introns of established DCM genes is standard for index case
• Whole exome/genome sequencing for complex multisystem cases or negative initial testing
• Cascade testing for family members once causative variant identified; surveillance every 2–3 years for variant carriers without phenotype
• Age at which screening starts informed by which disease gene is involved

Biomarkers

• NT-proBNP/BNP: most widely adopted for HF diagnosis and prognostication
• High-sensitivity troponin: myocardial injury marker; recurrently elevated levels → investigate for myocarditis
• Elevated creatine kinase: suggests skeletal muscle involvement (dystrophinopathies, mitochondrial CMP, glycogen storage disease)
• sST2, galectin-3, PICP (procollagen type I C-terminal propeptide), GDF-15: incremental prognostic value unclear; PICP + LGE combination provides additive prognostic information

Endomyocardial Biopsy

• Required for differentiation of inflammatory vs non-inflammatory disease; types of myocarditis; storage disorders (amyloidosis, Fabry, glycogenosis, haemochromatosis); genetic heart diseases
• Indications: suspected fulminant/acute myocarditis with HF/LV dysfunction/arrhythmias; autoimmune disorders with progressive HF; recent-onset DCM with moderate-to-severe LV dysfunction; suspected ICI-mediated cardiotoxicity; high-degree AVB; unexplained VA; myocarditis genotypes (DSP, TTN)
• Immunohistology (CD3+ T cells, CD68+ macrophages, HLA-DR) improved diagnostic sensitivity vs historical Dallas criteria (H&E only)
• Quantitative RT-PCR for cardiotropic viruses; virus detection relevant only with high viral load AND systemic infection

Management

Medical

• Guideline-directed medical therapy for HFrEF: ACEi/ARB, beta-blockers, MRA, SGLT2 inhibitors
• Sacubitril-valsartan for those remaining symptomatic on optimal treatment
• Genotype-specific response: TTNtv-DCM may experience greater early reverse remodelling (waning over time); LMNA-DCM appears to derive less benefit from conventional medical therapy
• TRED-HF trial (n=51): Withdrawal of medical therapy in non-ischaemic DCM with partial/complete LVEF recovery (>40% with normal NPs) → relapse in 44% within 6 months, with early LV remodelling changes even in non-relapsers → supports continuing therapy even after EF normalisation
• Oral anticoagulation for DCM + AF; LMNA-DCM thromboembolic risk up to 5× higher → anticoagulation strongly recommended

Sport and Training

• Low-to-moderate intensity recreational exercise or guided exercise training: integral part of management
• High-intensity exercise and competitive sports: risk of SCD; shared decision-making required
• Contraindications to high-intensity exercise: LVEF <45%, unexplained syncope, extensive CMR/biopsy fibrosis, high-risk genotype (LMNA, FLNC), frequent VT on Holter/exercise testing

Devices

• DANISH trial: Prophylactic ICD in symptomatic non-ischaemic systolic HF showed no significant all-cause survival benefit overall; however younger patients (<70 years) had lower mortality, CV death, and SCD on long-term follow-up
• ICD remains important for specific genetic/inflammatory subgroups (LMNA, sarcoidosis, FLNC, RBM20, DSP) where SCD risk is high regardless of LVEF
• Meta-analysis of RCTs confirms survival benefit from ICD in DCM overall
• ICD decision factors: age, family history of SCD, high-risk genotype (LMNA, FLNC, DSP, RBM20), degree of systolic dysfunction, myocardial fibrosis, ventricular ectopy burden
• LMNA and PLN risk calculators for life-threatening ventricular tachyarrhythmias available
• CRT indicated for symptomatic DCM + sinus rhythm + LVEF ≤35% + QRS >130 ms with LBBB; greater LVEF/cavity-size improvement and survival benefit in DCM vs ischaemic CMP

End-Stage

• Durable LVAD: outcomes strongly related to severity of HF and multiorgan dysfunction; generally favourable in DCM vs ischaemic (younger, less comorbidity)
• Cardiac transplantation: DCM is a common indication

Treatment of Myocarditis

• Acute myocarditis: Hospital admission ≥48 h if HF, elevated troponins, cardiac dysfunction, or arrhythmias; spontaneous systolic function recovery in up to 90% within days; standard HFrEF therapy advocated
• ICI-induced myocarditis: Hold ICI + high-dose prednisolone ± alemtuzumab or abatacept
• B19V/HHV-6 in heart: antiviral treatment only if high viral load AND systemic infection
• Chronic myocarditis with systolic dysfunction: Troponins stable/negative, no oedema on imaging; endomyocardial biopsy required to confirm inflammation and guide immunosuppression; immunosuppression should be considered in non-infectious confirmed inflammatory CMP

Future Therapeutic Perspectives

Phenoclustering and Risk Stratification

• Three cardiac molecular phenotypes identified: (1) metabolic (diabetes/severe systolic dysfunction), (2) inflammatory (systemic diseases/chronic myocarditis), (3) pro-fibrotic/metabolic (genetic DCM with moderate systolic dysfunction)
• Future large genetically/clinically characterised cohorts needed for subgroup-specific risk scores for SCD and HF progression
• LMNA risk score (lmna-risk-vta.fr) and PLN p.Arg14del risk score are first examples of genotype-driven SCD risk stratification

Precision Medicine Gene Therapy

• AAV gene replacement: AAV9 overexpressing wild-type LAMP2B in Danon disease (phase 1, NCT03882437) — promising without prohibitive toxicity
• ASO/siRNA gene silencing: PLN-antisense oligonucleotides in PLN-R14del mice → prevented PLN aggregation, reduced cardiac dysfunction, improved survival
• CRISPR-Cas9: Genome editing to overcome frameshift variants; being investigated in phase 3 in sickle cell disease ex vivo (NCT05329649); in vivo cardiac application awaits cardiac-specific delivery and minimal off-target effects
• When to initiate gene therapy, balancing benefit vs risks, remains an open question

Limitations of the Document

• Epidemiological data are incomplete and lacking in diverse ancestries
• Retrospective data dominate genotype-specific treatment efficacy comparisons (TTNtv, LMNA); prospective genotype-stratified RCTs largely absent
• REALM-DCM failure demonstrates pathophysiological complexity of LMNA-DCM and limits of single-pathway targeting
• Risk scores for SCD during specific exercise activities are scarce and underpowered
• Endomyocardial biopsy remains underutilised despite its diagnostic importance
• Gene therapy approaches remain early-phase; cardiac-specific delivery, immunogenicity, and long-term safety unresolved
• No systematic evaluation of sex-specific differences in therapy response

Key Concepts Mentioned

• concepts/VA-Risk-Stratification-DCM — genotype-guided ICD decision-making
• concepts/Late-Gadolinium-Enhancement — gene-specific LGE patterns; incremental prognostic value
• concepts/Phenotypic-Approach-to-Cardiomyopathy — MOGES classification; second hit paradigm
• concepts/Genetic-Testing-in-Cardiomyopathy — all DCM patients regardless of family history
• concepts/Gene-Silencing-Therapy — ASO/siRNA for PLN-R14del
• concepts/AAV-Gene-Delivery — AAV9 LAMP2B Danon disease phase 1
• concepts/CRISPR-Cas9-in-Channelopathies — CRISPR for frameshifts in genetic CMP
• concepts/iPSC-Derived-Cardiomyocytes — PLN-R14del hiPSC-CMs; TTNtv models
• concepts/HFpEF — TRED-HF; SGLT2i; HFrEF four-pillar therapy

Key Entities Mentioned

• entities/DCM — central entity; genotype-phenotype table; management; DANISH; TRED-HF; gene therapy
• entities/TTN — TTNtv pathomechanism; second hit; peripartum/alcoholic CMP association
• entities/LMNA — highly penetrant; REALM-DCM failure; AF/conduction disease; 5× thromboembolism
• entities/Atrial-Fibrillation — near 100% AF risk in LMNA-DCM; anticoagulation
• entities/Heart-Failure — HFrEF four-pillar therapy; TRED-HF; DANISH trial
• entities/Anderson-Fabry-Disease — mentioned in differential (Fabry EMB findings: lamellar bodies)
• entities/ATTR-Amyloidosis — mentioned in differential (EMB: amyloidosis detection)

Wiki Pages Updated

• wiki/sources/DCM-Lancet-2023.md — created
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated
• wiki/entities/DCM.md — updated (Lancet 2023 Seminar section added)
• wiki/entities/TTN.md — updated
• wiki/entities/LMNA.md — updated