Non-Dilated Left Ventricular Cardiomyopathy

Monogenic (Mendelian): a substantial share carry DCM/ACM-overlap variants (DSP, FLNC, DES, LMNA, TTN)^[1]

Acquired: includes post-myocarditis scar^[1]

Complex (likely polygenic): an umbrella phenotype; the non-monogenic remainder is heterogeneous and likely polygenic^[1]

Inheritance: Autosomal dominant most common (penetrance 30–50%); X-linked (TAZ, nearly 100% penetrance in males); mitochondrial (variable). For autosomal dominant forms, first-degree relatives have a 50% risk of inheriting the pathogenic variant.^[1]

Familial proportion: reported genetic yield in NDLVC varies widely (commonly cited in the ~40-50% range in some series) depending on phenotype severity, age at diagnosis, family history and how the cohort was selected, it is not a fixed universal figure; family history of cardiomyopathy is present in a variable minority of cases. Genetic testing using the DCM panel (R132) should be offered according to current NHS Genomic Medicine Service eligibility criteria for that panel, not presented as recommended for literally every case regardless of eligibility.^[1]

Genetic yield: varies by phenotype, age and selection (commonly cited around 40-50% in some series); overlaps extensively with the DCM gene panel

Genetic overlap with the DCM / ARVC spectrum:

• Arrhythmogenic / scar-associated: DSP, FLNC, DES, PLN, RBM20 (overlap with the ARVC spectrum; associated with LV fibrosis and arrhythmic risk, often disproportionate to LV impairment)
• Sarcomeric: MYH7 (~15%, penetrance 60-80%), MYBPC3 (~10%, penetrance 50-70%), ACTC1 (~5%), TNNT2 (~3-5%), TPM1 (rare)
• Cytoskeletal: TTN (~20-25%, penetrance 30-40%), LDB3/ZASP (~2-3%)
• Nuclear envelope: LMNA (~5%, high penetrance, arrhythmia risk)
• X-linked: TAZ (~1-2% overall, nearly 100% penetrance in males) - Barth syndrome (infantile CM, neutropenia, 3-methylglutaconic aciduria, growth delay)
• Other: DTNA, PRDM16, FKTN (rare)

Gene frequencies and penetrance figures derive largely from referral cohorts and vary with variant class and ascertainment; treat them as indicative rather than fixed.

Pathophysiology: Shares pathways with the DCM and arrhythmogenic cardiomyopathy spectrum (sarcomeric, cytoskeletal and desmosomal dysfunction) producing myocardial fibrosis/scar and LV systolic impairment without dilatation. Excessive trabeculation, if present, is now regarded as a phenotypic trait or epiphenomenon rather than the primary disease (the historical "arrested compaction" theory is disputed); 2023 ESC: trabeculations alone do NOT define the condition.

Genetic testing: Same gene panel as DCM (R132). Genetic diagnosis important for family screening, prognosis (LMNA, TAZ high-risk), and distinguishing from isolated trabeculations (common normal variant).

A category introduced by the 2023 ESC guidelines, so robust prevalence data are lacking and its true frequency is uncertain.^[1]

Separate issue: excessive LV trabeculation / "non-compaction" was historically over-diagnosed on non-specific echocardiographic criteria; the 2023 guideline reclassifies it as a phenotypic trait, not a distinct cardiomyopathy.^[1]

Can present at any age from infancy to late adulthood.

Confirmatory work-up: echocardiography establishes a non-dilated LV with systolic dysfunction; CMR with late gadolinium enhancement characterises fibrosis and helps exclude other phenotypes; and genetic testing (DCM/arrhythmogenic panel) is recommended, genotype drives arrhythmic risk and family screening.^[1]

2023 ESC Definition:

• Non-dilated LV with non-ischaemic LV scar / fibrofatty replacement (with or without systolic dysfunction), OR
• Isolated global LV hypokinesia without scar, in a non-dilated LV
• Does NOT meet criteria for HCM, DCM, ARVC or another specific cardiomyopathy
• Excessive trabeculation, if present, is not itself diagnostic

Key Change: NDLVC is defined by scar or dysfunction, not by trabeculation; excessive trabeculation alone is now a phenotypic trait, not a cardiomyopathy

Clinical Features:

• Heart failure symptoms
• Arrhythmias (AF, VT)
• Thromboembolic events
• Family history in ~40-50%

Echocardiography:^[1]

• Assess LV size, systolic function and non-ischaemic scar/fibrofatty replacement; LV systolic dysfunction is not required for diagnosis if non-ischaemic scar or fibrofatty replacement is present in a non-dilated LV
• Trabeculations may be present but are NOT diagnostic in isolation
• Exclude other causes of LV dysfunction (HCM, DCM, infiltrative)

Cardiac MRI:^[1]

• Better characterisation of trabeculations and myocardial structure
• Late gadolinium enhancement for fibrosis, prognostic significance
• Do NOT diagnose based on trabeculation measurements alone

Genetic testing: R132 DCM panel^[1]

1. General measures:

• Genetic counselling and family cascade testing (DCM panel, R132), see the Genetic Testing page

2. Medical therapy, as per standard heart failure guidelines:

• Guideline-directed medical therapy for HFrEF
• Early disease expression versus an unaffected carrier: in a relative with early disease, first-line heart-failure therapy (ACE inhibitor or ARB, beta-blocker, MRA) may be considered to slow progression of LV dilatation and dysfunction (ESC 2023 Class IIb). In a genotype-positive relative with no phenotype there is no evidence supporting any drug to prevent disease developing, and none should be started; the EARLY-Gene trial is testing this question. Surveillance, not treatment, is the intervention^[1]
• ACEi/ARB, beta-blockers, MRA, SGLT2i
• Anticoagulation if AF/flutter, LV thrombus, prior systemic embolism or another standard indication
• In sinus rhythm, anticoagulation is not routine solely for reduced LVEF; individualise if severe dysfunction, apical aneurysm, thrombus risk or prior embolic features are present

3. Device therapy:

• ICD/CRT as per standard HFrEF guidelines, but lower the ICD threshold for high-risk genotypes (LMNA, FLNC, PLN, DSP, RBM20), where arrhythmic risk exceeds that predicted by LVEF alone^[1]

4. Advanced heart failure and/or transplant referral:

• As per standard HFrEF advanced-therapy pathways for progressive disease refractory to GDMT

• Ventricular arrhythmia and sudden cardiac death: can precede systolic dysfunction, with risk driven by genotype (LMNA, FLNC, PLN, DSP, RBM20, DES)^[1]
• Progression to overt DCM and heart failure.
• Atrial fibrillation and conduction disease.

Risk stratification: Use standard DCM/HFrEF risk tools

Prognosis: Similar to dilated cardiomyopathy when matched for EF

ICD indications: Same principles as DCM, primary prevention generally considered once LVEF ≤35% despite optimal medical therapy, but the threshold is lowered for high-risk genotypes (LMNA, FLNC, PLN, DSP, RBM20), where arrhythmic risk can exceed that predicted by LVEF alone

Based on ESC 2023 Cardiomyopathy guidelines^[1].

Advanced / complicated = falling LVEF, significant ventricular arrhythmia, high-risk genotype (LMNA, FLNC, PLN, DSP, RBM20), or a device in situ.

Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.

	Genotype+ / Phenotype−	Uncomplicated / Stable	Advanced / Complicated
Frequency	Every 2–3 yrs (genotype-guided)	Every 1–2 years	Every 3–6 months
Clinical review	Symptoms	Symptoms, NYHA, arrhythmia history	As above + device check
ECG	Each screening visit	Annual 12-lead	Each visit
Echocardiography	Each screening visit	Every 1–2 years	6-monthly
Holter / ambulatory	If high-risk genotype	Annual (genotype-driven)	6-monthly
CMR	Consider (early fibrosis)	Baseline + if phenotype changes (LGE)	As indicated
Family screening	–	Cascade ECG + imaging (genotype-guided)	–

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

• Genetic testing using DCM panel (R132)^[1]
• Do NOT diagnose based on trabeculations alone; NDLVC is defined by non-ischaemic LV scar or fibrofatty replacement in a non-dilated LV, with or without systolic dysfunction, or by isolated LV systolic dysfunction without dilatation^[1]
• Prominent trabeculations are common normal variants
• Screen family members as for DCM
• Manage as DCM/HFrEF - not a separate disease entity^[1]