Left Ventricular Hypertrabeculation and Prognosis in Dilated Cardiomyopathy

Authors, Journal, Affiliations, Type, DOI

• Authors: Nerea Mora-Ayestarán and Noemi Ramos-Lopez (equal contribution), with Juan Pablo Ochoa, Ahmad S. Amin, Connie R. Bezzina and a large Spanish/Dutch investigator group; Jesus G. Mirelis and Pablo Garcia-Pavia as joint senior authors
• Affiliations: Department of Cardiology, Hospital Universitario Puerta de Hierro, and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid; 22 European centres across Spain and the Netherlands, many within ERN GUARD-Heart
• Journal: Circulation. 2026;154:440–453 (August 4, 2026); open access (CC BY-NC-ND); received 14 Nov 2025, accepted 5 Jun 2026
• Type: International, multicentre, retrospective, observational, longitudinal cohort study with centrally adjudicated CMR and genotype
• DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.078536

Overview

The largest study yet to ask whether left ventricular hypertrabeculation — formerly "noncompaction" — means anything prognostically once you know the genotype. In 1,160 patients with DCM from 22 European centres, all imaged by CMR and 86% genetically tested, hypertrabeculation was present in 30.5% — and it predicted nothing: not embolism, not ventricular arrhythmia, not advanced heart failure, either overall or within any genotype.

The paper's practical target is one recommendation. Older, smaller series reported thromboembolism rates of 22–29%, and on that basis several reviews and guidelines still advise prophylactic anticoagulation in hypertrabeculation with reduced ejection fraction even in sinus rhythm. Here the embolic rate was 3.2% over 5.1 years — no different in hypertrabeculation (3.7% vs 3.0%), and no different in the subgroup that matters most: sinus rhythm, no anticoagulation, LVEF ≤40% (HR 1.89, 95% CI 0.66–5.46). What predicted embolism was atrial fibrillation (HR 3.26) and low LVEF (HR 1.04 per 1% decrease).

The third finding is a genotype gradient that inverts the usual intuition: hypertrabeculation is commonest in the genotypes with the best prognosis — motor sarcomeric 58%, TTN 38%, genotype-negative 33% — and rarest in the worst: nuclear envelope genes 5%, cytoskeleton/Z-disk 7%.

Keywords

Cardiomyopathy · dilated · embolism · genes · prognosis

Key Takeaways

Design and cohort

• 1,160 consecutive patients with nonischemic DCM (LVEF <50% on CMR, no loading condition, no CAD, no other identifiable cause), recruited 2003–2023; 978 index cases and 181 relatives.
• Genetic testing in 997 (86%) by targeted NGS panels of >50 cardiomyopathy genes, or Sanger for a known familial variant; all CMR and all genotype calls were re-adjudicated centrally at the coordinating centre.
• Outcomes independently adjudicated by investigators blinded to hypertrabeculation status.
• Median age 55.5 years, 65.3% male, 98.1% White; median LVEF 36%; LGE present in 31.0%; AF at baseline 15.0%.

Two diagnostic methods, one answer

• Fractal analysis was used as the primary criterion because the Petersen ratio is limited by manual measurement, interobserver variability, and cannot capture three-dimensional trabecular complexity.

Outcomes at a median 5.1 years (IQR 2.8–7.4)

• The univariate story runs backwards. Unadjusted, hypertrabeculation was associated with fewer events — MVA HR 0.64 (0.42–0.97), AHF HR 0.54 (0.29–0.99) — and both associations disappeared after adjustment for genotype, LGE, NYHA class and LVEF. Hypertrabeculated patients were younger (54.1 vs 56.4 years), had higher LVEF (38.2% vs 34.9%) and less LGE (24.7% vs 33.7%). The apparent protection was a marker of milder disease.
• What actually predicted events: for MVA, nuclear envelope genotype (HR 4.4, 2.0–9.8), LGE (HR 3.1, 2.1–4.8) and lower LVEF (HR 1.03 per 1% decrease). For embolism, AF (HR 3.26, 1.47–7.23) and lower LVEF (HR 1.04 per 1% decrease, 1.01–1.08).
• Embolic events were mostly AF events. Of the 37, 15 (40.5%) had documented AF or flutter before the event and a further 6 (16.2%) had AF first identified at the time of the event or within the next 6 months — over half attributable to AF.

The subgroup that drives the anticoagulation question

• Among 496 patients in sinus rhythm, not anticoagulated, with LVEF ≤40%, embolic events occurred in 14 (2.8%): 8 (2.2%) without hypertrabeculation, 6 (4.4%) with (P=0.205).
• Adjusted HR for hypertrabeculation in that subgroup: 1.89 (95% CI 0.66–5.46) — a point estimate that cannot exclude meaningful harm, but an event rate too low to justify prophylaxis across the group.
• The paper's explicit position: do not anticoagulate on the basis of hypertrabeculation alone, even at LVEF ≤40%.

Prevalence by genotype — the inversion

• A DCM-related P/LP variant was found in 329 (28.4%): TTN 122 (37.1% of positives), DSP 31, FLNC 28, BAG3 23, MYH7 21, LMNA 20, RBM20 17.
• No genotype showed an outcome difference by hypertrabeculation status, with one nominal exception — advanced heart failure in TTN carriers, 10.5% without versus 0% with (P=0.024) — in a table of 21 comparisons, several with cells of one patient.
• The groups with the worst prognosis (nuclear envelope, 42.1% MVA without hypertrabeculation) had almost no hypertrabeculation to test; the nuclear-envelope row contains a single hypertrabeculated patient, who had an event.

Classification — trait or disease?

• The AHA calls LV hypertrabeculation a primary cardiomyopathy; the ESC 2023 guidelines call it a phenotypic trait. This paper sides with the ESC.
• Supporting argument: hypertrabeculation is found in other cardiomyopathies, neuromuscular disease, congenital heart disease, athletic training, pregnancy and healthy individuals (up to 43% in one healthy cohort), with no progressive remodelling over a 9.5-year follow-up in MESA.
• The alternative hypothesis — that hypertrabeculation is reactive, made visible by LV dilatation — is not supported here, because hypertrabeculated patients had less remodelled ventricles, not more.

Limitations of the document

• Retrospective and observational, with low event numbers. 37 embolic events and 62 AHF events limit power to exclude modest differences; a true HR of 1.5 for embolism is entirely compatible with these data even though it did not reach significance.
• Genetic testing was not uniform — different panels at different centres over 20 years, reflecting the evolution of DCM genetics, so some "genotype-negative" patients were tested with older, smaller panels.
• 98.1% White, in a trait reported to be commoner in Black individuals — the genotype distribution and prevalence may not transfer.
• Referral bias in both directions: CMR referral was clinically driven, and all centres specialise in inherited cardiac disease and heart failure, so the cohort is enriched for advanced phenotypes.
• The nuclear-envelope and desmosomal subgroups are too small to support their own conclusions. Nuclear envelope n=20 with 1 hypertrabeculated patient; the "no interaction by genotype" claim is really an absence of evidence.
• Possible contamination of the motor sarcomeric group: the authors concede they cannot exclude that some of the 11 MYBPC3 carriers had end-stage HCM rather than DCM — and MYBPC3 is the group with the second-highest hypertrabeculation prevalence.
• Fractal analysis has known false positives — apical thrombus and apically displaced papillary muscles can be read as trabeculae.
• Anticoagulation was a baseline covariate, not randomised, and the extended Cox model adjusts for it rather than testing it; the paper cannot say what anticoagulation did, only what it did not need to prevent.
• The abstract and the Results give different prevalence figures for the motor sarcomeric group — 58% in the Abstract and 56.6% (30 of 53) in the Results. This page uses the Results figure throughout. Similarly, Petersen-criterion prevalence is 29.7% in the Abstract and 29.65% in the Results.
• No data on LV thrombus, which is the mechanism the anticoagulation recommendation was built on — the study measures embolic events, not the substrate.

Key Concepts Mentioned

concepts/LV-Hypertrabeculation · concepts/VA-Risk-Stratification-DCM · concepts/Late-Gadolinium-Enhancement · concepts/Genetic-Testing-in-Cardiomyopathy

Key Entities Mentioned

entities/DCM · entities/TTN · entities/MYH7 · entities/MYBPC3 · entities/LMNA · entities/FLNC · entities/DSP · entities/DES · entities/SCN5A · entities/PLN

Named but unlinked: BAG3 · RBM20 · TNNC1 · TNNT2 · fractal dimension · Petersen criteria · MESA

Wiki Pages Updated

• sources/trabeculation-dcm-circ-2026 — created
• concepts/LV-Hypertrabeculation — created
• entities/DCM — hypertrabeculation as a prognostic null
• entities/TTN — 38% prevalence in TTN-DCM
• entities/MYH7 — 71% prevalence, the highest of any gene
• entities/LMNA — 5% prevalence, lowest of any gene
• entities/FLNC — 7% prevalence
• concepts/VA-Risk-Stratification-DCM — genotype beats trabeculation
• concepts/Late-Gadolinium-Enhancement — LGE HR 3.1 for MVA in genotyped DCM
• wiki/wikiindex · wiki/sourceindex