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Phenotype and Clinical Outcomes in Desmin-Related Arrhythmogenic Cardiomyopathy
Francisco J Bermudez-Jimenez1, Alexandros Protonotarios2, Soledad García-Hernández3
1Department of Cardiology, Virgen de las Nieves University Hospital, Granada, Spain; Instituto de Investigación Biosanitaria. ibs.GRANADA, Granada, Spain.
Insights
Desmin (DES) related arrhythmogenic cardiomyopathy (ACM) is linked to poor outcomes. Early identification through family screening and genetic studies is crucial for managing at-risk individuals.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Desmin (DES) pathogenic variants are a rare cause of arrhythmogenic cardiomyopathy (ACM).
- Limited outcome data exists for DES-related ACM.
Purpose of the Study:
- To investigate the clinical phenotype and outcomes of patients with DES-related ACM.
- To compare outcomes with other ACM genetic variants.
Main Methods:
- A multicenter cohort study of 16 families with DES-related ACM.
- Phenotypic and outcomes data collection.
- In vitro assessment of DES aggregates.
- Comparison with lamin A/C (LMNA-tv) and filament C (FLNC-tv) ACM cohorts.
Main Results:
- 82 patients analyzed; 11 experienced cardiac death before evaluation.
- Among survivors, 86% showed cardiomyopathy, predominantly left ventricular.
- Major adverse cardiac events occurred in 15 additional patients over a median follow-up of 6.73 years.
- Male sex, nonsustained ventricular tachycardia, and reduced ejection fraction (<50%) predicted adverse events.
- Males with DES variants had outcomes similar to FLNC-tv and LMNA-tv controls, while females had better outcomes than LMNA-tv.
- In vitro studies revealed DES aggregates in 7 of 12 variants.
Conclusions:
- DES-related ACM is associated with significant adverse outcomes.
- Predictive factors for poor outcomes were identified.
- Familial evaluation and genetic testing are essential for identifying at-risk individuals for timely intervention.
Background:
Desmin (DES) pathogenic variants cause a small proportion of arrhythmogenic cardiomyopathy (ACM). Outcomes data on DES-related ACM are scarce.
Objectives:
This study sought to provide information on the clinical phenotype and outcomes of patients with ACM caused by pathogenic variants of the DES gene in a multicenter cohort.
Methods:
We collected phenotypic and outcomes data from 16 families with DES-related ACM from 10 European centers. We assessed in vitro DES aggregates. Major cardiac events were compared to historical controls with lamin A/C truncating variant (LMNA-tv) and filament C truncating variant (FLNC-tv) ACM.
Results:
Of 82 patients (54% males, median age: 36 years), 11 experienced sudden cardiac death (SCD) (n = 7) or heart failure death (HFd)/heart transplantation (HTx) (n = 4) before clinical evaluation. Among 68 survivors, 59 (86%) presented signs of cardiomyopathy, with left ventricular (LV) dominant (50%) or biventricular (34%) disease. Mean LV ejection fraction was 51% ± 13%; 36 of 53 had late gadolinium enhancement (ring-like pattern in 49%). During a median of 6.73 years (Q1-Q3: 3.55-9.52 years), the composite endpoint (sustained ventricular tachycardia, aborted SCD, implantable cardioverter-defibrillator therapy, SCD, HFd, and HTx) was achieved in 15 additional patients with HFd/HTx (n = 5) and SCD/aborted SCD/implantable cardioverter-defibrillator therapy/sustained ventricular tachycardia (n = 10). Male sex (P = 0.004), nonsustained ventricular tachycardia (P = 0.017) and LV ejection fraction ≤50% (P = 0.012) were associated with the composite endpoint. Males with DES variants had similar outcomes to historical FLNC-tv and LMNA-tv controls. However, females showed better outcomes than those with LMNA-tv. In vitro experiments showed the characteristic finding of DES aggregates in 7 of 12 variants.
Conclusions:
DES ACM is associated with poor outcomes which can be predicted with potentially successful treatments, underscoring the importance of familial evaluation and genetic studies to identify at risk individuals.
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