Key result
Rare pathogenic cardiovascular variants are not linked to higher-risk heart failure profiles.
Why the study?
Heart failure outcomes remain variable and difficult to predict, and while genetic testing is recommended for suspected inherited cardiomyopathy or arrhythmia, its prognostic role in heart failure remains uncertain.
Is the presence of rare pathogenic or likely pathogenic genetic variants associated with a more adverse clinical phenotype in patients with heart failure?
Is the presence of rare pathogenic or likely pathogenic genetic variants associated with a more adverse clinical phenotype in patients with heart failure?
In a small cohort of heart failure patients, the presence of pathogenic or likely pathogenic genetic variants was not significantly associated with a higher-risk clinical phenotype.
Rare variants should not inform HF risk stratification; leaves open their phenotypic contribution pending larger genetic studies.
Background Heart failure (HF) is a complex clinical syndrome with heterogeneous aetiologies and impaired cardiac function, leading to high morbidity, mortality, and frequent hospitalisations. Despite advances in pharmacological and device therapy, outcomes remain variable and prognosis is often difficult to predict. Genetic testing is recommended in selected patients, particularly when an inherited cardiomyopathy or arrhythmia is suspected, but its prognostic role in HF remains uncertain. Purpose To evaluate whether the presence of rare pathogenic or likely pathogenic (P/LP) variants in genes related to inherited cardiovascular disease is associated with more adverse clinical phenotypes in patients with HF. Methods We included 196 patients with a clinical diagnosis of HF and a minimum follow-up of two years. Whole-exome sequencing was performed, and rare variants were filtered through a virtual panel of 190 genes associated with inherited cardiomyopathies and arrhythmias. Variant classification followed ACMG/AMP and ACGS standards. Clinical risk stratification considered: family history of cardiomyopathy (yes/no), left ventricular ejection fraction (LVEF <40% vs ≥40%), and major cardiovascular events (atrial fibrillation, ventricular tachycardia, or cardiac death; yes/no). Patients with ≤1 criterion were classified as lower-risk HF, while those with ≥2 criteria were classified as higher-risk HF. Results 88 patients (45%) were classified as higher-risk HF and 108 as lower-risk HF (55%). P/LP variants were identified in 12 patients: 6 in the lower-risk group and 6 in the higher-risk group [OR = 1.24; 95% CI: 0.39-4.00; p = 0.71]. Although not statistically significant, a trend towards a higher prevalence of P/LP variants was observed in the higher-risk group. Conclusions In this HF cohort, P/LP variants were not significantly enriched in patients with a more adverse clinical profile. Nevertheless, the observed trend suggests that integrating genetic testing with conventional risk stratification may enhance prognostic assessment. Larger studies are warranted to clarify the contribution of inherited variants to HF prognosis and to guide personalised therapeutic strategies.
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Saavedra et al. (2026) studied this question. Rare pathogenic variants in cardiovascular genes were not significantly enriched in heart failure patients with higher-risk clinical profiles (OR 1.24, 95% CI 0.39-4.00, p=0.71).
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