Key result
CPET identifies early cardiac limitations in ~73% of gene-positive, phenotype-negative relatives of cardiomyopathy patients.
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Why the study?
Conventional clinical screening in gene-positive cardiomyopathy families is often unremarkable, especially in younger individuals, leaving the role of CPET in detecting subclinical disease unclear.
Does cardiopulmonary exercise testing (CPET) detect subclinical disease in gene-positive phenotype-negative relatives of cardiomyopathy patients?
Observational (n=22)
No
Does cardiopulmonary exercise testing (CPET) detect subclinical disease in gene-positive phenotype-negative relatives of cardiomyopathy patients?
CPET can identify early cardiac functional limitations in a considerable proportion of gene-positive, phenotype-negative relatives of cardiomyopathy patients.
CPET may flag subclinical limitations in gene-positive relatives; hypothesis-generating case series leaves clinical adoption open.
INTRODUCTION: Cascade testing in gene-positive cardiomyopathy families facilitates the identification of relatives at risk of cardiomyopathy. Conventional clinical screening is often unremarkable, particularly in younger individuals. This study evaluated the potential role of cardiopulmonary exercise testing (CPET) in detecting subclinical disease among gene-positive phenotype-negative (G + P-) relatives. METHODS: In this single-centre case series, relatives of probands with likely/definite pathogenic cardiomyopathy variants underwent cascade testing. Gene-positive relatives underwent extensive phenotyping (ECG, echocardiography, holter monitor, cardiac MRI). Individuals with morpho-functional abnormalities suggestive of early cardiomyopathy and those fulfilling diagnostic criteria were excluded. Consecutively recruited (March 2017-December 2024) G + P- relatives underwent CPET ergometry. Those who completed a maximal test were included. A cardiac limitation was defined as VO2MAX <80% and/or ≥ 2 abnormal CPET variables. RESULTS: Twenty-two subjects were included (59.1% female, mean age of 32.1 ± 16.0 years). Most had a TTN (27.3%), ACTC1 (22.7%) and DSG2 (22.7%) variant. All subjects are under follow-up (42.4 ± 24.0 months). Nearly ¾ (72.7%) had evidence of cardiac limitation during CPET, irrespective of haemoglobin, creatinine and body mass index. More than a third (40.9%) had a reduced VO2MAX. Two thirds (59.1%) had abnormal stroke volume kinetics (O2/pulse). Nearly half (45.5%) had reduced ventilatory efficiency (VE/VCO2) and two thirds (63.6%) had reduced aerobic efficiency (VO2/WR). A fifth (22.7%) had ventricular arrhythmias at peak exercise. CONCLUSION: This is the first proof-of-concept study to demonstrate that CPET in cardiomyopathy families can identify a considerable proportion of G + P- relatives with early cardiac functional limitations. Long-term surveillance, and larger prospective studies are warranted to validate these findings.
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Abela et al. (2026) conducted an observational in Gene-positive, phenotype-negative relatives of cardiomyopathy probands (n=22). Cardiopulmonary exercise testing (CPET) was evaluated on Cardiac limitation (VO2MAX <80% and/or ≥ 2 abnormal CPET variables). Cardiopulmonary exercise testing identified early cardiac functional limitations in 72.7% of gene-positive, phenotype-negative relatives of cardiomyopathy patients.
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