Unmasking subclinical cardiomyopathy: The role of cardiopulmonary exercise testing when screening genotype-positive phenotype negative relatives

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.