Is there a role for cardiopulmonary exercise testing in genotype positive phenotype negative individuals?

Introduction Genetic testing in cardiomyopathy is now recommended by most scientific societies. It is useful for phenotypical characterisation, risk stratification and genetic segregation. Current guidelines recommend a comprehensive evaluation on all genotype positive (G+) phenotype negative (P-) that should also include advanced cardiac imaging. The role of exercise testing in those with pre-clinical disease has never been explored. Objective The main objective of this study was to evaluate cardiopulmonary exercise testing (CPET) data in G+ P- individuals. Only those with a cardiomyopathy gene would be included. Methodology G+ P- who were referred for CPET testing were included. CPET was performed on an ergometer using a ramp protocol. Cardiac limitation was defined as having ≥2 abnormal CPET variables: low VO2 MAX, low O2/Pulse, high VE/VCO2, low VO2/WR, low PETCO2 at peak exercise, low HR recovery, inappropriate blood pressure response, new ECG changes and ventricular arrhythmias. Results 16 subjects fulfilled the inclusion criteria (62.5% female, mean age 44.8±16.9 years). A fourth engaged in >4 hours of physical activity weekly. Most had a family history of cardiomyopathy (DCM 68.8%, AC 12.5%, Fabry 6.3%, HCM 6.3%). A third (31.3%) had a family history of sudden cardiac death. Patients were G+ for ACTC1 (29.4%), TTN (29.4%), MYBPC3 (11.8%), DSG2 (11.8%), GLA/NEXN/MYH7 (each 5.9%). Minority (31.3%) had symptoms. Resting ECG was abnormal in 37.5% of cases. Echocardiography was normal in all patients. Most (68.8%) underwent a cardiac MRI, none had features suggestive of cardiomyopathy. The remaining scans were pending at the time of submission or turned down by participants. All successfully completed a maximal exercise test. Most subjects fulfilled criteria for cardiac limitation during exercise (87.6%), most (68.8%) having 3 or more abnormal CPET variables (Table 1). Aerobic exercise capacity was reduced in half of participants. O2/Pulse was reduced in 37.5%, VE/VCO2 was increased in 31.3%, VO2/WR was reduced in 62.5% and PETCO2 at peak exercise was low in 56.3%. A fourth experienced new repolarisation changes. A third (31.3%) experienced ventricular arrhythmias during exercise. Conclusion Evidence of a cardiac limitation during CPET in G+ P- subjects is a frequent finding, potentially contributing to more elaborate phenotyping. Its predictive role in P- (at baseline) individuals should be explored in larger cohorts.