The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy

Abstract

Background: Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, an abnormal exercise stress test is predictive of heart failure outcomes. Our goal was to determine if an abnormal exercise response is associated with adverse outcomes in pediatric HCM patients. Methods: In an international cohort study with 20 centers, phenotype-positive children with primary HCM <18 years at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response, and new or worsened ST-T wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of an abnormal exercise test with transplant and SCD event-free survival. Results: Of 724 eligible patients, 630 underwent at least one exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8yrs (IQR 4.7yrs); 78% were male, 39% were receiving beta-blockers. 175 (28%) had an abnormal test. Patients with an abnormal test had more severe septal hypertrophy, higher left atrial diameter z-scores, higher resting LV outflow tract gradient, and higher frequency of myectomy compared to those with a normal test (p<0.05). Compared to those with a normal test, an abnormal test was independently associated with a lower 5-year transplant-free survival (97% vs. 88% respectively, p=0.005). Those with exercise-induced ischemia were most likely to experience all-cause death or transplant [Hazard ratio (HR) 4.86, CI 1.69-13.99], followed by those with an abnormal blood pressure response (HR 3.19, CI 1.32-7.71). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (HR 3.32, CI 1.27-8.70). Exercise-induced ectopy was not associated with survival. Conclusions: Exercise abnormalities are common in childhood HCM. An abnormal exercise test was independently associated with lower transplant-free survival especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.

Mechanisms and prognostic impact of myocardial ischaemia in hypertrophic cardiomyopathy

“…Another consideration is that despite the strong age-dependence of SCD risk in HCM, most analyses relating ischaemia and arrhythmic risk were performed in midlife cohorts (Table 4 ), which may be more likely to have a fibrotic substrate due to the presence of more advanced structural LV remodelling. Future analyses of imaging for ischaemia in younger HCM cohorts may have distinct implications, given that exercise-induced ECG changes are emerging as predictive of outcomes [ 176 ].…”

Letter by Monda and Limongelli Regarding Article, “The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy”

“…We read the article by Conway et al 1 with interest. The authors provided new data concerning a possible association between abnormal exercise response and adverse outcomes in pediatric patients with hypertrophic cardiomyopathy using data from PRIMaCY (Precision Medicine for Cardiomyopathy), a large international multicenter cohort.…”

Gene correction and overexpression of TNNI3 improve impaired relaxation in engineered heart tissue model of pediatric restrictive cardiomyopathy

“…Its incidence rate is low, accounting for only 4.5% of pediatric cardiomyopathies (Lee et al, 2017), but it has a poor prognosis. The 5‐year transplant‐free survival rate in patients with RCM is 34%–38% (Anderson et al, 2018; Russo & Webber, 2005; Webber et al, 2012), which is lower than that in patients with other major pediatric cardiomyopathies; for example, it is 70% for dilated cardiomyopathy (DCM) (den Boer et al, 2015; Towbin et al, 2006) and 95% for hypertrophic cardiomyopathy (HCM) (Conway et al, 2023; Nguyen et al, 2023). Currently, the only curative treatment for RCM is heart transplantation, and considering the shortage of pediatric heart donors in Japan, alternative therapies are needed.…”