Childhood-onset RASopathy-associated hypertrophic cardiomyopathy is associated with progressive left atrial dilatation, diastolic impairment and complex atrial arrhythmias

This retrospective international multicenter study analyzes longitudinal data from 217 patients with RASopathy-associated hypertrophic cardiomyopathy (HCM) and describes the evolvement of cardiac disease in these patients.

RASopathies are a large group of diseases caused by genetic changes that lead to disturbed development of several body parts parts (e.g. heart, skin, bone, eye) and learning problems. Around one child in 2,500 is thought to carry the genetic variant, and of these, one in five will develop thickening of the heart muscle, called hypertrophic cardiomyopathy (HCM). The disease course of HCM in these children, such as risk for progression, heart failure, and arrhythmias, has not been described in detail previously.

Overall, 8.9% of patients died during follow-up and the only independent predictor for poor outcome was heart failure at baseline.

In survivors, clinical cardiac outcome was favorable in RASopathy-associated HCM, as functional status (NYHA) improved, there was less medication use over time, and both wall thickness of the heart muscle as well as so-called outflow tract gradients reduced over time. However, there was progressive enlargement of the left atrium of the heart along with increase in so-called diastolic dysfunction (which means that the heart cannot relax properly between beats) over time, and 20% of the subgroup of patients that were observed beyond the age of 18 years displayed irregular atrial arrhythmias.

Evidence from this large dataset suggests that patients with RASopathy-associated HCM develop progressive diastolic dysfunction along with the enlargement of the left atrium of the heart over time, which may result in complex atrial arrhythmias during adulthood. Heart failure was an independent predictor for poor outcome.

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Boleti OD, Roussos S, Monda E, Norrish G, Field E, Cervi E, Bakalakos A, Fernandes P, McLeod K, Ilina M, Khodaghalian B, Jones C, Escudero F, Castro F, Ali MNL, Bharucha T, Nepali G, Bhole V, Delle Donne G, Brown E, Gimeno JR, Elliott PM, Wolf C, Limongelli G, Kaski JP. Childhood-onset RASopathy-associated hypertrophic cardiomyopathy, diastolic dysfunction, and arrhythmias. Eur Heart J. 2025 Dec 19:ehaf1012. doi: 10.1093/eurheartj/ehaf1012. Epub ahead of print. PMID: 41414925

Prepared by Cordula Wolf and Ruth Biller