Patients with ACVR1R206H mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of Fibrodysplasia Ossificans Progressiva

Samuel Kou, Carmen De Cunto, Geneviève Baujat, Kelly L Wentworth, Donna R Grogan, Matthew A Brown, Maja Di Rocco, Richard Keen, Mona Al Mukaddam, Kim-Hanh le Quan Sang, Umesh Masharani, Frederick S Kaplan, Robert J Pignolo, Edward C Hsiao, Samuel Kou, Carmen De Cunto, Geneviève Baujat, Kelly L Wentworth, Donna R Grogan, Matthew A Brown, Maja Di Rocco, Richard Keen, Mona Al Mukaddam, Kim-Hanh le Quan Sang, Umesh Masharani, Frederick S Kaplan, Robert J Pignolo, Edward C Hsiao

Abstract

Background: Genetic contributors to cardiac arrhythmias are often found in cardiovascular conduction pathways and ion channel proteins. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disease of massive heterotopic ossification caused by a highly recurrent R206H mutation in ACVR1/ALK2. This mutation causes abnormal activation of the bone morphogenetic protein (BMP) pathway in response to Activin A. Prior studies suggested increased risks of cardiopulmonary complications in FOP. We examined participants in a Natural History Study (NHS) of FOP (ClinicalTrials.gov #NCT02322255) to better understand their cardiovascular status.

Methods: The NHS is an ongoing 3 year international multi-center longitudinal study of 114 patients (ages 4-56 years) with genetically confirmed ACVR1/ALK2R206H FOP. Patients were clinically assessed at baseline and 12 months. Electrocardiograms (ECGs) were reviewed in a central ECG laboratory. Conduction abnormalities were compared against clinical data collected in the NHS, and echocardiograms collected from NHS and non-NHS patients.

Results: Conduction abnormalities were present in 45.3% of baseline ECGs, with the majority of abnormalities classified as nonspecific intraventricular conduction delay (37.7%). More specifically, 22.2% of patients > 18 years old had conduction abnormalities, which was significantly higher than a prior published study of a healthy population (5.9%; n = 3978) (p < 0.00001). Patients with FOP < 18 years old also had a high prevalence of conduction abnormalities (62.3%). The 12-month follow up data was similar to baseline results. Conduction abnormalities did not correlate with chest wall deformities, scoliosis, pulmonary function test results, or increased Cumulative Analog Joint Involvement Scale scores. Echocardiograms from 22 patients with FOP revealed 8 with structural cardiac abnormalities, only 1 of which correlated with a conduction abnormality.

Conclusions: We found that patients with FOP may have subclinical conduction abnormalities manifesting on ECG, independent of heterotopic ossification. Although clinically significant heart disease is not typically associated with FOP, and the clinical implications for cardiovascular risk remain unclear, knowledge about ECG and echocardiogram changes is important for clinical care and research trials in patients with FOP. Further studies on how ACVR1/ALK2R206H affects cardiac health will help elucidate the underlying mechanism.

Keywords: Cardiovascular disease; ECG; Electrocardiogram; FOP; Fibrodysplasia Ossificans Progressiva; Heterotopic ossification; Natural history study in FOP.

Conflict of interest statement

DRG was a Clementia employee at the time the study was conducted and data were obtained. CDC, GB, MAB, MDR, RK, MAM, FSK, RJP, UM, KLW, and ECH received funding from Clementia to support the Natural History Study and separate interventional studies sponsored by Clementia, an Ipsen company. ECH, MDR, MAM, FSK and RJP, RK, MAB received clinical trials research funding from Regeneron Pharmaceuticals.

ECH, DRG, GB, CDC, RK, MAB, MAM, FSK and RJP serve in a volunteer capacity on the Medical Registry Advisory Board of the International Fibrodysplasia Ossificans Progressiva Association. ECH serves in a volunteer capacity on the Fibrous Dysplasia Foundation Medical Advisory Board. ECH, CDC, GB, MAB, MDR, RK, MAM, FSK, and RJP are elected members of the International Clinical Council on FOP. These pose no conflicts for this study.

Figures

Fig. 1
Fig. 1
Study Design. Demographics (sex and age distribution) and enrollment exclusion criteria from subjects participating in the Natural History Study of Fibrodysplasia
Fig. 2
Fig. 2
Baseline QRS Interval Duration, Age, and CAJIS scores. Left: QRS duration of subjects with respect to age. Solid lines represent the criteria used to determine IVCD; Right: Correlation analysis of CAJIS scores with respect to age (r = 0.65, p < 0.00001)

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