Patients with ACVR1 R206H mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of Fibrodysplasia Ossificans Progressiva | Orphanet Journal of Rare Diseases | Full Text

Patients with ACVR1 R206H mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of Fibrodysplasia Ossificans Progressiva | Orphanet Journal of Rare Diseases | Full Text

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 

Orphanet Journal of Rare Diseases volume 15, Article number: 193 (2020) Cite this article

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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.