Understanding Ejection Fraction Data from CMI Studies for oHCM

A recurring theme in cardiac myosin inhibitor (CMI) safety data is the overlap between atrial fibrillation (AFib) and transient drops in ejection fraction (EF), 2 findings that are difficult to fully disentangle from one another. In this segment, Mariko Harper, MD, MS, FACC, director of the Hypertrophic Cardiomyopathy Center of Excellence at Virginia Mason Franciscan Health, and James MacNamara, MD, a non-invasive cardiologist and hypertrophic cardiomyopathy (HCM) specialist at UVA Health, work through what the association means for CMI management. Harper opens by flagging 2 nuances in interpreting the EF and AFib data discussed so far: across these studies, AFib is temporally associated with EF drops but is not always newly diagnosed AFib, and most studies do not clearly separate prior AFib history from new or recurrent episodes. She notes that AFib itself, independent of any drug effect, can reduce cardiac output and precipitate a low-EF state, particularly with rapid ventricular rates, which by mechanism overlaps with the negative inotropic effect CMIs are designed to produce, making causality difficult to disentangle. MacNamara agrees that proving causation remains elusive, but says that both published data and his own review of echocardiograms suggest a clear association between atrial arrhythmias and left ventricular ejection fraction (LVEF) drops in patients on CMI therapy. He cites the multicenter registry Harper was part of, and notes MARBLE identified AFib in about 50% of patients who experienced a transient low-EF event, while a separate study put that figure at 70%. MacNamara says these late EF drops, occurring after the titration phase has settled, prompt him to actively search for AFib, since there is usually an identifiable trigger. Harper and MacNamara agree that when both a reduced EF and AFib are found together, aggressive management of the arrhythmia becomes the priority. MacNamara notes that this scenario adds real complexity to CMI management: clinicians must simultaneously manage the arrhythmia and adjust CMI dosing, which can range from a temporary hold to down-titration. He shares that in his experience, once patients are restored to sinus rhythm through ablation, cardioversion, or a combination, they can typically resume the CMI without losing meaningful control over obstruction or symptoms, though he notes that formal outcomes data on this restart approach remain limited. Harper adds that even when patients present asymptomatic in AFib with a preserved EF, she treats the arrhythmia seriously and proactively, given the complexity that a delayed diagnosis introduces into CMI titration. Both agree that pre-CMI-era data already showed patients with HCM have elevated recurrence rates after catheter ablation or cardioversion compared with the general population, adding another layer of difficulty to long-term rhythm management in this group.