Mariko Harper, MD

Closing out this discussion of atrial fibrillation (AFib) and cardiac myosin inhibitor (CMI) safety in obstructive hypertrophic cardiomyopathy (oHCM), 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, translate the data into practical counseling and monitoring guidance for community cardiologists.

Practical Takeaways in oHCM from Contemporary Data

Harper asks MacNamara what he would tell a community cardiologist counseling a patient about AFib risk before starting a CMI. MacNamara emphasizes leading with the therapy's overall benefit, improved fitness, quality of life, obstruction relief, and favorable cardiac remodeling, so the AFib conversation does not overshadow the broader picture. He notes that while a meaningful proportion of patients with baseline AFib will experience recurrence, new AFib incidence remains low in general use, and there is no data suggesting worse hard outcomes like stroke, so AFib risk alone is not a reason to withhold these therapies.

MacNamara frames counseling around treatment phase: the titration phase is more dynamic, with possible transient ejection fraction (EF) drops and a longer runway before symptoms fully resolve, while the maintenance phase is comparatively stable. If a patient develops new symptoms or an unexplained EF drop during maintenance, he says AFib should be near the top of the differential.

Harper adds that clinicians should use every clinic visit as an opportunity to screen for AFib, particularly when an unexplained EF change appears, and notes that a full echocardiogram, capturing atrial function, is more informative than a limited study. She and MacNamara then walk through practical management: MacNamara typically holds the CMI when EF is low, given the long half-life of both approved agents that allows time before restarting, and proceeds to cardioversion when feasible. He starts every patient with new AFib on anticoagulation regardless of symptom status, explicitly avoiding the CHA2DS2-VASc score, which he says underestimates stroke risk in HCM. Management occurs entirely in the outpatient setting; MacNamara notes that in his career, the only CMI patients who have required emergency department visits, a small number overall, presented specifically with an atrial arrhythmia.

Asked to name the single point that should most change how a community cardiologist approaches this conversation, MacNamara stresses that CMIs remain good options within the broader oHCM treatment landscape, that clinicians should be vigilant and honest with patients about the unknowns, and that he does not currently differentiate AFib risk counseling between mavacamten and aficamten as a class, since neither agent's causal role has been established. Harper closes with 4 take-home points: CMIs remain highly effective for symptomatic oHCM; AFib is common in this population, with baseline prevalence likely higher than previously understood; routine periodic AFib screening should continue regardless of CMI status, with additional monitoring touchpoints created by CMI surveillance; and when a transient EF drop occurs, AFib should be assumed to be a possible driver and managed aggressively even without overt symptoms.

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Specialists outline practical counseling, monitoring, and anticoagulation strategies for community cardiologists managing oHCM.

With cardiac myosin inhibitors (CMIs) now established as first-line therapy for obstructive hypertrophic cardiomyopathy (oHCM), clinicians are reassessing how atrial fibrillation (AFib) fits into an evolving treatment landscape, including an unresolved paradox in the cardiac remodeling data. 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 both issues.

AF Management in oHCM in Era of Cardiac Myosin Inhibitors

Harper asks MacNamara how AFib management has evolved now that CMIs are an established treatment class, specifically whether he still reaches for beta-blockers, disopyramide, or other antiarrhythmics. MacNamara says his practice remains focused on procedural management, cardioversion followed by catheter ablation, while using antiarrhythmics cautiously given toxicity and cardiomyopathy-related contraindications. He notes dofetilide remains a tool he uses to maintain sinus rhythm, and that his patients with HCM are likely the group he pursues sinus rhythm most aggressively for compared with his general cardiology practice.

Harper notes that disopyramide remains guideline-supported for obstructive symptom control, separate from any AFib indication, but says she rarely reaches for it given how effective CMIs have become, and would not favor it simply because a patient also has AFib. She describes her approach as early electrophysiology referral for procedural options such as pulsed field ablation. MacNamara agrees, adding that reassessment should be ongoing rather than a one-time decision, noting that CMI therapy offers more flexibility than permanent interventions like myectomy or alcohol septal ablation. He points out that AFib is not unique to CMI therapy either, with septal reduction procedures reporting 20% to 40% AFib incidence in less rigorous but longer-standing datasets, reinforcing that AFib simply complicates CMI management rather than uniquely causing it.

The discussion then turns to a paradox in the remodeling data. Harper notes that multiple studies, including long-term mavacamten extension data, show persistent favorable remodeling with CMI therapy: a smaller left atrium, improved diastolic function, near-complete resolution of systolic anterior motion, and reduced mitral regurgitation, changes traditionally associated with lower long-term AFib risk. MacNamara agrees this creates a paradox, since nearly every structural marker improves except AFib itself, which remained no worse than placebo in the pivotal trials but did not improve either. He notes biologic plausibility for a direct atrial effect, since atrial tissue also contains sarcomeres, but stresses this mechanistic link has not been established. MacNamara adds that left atrial size and left ventricular remodeling data have been consistent across both approved agents, though he flags that his own center has observed a reduction in left atrial strain in preliminary, unpublished data that runs counter to the broader trial literature, suggesting the atrial story may be more complex than currently understood.

Specialists detail antiarrhythmic use, procedural referral timing, and the atrial remodeling paradox seen with cardiac myosin inhibitors.

Even as atrial fibrillation (AFib) incidence data with cardiac myosin inhibitors (CMIs) accumulates, one question remains central to patient counseling: does any of this translate into higher stroke risk? In this segment, James MacNamara, MD, a non-invasive cardiologist and hypertrophic cardiomyopathy (HCM) specialist at UVA Health, and Mariko Harper, MD, MS, FACC, director of the Hypertrophic Cardiomyopathy Center of Excellence at Virginia Mason Franciscan Health, address that question and turn to what early data suggests about aficamten's AFib profile relative to mavacamten.

Understanding Risks Associated with AF in oHCM Management

MacNamara raises a question the conversation had not yet directly addressed: stroke risk. He notes that despite the extensive discussion of detection bias and new vs recurrent AFib, no published data he is aware of shows an increased stroke rate associated with CMI therapy, and he suspects the HCM field is now learning lessons the broader AFib community absorbed decades earlier.

Harper agrees, noting that the AFib event rate in EXPLORER-HCM was about 2%, with a similar figure in SEQUOIA-HCM for aficamten, and that neither trial signaled meaningfully increased adverse events. She points to the mavacamten risk evaluation and mitigation strategy (REMS) database, which, while not designed to specifically track AFib, includes more than 11,000 real-world patients and shows a hospitalization rate for low ejection fraction (EF) of just 0.5%. MacNamara calls that figure remarkably low and says he counsels patients that if their drug does need to be held for a low EF, they will likely be more frustrated by the interruption than by any symptoms, since the REMS data suggest patients rarely feel unwell when this occurs. Both speculate, without being able to confirm from REMS data alone, how many of those rare low-EF hospitalizations may be linked to underlying AFib.

The conversation then turns to aficamten specifically. MacNamara notes that the field is essentially retracing where it stood with mavacamten in 2022 and 2023, when AFib was not yet a prominent concern. He highlights 1 recent analysis that pooled FOREST (the aficamten long-term extension), REDWOOD-HCM (phase 2), and SEQUOIA-HCM (phase 3) data, comparing observed AFib rates against 2 predictive risk scores, HCM-AF and CHARGE-AF. The analysis found new AFib incidence just under 2%, closely matching what CHARGE-AF would have predicted and notably lower than the HCM-AF prediction. MacNamara cautions this design does not eliminate the field's core limitation, the absence of a randomized control group, and stresses there is no head-to-head data comparing AFib risk between mavacamten and aficamten. He notes that when he has applied these risk scores retrospectively to his own CMI patients who developed AFib, they consistently scored high risk, reinforcing the possibility that many of the same factors driving oHCM disease severity also predispose to AFib independent of drug exposure.

Specialists discuss stroke risk, REMS hospitalization data, and how aficamten's early AFib signal compares against mavacamten.

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.

Understanding Ejection Fraction Data from CMI Studies for oHCM

Clinicians examine the association between atrial arrhythmias and transient ejection fraction drops during cardiac myosin inhibitor therapy.

Mariko Harper, MD

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