Evaluation and management of treatment failure and non-response to cardiac myosin inhibitors in obstructive hypertrophic cardiomyopathy

The recent emergence of cardiac myosin inhibitors (CMIs) has established an era of targeted medical therapy for obstructive hypertrophic cardiomyopathy (oHCM), with trials showing decreases in obstructive gradients and improvements in symptoms and exercise capacity. However, not all patients achieve satisfactory responses with CMIs, which can include a "non-response" to medication due to persistent obstruction or continued symptoms despite gradient resolution, or medication failure in cases of discontinuation due to side effects or cost. We present a differential framework for evaluation of CMI non-response or failure, including evaluation for contributors to reduced systolic function, non-oHCM sources of obstruction, or other cardiac and non-cardiac causes of dyspnea. Patients without satisfactory improvement with CMI therapy should undergo a thorough workup according to this framework to identify other potentially addressable concerns that may allow for success with CMIs or indicate other appropriate therapies to address symptoms.