Clinical bottom line
Novel oral selective cardiac myosin inhibitors represent a promising therapeutic approach for patients with dilated cardiomyopathy (DCM) by targeting the molecular motor function of beta-cardiac myosin. Early mechanistic and biophysical studies suggest these agents may stabilize myosin in a super-relaxed state, potentially reducing pathological hypercontractility and adverse cardiac remodeling. However, clinical outcome data in DCM remain limited, and the therapeutic role of these inhibitors is currently hypothesis-generating and warrants further validation in well-powered clinical trials.
What the evidence shows
Dilated cardiomyopathy is characterized by impaired systolic function and adverse cardiac remodeling, often linked to mutations in sarcomeric proteins including beta-cardiac myosin. Molecular studies have identified specific mutations, such as E525K in human beta-cardiac myosin, that stabilize the interacting-heads motif and promote a super-relaxed state of myosin, which is associated with reduced ATPase activity and contractile function (Sellers et al., 2022). These findings provide a mechanistic rationale for modulating myosin activity pharmacologically.
Small molecule cardiac myosin inhibitors have been developed to selectively reduce myosin ATPase activity and contractility. While most clinical experience to date has been in hypertrophic cardiomyopathy (HCM), where hypercontractility is a hallmark, the potential application in DCM is emerging. Tang et al. (2018) demonstrated that small molecule regulators could modulate human beta-cardiac myosin function, suggesting a therapeutic avenue for DCM by normalizing aberrant myosin activity.
Although direct clinical trial data in DCM patients are sparse, insights from related conditions provide context. Bittencourt et al. (2026) reviewed cardiac myosin inhibitors in HCM, highlighting their ability to improve cardiac structure and reduce fibrosis, which may translate to benefits in DCM given shared pathophysiological mechanisms of maladaptive remodeling. Lu et al. (2026) further confirmed that cardiac myosin inhibitors reduce myocardial fibrosis and improve cardiac magnetic resonance parameters in obstructive HCM, supporting the concept that these agents can favorably modify cardiac remodeling.
Caveats and uncertainty
The majority of evidence supporting cardiac myosin inhibitors in DCM is preclinical or extrapolated from HCM studies. The pathophysiology of DCM involves systolic dysfunction and often reduced contractility, whereas HCM is characterized by hypercontractility; thus, the net effect of myosin inhibition in DCM requires careful evaluation. The E525K mutation studied by Sellers et al. (2022) represents a specific genetic subset, and the generalizability of findings to broader DCM populations is uncertain.
No large-scale randomized controlled trials have yet established the safety, efficacy, or optimal dosing of oral selective cardiac myosin inhibitors in DCM. Potential risks include excessive negative inotropy and worsening heart failure symptoms. Additionally, long-term effects on myocardial fibrosis, arrhythmia risk, and clinical outcomes remain unknown. Anesthetic management considerations in DCM patients receiving such agents also require further study (Wani et al., 2016).
How this may change practice
If ongoing and future clinical trials confirm safety and efficacy, oral selective cardiac myosin inhibitors could become a novel class of targeted therapy for DCM, complementing existing guideline-directed medical therapies. They may offer a precision medicine approach for patients with specific sarcomeric mutations or phenotypes characterized by aberrant myosin function.
Clinicians should remain aware of emerging data but exercise caution until robust clinical evidence is available. Genetic testing and molecular phenotyping may be increasingly important to identify candidates who might benefit from myosin modulation. Multidisciplinary collaboration involving cardiologists, geneticists, and pharmacologists will be essential to integrate these agents safely into practice.