Key result
Mavacamten surrogate MYK-581 eliminates LVOT obstruction and reduces end-diastolic stiffness ~25% in feline HCM.
Why the study?
Direct myosin-inhibition with mavacamten may improve ventricular filling beyond dynamic LVOT obstruction reprieve, but its acute in vivo hemodynamic effects required investigation in an oHCM model.
Does MYK-581 improve cardiac hemodynamics and ventricular filling in a feline model of obstructed hypertrophic cardiomyopathy?
Does MYK-581 improve cardiac hemodynamics and ventricular filling in a feline model of obstructed hypertrophic cardiomyopathy?
Absolute Event Rate: 0% vs 38%
p-value: p=<0.05
In a feline model of obstructed hypertrophic cardiomyopathy, acute treatment with the mavacamten surrogate MYK-581 alleviated LVOT obstruction and improved ventricular filling and end-diastolic pressures.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We know that the HCM heart is plagued by two central problems: excessive contractility and impaired diastolic relaxation. We've shown in clinical studies that by modulating myosin, mavacamten can reduce hypercontractility, as demonstrated by the reduction or elimination of the left ventricle outflow tract obstruction. A growing body of evidence from our preclinical studies and PIONEER-HCM Phase 2 in patients with obstructive HCM indicates that mavacamten may also have a beneficial effect on diastolic function by increasing the ability for the left ventricle to relax and fill.”
“This is an exciting discovery for both animals and humans – an excellent representation of the One Health concept in action. The positive result in these five cats shows that MYK-461 is viable for use in cats as a possible option to halt or slow the progression of HCM.”
Acute MYK-581 may relieve LVOT obstruction in HCM; leaves open durability, safety, and clinical translation.
Introduction Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with oHCM, providing sustained symptomatic relief. However, mavacamten can also improve ventricular filling by limiting residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction reprieve. This study leveraged a feline model of oHCM, cats with the A31P MYBPC3 variant, to study the acute in vivo effects of MYK-581, a mavacamten surrogate, on cardiac hemodynamics and filling. Methods A31P-homozygous cats with HCM (A31P, n=10) and wild-type healthy controls (CTRL, n=9) were anesthetized and instrumented for invasive pressure-volume (PV) measurements as well as trans-thoracic echocardiographic recording. A subset of cats were assigned to receive either vehicle (VEH, n=7) or MYK-581 (MYK, n=8) with a short IV infusion. Cardiac hemodynamics, function, and geometry were assessed at steady state before and during dobutamine challenges (2.5 μg/kg/min IV). Results A31P cats had thicker ventricular walls (6.4±0.1 vs. 5.2±0.2 mm, P<0.05) and hyperdynamic contraction (FS: 61±4 vs. 50±3%, P<0.05) relative to controls and presented with dynamic LVOT obstruction in 54% of cases. HCM cats had elevated end-diastolic pressures (17±1.4 vs. 9±1.0 mmHg, P<0.05), with prolonged time constants of relaxation (60±4.1 vs. 36±2.4 ms, P<0.05) and elevated end-diastolic stiffness (Eed: 0.44±0.06 vs. 0.25±0.01 mmHg/mL). Acute treatment with MYK-581 alleviated LVOT obstruction (0% vs. 38%), normalized contractility (FS: −7±2%), and increased systolic/diastolic chamber dimensions (e.g., LVIDd: +13±4%) (all P<0.05), while reducing EDP (15±2 to 13±2 mmHg, P<0.05), suggesting acute improvement in ventricular distensibility. Indeed, MYK-581 treatment reduced end-diastolic stiffness (Eed: 0.48±0.11 vs. 0.36±0. 10 mmHg/mL, P<0.05) and normalized trans-mitral motion patterns during filling. Conclusions Bred cats, homozygous for the A31P MYBPC3 variant, presented a cardiac phenotype that models multiple characteristics of the human oHCM phenotype including dynamic LVOT obstruction. Acute treatment with the mavacamten surrogate, MYK-581, not only alleviated hypercontractility and LVOT obstruction, but improved ventricular filling and end-diastolic pressures. Taken together, these pre-clinical observations show potential salutary effects beyond obstruction relief in patients with HCM. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): MyoKardia
No takes yet. Share an insight, caveat, or question.
Ferguson et al. (2020) studied obstructed hypertrophic cardiomyopathy (n=19). MYK-581 vs. vehicle was evaluated on LVOT obstruction (p=<0.05). Acute treatment with the mavacamten surrogate MYK-581 alleviated LVOT obstruction (0% vs. 38%) and reduced end-diastolic stiffness (0.48 to 0.36 mmHg/mL, P<0.05) in a feline model of HCM.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: