Favorable effect of aficamten on left atrial mechanics in obstructive hypertrophic cardiomyopathy: insights from the SEQUOIA-HCM trial
Y Hamatani, A Manafi, B Claggett, I Kulac, C Coats, M Maron, A Masri, I Olivotto, D Jacoby, S Heitner, S Kupfer, F Malik, N Prasad, S Solomon, S HegdeAbstract
Background
Aficamten, a next-in-class cardiac myosin inhibitor, relieves left ventricular outflow tract (LVOT) obstruction and improves peak oxygen uptake (pVO2) in patients with obstructive hypertrophic cardiomyopathy (HCM). Left atrial (LA) function contributes to left ventricular performance in HCM. The effects of aficamten on LA mechanics have not been characterized.
Objective
We aimed to examine whether aficamten improves LA function in obstructive HCM.
Methods
In the randomized, double-blind, placebo-controlled trial of aficamten in obstructive HCM (SEQUOIA-HCM), we assessed LA mechanics by LA reservoir, conduit, and contractile strains at baseline and week 24 using speckle-tracking echocardiography. Of 282 randomized participants, 10 with atrial fibrillation at index echocardiography or poor image quality were excluded. We assessed the treatment effect of aficamten on LA mechanics from baseline to week 24 and examined the associations between changes in pVO2 and changes in LA size and function using multivariable linear regression models.
Results
Among 272 patients (aficamten/placebo: 138/134, mean age: 59±13 years, women: 41%, mean LVOT gradient at rest: 55±30 mmHg, mean LVEF: 75±6%, and mean LA volume index: 41±14 ml/m2), mean absolute baseline LA strain values were 22.5±9.2% for reservoir, 12.0±6.3% for conduit, and 10.5±5.7% for contractile function, all lower than reported absolute reference values (≥39%, ≥23%, and ≥17%, respectively). Over 24 weeks, aficamten significantly improved LA reservoir (+2.8%, 95%CI: +0.8% to +4.9%) and conduit (+2.1%, 95%CI: +0.6% to 3.5%) strain compared with placebo, while contractile strain was unchanged (+0.8%, 95%CI: -0.5% to +2.4%), independent of LA volume index (Figure 1). These favorable effects were consistent across key clinical subgroups, including sex, age, and LVOT gradient. Improvement in LA reservoir and conduit strain, but not LA volume index or LA contractile strain, was associated with improvement in pVO2 independent of randomized treatment (Figure 2).
Conclusions
Aficamten, compared with placebo, significantly improved LA mechanics beyond the effects on LA size, and parameters that reflect dynamic filling (LA reservoir) and passive emptying of the LA (LA conduit) correlated with improvement in functional capacity in obstructive HCM.Treatment Effect on LA strainFor image description, please refer to the figure legend and surrounding text.Relationship of LA parameter with pVO2For image description, please refer to the figure legend and surrounding text.