Baseline global longitudinal strain and mechanical dispersion predict ejection fraction decline during mavacamten therapy in obstructive hypertrophic cardiomyopathy

Background

Hypertrophic obstructive cardiomyopathy (HOCM) features a hypercontractile phenotype with supranormal left ventricular ejection fraction (LVEF), yet with mechanical heterogeneity resulting in varying degrees of longitudinal LV systolic dysfunction.

Mavacamten, a cardiac myosin inhibitor, reduces LV contractility and promotes remodelling, with LVEF reduction usually modest but occasionally progressing to overt LV systolic dysfunction in a subset of patients (pts).

Purpose

To identify imaging parameters associated with LVEF reduction during Mavacamten therapy.

Methods

We prospectively evaluated 38 consecutive pts with HOCM treated with Mavacamten at a single tertiary referral centre. Comprehensive TTE was performed at baseline and after 3 months of Mavacamten, assessing LVOT gradient, LVWT, LVEF, GLS, mechanical dispersion (MD), RV longitudinal functional parameters, LA strain and emptying fractions. All pts also underwent baseline CMR for morphological and tissue characterization. Mavacamten was initiated at 5 mg and titrated according to LVOT gradient response (range 2.5-10 mg).

Results

Mean age was 61 ± 12 years, with equal sex distribution; 76% were in NYHA class II and 24% in class III at baseline, with a median NT-proBNP of 1143 pg/mL.

At 3 months, Mavacamten treatment led to a marked reduction in LVOT gradient (median 95 mmHg to 21 mmHg, p<0.001) and significant changes in LVWT, LVEF, MD, LA volumes, TR velocity, and RV longitudinal functional parameters (all p≤0.005).

Eight pts (21%) had LVEF <60% at 3 months and, compared with those with LVEF ≥60%, exhibited worse baseline GLS (−10.6 vs −17.4%, p<0.001), higher MD (104 vs 89 ms, p=0.028), higher CMR-derived LV mass index (109 vs 92 g/m², p=0.018), and a higher prevalence of LGE ≥5% (37% vs 30%, p=0.013). In univariate regression analysis, only GLS, MD, and LV mass index were significantly associated with LVEF decline (all p<0.03). LVEF reduction did not differ according to Mavacamten dose or CYP2C19 metabolizer genotype.

ROC analysis demonstrated that baseline GLS showed the highest discriminative performance for predicting LVEF<60% at 3 months (AUC 0.919; cut-off −14.5%), followed by LV mass index (AUC 0.803; cut-off 102.5 g/m²) and MD (AUC 0.754; cut-off 96 ms).

A clinical model based on impaired GLS alone (GLS>−14.5%) demonstrated good discriminative performance for LVEF decline (AUC 0.854, sensitivity 87%, specificity 83%, PPV 58%). The addition of MD>96 ms to GLS enhanced model performance, increasing the AUC to 0.921, while maintaining high sensitivity (87%) and markedly improving specificity to 96% and PPV to 87%.

Conclusions

In our cohort, impaired GLS, increased MD, and higher LV mass index were associated with a pronounced decline in LVEF. Baseline LV longitudinal systolic dysfunction and increased LV mechanical heterogeneity may therefore help identify pts with HOCM at higher risk of developing LV systolic dysfunction during treatment with Mavacamten.Baseline and 3-month parametersUnivariate analysis