The Efficacy of Cardiac Myosin Inhibitors Versus Placebo in Patients With Symptomatic Hypertrophic Cardiomyopathy: A Meta-Analysis and Systematic Review.

We aimed to assess the overall clinical impact of cardiac myosin inhibitors in hypertrophic cardiomyopathy (HCM). We performed a meta-analysis of published trials assessing the effect of cardiac myosin inhibitors (mavacamten and aficamten) on resting and Valsalva left ventricular outflow tract (LVOT) gradients and functional capacity in symptomatic HCM. The co-primary outcomes were mean percent change (mean difference [MD]) from baseline in LVOT gradient at rest and Valsalva LVOT gradient and the proportion of patients achieving New York Heart Association class improvement ≥1. The secondary outcomes included the mean percent change from baseline N-terminal pro-B-type natriuretic peptide, troponin I, and left ventricular ejection fraction (LVEF). A total of 4 studies (all randomized controlled trials, including 3 mavacamten-focused and 1 aficamten-focused trials) involving 463 patients were included in the meta-analysis. Compared with placebo, the cardiac myosin inhibitor group demonstrated statistically significant differences in the baseline percent change in mean LVOT gradient at rest (MD -62.48, confidence interval [CI] -65.44 to -59.51, p <0.00001) and Valsalva LVOT gradient (MD -54.21, CI -66.05 to -42.36, p <0.00001) and the proportion of patients achieving New York Heart Association class improvement ≥1 (odds ratio 3.43, CI 1.90 to 6.20, p <0.0001). Regarding the secondary outcomes, the intervention group demonstrated statistically significant reductions in mean percent change from baseline in N-terminal pro-B-type natriuretic peptide (MD -69.41, CI -87.06 to -51.75, p <0.00001), troponin I (MD, -44.19, CI -50.59 to -37.78, p <0.00001), and LVEF (MD -6.31, CI -10.35, -2.27, p = 0.002). In conclusion, cardiac myosin inhibitors may confer clinical and symptomatic benefits in symptomatic HCM at the possible expense of LVEF. Further trials with large sample sizes are needed to confirm our findings.

Clinical Outcomes of Transcatheter Aortic Valve Replacement With and Without Percutaneous Coronary Intervention-An Updated Meta-Analysis and Systematic Review.

Transcatheter aortic valve replacement (TAVR) is indicated for high-risk patients with severe degenerative aortic stenosis (AS). Given the shared risk factors and coexistence of obstructive coronary artery disease (CAD) and AS, there is inconsistent clinical data regarding potential survival benefits of paired percutaneous coronary intervention (PCI) with TAVR procedures. We performed a literature search using PubMed, Embase, and Cochrane Library from inception through June 2023 assessing the impact of concomitant PCI in patients with obstructive CAD undergoing TAVR. The primary outcomes were 30-day all-cause mortality, 30-day cardiovascular mortality, and 6 months-1 year all-cause mortality. Secondary outcomes included 30-day myocardial infarction, stroke, major bleeding complications, and acute kidney injury (AKI). A total of 11 studies involving 2804 patients were included in the final analysis. Compared to patients undergoing TAVR alone, the TAVR+PCI group showed no significant difference in 30-day all-cause mortality (RR 0.90, CI 0.66, 1.22, P = 0.49), 30-day cardiovascular mortality (RR 0.71 CI 0.44, 1.14, P = 0.16), or 6 months-1 year all-cause mortality (RR 0.94, CI 0.75, 1.18, P = 0.57). Regarding secondary outcomes, 30-day myocardial infarction was higher in the TAVR+PCI group (RR 3.09, CI 1.26, 7.57, P = 0.01), with no significant differences noted in rates of 30-day stroke (RR 1.14, CI 0.56, 2.33, P = 0.72), major bleeding/vascular complications (RR 1.11, CI 0.79, 1.56, P = 0.55), and AKI (RR 1.07, CI 0.75, 1.54, P = 0.71). Concomitant PCI does not confer any mortality benefit in patients with obstructive CAD and high-grade AS undergoing TAVR. Further trials are needed to confirm our findings.

Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function.

We have previously shown that the DBA/2J versus AKR/J mouse strain is associated with decreased autophagy-mediated lysosomal hydrolysis of cholesterol esters. Our objective was to determine differences in lysosome function in AKR/J and DBA/2J macrophages, and identify the responsible genes. Using a novel dual-labeled indicator of lysosome function, DBA/2J versus AKR/J bone marrow derived macrophages had significantly decreased lysosome function. We performed quantitative trait loci mapping of lysosome function in bone marrow macrophages from an AKR/J × DBA/2J strain intercross. Four distinct lysosome function loci were identified, which we named macrophage lysosome function modifier (Mlfm) Mlfm1 through Mlfm4. The strongest locus Mlfm1 harbors the Gpnmb gene, which has been shown to recruit autophagy protein light chain 3 to autophagosomes for lysosome fusion. The parental DBA/2J strain has a nonsense variant in Gpnmb. siRNA knockdown of Gpnmb in AKR/J macrophages decreased lysosome function, and Gpnmb deletion through CRISP/Cas9 editing in RAW 264.7 mouse macrophages also demonstrated a similar result. Furthermore, a DBA/2 substrain, called DBA/2J-Gpnmb+/SjJ, contains the wildtype Gpnmb gene, and macrophages from this Gpnmb-preserved DBA/2 substrain exhibited recovered lysosome function. In conclusion, we identified Gpnmb as a causal modifier gene of lysosome function in this strain pair.