OBJECTIVES: Using diffusion tensor cardiac magnetic resonance (DT-CMR) we assessed myocardial disarray and fibrosis in both SARC+LVH- and HCM patients and evaluated the relationship between microstructural alterations and electrocardiographic (ECG) parameters associated with arrhythmic risk.
METHODS: Sixty-two individuals (24 SARC+LVH-, 24 HCM and 14 matched controls) were evaluated with multiparametric CMR including stimulated echo acquisition mode (STEAM) DT-CMR, and blinded quantitative 12-lead ECG analysis.
RESULTS: Mean diastolic fractional anisotropy (FA) was reduced in HCM compared to SARC+LVH- and controls (0.49±0.05 vs 0.52±0.04 vs 0.53±0.04, p=0.009), even after adjustment for differences in extracellular volume (ECV) (p=0.038). Both HCM and SARC+LVH- had segments with significantly reduced FA relative to controls (54% vs 25% vs 0%, p=0.002). Multiple repolarization parameters were prolonged in HCM and SARC+LVH-, with corrected JT interval (JTc) being most significant (354±42ms vs 356±26ms vs 314±26ms, p=0.002). Among SARC+LVH-, JTc duration correlated negatively with mean FA (r=-0.6, p=0.002). In HCM, the JTc interval showed a stronger association with ECV (r=0.6 p=0.019) than FA (r=-0.1 p=0.72). JTc discriminated SARC+LVH- from controls (Area-under-the-receiver-operator-curve 0.88, CI 0.76-1.00, p<0.001), and in HCM correlated with the ESC HCM sudden cardiac death risk score (r=0.5, p=0.014).
CONCLUSION: Low diastolic FA, suggestive of myocardial disarray, is present in both SARC+LVH- and HCM. Low FA and raised ECV were associated with repolarization prolongation. Myocardial disarray assessment using DT-CMR and repolarization parameters such as the JTc interval demonstrate significant potential as markers of disease activity in HCM.
METHODS: Twenty seven HFpEF (clinical features of HF, left ventricular EF >50%, evidence of mild diastolic dysfunction and evidence of exercise limitation as assessed by cardiopulmonary exercise test) and 14 controls underwent 1H-cardiovascular magnetic resonance spectroscopy (1H-CMRS) to measure MTG (lipid/water, %), 31P-CMRS to measure myocardial energetics (phosphocreatine-to-adenosine triphosphate - PCr/ATP) and feature-tracking cardiovascular magnetic resonance (CMR) imaging for diastolic strain rate.
RESULTS: When compared to controls, HFpEF had 2.3 fold higher in MTG (1.45 ± 0.25% vs. 0.64 ± 0.16%, p = 0.009) and reduced PCr/ATP (1.60 ± 0.09 vs. 2.00 ± 0.10, p = 0.005). HFpEF had significantly reduced diastolic strain rate and maximal oxygen consumption (VO2 max), which both correlated significantly with elevated MTG and reduced PCr/ATP. On multivariate analyses, MTG was independently associated with diastolic strain rate while diastolic strain rate was independently associated with VO2 max.
CONCLUSIONS: Myocardial steatosis is pronounced in mild HFpEF, and is independently associated with impaired diastolic strain rate which is itself related to exercise capacity. Steatosis may adversely affect exercise capacity by indirect effect occurring via impairment in diastolic function. As such, myocardial triglyceride may become a potential therapeutic target to treat the increasing number of patients with HFpEF.
OBJECTIVES: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM.
METHODS: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints.
RESULTS: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better VE/Vco2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of -2.1 (95% CI: -3.6 to -0.6; P = 0.006), with no significant difference in peak VO2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: -2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04).
CONCLUSIONS: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study.