Indoxyl sulfate (IS) is associated with either chronic kidney disease or renal failure, which may predict cardiovascular events via cardiorenal syndrome. The present study aimed to elucidate whether the plasma levels of IS can predict the occurrence of cardiovascular events in patients with chronic heart failure (CHF) and investigate which causes of CHF leading to cardiovascular events are highly influenced by plasma IS levels. We measured the plasma IS levels in 165 patients with CHF [valvular disease: 78, dilated cardiomyopathy: 29, hypertrophic cardiomyopathy (HCM): 25 and others: 33] admitted to our hospital in 2012, and we followed up these patients for more than 5 years (the median follow-up period: 5.3 years). We measured the plasma IS level in 165 patients with CHF, and Kaplan–Meier analyses showed that high plasma IS levels (≥ 0.79 µg/mL, the median value) could predict the occurrence of cardiovascular events, i.e., cardiovascular death or rehospitalization due to the worsening of CHF. The sub-analyses showed that the high IS level could predict cardiovascular events in patients with CHF due to HCM and that the plasma IS levels were closely associated with left ventricular (LV) dimension, LV systolic dysfunction, and plasma B-type natriuretic peptide levels, rather than LV diastolic dysfunction. Plasma IS level predicts cardiovascular events in patients with CHF, especially those with HCM along with cardiac dysfunction. Besides, IS may become a proper biomarker to predict cardiovascular events in patients with CHF.

Background: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3 , regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure. Methods: We generated the knock-in mice ( Mylk3 +/fs and Mylk 3 fs/fs ) with a familial dilated cardiomyopathy–associated MYLK3 frameshift mutation ( MYLK3 +/fs ) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell–derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154). Results: Both mice ( Mylk3 +/fs and Mylk 3 fs/fs ) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose–dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9_ MYLK3 vector. MYLK3 +/fs induced pluripotent stem cell–derived cardiomyocytes reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9_ MYLK3 vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the V max for ventricular myosin regulatory light chain phosphorylation without affecting the K m . LEUO-1154 treatment of human MYLK3 +/fs induced pluripotent stem cell–derived cardiomyocytes restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower MYLK3 / PPP1R12B messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes. Conclusions: cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure.

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Aims Natriuretic peptides have reportedly been associated with cardiac hypertrophy and insulin resistance; however, it has not been established if B‐type natriuretic peptide (BNP) is associated with either insulin resistance or cardiac remodelling in a population with normal plasma BNP levels. We investigated the relationship among plasma BNP levels, insulin resistance, and left ventricular (LV) remodelling in a population with normal physiological plasma BNP levels. Methods and results Among 1632 individuals who participated in annual health checks between 2005 and 2008 in Arita‐cho, Saga, Japan, 675 individuals [median (interquartile range) for age 62 (51–69) years; 227 men (34%)] with LV ejection fraction 50% and BNP level <35 pg/mL were enrolled in this study. Insulin resistance was assessed using homeostatic model assessment of insulin resistance (HOMA‐IR). LV geometry, including LV concentric remodelling, was classified based on relative wall thickness (RWT) and LV mass index values derived from echocardiographic findings. Factors associated with insulin resistance and LV geometry were investigated using multiple logistic regression analysis. Tertiles of BNP were inversely associated with HOMA‐IR [1st tertile, 1.33 (0.76–1.74); 2nd tertile, 1.05 (0.72–1.59); 3rd tertile, 0.95 (0.66–1.58), P = 0.005]. Lower BNP was associated with the prevalence of insulin resistance, defined as HOMA‐IR ≥1.37, even after full multivariate adjustment [1 SD increment in BNP = adjusted odds ratio (aOR) 0.740; 95% confidence interval (CI) 0.601–0.912; P = 0.005]. LV concentric remodelling (RWT >0.42; LV mass index ≤115 g/m2 in men and ≤95 g/m2 in women) was observed in 107 (16%) participants, while normal LV geometry (RWT ≤0.42; LV mass index ≤115 g/m2 in men and ≤95 g/m2 in women) was seen in 423 (63%), and LV hypertrophy (LV mass index >115 g/m2 in men and >95 g/m2 in women) in 145 (21%). Both low BNP level and higher insulin resistance were independently linked to LV concentric remodelling after multivariate adjustment (1 SD increment in BNP = aOR 0.714, 95% CI 0.544–0.938, P = 0.015; HOMA‐IR ≥ 1.37 vs. <1.37: aOR 1.694, 95% CI 1.004–2.857, P = 0.048, respectively). Conclusions Lower BNP levels are linked to either insulin resistance or LV concentric remodelling in a population with normal plasma BNP levels, suggesting that participants with lower natriuretic peptide level might be vulnerable to the development of metabolic disorders and LV morphological abnormalities.

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