Daily Cardiology Research Analysis

BACKGROUND: Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder and a leading cause of sudden cardiac death in young adults, exhibits substantial genetic and clinical heterogeneity. Although sarcomere gene sequence variations account for a major proportion of HCM cases, nearly half of patients lack identifiable genetic defects, implying the involvement of undiscovered mechanisms that may converge on a common pathogenic pathway. However, a unified molecular basis underlying HCM pathogenesis remains undefined. METHODS: We conducted an integrated analysis of hypertrophied interventricular septum tissues from 269 patients with obstructive HCM undergoing surgical myectomy. Targeted sarcomere gene screening, bulk RNA sequencing, and weighted gene coexpression network analysis were used to identify candidate drivers of disease. Cross-species validation was performed using a RESULTS: CRLF1, predominantly secreted by activated cardiac fibroblasts, emerged as a key paracrine factor driving cardiomyocyte hypertrophy across patients with genetically heterogeneous HCM. CRLF1 levels were significantly elevated in hypertrophied myocardium and circulation. CRLF1 activated the LIFR (leukemia inhibitory factor receptor)-JAK1/2 (Janus kinase)-STAT3 (signal transducer and activator of transcription 3) signaling cascade to promote hypertrophy in both murine and human HCM models. Genetic ablation of CONCLUSIONS: Our findings uncover a common, nongenetic paracrine mechanism underlying HCM pathogenesis and establish CRLF1 as a promising universal therapeutic target for this heterogeneous disease.

BACKGROUND: Cardiomyocyte mitochondria align with sarcomeres during heart development. Mitochondrial motility is controlled by RHOT (ras homolog family member T) 1 and RHOT2. RHOT1 and RHOT2 are atypical Rho-like small GTPases that are anchored to the outer mitochondrial membrane and couple mitochondria to kinesin and dynein motors. We hypothesized that RHOT protein expression and mitochondrial motility are required for mitochondrial positioning during cardiomyocyte development. METHODS: We generated mice with cardiomyocyte-selective deletion of RESULTS: cRhot1/2-KO mice developed fatal cardiomyopathy associated with sarcomere disarray and perinuclear accumulation of mitochondria and ATP production. Mitochondria isolated from cRhot1/2-KO hearts exhibited impaired motility but preserved respiratory capacity. Mechanistically, proteome analysis identified that RHOT proteins bind mitochondria to contractile muscle fiber proteins. In contrast, inducible deletion of CONCLUSIONS: RHOT proteins bind mitochondria to contractile muscle fiber proteins and are required for mitochondrial positioning in cardiomyocytes during development. Our study links mitochondrial motility and local ATP production to structural and functional maturation of the heart.

Heart failure (HF) affects over 64 million individuals worldwide and is strongly associated with cognitive impairment (CI), yet the underlying mechanisms remain poorly understood. Here, we identify solute carrier family 22 member 3 (SLC22A3) might be a candidate gene for HF-induced CI through Mendelian randomization and bioinformatics analysis. To investigate its functional role in vivo, we established a mouse model of HF after myocardial infarction (MI). Cognitive performance was evaluated using the Morris water maze. Expression of SLC22A3, blood-brain barrier (BBB) integrity, and neuroinflammatory signalling were examined via immunofluorescence and Western blotting. The involvement of the HA/H1R/NLRP3 signalling pathway was further evaluated using cardiac-specific SLC22A3 overexpression mice, hippocampal-specific H1R knockdown mice, NLRP3 knockout mice, and BV2 cell assays. Consistent with the findings in HF patients, cardiac SLC22A3 expression was dramatically downregulated in HF mice, accompanied by an increase in peripheral histamine (HA) levels, while HA levels in the mouse brain were also significantly raised. Using cardiac-specific SLC22A3 overexpression in HF mice, we demonstrated that restoring SLC22A3 reduced HA accumulation and improved cognitive performance. Mechanistically, HA breached the compromised BBB in HF mice, activating hippocampal microglia H1 receptor (H1R) and the NLRP3 inflammasome. In BV2 cells, HA stimulation elevated NLRP3 expression in a dose-dependent manner, an effect blocked by H1R antagonist. Knockdown of H1R or NLRP3 in the hippocampus attenuated neuroinflammation and rescued HF-induced CI. Our findings unveil a novel cardio-neuroinflammatory axis driven by SLC22A3 deficiency, highlighting HA/H1R/NLRP3 pathway as a therapeutic target for HF-induced CI.