Evidence regarding the role of chronic low-grade inflammation in the progression of cardiometabolic diseases (CMDs) and cardiometabolic multimorbidity (CMM) is currently limited. This prospective cohort study, utilising data from the UK Biobank, included 273,804 adults aged 40–69 years initially free of CMD at baseline. CMM was defined as the coexistence of two or more CMDs, such as coronary artery disease, type 2 diabetes mellitus, hypertension and stroke. The aggregated inflammation score (INFLA-score), incorporating C-reactive protein, white blood cell count, platelet count and granulocyte-to-lymphocyte ratio, quantified chronic low-grade inflammation. Absolute risks (ARs), hazard ratios (HRs) and 95% confidence intervals (CIs) assessed the association of increased INFLA-score with the risk of CMMs and CMDs. The accelerated failure time model explored the effect of INFLA-score on the time to CMM onset, and a restricted cubic spline characterised the dose-dependent relationship between INFLA-score and CMM risk. After a median follow-up of 166.37 months, 13,755 cases of CMM were identified. In quartiles with increasing INFLA-score levels, CMM ARs were 4.41%, 4.49%, 5.04% and 6.01%, respectively; HR increased by 2%, 15% and 36%, respectively, compared to the lowest quartile. The INFLA-score and CMM risk relationship was nonlinear (P for nonlinear < 0.001), exhibiting a significant risk trend change at a score of 9. For INFLA-score < 9, CMM risk increased by 1.9% for each 1-point increase; for INFLA-score ≥ 9, the risk increased by 5.9% for each 1-point increase. Additionally, a higher INFLA-score was associated with an earlier onset of CMM (P < 0.001). Compared to the first INFLA-score quartile, the AFT model revealed adjusted median times to CMM occurrence were 2.92, 6.10 and 13.19 months earlier in the second, third and fourth quartile groups, respectively. Chronic low-grade inflammation is associated with a higher risk of cardiometabolic multimorbidity and earlier onset among middle-aged and older adults. Monitoring and screening the INFLA-score in adults without CMDs may improve early prevention of CMM.

Mitochondria-associated membrane (MAM) serve as crucial contact sites between mitochondria and the endoplasmic reticulum (ER). Recent research has highlighted the significance of MAM, which serve as a platform for various protein molecules, in processes such as calcium signaling, ATP production, mitochondrial structure and function, and autophagy. Cardiac diseases caused by any reason can lead to changes in myocardial structure and function, significantly impacting human health. Notably, MAM exhibits various regulatory effects to maintain cellular balance in several cardiac diseases conditions, such as obesity, diabetes mellitus, and cardiotoxicity. MAM proteins independently or interact with their counterparts, forming essential tethers between the ER and mitochondria in cardiomyocytes. This review provides an overview of key MAM regulators, detailing their structure and functions. Additionally, it explores the connection between MAM and various cardiac injuries, suggesting that precise genetic, pharmacological, and physical regulation of MAM may be a promising strategy for preventing and treating heart failure.

FUNDC1-mediated mitochondria-associated endoplasmic reticulum membrane (MAM) Ca²⁺ conduction is crucial in cardiac hypertrophy. N6-methyladenosine (m6A) methylation, a crucial mRNA modification, is implicated in this process. We hypothesise that m6A regulation of FUNDC1-mediated MAM-associated Ca²⁺ overload contributes to obesity hypertension (OBH) cardiac hypertrophy. We investigated OBH in spontaneously hypertensive rats fed a high-fat diet, with WKY rats as controls. Assessments included blood pressure, cardiac hypertrophy, pyroptosis, protein expression of MAM-related (FUNDC1, IP3R2) and m6A-related gene (METTL3, IGF2BP2). MeRIP assay detected m6A methylation in mRNA. We also examined cardiomyocyte morphology, viability, mitochondrial function (mtROS, SOD, MDA and ATP levels), and expression of pyroptosis-related factors (IL-1β, IL-18, NLRP3, GSDMD-N and Caspase-1/p10) in vitro. Silencing and overexpression of FUNDC1 and METTL3 clarified MAM effects on cardiac hypertrophy. FUNDC1 and IP3R2 interaction was assessed by co-immunoprecipitation. OBH rats exhibited significantly elevated blood pressure, cardiac hypertrophy, MAM dysfunction, elevated FUNDC1, IP3R2 and METTL3 expression, and pyroptosis. Ang II treatment in vitro upregulated FUNDC1, causing mitochondrial dysfunction, inflammation and pyroptosis in cardiomyocytes. FUNDC1 knockdown improved cardiomyocyte morphology and function, reduced mitochondrial Ca²⁺ concentration, enhanced mitochondrial function and attenuated pyroptosis while increasing IP3R2 ubiquitination. Mito Tempo reversed cardiomyocyte hypertrophy, mitochondrial dysfunction, inflammatory response and pyroptosis induced by FUNDC1 overexpression. Additionally silencing METTL3 and IGF2BP2 reduced m6A methylation of FUNDC1, inhibiting its expression. METTL3 regulates FUNDC1 m6A methylation modification via IGF2BP2, thereby affecting FUNDC1 expression. FUNDC1 binding to IP3R2 regulates MAM-associated Ca²⁺ overload, inducing mitochondrial dysfunction and pyroptosis, leading to cardiac hypertrophy in OBH.