Despite established associations between insulin resistance (IR)-related indices and cardiometabolic diseases (CMDs), most studies are limited to single CMD outcomes. The study aimed to examine the influence of IR-related indices on the incidence, predictive value, and progression trajectory of cardiometabolic multimorbidity (CMM), as well as potential biological mechanisms. This prospective study included 374,274 individuals from the UK Biobank who were free of CMDs at baseline. CMM was defined as the presence of two or more CMDs, including type 2 diabetes (T2D), coronary heart disease (CHD), and stroke. Five indices were developed to assess IR levels: triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), TyG-waist-height ratio (TyG-WHtR), and triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio. Cox proportional hazards and multi-state models were utilized to examine the associations between IR-related indices and CMM incidence and transition, respectively, with results expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). The predictive utility of these indices was assessed using the net reclassification index (NRI) and integrated discrimination improvement index (IDI). Mediation analyses were conducted to quantify the potential mediating roles of biomarkers. During a mean follow-up period of 13.7 years, 5048 (1.3%) individuals developed CMM. Elevated baseline IR-related indices were associated with higher risks of incident CMM. The HRs (95% CIs) for each 1-standard deviation increase were as follows: 1.30 (1.26–1.34) for the TyG index, 1.42 (1.39–1.46) for the TyG-BMI, 1.54 (1.49–1.59) for the TyG-WC, 1.52 (1.48–1.57) for the TyG-WHtR, and 1.19 (1.17–1.21) for the TG/HDL-C ratio. Besides, TyG-WHtR and TyG-WC exhibited significantly higher NRI and IDI, indicating superior predictive performance for CMM risk. These indices played critical yet distinct roles in the progression of CMM. For transitions from being free of CMDs to single CMDs, these indices had the strongest impact on T2D (all P < 0.001). Participants initially diagnosed with CHD were more likely to progress to CMM when exposed to higher IR-related indices (all P < 0.001). The effect sizes for TyG-WC and TyG-WHtR were greater than those of other indices across all transitions. Mediation analyses revealed that biomarkers associated with liver function, renal function, and inflammation collectively mediated approximately one-third of the associations of the TyG-WHtR and TyG-WC indices with incident CMM. Our findings highlight the critical role of IR-related indices, particularly TyG-WHtR and TyG-WC, in the incidence, progression, and prevention of CMM. The mediation effects of biomarkers indicate the potential for targeted interventions to reduce CMM risk in high-IR individuals.

The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a primary driver of these conditions, commencing silently at an early age and culminating in adverse cardiovascular events that severely impact patients’ quality of life or lead to fatality. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in AS pathogenesis as an independent risk factor. Research indicates that abnormal LDL-C accumulation within arterial walls acts as a crucial trigger for atherosclerotic plaque formation. As the disease progresses, plaque accumulation may rupture or dislodge, resulting in thrombus formation and complete blood supply obstruction, ultimately causing myocardial infarction, cerebral infarction, and other common adverse cardiovascular events. Despite adequate pharmacologic therapy targeting LDL-C reduction, patients with cardiometabolic abnormalities remain at high risk for disease recurrence, highlighting the importance of addressing lipid risk factors beyond LDL-C. Recent attention has focused on the causal relationship between triglycerides, triglyceride-rich lipoproteins (TRLs), and their remnants in AS risk. Genetic, epidemiologic, and clinical studies suggest a causal relationship between TRLs and their remnants and the increased risk of AS, and this dyslipidemia may be an independent risk factor for adverse cardiovascular events. Particularly in patients with obesity, metabolic syndrome, diabetes, and chronic kidney disease, disordered TRLs and its remnants levels significantly increase the risk of atherosclerosis and cardiovascular disease development. Accumulation of over-synthesized TRLs in plasma, impaired function of enzymes involved in TRLs lipolysis, and impaired hepatic clearance of cholesterol-rich TRLs remnants can lead to arterial deposition of TRLs and its remnants, promoting foam cell formation and arterial wall inflammation. Therefore, understanding the pathogenesis of TRLs-induced AS and targeting it therapeutically could slow or impede AS progression, thereby reducing cardiovascular disease morbidity and mortality, particularly coronary atherosclerotic heart disease.

Background: The renin-angiotensin-aldosterone system (RAAS) members, especially Ang II and aldosterone, play key roles in the pathogenesis of diabetic cardiomyopathy (DCM). Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers combined with aldosterone receptor antagonists (mineralocorticoid receptor antagonists) have substantially improved clinical outcomes in patients with DCM. However, the use of the combination has been limited due to its high risk of inducing hyperkalemia.Methods: Type 1 diabetes was induced in 8-week-old male C57BL/6J mice by intraperitoneal injection of streptozotocin at a dose of 55 mg/kg for 5 consecutive days. Adeno-associated virus 9-mediated short-hairpin RNA (shRNA) was used to knock down the expression of ADAM17 in mice hearts. Eplerenone was administered via gavage at 200 mg/kg daily for 4 weeks. Primary cardiac fibroblasts were exposed to high glucose (HG) in vitro for 24 h to examine the cardiac fibroblasts to myofibroblasts transformation (CMT).Results: Cardiac collagen deposition and CMT increased in diabetic mice, leading to cardiac fibrosis and dysfunction. In addition, ADAM17 expression and activity increased in the hearts of diabetic mice. ADAM17 inhibition and eplerenone treatment both improved diabetes-induced cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction, ADAM17 deficiency combined with eplerenone further reduced the effects of cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction compared with single therapy in vivo. High-glucose stimulation promotes CMT in vitro and leads to increased ADAM17 expression and activity. ADAM17 knockdown and eplerenone pretreatment can reduce the CMT of fibroblasts that is induced by high glucose levels by inhibiting TGFβ1/Smad3 activation; the combination of the two can further reduce CMT compared with single therapy in vitro.Conclusion: Our findings indicated that ADAM17 knockout could improve diabetes-induced cardiac dysfunction and remodeling through the inhibition of RAAS overactivation when combined with eplerenone treatment, which reduced TGF-β1/Smad3 pathway activation-mediated CMT. The combined intervention of ADAM17 deficiency and eplerenone therapy provided additional cardiac protection compared with a single therapy alone without disturbing potassium level. Therefore, the combination of ADAM17 inhibition and eplerenone is a potential therapeutic strategy for human DCM.

The C-reactive protein-triglyceride-glucose index (CTI), a composite biomarker reflecting insulin resistance and systemic inflammation, has been linked to metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic diseases (CMDs). However, the role of CTI and its obesity-related derivatives in cardiometabolic multimorbidity (CMM) development and progression among MASLD patients remains unclear. The study evaluated associations of CTI-related indices with the incidence and progression of CMM, assessed their incremental predictive value, and explored potential biomarkers. This cohort study included 109,181 UK Biobank participants with MASLD and without CMDs at baseline. CMM was defined as the coexistence of ≥ 2 CMDs, including type 2 diabetes mellitus (T2DM), ischemic heart disease (IHD), and stroke. Four CTI-related indices were calculated: CTI, CTI-body mass index (CTI-BMI), CTI-waist circumference (CTI-WC), and CTI-waist-to-height ratio (CTI-WHtR). Associations with CMM incidence and progression were analyzed using traditional Cox and multistate models. Predictive performance was assessed using the C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Exploratory mediation analyses were conducted to examine whether metabolic, inflammatory, hepatic, and renal biomarkers statistically accounted for part of the associations. Over a median follow-up of 16 years, 4,219 participants developed CMM. All four indices were positively associated with incident CMM, with CTI-WHtR and CTI-WC showing more pronounced associations. Hazard ratios (HRs) (95% confidence interval) per 1-SD increase were 1.62 (1.58-1.66) for CTI-WHtR, 1.57 (1.53-1.61) for CTI-WC, 1.53 (1.49-1.57) for CTI-BMI, and 1.50 (1.45-1.54) for CTI (all P < 0.001). Multistate analyses indicated consistent positive associations with transitions from baseline to first CMD (FCMD) (HRs: 1.41-1.53), FCMD to CMM (HRs: 1.17-1.24), and CMM to death (HRs: 1.07-1.21), particularly for CTI-WHtR and CTI-WC. Subtype-specific analyses confirmed their pronounced associations, notably for T2DM incidence and IHD-to-CMM progression. Adding CTI-related indices to the conventional model resulted in modest but statistically significant improvements in predictive performance, with CTI-WC and CTI-WHtR showing the greatest improvements in the C-index, NRI, and IDI. Biomarkers of glycemic dysregulation, lipid metabolism, systemic inflammation, and organ dysfunction may partly account for the associations between CTI indices and incident CMM. CTI-related indices, particularly CTI-WHtR and CTI-WC, were significantly associated with the incidence and progression of CMM in individuals with MASLD. These indices provided modest incremental predictive value and may serve as complementary markers for risk stratification. Further external validation and clinical utility assessment are needed before their routine use in clinical practice.

Frailty was associated with neurological disorders, but has not been extrapolated to migraine. It’s unclear whether maintaining healthy sleep mitigates this association. We examined the independent, joint, and interactive relationships between frailty status and sleep quality and migraine risk. 356,326 participants from the UK Biobank without migraine at baseline were included. The five-component Fried phenotype was used to assess frailty status and categorized participants as non-frail, pre-frail, and frail. A five-factor sleep questionnaire was employed to quantify sleep quality and categorize individuals into poor, intermediate, and healthy sleep. Cox proportional hazard models were applied to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Their interactions on the multiplicative and additive scales were also assessed. During a median follow-up of 13.6 years, 4,641 (1.3%) participants experienced migraine. Compared with non-frail individuals, the HRs (95% CIs) for migraine were 1.149 (1.079–1.222) and 1.413 (1.225–1.630) for those with pre-frailty and frailty. Individuals with intermediate (HR = 1.170; 95% CI: 1.101–1.243) and poor (HR = 1.353; 95% CI: 1.146–1.598) sleep showed an increased risk of migraine compared to those with healthy sleep. The joint test suggested that frail individuals with poor sleep faced the highest migraine risk (HR = 1.897; 95% CI: 1.339–2.687), with evidence of an additive interaction. Also, healthy sleep weakened the frailty-migraine relationship, with evidence of a multiplicative interaction (P for interaction = 0.014). Although both frailty and poor sleep quality are associated with a higher risk of migraine, achieving healthy sleep might mitigate the adverse impact of frailty.