Yun-Jiu Cheng

Background: Higher METS-IR has been shown to be associated with a higher risk of major adverse cardiovascular events, but data are lacking regarding cardiac arrhythmias. Objectives: The aim of this study was to assess the association between METS-IR and atrial fibrillation/flutter, ventricular arrhythmia and bradyarrhythmia. Methods: Data from the Atherosclerosis Risk in Communities study spanning 1987 to 2013 was utilized for this analysis. METS-IR scores were assessed at baseline (1987-1989) and arrhythmia episodes were identified using ICD-9 codes. Multivariate-adjusted Cox proportional hazard models were constructed to evaluate the relationship between METS-IR and arrhythmia risk, with dose-response analyses conducted. In addition, we analyzed the predictive value of METS-IR for arrhythmias. Results: Over a mean follow-up of 21.9 years, 2493 cases of AF, 688 cases of bradyarrhythmia, and 1315 cases of ventricular arrhythmia were recorded. Each interquartile range increase in METS-IR was associated with a 49% higher risk of atrial fibrillation( P P P P overall0.05). Most of the results of the subgroup analyses were not significantly different. The inclusion of METS-IR in the base model improves the predictive value of the risk of arrhythmogenesis. Conclusions: There is a significant association between METS-IR and increased risk of arrhythmias. What’s new?: This study found a significant correlation between METS-IR and the risk of developing arrhythmias in a large population-based cohort. Specifically, individuals with higher METS-IR had a significantly increased risk of developing arrhythmias, even after adjusting for other cardiovascular risk factors. In addition, there was a linear relationship between METS-IR and arrhythmia. The ability to predict the risk of new arrhythmias was significantly improved by adding METS-IR to the basic risk prediction model. Furthermore, a visualization tool (nomogram) incorporating METS-IR was developed, which demonstrated substantial clinical net benefit in decision curve analysis, showing comparable performance to other established insulin resistance indices (TyG, SPISE). What Are the Clinical Implications?: The identification of high-risk patients for arrhythmias using the METS-IR Index can facilitate personalized care interventions. Healthcare providers can potentially prevent arrhythmic events by addressing modifiable risk factors such as weight loss, lipid control, and improved insulin sensitivity. This proactive approach could lead to substantial public health advantages.

To investigate the association between cardiorespiratory fitness (CRF) and the risk of incident microvascular complications in patients with type 2 diabetes mellitus (T2DM), and to assess the effect of genetic risk and potential mediation by circulating biomarkers. This prospective analysis included 3,102 adults with T2DM from the UK Biobank. CRF was estimated as maximal oxygen uptake using a submaximal cycle test and categorized as low, moderate, or high. Cox proportional hazards models were used to estimate hazard ratios (HRs) for incident diabetic nephropathy, retinopathy, and neuropathy. Interactions with a polygenic risk score and mediating roles of biomarkers were evaluated. Over a median 12.47-year follow-up, 331 nephropathy, 268 retinopathy, and 88 neuropathy cases were recorded. Compared to low CRF, moderate and high CRF were associated with 22% (HR, 0.78; 95% confidence interval [CI], 0.61 to 0.99) and 45% (HR, 0.55; 95% CI, 0.36 to 0.85) lower risks of nephropathy, respectively. Each 1-metabolic equivalent of task increment in CRF was linked to 11% lower nephropathy risk. No significant associations were found for retinopathy or neuropathy. Genetic predisposition did not modify the association between CRF and diabetic nephropathy. Triglycerides and white blood cell count accounted for 7.46% and 12.88% of the association, respectively. Higher CRF is independently associated with lower risk of diabetic nephropathy in T2DM, and genetic risk does not alter this relationship. The association was partially mediated by triglycerides and white blood cell count. Assessing CRF may improve risk stratification and prevention of diabetic kidney disease.

Background: Lipoprotein(a) [Lp(a)] is an established risk factor for atherosclerotic cardiovascular disease and aortic stenosis; however, its associations with incident arrhythmias remains limited. Methods: We conducted a prospective analysis of 369,058 participants from the UK Biobank without prevalent arrhythmia. Plasma Lp(a) levels were measured, and a genetic risk score was constructed using 41 variants to calculate genetically predicted Lp(a). Participants were categorized by Lp(a) percentiles. Multivariable Cox models were used to assess associations with incident arrhythmias. The associations with arrhythmia with Lp(a) levels as a continuous variable were assessed using restrictive cubic spine (RCS) analysis. Two-sample Mendelian randomization (MR) was performed to evaluate causality. Findings were validated in the Atherosclerosis Risk In Communities (ARIC) study (n=12,941). Results: Over a median follow-up of 14.2 years (IQR 14.3-15.0), elevated Lp(a) levels (≥90th percentile vs. low levels, <50th percentile) were associated with increased risks of any arrhythmias (HR 1.10, 95% CI 1.06-1.14), atrial fibrillation/flutter (AF/AFL) (HR 1.09, 1.04-1.13), atrioventricular (AV) block (HR 1.09, 1.01-1.18), pacemaker (PM) implantation (HR 1.24, 1.15-1.33), ventricular arrhythmias (HR 1.17, 1.01-1.36), and sudden cardiac arrest (SCA) (HR 1.19, 1.04-1.35). Genetically predicted Lp(a) showed consistent associations, supporting a potential causal relationship. RCS showed dose-response relationships for both measured and genetically predicted Lp(a). MR analyses indicated that a 100 nmol/L higher genetically predicted Lp(a) was associated with increased risks of any arrhythmias (IVW-OR 1.07, 1.03-1.11), AF/AFL (OR 1.15, 1.09-1.21), AV block (OR 1.17, 1.06-1.29), PM implantation (OR 1.10, 1.04-1.16), ventricular arrhythmias (OR 1.29, 1.03-1.61) and SCA (OR 1.17, 1.06-1.29). Associations were independent of ASCVD and consistent in the ARIC cohort. Conclusion: Elevated Lp(a) levels, both observed and genetically predicted, are associated with increased risks of a broad spectrum of arrhythmias. Genetic evidence supports a potential causal role.

Background: There is growing evidence that genetic factors may play a crucial role in the development of ventricular fibrillation (VF) following acute ST-segment elevation myocardial infarction (STEMI). Previous studies have demonstrated that both truncating and missense mutations in the TTN gene, which encodes a large cellular structural protein, are linked to arrhythmogenesis. However, the precise role of TTN mutations in the onset of primary VF after acute STEMI remains poorly understood. Objectives: The primary objective of this study was to comprehensively determine the role and elucidate the electrophysiological mechanism of TTN missense mutations in VF development after acute STEMI. This was achieved by leveraging the unique capabilities of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Methods: Whole-genome sequencing identified TTN mutations in four out of six unrelated patients who experienced VF after STEMI (STEMI/VF). Induced pluripotent stem cells were successfully generated from the peripheral blood mononuclear cells obtained from a 47-year-old male carrying a novel TTN variant (c.43803T>A/p.D14601E) and from an unrelated healthy control. Subsequently, a directed differentiation protocol was employed to create iPSC-CMs, followed by rigorous electrophysiological and functional analyses to elucidate the mechanisms underlying the observed phenotypes. Results: Compared with the control iPSC-CMs, the patient-derived iPSC-CMs with STEMI/VF exhibited a significant shortening of the action potential duration (APD). Specifically, peak sodium channel current (I _Na ) and L-type calcium channel current (I _Ca–L ) of the STEMI/VF iPSC-CMs were significantly reduced by 51.64% and 71.56%, respectively. However, the transient outward potassium current remained comparable between the two groups. Moreover, the expression of total TTN in STEMI/VF iPSC-CMs was downregulated. Confocal microscopy analysis revealed that although STEMI/VF iPSC-CMs retained the ability to assemble well-aligned titin striations similar to control cells, there were localized disruptions in the sarcomeric patterning. Conclusions: The iPSC-CMs obtained from the patient carrying a TTN missense mutation and who suffered from VF after STEMI exhibited a decrease in I _Na , I _Ca–L , and shortened APD, providing novel insights into the potential electrophysiological mechanisms underlying the development of VF in the context of acute STEMI and TTN mutations.

Emerging epidemiological evidence implicates pulmonary dysfunction in cardiovascular pathogenesis, yet its arrhythmogenic potential remains poorly defined. We aimed to assess the link between ventilatory parameters, pulmonary disease phenotypes and risk of incident arrhythmias across diverse populations. We analyzed data from 17,684 adults in two prospective cohort studies-the Atherosclerosis Risk in Communities (ARIC; n = 12,929) and Cardiovascular Health Study (CHS; n = 4,755). Adjudicated arrhythmia diagnoses (atrial fibrillation/flutter [AF/AFL], ventricular arrhythmias [VAs], high-grade atrioventricular [AV] block, and premature atrial/ventricular complexes [PAC/PVC]) were identified via hospitalization records and mortality data. Multivariable-adjusted Cox proportional hazards models quantified associations between forced expiratory volume in 1 s (FEV1%) predicted and forced vital capacity (FVC%) predicted quartiles with arrhythmia risk, adjusting for traditional cardiovascular risk factors. Over a median follow-up of 12.6 years, impaired FEV1% and FVC% corresponded to a graded increase in arrhythmia risk. Compared to the highest quartile, the lowest FEV1% predicted quartile had elevated hazards for any arrhythmias (HR 1.32, 95% CI 1.23–1.42), AF/AFL (HR 1.68, 1.52–1.85), VAs (HR 1.55, 1.29–1.86), high-grade AV block (HR 1.37, 1.08–1.73), and PAC/PVC (HR 1.42, 1.20–1.69). Similar trends were observed for FVC% predicted quartiles. These associations remained consistent in never-smoking individuals and across cohorts. Obstructive spirometry pattern was associated with the strongest arrhythmia risk, while restrictive ventilatory patterns showed relatively lower risk elevations. No association was observed with sick sinus syndrome. Reduced pulmonary function suggested independent associations with incident arrhythmias across supraventricular, ventricular, and conduction system pathologies in two historical cohorts. These findings suggest that spirometric indices could potentially represent novel independent indicators for arrhythmia development worthy of further validation in contemporary settings,, with associations distinct from conventional cardiometabolic risk factors.

Background: The prognostic significance of small left ventricle (LV) in the general population and its association with cardiovascular disease remain elusive. Methods: Using data from the UK Biobank, 39 363 participants underwent baseline cardiovascular magnetic resonance imaging and were categorized into 3 groups based on left ventricular end‐diastolic volume index: small, normal, and large LV. Cox proportional hazards models were applied to evaluate the association between LV size and composite cardiovascular outcomes. Results: An elevated prevalence of small LV was observed among the 4305 participants, with a notable trend toward increased occurrence in older individuals. Over a median follow‐up of 5.21 years, 1500 cases of major adverse cardiovascular events, 1096 coronary heart disease, 288 ischemic stroke, and 722 deaths from any cause occurred. After adjusting for multiple confounders, hazard ratios (HRs) of small LV comparing the normal LV were 1.24 (95% CI, 1.07–1.44) for major adverse cardiovascular events, 1.29 (95% CI, 1.09–1.53) for coronary heart disease, 1.53 (95% CI, 1.11–2.09) for ischemic stroke, and 1.33 (95% CI, 1.08–1.64) for death from all causes. Notably, a U‐shaped relationship was identified between left ventricular end‐diastolic volume index and cardiovascular outcomes. Subgroup analysis revealed that, compared with women, the presence of a small LV in men exhibited a significant correlation with adverse cardiovascular events, thereby demonstrating potential value in disease prediction and risk stratification. Conclusions: These findings highlight the importance of considering small LV as a prognostic marker for cardiovascular disease and underscore the need for further research to elucidate the underlying mechanisms and develop targeted interventions.

Background: The early repolarization pattern (ERP) is associated with cardiovascular death, but its connection with arrhythmias remains unknown. This study evaluated relationships between ERP and incident arrhythmias, including ventricular arrhythmias, bradyarrhythmias, and atrial fibrillation (AF)/flutter (Afl).Methods and Results: We analyzed 14,679 middle-aged (45–64 years) participants from the Atherosclerosis Risk in Communities cohort, a prospective population-based study in the US. Participants were monitored for ERP status at baseline and at 3 subsequent follow-up visits. We examined associations between incident arrhythmias and baseline ERP, time-varying ERP, time-updated ERP, and changes in ERP over time using Cox models to estimate hazard ratios (HRs) adjusted for potential confounders. Over a 20-year follow-up, there were 1,252 ventricular arrhythmias, 890 bradyarrhythmias, and 2,202 cases of AF. Time-updated ERP was associated with increased HRs for ventricular arrhythmias (1.55; 95% confidence interval [CI] 1.35–1.77), bradyarrhythmias (1.76; 95% CI 1.48–2.08), and AF (1.25; 95% CI 1.10–1.43). Time-varying ERP also showed associations with these outcomes. Compared with individuals with consistently normal electrocardiogram results, those with new-onset or persistent ERP had increased risks of incident arrhythmias. In subjects with time-updated ERP, anterior leads and J wave amplitudes ≥0.2 mV were associated with a higher incidence of arrhythmias.Conclusions: Several types of ERP, including time-varying, time-updated, new-onset, and consistent, are associated with the incidence of arrhythmias in the middle-aged biracial (Black and White) population.

The reported incidence of arterial thromboembolism (ATE) and venous thromboembolism (VTE) after cancer varies. A meta-analysis was performed to define the incidence of thromboembolism (TE) in cancer patients. Articles were searched in PubMed and Embase from inception to November 1, 2023. Studies reporting the incidence data or data from which incidence could be estimated among patients with cancer and the explicit follow-up duration were included. Seventy-four studies involving 5,059,134 cancer patients were identified. The incidence rate per 1000 person-years was 11.60 (95% CI 7.62–15.58) for ATE, 6.11 (95% CI 3.70–8.53) for myocardial infarction, 9.07 (95% CI 7.48–10.66) for ischemic stroke, 2.11 (95% CI 0.89–3.31) for another ATE, 26.32 (95% CI 24.46–28.18) for VTE, 12.69 (95% CI 11.51–13.87) for deep vein thrombosis, 5.94 (95% CI 5.29–6.59) for pulmonary embolism, and 13.18 (95% CI 9.93–16.42) for another VTE. In addition, the highest incidence of ATE was observed in patients with gastrointestinal cancer, while patients with pancreatic cancer had the highest incidence of VTE. The risk of ATE and VTE increased at the initial stage of cancer, and then declined and became non-significant. This meta-analysis provided overall estimates of ATE and VTE incidence in cancer patients, adding an important insight into the trajectory of the development of TE in cancer patients, which could help the early detection of TE in cancer patients in the future. Graphical Abstract

Background: Atrial fibrillation (AF) significantly increases the ischemic stroke risk. However, the relationship between age at diagnosis of AF and subsequent stroke risk remains poorly understood. Methods and Results: We analyzed data from 5 prospective cohorts: ARIC (Atherosclerosis Risk in Communities) study, CHS (Cardiovascular Health Study), CARDIA (Coronary Artery Risk Development in Young Adults), MESA (Multi‐Ethnic Study of Atherosclerosis), and Framingham Heart Study (including Offspring cohort and the Third‐Generation cohorts). Cox regression models and competing risk survival analyses were used to assess incidence rates and hazard ratios (HRs) for ischemic stroke stratified by age groups. Among 47 239 participants (median follow‐up: 21.1 years), 6689 (14.2%) developed AF, and 536 (8.0%) subsequently experienced ischemic stroke. Younger age at AF diagnosis was significantly associated with a higher ischemic stroke risk. Fully adjusted HRs for ischemic stroke were 5.35 (95% CI, 3.56–8.03), 2.99 (95% CI, 2.32–3.86), 2.13 (95% CI, 1.75–2.58), and 1.93 (95% CI, 1.59–2.34) for AF diagnosed at ages 55, 65, 75, and 85, respectively. Compared with participants without AF at age 55, HRs for ischemic stroke were 7.30 (95% CI, 3.27–16.31) for AF diagnosed >10 years earlier, 4.98 (95% CI, 2.99–8.29) for 6 to 10 years earlier, and 4.60 (95% CI, 1.48–14.34) for ≤5 years earlier ( P ‐trend <0.001). The presence of AF yielded a 13.9 years earlier occurrence of ischemic stroke among those with AF diagnosis at 55 years compared with 1.5 years earlier at age 85. Conclusions: Younger age at AF diagnosis was associated with a higher risk of subsequent ischemic stroke.