The SELECT trial previously reported a 20% reduction in major adverse cardiovascular events with semaglutide (n = 8,803) versus placebo (n = 8,801) in patients with overweight/obesity and established cardiovascular disease, without diabetes. In the present study, we examined the effect of once-weekly semaglutide 2.4 mg on kidney outcomes in the SELECT trial. The incidence of the pre-specified main composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15 ml min⁻¹ 1.73 m⁻², persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria) was lower with semaglutide (1.8%) versus placebo (2.2%): hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.63, 0.96; P = 0.02. The treatment benefit at 104 weeks for eGFR was 0.75 ml min⁻¹ 1.73 m⁻² (95% CI 0.43, 1.06; P < 0.001) overall and 2.19 ml min⁻¹ 1.73 m⁻² (95% CI 1.00, 3.38; P < 0.001) in patients with baseline eGFR <60 ml min⁻¹ 1.73 m⁻². These results suggest a benefit of semaglutide on kidney outcomes in individuals with overweight/obesity, without diabetes.ClinicalTrials.gov identifier: NCT03574597.

Insights from epidemiological, clinical and basic research are illuminating the interplay between metabolic disorders, cardiovascular disease (CVD) and kidney dysfunction, termed cardio‐renal‐metabolic (CRM) disease. Broadly defined, CRM disease involves multidirectional interactions between metabolic diseases such as type 2 diabetes (T2D), various types of CVD and chronic kidney disease (CKD). T2D confers increased risk for heart failure, which—although well known—has only recently come into focus for treatment, and may differ by ethnicity, whereas atherosclerotic heart disease is a well‐established complication of T2D. Many people with T2D also have CKD, with a higher risk in Asians than their Western counterparts. Furthermore, CVD increases the risk of CKD and vice versa, with heart failure, notably, present in approximately half of CKD patients. Molecular mechanisms involved in CRM disease include hyperglycaemia, insulin resistance, hyperactivity of the renin‐angiotensin‐aldosterone system, production of advanced glycation end‐products, oxidative stress, lipotoxicity, endoplasmic reticulum stress, calcium‐handling abnormalities, mitochondrial malfunction and deficient energy production, and chronic inflammation. Pathophysiological manifestations of these processes include diabetic cardiomyopathy, vascular endothelial dysfunction, cardiac and renal fibrosis, glomerular hyperfiltration, renal hypoperfusion and venous congestion, reduced exercise tolerance leading to metabolic dysfunction, and calcification of atherosclerotic plaque. Importantly, recognition of the interaction between CRM diseases would enable a more holistic approach to CRM care, rather than isolated treatment of individual conditions, which may improve patient outcomes. Finally, aspects of CRM diseases may differ between Western and East Asian countries such as Japan, a super‐ageing country, with potential differences in epidemiology, complications and prognosis that represent an important avenue for future research.

This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation. Patients undergoing atrial fibrillation ablation and endomyocardial atrial biopsy were included (n = 230; 67 ± 12 years old; 69 women). Electroanatomic mapping was performed during right atrial pacing. Voltage at the biopsy site (V_biopsy), global left atrial voltage (V_GLA), and the proportion of points with fractionated electrograms defined as ≥5 deflections in each electrogram (%Fractionated EGM) were evaluated. SCZ_total was calculated as the total width of slow conduction zones, defined as regions with a conduction velocity of <30 cm/s. Histological factors potentially associated with electroanatomic characteristics were evaluated using multiple linear regression analyses. Ultrastructural features and immune cell infiltration were evaluated by electron microscopy and immunohistochemical staining in 33 and 60 patients, respectively. Fibrosis, intercellular space, myofibrillar loss, and myocardial nuclear density were significantly associated with V_biopsy (P = .014, P < .001, P < .001, and P = .002, respectively) and V_GLA (P = .010, P < .001, P = .001, and P < .001, respectively). The intercellular space was associated with the %Fractionated EGM (P = .001). Fibrosis, intercellular space, and myofibrillar loss were associated with SCZ_total (P = .028, P < .001, and P = .015, respectively). Electron microscopy confirmed plasma components and immature collagen fibrils in the increased intercellular space and myofilament lysis in cardiomyocytes, depending on myofibrillar loss. Among the histological factors, the severity of myofibrillar loss was associated with an increase in macrophage infiltration. Histological correlates of atrial structural remodelling were fibrosis, increased intercellular space, myofibrillar loss, and decreased nuclear density. Each histological component was defined using electron microscopy and immunohistochemistry studies. Histological factors associated with atrial structural remodelling in patients with atrial fibrillation. LA, left atrium; RA, right atrium.

Postprandial hyperglycemia is characterized by hyperglycemic spikes that induce endothelial dysfunction, inflammatory reactions and oxidative stress, which may lead to progression of atherosclerosis and occurrence of cardiovascular events. Emerging data indicate that postprandial hyperglycemia or even impaired glucose tolerance may predispose to progression of atherosclerosis and cardiovascular events. There is evidence that postprandial hyperglycemia, but not fasting hyperglycemia, independently predicts the occurrence of cardiovascular events. We proposed a concept of 'vascular failure' as a comprehensive syndrome of vascular dysfunction extending from risk factors to advanced atherosclerotic disease. Postprandial hyperglycemia is therefore one of the very important pathophysiological states contributing to vascular failure. Accordingly, controlling postprandial hyperglycemia should be the focus of future clinical investigation as a potential target for preventing vascular failure.

Background: Heart failure (HF) and atrial fibrillation (AF) are growing in prevalence worldwide. Few studies have assessed to what extent stage 1 hypertension in the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) blood pressure (BP) guidelines is associated with incident HF and AF. Methods: Analyses were conducted using a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2018 (n=2,196,437; mean age, 44.0±10.9 years; 584% men). No participants were taking antihypertensive medication or had a known history of cardiovascular disease. Each participant was categorized as having normal BP (systolic BP [SBP]<120 mm Hg and diastolic BP [DBP]<80 mm Hg; n=1,155,885); elevated BP (SBP 120-129 mm Hg and DBP<80 mm Hg; n=337,390); stage 1 hypertension (SBP 130-139 mm Hg or DBP 80-89 mm Hg; n=459,820); or stage 2 hypertension (SBP≥140 mm Hg or DBP≥90 mm Hg; n=243,342). Using Cox proportional hazards models, we identified associations between BP groups and HF/AF events. We also calculated the population attributable fractions (PAFs) to estimate the proportion of HF and AF events that would be preventable if participants with stage 1 and stage 2 hypertension were to have normal BP. Results: Over a mean follow-up of 1,112±854 days, 28,056 incident HF and 7,774 incident AF events occurred. After multivariable adjustment, hazard ratios for HF and AF events were 1.10 (95% Confidence interval [CI], 1.05-1.15) and 1.07 (95% CI, 0.99-1.17), respectively, for elevated BP; 1.30 (95% CI, 1.26-1.35) and 1.21 (95% CI, 1.13-1.29), respectively, for stage 1 hypertension; and 2.05 (95% CI, 1.97-2.13) and 1.52 (95% CI, 1.41-1.64), respectively, for stage 2 hypertension vs normal BP. PAFs for HF associated with stage 1 and stage 2 hypertension were 23.2% (95% CI, 20.3%-26.0%) and 51.2% (95% CI, 49.2%-53.1%), respectively. The PAFs for AF associated with stage 1 and stage 2 hypertension were 17.4% (95% CI, 11.5%-22.9%) and 34.3% (95% CI, 29.1%-39.2%), respectively. Conclusions: Both stage 1 and stage 2 hypertension were associated with a greater incidence of HF and AF in the general population. The ACC/AHA BP classification system may help identify adults at higher risk for HF and AF events.