Attila Kiss

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome in which translational progress is limited by experimental models that insufficiently reflect the cardiometabolic phenotype while affecting endogenous endothelial function. We aimed to characterize a cardiometabolic ‘two-hit’ HFpEF model combining metabolic stress (db/db) with chronic mineralocorticoid excess (d-aldosterone). Female db/db mice received 4-week d-aldosterone (0.3 μg/h) or vehicle via osmotic minipumps. Metabolic profiling, high-resolution echocardiography including strain and left atrial mechanics, invasive right-heart catheterization and thoracic aortic wire myography were performed. Aldosterone-treated db/db mice developed cardiac hypertrophy and pulmonary congestion with preserved left ventricular ejection fraction but marked diastolic dysfunction, left atrial remodeling with increased stiffness and impaired global longitudinal left ventricular strain. Pulmonary hypertension with right ventricular dysfunction was evidenced by elevated right ventricular systolic pressure, reduced ratio of pulmonary acceleration time to pulmonary ejection time, and reduced tricuspid annular plane systolic excursion. Thoracic aortae from untreated db/db mice already showed impaired endothelium-dependent relaxation, which was further aggravated by aldosterone, whereas maximal endothelium-independent relaxation remained largely preserved. The db/db+d-aldosterone model recapitulates key features of cardiometabolic HFpEF across the cardiac-vascular-pulmonary axis and provides a translational platform for mechanistic and therapeutic studies targeting endothelial and ventricular-vascular dysfunction in HFpEF.

BACKGROUND: Androgen deprivation therapy (ADT) improves outcomes in advanced prostate cancer but is associated with increased cardiovascular morbidity and mortality. Arterial inflammation, measurable by [ ^{1 8} F]fluorodeoxyglucose positron emission tomography, may represent an intermediate pathway linking ADT to cardiovascular risk. We quantified intraindividual changes in arterial inflammation on [ ^{1 8} F]fluorodeoxyglucose positron emission tomography/magnetic resonance across ADT exposure, characterized their temporal trajectory, and explored associated clinical factors. METHODS: Forty-three men with prostate cancer underwent 2 longitudinal [ ^{1 8} F]fluorodeoxyglucose positron emission tomography/magnetic resonance examinations across the course of ADT exposure. The maximum standardized uptake value was measured in the common carotid arteries, aortic arch, ascending and descending thoracic aorta, abdominal aorta, and common iliac arteries. Arterial inflammation was expressed as the maximum target-to-background ratio (TBR _max ) by normalizing arterial (maximum standardized uptake value) to the venous blood-pool mean standardized uptake value. Segmental values were aggregated into all-artery, aorta, and branch composite measures. Paired changes were assessed using paired tests, and longitudinal trajectories were modeled using linear mixed-effects models. RESULTS: ADT was associated with significant intraindividual increases in TBR _max in the carotid arteries (1.54±0.32 to 1.75±0.31; P P P P =0.005), and ascending aorta ( P =0.02). All-artery, aorta, and branch composite TBR _max increased significantly (all P max , with the largest monthly increments in iliac arteries (0.0205/mo; P P P =0.038). CONCLUSIONS: In patients with prostate cancer, ADT is associated with consistent and progressive arterial inflammation, most prominently in carotid, iliac, and abdominal aortic regions. These findings support arterial inflammation as a potential imaging phenotype of ADT-associated cardiovascular risk.

Sodium–glucose cotransporter-2 inhibitors (SGLT2i) provide substantial cardiovascular benefits across a broad spectrum of patients at high atheroscle

Background and Aim: Glucagon-like peptide-1 receptor (GLP1R) agonists improve glycaemic control, induce weight loss, and consistently reduce major adverse cardiovascular events. However, the mechanistic basis of their cardioprotective effects remains incompletely understood, particularly whether benefits arise solely from systemic actions or also involve direct cardiac GLP1R signalling. With prior studies suggesting differences in receptor expression across species and cell type, we sought to comprehensively map GLP1R mRNA expression to provide a framework for future mechanistic studies. Methods: We performed integrated single-cell and single-nucleus transcriptomics to map GLP1R gene expression across species, cardiac cell type, and disease state. Six public datasets were used, including human and mouse multi-organ atlases, human cardiomyopathies, mouse models of heart failure, and a hiPSC-derived cardiac organoid model. Results: In humans, GLP1R expression was predominantly pancreatic, with low cardiac expression largely restricted to cardiomyocytes and consistently upregulated across ischaemic, dilated, and hypertrophic cardiomyopathy. In contrast, murine cardiac Glp1r expression was confined to endocardial cells and remained unchanged in heart disease. Other cardiac cell types, including fibroblasts, endothelial cells, and mural cells, showed minimal GLP1R expression in both species. Human cardiac organoids recapitulated ventricular GLP1R patterns closer to adult human myocardium than murine tissue. Conclusions: These findings indicate that GLP1R is primarily extracardiac but selectively induced in failing human myocardium. Interspecies differences in cardiac GLP1R distribution highlight important limitations of murine models for mechanistic studies. In contrast, hiPSC-derived cardiac organoids recapitulate ventricular expression seen in adult human tissue and represent a possible complementary platform. Together, these data support a model in which myocardial GLP1R signalling augments systemic mechanisms to confer GLP1R agonist-mediated cardioprotection.

Background: The systemic inflammatory response index (SIRI)—an inflammatory index derived from neutrophil, monocyte, and lymphocyte counts—has shown potential in predicting cardiovascular risk. However, its prognostic value in patients with acute coronary syndrome (ACS) treated with primary percutaneous coronary intervention (pPCI) remains unclear. This study was aimed at evaluating the prognostic significance of SIRI in this specific high-risk population. Methods: We conducted a systematic search of PubMed, Embase, and The Cochrane Library up to June 2025 to identify all relevant studies about SIRI applied to patients with ACS after pPCI. The primary outcome was all-cause mortality. Among major adverse cardiovascular events (MACE), new-onset acute myocardial infarction (AMI), revascularization, and stroke were included as secondary outcomes. Risk estimates were pooled as odds ratios (OR) with 95% confidence intervals (CI). Results: A total of nine studies involving 7679 patients were included. The pooled analysis demonstrated that an elevated SIRI was a significant predictor for both all-cause mortality (OR 3.32; 95% CI 1.29 to 8.54; p = 0.01), MACE (OR 2.45; 95% CI 1.74 to 3.45; p = 0.001), new-onset AMI (OR 1.86; 95% CI 1.25 to 2.77; p = 0.001), and myocardial revascularization (OR 1.64; 95% CI 1.35 to 1.98; p = 0.001). Conclusions: Our meta-analysis demonstrates that an elevated SIRI is a useful predictor of all-cause mortality, MACE, new-onset AMI, and revascularization in patients with ACS undergoing PCI. As a simple and cost-effective index, SIRI shows significant potential for early risk stratification and may help guide clinical management in this patient population. Graphical

Sodium-glucose co-transporter (SGLT) inhibitors are a novel class of glucose-lowering drugs with beneficial pleiotropic effects that have been widely investigated in the past decade in several experimental models and patients in the absence of diabetes. There are two types of transporters: the SGLT1 isoform that is distributed across a broad range of tissues, including the cardiovascular system, and the SGLT2 isoform, which is mostly expressed in renal proximal tubular cells. It is known that inflammation and oxidative stress are key contributors to vascular damage and the progression of atherosclerosis. SGLT inhibitors have demonstrated multiple benefits that contribute to improved vascular health, including alleviation of endothelial function, anti-inflammatory and antioxidative effects, and mitigation of arterial stiffness, all contributing to blood pressure decrease. An increasing body of research has tackled the molecular and cellular mechanisms of their chronic and, more recently, acute cardiovascular beneficial effects. This narrative review specifically delves into the direct vasculoprotective effects of SGLT2 and dual SGLT1/2 inhibitors, summarizing their off-target mechanisms described in various experimental settings (animal models, animal and human cell lines/samples).

Glucagon-like peptide-1 receptor (GLP1R) agonists improve glycaemic control, induce weight loss, and consistently reduce major adverse cardiovascular events. However, the mechanistic basis of their cardioprotective effects remains incompletely understood, particularly whether benefits arise solely from systemic actions or also involve direct cardiac GLP1R signalling. To address this, we performed integrated single-cell and single-nucleus transcriptomics to map GLP1R gene expression across human and murine organs, cardiac cell types, disease states, and hiPSC-derived cardiac organoids. In humans, GLP1R expression was predominantly pancreatic, with low cardiac expression largely restricted to cardiomyocytes and consistently upregulated across ischaemic, dilated, and hypertrophic cardiomyopathy. In contrast, murine cardiac Glp1r expression was confined to endocardial cells and remained unchanged in heart disease. Other cardiac cell types, including fibroblasts, endothelial cells, and mural cells, showed minimal GLP1R expression in both species. Human cardiac organoids recapitulated ventricular GLP1R patterns closer to adult human myocardium than murine tissue. Together, these findings indicate that GLP1R is primarily extracardiac but selectively induced in failing human myocardium, supporting a model in which myocardial GLP1R signalling augments systemic mechanisms to confer GLP1R agonist-mediated cardioprotection.