Organoids are considered a novel modeling platform for studying human biology and advancing health research. With the ability to demonstrate complex 3D structure and multicellular interactions, organoids have advanced studies in all major organs as a reliable model. In this study, we generated an advanced cardiovascular organoid by using a genome-edited human pluripotent stem cell line with inducible SOX17 expression, enabling controlled endothelial specification, adjustable cell-type composition, and human heart-like morphology. Our organoids recapitulated the cardiotoxic phenotypes of FDA-approved chemotherapeutic doxorubicin, manifesting as decreased cell viability and diminished contractile activity. Cryoinjury-induced myocardial infarction in our organoids led to reduced beating, viability, and α-actinin expression, along with increased fibroblast formation, which were mitigated by Captopril. Lastly, isoproterenol treatment increased peak Ca transient amplitude and shortened APD in our organoids, consistent with previously reported β-adrenergic responses. In summary, we established a protocol for generating in vitro 3D cardiovascular organoids with controllable cellular composition and heart-like structures, providing a robust and easy-to-produce platform for future studies of human heart disease.

BACKGROUND: COVID-19 has been closely associated with coagulation abnormalities. However, existing biomarkers, including D-dimer and fibrin degradation products (FDP), exhibit limited accuracy in stratifying disease severity and predicting long-term clinical outcomes. OBJECTIVES: This study aimed to use proteomic analysis to identify plasma biomarkers associated with COVID-19 severity and prognosis, and validate their predictive utility for mortality and thromboembolic complications. METHODS: Plasma proteomic profiles were analyzed across three COVID-19 severity classes. Differential expression analysis and functional analysis were performed. Clustering analysis was used to identify proteins correlated with disease severity. Candidate biomarkers were validated in an independent cohort. Predictive performance of the biomarkers for mortality, sepsis and venous thromboembolism was evaluated using bootstrap-corrected ROC analyses and multivariable regression analyses. RESULTS: Proteomic analysis revealed progressive involvement of the coagulation and complement pathway with increasing disease severity. SERPINA1 and CD59 were identified as candidate biomarkers and exhibited significantly higher plasma levels in severe cases. Bootstrap-corrected ROC analyses demonstrated strong predictive performance: SERPINA1 achieved AUCs of 0.775 and 0.924 for 30-day and 12-month mortality, and CD59 achieved AUCs of 0.720 for sepsis; the combined model further improved prediction of 12-month mortality (AUC 0.946) and sepsis (AUC 0.904), outperforming D-dimer and FDP. Multivariable regression confirmed their independent prognostic value. CONCLUSION: This exploratory study identifies SERPINA1 and CD59 as candidate prognostic biomarkers in COVID-19, highlighting the role of coagulation and complement-related pathways in disease severity and warranting further prospective validation.

While pirtobrutinib is established in Bruton tyrosine kinase inhibitor (BTKi)-refractory disease, its role in BTKi-naïve relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) remains unclear because of the absence of direct comparative trials with second-generation covalent BTKis. We conducted a systematic literature review and Bayesian network meta-analysis of randomized controlled trials (ELEVATE-RR, ALPINE, BRUIN-CLL-314) linked by a common comparator (ibrutinib). Across 814 patients, pirtobrutinib demonstrated efficacy comparable to acalabrutinib and zanubrutinib, with no significant differences in progression-free survival (PFS) (vs acalabrutinib: HR 0.73, 95% CrI 0.44-1.20 vs zanubrutinib: HR 1.12, 95% CrI 0.67-1.89), overall survival (OS), or overall response rate (ORR). Subgroup analyses by genomic risk were inconclusive. Safety profiles were broadly similar; however, pirtobrutinib was associated with a lower risk of cardiovascular adverse events compared with zanubrutinib (OR 0.52, 95% CrI 0.31-0.88) and similar risk relative to acalabrutinib (OR 1.09, 95% CrI 0.62-1.92). In conclusion, pirtobrutinib demonstrated efficacy and tolerability comparable to those of second-generation covalent BTKis, with a potential cardiovascular safety advantage over zanubrutinib in patients with R/R BTKi-naive CLL. However, given the indirect nature of the comparison, the limited evidence base, and between-study heterogeneity, these findings should be considered exploratory.

OBJECTIVE: Mitral annular disjunction (MAD), frequently associated with Barlow's disease, links degenerative mitral regurgitation to postoperative ventricular arrhythmias and sudden cardiac death, even after technically successful valve repair. However, despite advances in mitral repair, the arrhythmic substrate associated with MAD remains insufficiently addressed in current surgical paradigms. METHODS: A systematic search of PubMed and Google Scholar (2000-2025) was conducted using keywords including "mitral annular disjunction," "mitral regurgitation," "arrhythmic mitral valve prolapse," and "mitral valve surgery." Of 264 records screened, 41 peer‑reviewed articles, prioritizing high‑impact registries and surgical cohorts, were selected for synthesis. RESULTS: MAD is associated with paradoxical annular curling and traction‑related myocardial remodeling, which may contribute to fibrosis through pathological stretch. Observational studies suggest that higher‑risk features-such as extensive MAD (≥ 5 mm, particularly ≥ 8.5 mm), late gadolinium enhancement, or syncope-are linked to increased arrhythmic vulnerability. Although modern repair techniques can eliminate anatomical MAD, pre‑existing substrate abnormalities may persist, and ventricular arrhythmias can still occur after technically successful repair. CONCLUSIONS: The extent of disjunction and the presence of associated substrate abnormalities appear to influence long‑term rhythm stability. A conceptual, hypothesis‑generating framework that integrates structural, electrical, imaging, and clinical information may help inform risk stratification. Prospective studies are needed to determine whether a risk‑stratified approach or optimized intervention timing can modify arrhythmic risk or potentially affect long‑term outcomes.

BACKGROUND: Atrial arrhythmias are a frequent and clinically significant complication in left ventricular assist device (LVAD)-supported patients, with the potential to impair right ventricular (RV) function, compromise device hemodynamics, and reduce quality of life. While atrial fibrillation (AF) has received considerable attention in this population, the distinct hemodynamic impact of typical cavotricuspid isthmus (CTI)-dependent atrial flutter and the role of catheter-based rhythm control remain poorly characterized. CASE PRESENTATION: A 60-year-old male with non-ischemic cardiomyopathy who underwent HeartMate 3 LVAD implantation as a bridge to transplantation developed typical CTI-dependent atrial flutter refractory to medical therapy, associated with marked deterioration in RV systolic function (TAPSE: 1.2 → 0.82 cm; Sm: 6.9 → 5.3 cm/s) and adverse LVAD hemodynamics. Electrical cardioversion had been attempted but failed to maintain sinus rhythm. Electrophysiological study using three-dimensional electroanatomic mapping (CARTO system, Biosense Webster) confirmed counterclockwise CTI-dependent atrial flutter. Radiofrequency (RF) ablation of the cavotricuspid isthmus achieved bidirectional conduction block and restored sinus rhythm. The procedure was performed under uninterrupted therapeutic anticoagulation with warfarin. RESULTS: At one-month follow-up, RV systolic function improved substantially (TAPSE: 0.82 → 1.19 cm; Sm: 5.3 → 6.5 cm/s), with concurrent normalization of LVAD hemodynamic parameters and complete resolution of palpitations and dyspnea. CONCLUSIONS: Catheter ablation of CTI-dependent atrial flutter in a carefully selected LVAD-supported patient yielded significant improvement in RV function, device hemodynamics, and quality of life (QoL), underscoring the potential role of rhythm control in this population.

BACKGROUND Subarachnoid hemorrhage (SAH) is a neurological emergency accounting for 5% of all strokes, with mortality exceeding 50% in patients over 80 years of age. Aneurysmal SAH is particularly lethal in the elderly due to atypical presentations, including ECG abnormalities mimicking acute coronary syndromes, leading to delayed diagnosis and high complication rates. This case report highlights the diagnostic pitfalls of SAH-induced STEMI mimicry. CASE REPORT A in their 90s White woman with a remote history of diabetes presented to the Emergency Department (ED) with sudden-onset occipital headache, nausea, and hypertensive crisis (214/68 mmHg). Initial electrocardiography (ECG) showed ST-segment elevations (STEMI) in leads I/aVL with reciprocal depressions in III/aVF, prompting STEMI activation despite normal troponin levels. Emergency computed tomography angiography (CTA) revealed a ruptured 3×1 mm anterior communicating artery (ACOM) aneurysm with Fisher Grade 3 SAH. Echocardiography at admission showed normal ejection and no wall motion abnormalities. ECG performed 1 day after admission showed complete resolution of the ST-T segment changes and the patient did not require any coronary intervention. Despite successful endovascular coiling, her hospital course was complicated by Cronobacter sakazakii bacteremia, embolic infarcts, and refractory cachexia. Palliative care was initiated on hospital day 14 due to irreversible functional decline, culminating in hospice transition. CONCLUSIONS SAH-mediated autonomic dysregulation can produce STEMI-like ECG changes even in the absence of coronary ischemia. Geriatric SAH management requires balancing intervention risks against frailty and comorbidities. Early recognition of SAH-induced ECG changes from autonomic-mediated repolarization abnormalities is essential to avoid misdiagnosis and guide appropriate intervention, particularly in older patients in whom comorbidities and frailty complicate recovery trajectories.

BACKGROUND: Thyroid-stimulating hormone (TSH)-secreting pituitary adenoma (TSHoma) is a rare functional pituitary tumor that secretes TSH independently, thus stimulating the synthesis and secretion of thyroid hormone. Its clinical manifestation is central hyperthyroidism, and it is easily misdiagnosed as Graves' disease. At present, the treatment of TSHoma includes surgery, medication, and radiotherapy, and transsphenoidal pituitary surgery remains the first-line treatment. CASE PRESENTATION: This case involved a 61-year-old Chinese male with clinical manifestations of weight loss, heart palpitations, and shortness of breath, both thyroid hormone and TSH are elevated. The patient was diagnosed with a TSH/growth hormone (GH) co-secreting pituitary adenoma by serological examination, magnetic resonance imaging of the pituitary gland, and related functional tests. Due to thrombocytopenia and heart disease, the patient was deemed a poor candidate for immediate surgery and was therefore treated with octreotide. Thyroid function tests normalized after medication, and the diagnosis of TSHoma was verified. CONCLUSION: Although TSHoma is rare, it is not difficult to diagnose based on clinical presentation, ancillary examination, and functional testing. Thyroid hormone resistance syndrome is very similar to it and is therefore easily misdiagnosed. Early diagnosis and appropriate treatment can effectively control the disease and even achieve a clinical cure.

BACKGROUND: Turner syndrome (TS) is associated with cardiovascular abnormalities and metabolic risk, but karyotype-specific phenotypes remain incompletely defined, particularly in pediatric and adolescent cohorts assessed by transthoracic echocardiography (TTE). METHODS: We conducted a retrospective cross-sectional study of 289 patients with TS evaluated between October 2016 and October 2023. Patients were grouped as 45,X monosomy (n = 149) or mosaic/structural karyotypes (n = 140). Baseline or preoperative TTE data were used. The primary endpoint was a clinically relevant structural cardiovascular disease (CVD) composite based on explicit baseline/preoperative diagnoses of major lesions; patent foramen ovale, isolated persistent left superior vena cava, and minor valve regurgitation were treated as descriptive findings. Aortic dilatation based on ASI > 20 mm/m² was analyzed separately as an aortic-size phenotype. RESULTS: The structural CVD composite was more frequent in the 45,X group than in the mosaic/structural group (49/149 [32.9%] vs. 26/140 [18.6%], p = 0.006). In multivariable logistic regression, 45,X remained associated with the structural CVD composite after adjustment for age, BMI, systolic blood pressure, LDL-C, and HOMA-IR (OR 1.88, 95% CI 1.05-3.35; p = 0.033). Aortic dilatation by ASI > 20 mm/m² did not differ significantly between groups (28.9% vs. 32.9%, p = 0.462). Elevated total cholesterol was more frequent in the 45,X group, and LDL-C was independently associated with the structural CVD composite. LVDD was modestly lower in the 45,X group (33.6 ± 6.6 vs. 35.4 ± 6.4 mm; p = 0.017). CONCLUSIONS: In this single-center TS cohort, 45,X monosomy was associated with a higher burden of clinically relevant structural cardiovascular abnormalities and an adverse lipid profile, whereas ASI-defined aortic dilatation alone did not differ significantly by karyotype. These findings support karyotype-aware cardiovascular surveillance, while underscoring the need for cautious interpretation of small TTE differences and validation in multicenter longitudinal studies.

BACKGROUND: Multimorbidity, defined here as the co-occurrence of cardiovascular disease (CVD), type 2 diabetes (T2D), and/or cancer is a major public health challenge. However, its underlying biological mechanisms remain unclear, limiting progress toward identifying shared interventional targets. METHODS: We applied large-scale plasma proteomics (SomaScan 7k; 7,289 aptamers) in 13,270 European Prospective Investigation into Cancer and Nutrition (EPIC) participants to identify protein signatures of multimorbidity. We modelled multimorbidity progression as sequential disease transitions, i.e., from the disease-free state at baseline to a first disease and from the first disease to a second disease. Using weighted multivariable Cox regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for risk of cancer, CVD, and T2D. Risk associations were replicated using Olink proteomics in UK Biobank (N = 44,567). RESULTS: We identified 422 aptamers associated with more than one disease (FDR-corrected P < 0.05), e.g., 265 aptamers were shared between CVD and T2D. Thirty-eight aptamers were associated with multimorbidity progression. Among these, 27 aptamers showed consistent positive associations across sequential disease transitions, including SEMA6A (disease-free to cancer HR: 1.14; 95% CI 1.05, 1.23; cancer to T2D HR: 2.61; 95% CI 1.76, 3.80). Four aptamers showed consistent inverse associations, including NLGN1 (disease-free to T2D HR: 0.72; 95% CI 0.61, 0.84; T2D to cancer HR: 0.57; 95% CI 0.43, 0.75). Nineteen of the identified proteins were also measured in UK Biobank, with broadly consistent associations. CONCLUSIONS: This study identifies candidate proteins that may indicate molecular pathways to multimorbidity of cardiometabolic diseases and cancer. Future studies should evaluate the causal roles of these proteins for targeted interventions and risk stratification.

BACKGROUND: Chronic Kidney Disease (CKD) affects over 674 million people globally and can lead to kidney failure, which significantly impairs quality and duration of life. While various oral pharmacological treatment options are available, limited research exists on how patients and carers prioritise treatment attributes. This study explored preferences for oral CKD medication across eight countries, involving 2,324 participants (1,511 patients and 813 carers). METHODS: A Discrete Choice Experiment (DCE) was conducted in which participants completed seven hypothetical scenarios, each with two unlabelled treatment options and a "neither" (or "stay on current treatment") option. Five attributes were assessed: delay in dialysis or transplant, life extension, reduced risk of heart failure hospitalisation, risk of side effects, and out-of-pocket costs. Data were analysed using Mixed Multinomial Logit models, generating separate patient and carer models for each country (16 models), enabling cross-country comparisons. RESULTS: Participants across countries placed the highest importance on delaying dialysis or transplant, followed by life extension, with minimising treatment side effects ranked next. They preferred longer delays for dialysis or transplant, with the seven-year delay being most preferred. Regional and patient-carer variations were observed in attribute importance. Model parameters were used to calculate utility for treatment profiles and simulate preference shares, enabling country-level comparisons. CONCLUSION: Patients and carers consistently prioritised oral medications that delay the need for dialysis or transplant and extend life, although the relative importance of these attributes differed by country and respondent group. The choice of oral medication in CKD is preference-sensitive, and these results have direct implications for shared decision-making in clinical practice. To support application of these findings, we have developed an interactive dashboard that simulates the impact of medication attributes on predicted uptake across all eight countries: https://cappre.shinyapps.io/CKD_Dapa_DCE/.

BACKGROUND: Splice-altering variants (SAVs), particularly those outside canonical splice sites, are an underappreciated contributor to inherited cardiovascular diseases. In arrhythmogenic cardiomyopathy (ACM), these variants frequently remain classified as of uncertain significance (VUS) due to limited predictive power and lack of transcript-level evidence, constraining genetic yield and clinical management. Our study aimed to determine the functional impact of SAVs in ACM genes and refine their classification using ACMG/AMP and ClinGen SVI criteria. METHODS: SAVs identified in 200 ACM probands underwent SpliceAI prediction, GTEx cardiac exon-usage annotation, and functional assessment using pSPL3-based minigene assays. Aberrant transcripts were quantified using Percent Splicing Alteration (PSA). Segregation data and ACMG/AMP criteria refined by ClinGen SVI were applied to integrate functional and clinical evidence for classification. RESULTS: Aberrant splicing was confirmed in 9/20 variants (45%), including synonymous, missense, and non-canonical intronic changes. SpliceAI scores correlated strongly with PSA values (R²=0.86). Case-control burden testing revealed significant enrichment of splice-altering variants in DSP, DSG2, DSC2 and FLNC. Integrating predictive algorithms with experimental validation and segregation analysis markedly enhances reclassification of 16/20 variants (80%). CONCLUSION: Splicing defects beyond canonical sites significantly shape ACM genetic landscape. Integrating predictive models with experimental validation clarifies uncertain variants bridging the gap between genomic uncertainty and clinical decision-making.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

OBJECTIVE: The relationships of dietary live microbe intake (DLMI) with all-cause mortality (ACM) and cardiovascular mortality (CVM) in stroke patients remain unclear. This study examined the links of DLMI with ACM and CVM in stroke patients. METHODS: A secondary analysis of the publicly available, fixed-cycle National Health and Nutrition Examination Survey (NHANES) dataset was performed in this study. As such, no a priori sample size calculation was performed. All eligible participants aged ≥ 40 years with complete data from the 2003-2018 survey cycles served as the analytical sample. The stroke history was based on self-report without further specification of subtype (ischemic vs. hemorrhagic). Participants were followed until December 31, 2019, with a median follow-up of 6.0 years. DLMI was estimated based on a single 24-hour dietary recall and classified into low, medium, and high intake categories as an indicator of a dietary pattern characterized by the consumption of live-microbe-rich foods. Cox models, stratified, and sensitivity analyses were employed to ascertain the links of DLMI with ACM and CVM in stroke patients. RESULTS: This study included 1,313 stroke patients, among whom 539 experienced ACM and 209 experienced CVM. In the Cox models, compared with low DLMI, high DLMI had a lower incidence of ACM [Model 1: HR = 0.63 (95% CI: 0.44-0.91, p = 0.013); Model 2: HR = 0.61 (95% CI: 0.44-0.84, p = 0.003); Model 3: HR = 0.63 (95% CI: 0.46-0.88, p = 0.007)]. However, no significant association was observed between high DLMI and CVM. Subgroup and sensitivity analyses generally supported the robustness of these results. CONCLUSION: Higher DLMI was associated with a lower risk of ACM among stroke survivors in this study. These exploratory findings highlight DLMI as a candidate for further investigation in dietary intervention strategies for this population. Future prospective studies are needed to establish its role and optimal implementation.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death globally. The C-reactive protein-triglyceride-glucose index (CTI) integrates inflammation and insulin resistance. However, research on cumulative effects and longitudinal patterns of CTI combined with body shape indices for CVD risk assessment is limited. We examined association of cumulative CTI-CVAI (CumCTI-CVAI) exposure and longitudinal patterns with new-onset CVD, heart disease, and stroke in middle-aged and older Chinese adults. METHODS: Data were from the CHARLS. A two-stage design (cross-sectional screening + longitudinal validation) was employed. Cross-sectional analysis (n = 9,475) identified CTI-CVAI as the optimal composite indicator. In longitudinal analysis (n = 3,803; median follow-up 56.6 months), cumulative CTI-CVAI was calculated using time-weighted averages (2011-2015). The landmark time was set at 2015 to avoid immortal time bias. Cox regression, RCS, K-means clustering, subgroup analyses, and sensitivity analyses (lag analysis, interval deletion analysis, competing risk model, etc.) were performed. NRI and IDI were calculated. A nomogram was constructed using LASSO regression, with AUC for discrimination and calibration/DCA for clinical utility. RESULTS: Cross-sectional analysis identified CTI-CVAI as the optimal indicator (AUC = 0.617). In longitudinal analysis, each 1-SD increase in CumCTI-CVAI was associated with a 9% higher CVD risk (HR = 1.09, 95%CI:1.04-1.14, P < 0.001). The highest tertile had a 63% higher risk than the lowest (HR = 1.63, 95%CI:1.33-2.00). A nonlinear dose-response relationship was observed (P < 0.001; inflection point:6192.15). For secondary outcomes, each 1-SD increase in CumCTI-CVAI was associated with a 7% higher risk of heart disease (HR = 1.07, 95%CI:1.01-1.14) and a 16% higher risk of stroke (HR = 1.16, 95%CI:1.06-1.27). K-means clustering identified three exposure patterns: low-stable, moderate-stable, and high-stable. Compared to the low-stable group, the high-stable group had 68% higher CVD risk (HR = 1.68), 43% higher heart disease risk (HR = 1.43), and 133% higher stroke risk (HR = 2.33). Hierarchical NRI/IDI analysis showed that adding inflammation to TyG-CVAI significantly improved reclassification (IDI: from 0.018 to 0.090, P < 0.001). The nomogram (age, lung disease, CumCTI-CVAI) achieved AUCs of 0.618-0.638. CONCLUSION: Elevated cumulative CTI-CVAI exposure and unfavorable longitudinal patterns are independently associated with increased CVD risk in middle-aged and older Chinese adults. CTI-CVAI provides incremental predictive value beyond obesity and insulin resistance alone, supporting its potential as an adjunctive screening tool in primary care.

AIMS: The stress hyperglycemia ratio (SHR) has been associated with adverse outcomes in patients with cardiovascular diseases. Recent studies have also linked higher SHR to increased mortality after cardiac surgery, including analyses using the MIMIC-IV database, and in patients undergoing CABG for acute myocardial infarction. Therefore, the present study should be viewed as an incremental and exploratory analysis rather than as a wholly novel investigation. However, the dose-response pattern and clinically relevant risk thresholds of SHR in an undifferentiated extracorporeal circulation (ECC)-assisted open-heart surgery population remain incompletely characterized. Given the uncertain perioperative timing of glucose measurements in MIMIC-IV, SHR was interpreted as an aggregated prognostic marker rather than a direct measure of intraoperative or immediate postoperative metabolic stress. This study aims to investigate the association between SHR and short-term mortality risk in this patient cohort. METHODS: A retrospective cohort study was conducted by analyzing data from 1,221 patients who underwent extracorporeal circulation during open-heart surgery, obtained from the MIMIC-IV (version 3.1) database. Patients were divided into quartiles based on SHR levels. Cox proportional hazards models, including a segmented variant, were used to evaluate the association between SHR and 180-day mortality. Glucose and HbA1c values were obtained from available laboratory records within the first 24 h of ICU admission; however, precise timing relative to surgery, ECC initiation, or ICU arrival could not be standardized. Important intraoperative parameters, including cardiopulmonary bypass duration and aortic cross-clamp time, were not available as reliable structured variables and therefore could not be adjusted for. In addition, a substantial proportion of potentially eligible patients were excluded because SHR could not be calculated owing to missing glucose or HbA1c measurements, which may have introduced selection bias. RESULTS: Within the study cohort, 63 patients (5.16%) died within 180 days. Following multivariable adjustment, SHR showed a nonlinear, threshold-like association with 180-day mortality, with an estimated inflection point at 0.97. The increase in mortality risk was more clearly observed at SHR levels above this point, whereas the association below this point was not statistically significant. Therefore, the spline-derived point should be interpreted as exploratory rather than as a clinically validated cutoff or treatment target. Compared to participants with SHR levels below the inflection point, those with higher SHR levels exhibited a fourfold increased risk of 180-day mortality (HR 4.62; 95% CI 2.67-7.95). CONCLUSION: Our findings indicate that an elevated SHR, measured by the glucose/HbA1c ratio, is associated with an increased risk of short-term mortality in patients undergoing extracorporeal circulation during open-heart surgery. Because of the retrospective design, lack of precise perioperative glucose timing, substantial exclusion of patients with missing glycemic data, uncertain completeness of post-discharge mortality ascertainment, and inability to adjust for key intraoperative variables, these findings should be interpreted as prognostic and hypothesis-generating rather than causal. The observed nonlinear pattern may help refine risk stratification, but the proposed inflection point requires validation in prospective studies with standardized perioperative glucose monitoring.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Type 1 Diabetes (T1D), but a subset of individuals remains free from macrovascular or renal complications despite decades of hyperglycaemia and a significant risk factor burden. We used a targeted proteomic approach (Olink Cardiovascular panel III, targeting 92 proteins) to characterize the proteomic profile of cardiovascular resilience in T1D by comparing 92 patients with long-standing T1D (age 59.8 [53.2, 69.1], duration 40.0 [35.0, 45.2] years) free from macrovascular complications or nephropathy against a reference group of 57 T1D patients with accelerated vascular pathology (age 42.0 [32.0, 56.0], duration 22.0 [18.0, 27.0] years), proliferative retinopathy and/or nephropathy in relation to diabetes duration, termed Rapid Progressors (RP). Twenty proteins differed significantly between RP and Escapers (False Discovery Rate [FDR] < 0.05) after adjustment for age, sex, HbA1c, and eGFR: Caspase-3 was significantly higher in RP (Adjusted difference: + 2.12 Normalized Protein eXpression [NPX], p < 0.001). Proteins associated with platelet activation and leukocyte adhesion with increased levels in RP included Junctional Adhesion Molecule A (+ 1.40 NPX), Glycoprotein VI (GP6: + 1.29 NPX), and P-Selectin (+ 0.82 NPX) (all p < 0.001). PECAM-1 (+ 0.55 NPX) and TNFRSF14 (+ 0.43 NPX), were also elevated. RP also showed higher levels of metabolic and tissue-remodelling proteins; Transferrin Receptor (+ 0.53 NPX) and Fatty Acid Binding Protein 4 (+ 0.52 NPX), as well as higher Bleomycin Hydrolase, Trefoil Factor 3, GDF-15, U-PAR, and Cystatin B. Conversely, von Willebrand Factor (vWF) levels (- 1.35 NPX, p < 0.001) and Paraoxonase 3 (PON3) was lower in RP (- 0.34 NPX, p = 0.003). In conclusion, escaping complications in long-term T1D appears to be associated with active molecular mechanisms. Progression is marked by apoptosis (Caspase-3), fibrosis (CHI3L1) and platelet activation (GP6), whereas resilience is associated with a distinct signature involving higher vWF and PON3. These findings highlight a profound biological divergence between extreme T1D phenotypes and provide a foundation for further research into vascular resilience.

BACKGROUND: Lower-extremity peripheral artery disease often requires endovascular therapy. Target-lesion restenosis (TLRS) remains frequent, but current risk stratification is limited. METHODS: We retrospectively analyzed 1,005 lesions from 917 patients undergoing endovascular therapy for lower-extremity atherosclerotic disease at a single center (2019-2024) with scheduled surveillance (approximately 6, 12, and 24 months) and administrative censoring at 36 months. The primary endpoint was time to first TLRS ≥ 50%, adjudicated by duplex ultrasound (peak systolic velocity ratio criteria) or CTA/DSA when available. Lesion‑level Fine-Gray competing‑risk models (death as a competing event) with patient‑level clustering were used. A prespecified Core model (clinical, anatomic, procedural/device covariates and C‑reactive protein) was compared with an Extended model additionally including the Atherogenic Index of Plasma (AIP) and log‑transformed Systemic Immune-Inflammation Index (SII). Models were internally validated by 1,000 bootstrap resamples and assessed at the 24‑month horizon using the C‑index, calibration, Brier score, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision‑curve analysis. RESULTS: Among 917 patients (1,005 lesions), mean age was 75.2 ± 11.7 years and 68.6% were male. At 24 months, cumulative incidences were 31.4% for TLRS, 14.9% for clinically driven target‑lesion revascularization, and 12.3% for death. In multivariable analyses, GLASS stage III, lesion length ≥ 150 mm, residual stenosis > 20%, chronic kidney disease, and Rutherford class 4-6 predicted higher TLRS risk, whereas good distal runoff was protective. In the Extended model, AIP and SII remained independent predictors and improved the optimism‑corrected 24‑month C‑index from 0.68 to 0.73 (Δ0.05, p = 0.002), reduced the Brier score (0.19 to 0.17), yielded positive IDI and NRI, and preserved good calibration. Exploratory analyses suggested lower TLRS risk with cilostazol and low‑dose rivaroxaban plus aspirin. CONCLUSIONS: AIP and SII improved lesion-level prediction of TLRS beyond conventional covariates. The Extended model may support risk-tiered surveillance after endovascular therapy; external validation is warranted.

BACKGROUND AND PURPOSE: Alcoholic cardiomyopathy (ACM) is a serious complication of chronic and acute alcohol abuse that can progress to heart failure (HF). Currently, no curative drug exists for ACM, and heart transplantation remains the only definitive option. Although mineralocorticoid receptor (MR) antagonists (MRAs) are a cornerstone of HF management, their role in ethanol cardiotoxicity remains poorly defined. Because ethanol elevates aldosterone levels, targeting the aldosterone/MR axis may represent a promising therapeutic strategy. This study investigated the effects of finerenone, a next-generation non-steroidal MRA, in both in vitro and in vivo models of acute alcoholic myocardial injury. METHODS: H9c2 cardiomyocytes were exposed to ethanol with or without finerenone, and cell viability, apoptosis, mitochondrial dynamics, and proinflammatory signaling were assessed to evaluate cytoprotective effects. In vivo, a murine acute alcoholic myocardial injury model was generated by three days of ethanol exposure with concurrent finerenone administration. Circulating myocardial injury marker CK-MB was measured, and myocardial tissue was analyzed for MR/aldosterone levels, apoptosis, inflammation, macrophage infiltration, and mitochondrial fission/fusion dynamics. RESULTS: Finerenone attenuated ethanol-induced MR upregulation, apoptosis, mitochondrial fragmentation, and pro-inflammatory signaling in H9c2 cardiomyocytes. In mice, finerenone further reduced the ethanol-induced increase in serum CK-MB and attenuated ethanol-induced myocardial cell death and damage. Moreover, ethanol-induced myocardial inflammation, oxidative stress, and mitochondrial dysfunction were further reduced in this mouse model of ethanol cardiotoxicity following finerenone administration. Together, the non-steroidal MRA finerenone may attenuate acute ethanol-induced cardiotoxicity by regulating inflammatory pathways, oxidative stress, and mitochondrial function. CONCLUSIONS AND IMPLICATIONS: Overall, these findings support the conclusion that the next-generation MRA finerenone attenuates acute ethanol-induced myocardial cell death, inflammation, oxidative stress, and mitochondrial dysfunction in vitro and in vivo. Finerenone may act as a novel protective agent against acute alcoholic myocardial injury in the future, but further clinical evidence is required to support this preclinical finding.

BACKGROUND: Cardiac surgery, particularly open-heart procedures such as coronary artery bypass grafting and valve surgery, is one of the most common curative options for ischemic heart disease, congenital heart defects, and valvular disease but is also associated with severe hemodynamic hazards. Intravenous anesthetic agents such as propofol and dexmedetomidine are employed to sedate such patients in routine clinical practice. There is, however, conflicting and sporadic evidence in the literature regarding the relative effects of these two agents on hemodynamic parameters. This review systematically analyzed and contrasted the hemodynamic effects of dexmedetomidine and propofol in patients undergoing cardiac surgery. METHODS: Systematic searches in the PubMed, Scopus, Embase, Web of Science, CINAHL, Cochrane Library, and Google Scholar databases were performed for randomized controlled trials published between December 2000 and 18 January 2025. Studies in which adult patients underwent cardiac surgery (e.g., coronary artery bypass grafting or valve surgery) and received dexmedetomidine or propofol for intraoperative or immediate postoperative intensive care unit (ICU) sedation were included. This was a PRISMA-guided review, and the extracted data were meta-analyzed and descriptively analyzed. The primary outcomes were hypotension and bradycardia. Secondary outcomes included vasopressor requirements, tachycardia, heart rate, atrial fibrillation (AF), ventricular tachycardia, and bleeding. Odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs) were pooled via random-effects models. Sensitivity analysis and assessment of publication bias were performed as needed. RESULTS: Compared with propofol, dexmedetomidine significantly increased the risk for hypotension (OR = 1.76; 95% CI: 1.25-2.48; p < 0.001) and bradycardia (OR = 2.89; 95% CI: 1.28-6.49; p = 0.01). Alternatively, dexmedetomidine significantly reduced vasopressor requirements (OR = 0.52; 95% CI: 0.32-0.84; p = 0.007) and lowered the heart rate (MD = - 4.78 beats/min; 95% CI: - 7.47 to - 2.26; p < 0.001). No considerable differences were observed in tachycardia, ventricular tachycardia, AF, or bleeding. Sensitivity analysis was employed to check for the stability of the findings, and no publication bias was detected. CONCLUSION: This meta-analysis revealed that, compared with propofol, dexmedetomidine is associated with a greater incidence of hypotension and bradycardia but lower vasopressor requirements. No considerable differences were observed in ventricular tachycardia, AF, bleeding or any other hemodynamic parameters. Evidence for several secondary outcomes remains limited; therefore, findings for less frequently reported endpoints should be interpreted cautiously. CLINICAL TRIAL NUMBER: Not applicable.

Patient Preference Information (PPI) is increasingly applied across the medical device lifecycle to inform product design, clinical trial planning, regulatory submissions, labeling, and shared decision-making. However, cross-company learnings remain fragmented. This review synthesizes five recent industry case studies illustrating diverse applications of PPI: Edwards Lifesciences (transcatheter tricuspid valve replacement), CVRx (Barostim neuromodulation therapy for heart failure), Medtronic (renal denervation for hypertension), Johnson and Johnson (lung cancer interception therapy), and Abbott (leadless pacemaker feature optimization). Across cases, quantitative stated-preference methods, particularly discrete-choice experiments, predominated. Evidence informed pivotal trial design and regulatory submissions (Edwards Lifesciences, Medtronic), FDA-approved labeling (CVRx), preventive therapy development (Johnson and Johnson), and device feature prioritization post-approval (Abbott). Common enablers included early engagement with regulators, rigorous instrument development with qualitative pretesting, and proactive dissemination. Recurring challenges involved recruiting representative samples, addressing preference heterogeneity, and demonstrating return on investment. These findings underscore the feasibility and value of PPI in advancing patient-centered innovation and regulatory decision-making across the medical device lifecycle.

BACKGROUND: Emerging evidence shows that morning chronotype is associated with a reduced risk of breast cancer, yet biological mechanisms remain unclear. This study aimed to identify circulating proteins that mediate this association. METHOD: We employed a two-step Mendelian randomization approach using European-ancestry genome-wide association studies. Exposure data on self-reported morning chronotype were from the UK Biobank and 23andMe (372,765 cases, 278,530 controls). Mediators included 4907 plasma proteins measured by SomaScan in 35,559 Icelandic individuals. Outcome data for overall breast cancer and subtypes were sourced from the Breast Cancer Association Consortium (133,384 cases, 113,789 controls) and FinnGen DF 11 (20,586 cases, 201,494 controls). We identified mediators through concordant step 1 and step 2 associations, followed by colocalization (posterior probability > 0.80) and mediation analyses. Single-cell RNA sequencing in human breast cancer tissues was used to assess biological relevance. RESULTS: Genetically predicted morning chronotype is associated with a lower risk of breast cancer (odds ratio, 0.93; 95% confidence interval, 0.89 to 0.98). Morning chronotype is associated with 895 plasma proteins, of which seven proteins show inverse associations with overall breast cancer (false discovery rate <0.05). Colocalization support five mediators sharing causal variants for protein levels and breast cancer susceptibility. Mediation and single-cell RNA sequencing analyses further confirm their biological roles. DISCUSSION: These findings uncover plausible biological pathways linking morning chronotype to reduced breast cancer risk, nominating ADAM15, BTN2A1, CASP8, PDCD6, and RSPO3 as potential therapeutic targets. This work bridges epidemiological observations with mechanistic insights, offering a translational roadmap for chronotype-based interventions.

BACKGROUND: Vascular cognitive impairment (VCI) is a devastating clinical endpoint of microvascular senescence. However, the mechanisms by which age-related focal vascular insults cause systemic brain network failure and molecular vulnerability remain unknown. To decode the multi-scale neurobiology of VCI, we conducted a systematic review and meta-analysis of whole-brain voxel-based morphometry studies comparing patients with VCI and healthy controls. METHODS: We used coordinate-based network mapping on a normative functional connectome to identify convergent structural atrophy networks. To decode multi-scale biological substrates, we checked the resulting macroscopic topography against the Allen Human Brain Atlas and 28 positron emission tomography-derived neurotransmitter maps. RESULTS: 18 studies contributed to the analysis, including 682 VCI patients and 643 healthy controls. VCI-related atrophy, despite appearing disparate, functionally converges onto a robust macroscopic architecture that is anchored predominantly in the somatomotor and salience networks. Transcriptomic profiling further showed that this network colocalizes significantly with Layer 6 corticothalamic and subcortical projection neurons. These neuron populations feature exceptionally long axonal projections, a property that heightens their metabolic susceptibility to chronic hypoperfusion. At the neurochemical level, this structural degradation exhibited profound spatial coherence with the macroscopic distribution of dopamine transporter (DAT) and 5-hydroxytryptamine transporter (5‑HTT). CONCLUSION: These findings suggest that VCI may represent a quintessential "disconnection syndrome" associated with the vulnerability of long-range projection pathways to vascular aging, providing a novel multi-scale neurobiological template to identify network-level targets for intervention.

Hypertension (HTN) is a leading global cause of cardiovascular disease (CVD) and all-cause mortality, underscoring the need for early detection and intervention. This study aimed to develop a machine learning (ML)-based predictive framework for HTN using routinely available hematologic and clinical parameters. We analyzed data from the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) study (2010-2020). From an initial 9,704 participants, 4,923 individuals (3,033 without and 1,890 with incident HTN) were included after applying predefined inclusion/exclusion criteria and preprocessing. Predictors included hematologic biomarkers (WBC, RBC, MCV, PLT, RDW, PDW, NLR) and clinical/demographic variables (age, sex, smoking, BMI, GFR, physical activity). Missing values (< 10% for most variables) were addressed via median imputation for continuous features. We employed multiple ML algorithms (XGBoost, LightGBM, logistic regression, decision trees, random forests, gradient boosting, k-nearest neighbors, naive Bayes, ExtraTrees, AdaBoost) to develop and compare models. Following model training and performance-based ranking, XGBoost emerged as the top-performing classifier, achieving a ROC-AUC of 0.66 (95% CI: 0.63-0.69). Feature importance analysis identified age, BMI, RBC count, and MCV as the most influential predictors, with consistent rankings across other models. All models exhibited stable performance across training and test sets, indicating minimal overfitting. Our findings demonstrate an ML-driven framework exploring potential signals in HTN risk using routinely available clinical and hematologic data. While the predictive performance reflects the inherent challenge of forecasting a multifactorial disease from baseline variables, this work establishes a transparent, interpretable exploratory benchmark and identifies key modifiable predictors for future validation and enhancement in more comprehensive datasets.

BACKGROUND: Chromodomain helicase DNA-binding (CHD) proteins are ATP-dependent chromatin remodelers that regulate chromatin accessibility, genome organization, and lineage-specific transcription during embryonic development. There are nine members of this family of proteins. Increasing genetic and functional evidence links mutations in multiple CHD genes to congenital-heart disease, arrhythmias, and cardiomyopathies. However, the stage-specific contributions of individual CHD-family members to cardiac development and functional maturation remain incompletely defined. DATA SOURCES: This narrative review summarizes studies retrieved from the PubMed database that investigate CHD chromatin remodelers in heart development and cardiac disease, with an emphasis on genetic models, developmental analyses, and recent multi-omics approaches. RESULTS: Available evidence indicates that distinct CHD-family members contribute to cardiac development with different levels of support across human genetics, in vivo models, and stem-cell systems. CHD7 has the strongest combined evidence base, including human syndromic genetics and mouse lineage-specific studies, supporting roles in enhancer accessibility, second-heart-field or neural-crest programs, outflow-tract morphogenesis, and later cardiomyocyte maturation. CHD3 and CHD4, as ATPase subunits of the nucleosome remodeling and deacetylase complex, are supported mainly by mouse developmental studies and emerging human genetic data indicating functions in chamber specification, maintenance of lineage boundary, and developmental gene silencing. For CHD8, direct cardiac evidence remains limited. Available data suggest roles in cardiomyocyte survival, ventricular growth, sarcomeric organization, and metabolic homeostasis, but several mechanistic interpretations are inferred from stem-cell or non-cardiac systems. Direct cardiac roles of CHD1, CHD2, CHD5, CHD6, and CHD9 remain poorly defined. CONCLUSIONS: Current studies support a working model in which CHD remodelers shape enhancer activity, transcription-factor occupancy, and chromatin accessibility during cardiac morphogenesis and maturation. However, coordinated regulation across CHD-family members has not yet been directly established experimentally. Future progress will depend on integrative genetics, time-resolved multi-omics, and cardiac organoid/in vivo validation.