Citations

ABSTRACT This study aims to identify and characterize fenestrations in the aortic and pulmonary valves using an endoscopic approach and compare their prevalence and morphology in adult and fetal hearts. The research explores whether these fenestrations are congenital or acquired and their potential clinical implications. We analyzed 41 adult human hearts (mean age: 74.25 years; range: 62–92) and 97 fetal human hearts (mean gestational age: 26 weeks; range: 12–40). Specimens were preserved in alcohol‐phenol‐formaldehyde and examined using a Stryker 5 mm 0 degree endoscope to visualize valve structures in situ, followed by post‐endoscopic dissection. Two independent investigators assessed the specimens for fenestration prevalence, distribution, and morphology, categorized into ovoid, filamentous, and fenestrated types. Fenestrations were absent in all fetal hearts. Fenestrations were identified in 75.61% of adult hearts (31/41), with 74 fenestrations observed in total. Of these, 41 were in the pulmonary valve and 33 in the aortic valve. Ovoid fenestrations predominated in both valves (aortic: 76.3%, pulmonary: 85%), with significant distribution along leaflet edges, particularly in the left coronary and semilunar leaflets. No correlation with age or sex was found. The findings from this study suggest that valve fenestrations are more likely to be acquired postnatally, rather than representing congenital anomalies. The complete absence of fenestrations in all fetal heart specimens, contrasted with their high prevalence in adult hearts, supports this hypothesis. While our results do not directly prove a causal relationship, they align with prior literature proposing that biomechanical factors, such as cumulative leaflet stress, turbulent flow, and repeated coaptation, may contribute to the formation of fenestrations over time. These insights into the prevalence, morphology and leaflet distribution of fenestrations provide a valuable foundation for future research investigating their etiology, clinical significance, and potential role in valve dysfunction.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

ABSTRACT Background and Aims It remains unclear whether different factors influence 30‐ and 90‐day readmission rates. We identified predictors of 90‐day mortality in a global cohort of hospitalised patients with cirrhosis. Methods Variables associated with 30‐ and 90‐day post‐discharge readmission, liver transplantation (LT), and mortality were compared in prospectively enrolled, non‐electively hospitalised adult patients with cirrhosis. Results We enrolled 4208 patients from 125 centres across 37 countries. Alcohol‐related liver disease was the most common aetiology of cirrhosis (40%), followed by hepatitis B virus infection (21%); 47% were readmitted, 8% received liver transplantation (LT), and 23% died within 90 days post‐discharge. In multivariable analysis, country income was significantly associated with both 30‐ and 90‐day readmission rates, the receipt of LT, and mortality within 30 and 90 days post‐discharge (all p ‐values < 0.001). Independent predictors of higher rates of 30‐ and 90‐day readmissions, respectively, were disease severity ( p < 0.001, p = 0.003), prior ascites ( p = 0.025, p = 0.016), prior hospitalisation ( p < 0.001), hyponatremia ( p < 0.001, p = 0.008), and in‐hospital vasopressor use ( p = 0.002, p = 0.011). Prior variceal bleeding independently predicted higher 90‐day readmission rates, whereas age, disease severity, mechanical ventilation, and in‐hospital vasopressor use (all, p < 0.001) increased odds of 30‐ and 90‐day post‐discharge death. Additionally, admission ( p = 0.011) and nosocomial ( p = 0.022) infections increased the odds of 90‐day post‐discharge death. Conclusion In a global cohort of hospitalised patients with cirrhosis, patients in high‐income countries exhibited the highest rates of 30‐ and 90‐day readmission, alongside lower mortality rates and a higher incidence of LT. Variables that predict 30‐day readmission also predicted 90‐day readmission. Understanding these disparities is essential for achieving health equity.

Background: Total kidney volume (TKV), a prognostic biomarker in ADPKD, is used to stratify high risk individuals. eGFR measures may carry significant error in ADPKD compared to measured GFR(mGFR). This retrospective study investigates the association between height adjusted TKV (htTKV) and eGFR derived from race-free CKD-EPI equations utilizing creatinine and cystatin C. Methods: eGFR was calculated using 3 race-free CKD-EPI formulas: creatinine-based (CKD-EPI creatinine), cystatin C (CKD-EPI cys), and creatinine-cystatin C (CKD-EPI creatinine-cystatin C) equations on 697 Mayo Clinic ADPKD patients. Correlations between eGFR and TKV measures were estimated and stratified by MIC class risk groups and CKD. Linear regression models were computed to predict ln(htTKV) from the 3 eGFR data sets. The eGFR measures were compared to iothalamate-based mGFR in a subset of patients (n=50). Results: A correlation between eGFR measures and htTKV (Pearson correlation r of -0.53 to -0.54), varied by MIC stratification. Pearson correlation was -0.47 to -0.48 for MIC 1A and 1B, -0.67 to -0.71 for MIC 1C, and -0.67 to -0.68 for MIC 1D and 1E. All equations were significantly associated with htTKV levels, with similar adjusted beta values (95% CI) of -0.15 (-0.17 to -0.13), -0.14 (-0.16 to -0.12), -0.15 (-0.16 to -0.13), for CKD-EPI creatinine, CKD-EPI cystatin C, and CKD-EPI creatinine-cystatin C, respectively. Compared to mGFR, the CKD-EPI creatinine-cystatin C equation was the least biased (mean -0.86 (95% CI: -3.09 to 1.37)) versus CKD-EPI creatinine (2.31 (-0.73 to 5.34)) or CKD-EPI cystatin C (-3.54 (-5.86 to -1.21)), and most precise, with 1-P30 of 16% (95% CI 7.2% to 29.1%), compared to 18% (8.6% to 31.4%) for CKD-EPI creatinine, or 20% (10.0% to 33.7%) for CKD-EPI cystatin C. Conclusion: A moderate correlation between eGFR and htTKV associated with MIC stratification. Associations between htTKV and all 3 CKD-EPI equations were similar. CKDEPIcrcys tended to be the least biased and most precise equation when compared to mGFR and may be a reasonable alternative.

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

ABSTRACT Background Genetic testing for cardiomyopathy and arrhythmia (CM/ARRH) provides diagnostic information and informs screening for at-risk relatives. Clinical guidelines recommend genetic testing for these conditions; however, data on how genetic test results influence clinical management recommendations are limited. Here, we determined the frequency of cardiologist-recommended management changes for patients following CM/ARRH genetic testing. Methods This was a retrospective cross-sectional study of patients referred for multigene panel testing between April 2016 and April 2024. Genetically-experienced cardiologists at multicenter academic clinical practices were recruited for participation to complete surveys indicating clinical decision making on patients who had genetic testing. Cases for review were randomly selected to have both positive and non-positive results. Results Among 249 patients (138 positive, 111 non-positive), 136 (54.6%) received clinical management recommendations for their own or their at-risk relatives’ care. Of these, 75 (55.1%) received recommendations for the patient’s own care, most frequently additional diagnostic tests/procedures (n=33). Compared to non-positive results, patients with positive results were more likely to receive recommendations for their own management (66/138, 47.8% vs 9/111, 8.1%; P<0.00001). Patients with positive results in arrhythmogenic cardiomyopathy genes had 263% higher odds of recommended management changes compared to those with TTN (OR=3.63, CI:1.40-9.84, P=0.009). Conclusions The results from CM/ARRH genetic testing on affected patients influenced cardiologists’ medical decision making and management recommendations. Additional research is needed to evaluate how genetic testing for CM/ARRH impact health outcomes.

Abstract Inflammation is a key driver of coronary syndromes across the continuum from chronic coronary syndromes to acute coronary syndromes. It contributes to atherogenesis, plaque destabilization, and ischaemic events and influences myocardial injury, repair, and remodelling. Inflammatory activity is further amplified by metabolic and autoimmune comorbidities such as diabetes, obesity, and connective tissue diseases, with obesity representing a major driver of chronic low-grade inflammation through adipose tissue dysfunction and cytokine activation, while psychosocial stress and environmental exposures including air pollution serve as additional triggers. Genetic variations, including human leucocyte antigen genotypes, modulate individual susceptibility to vascular inflammation and myocardial injury. This expert consensus from the European Society of Cardiology’s Association for Acute CardioVascular Care summarizes the current understanding of inflammation across the full spectrum of coronary syndromes, including underlying mechanisms, relevant biomarkers, and imaging approaches that characterize vascular inflammation, and integrates insights from experimental and clinical studies. Importantly, this document provides explicit consensus-based guidance on when, how, and in whom inflammation should be assessed and treated in routine clinical practice. While the causal association between inflammation and atherosclerotic cardiovascular disease is well established, pharmacological modification of inflammation has produced conflicting evidence. Some agents, such as low-dose colchicine, have demonstrated modest reductions in cardiovascular events, although results across trials have been inconsistent. Other anti-inflammatory therapies have not shown clinical benefit, whereas selective cytokine inhibition with canakinumab has reduced cardiovascular risk at the cost of increased infection rates. The present manuscript also focuses on the evaluation of inflammatory activity in cardiovascular patients in routine clinical practice. It further discusses criteria for patient selection and clinical decision-making regarding the introduction of anti-inflammatory therapy in individuals with established atherosclerotic cardiovascular disease.

Purpose: The purpose of the current study was to cross-validate previously developed RMR prediction equations using laboratory measurements of RMR as a criterion. Methods: National Collegiate Athletic Association (NCAA) Division I (n = 60) and III (n = 113) male wrestlers participated in the current study (n = 173; Age: 19.6 ± 1.5 yrs.; Height: 176.3 ± 6.3 cm; Weight: 76.6 ± 10.9 kg; Body Fat: 11.4 ± 3.0%). Indirect calorimetry was used to measure RMR and Skinfold thickness was used to estimate body fat percentage (BF%) during the preseason period under standardized dress (underwear only), fasting, and resting conditions. Results: Mean measured RMR was 2102±341 kcal·d −1 . All body mass-based RMR prediction equations significantly underestimated the measured RMR, with the exception of the Jagim and Schofield equations. The Tinsley fat-free mass (FFM) equation and the Cunningham equation had the lowest constant error (CE) values when compared to measured RMR (mean bias ± standard error: 80 ± 20 kcal and 126 ± 20 kcal·d −1 , respectively). Linear regression indicated the Tinsley FFM (R 2 = 0.422, RMSE = 279 kcals, %RMSE = 13.3%), and Cunningham FFM equations had the closest agreement to measured RMR (R 2 = 0.422, RMSE = 301 kcals, %RMSE = 14.3%), along with the Jagim equation for a body mass-based prediction equation (R 2 = 0.377, RMSE = 338 kcals, %RMSE = 16.1%). The standard error of the estimate (SEE) ranged from 260 to 272 kcal·day −1 across equations. Coefficients of determination (R 2 ) ranged from 37% to 42%. The new body mass and FFM-based equations exhibited good agreement based on the CE (26 and -13 kcal·day −1 ), RMSE (274 and 252 kcal·day −1 ), respectively. Conclusions: The newly developed equations demonstrated mean bias <2% of measured RMR.