Khan, Sadiya S.

Background We examined the relationship between infection‐related hospitalization (IRH) and heart failure (HF) in a large clinical health system and assessed whether IRH improved prediction beyond HF risk equations. Methods We studied 80 880 adults (14 150 with IRH and 66 730 age‐ and sex‐matched comparators) aged ≥18 years without HF in the Rochester Epidemiology Project from 1/1/2005–12/31/2019. IRH was identified using International Classification of Diseases ( ICD ) codes. HF incidence was defined as ≥1 HF‐related ICD code. Multivariable Cox models assessed the association between IRH and incident HF. Among 29 219 adults aged 30 to 79 years without baseline cardiovascular disease in the Rochester Epidemiology Project, Harrell's concordance statistic assessed whether IRH improved discrimination of the Predicting Risk of Cardiovascular Disease EVENTs–Heart Failure (PREVENT‐HF) equations. Results Participants were 53.3% women, 85.6% White individuals, and 95.1% non‐Hispanic individuals, with a mean age of 56.0±20.0 years. Median follow‐up time was 6.2 years. Among the IRH group, 2729 developed incident HF (2.75/100 person‐years) versus 4854 (1.00/100 person‐years) in the comparator. The multivariable adjusted hazard ratio for incident HF among participants with versus without an IRH was 1.85 (95% CI, 1.76, 1.94). In a separate cohort, incorporating IRH into PREVENT‐HF increased the concordance statistic from 0.776 to 0.779 (change, 0.003 [95% CI, 0.001–0.004]). The PREVENT‐HF risk score underestimated the 10‐year risk of HF by up to 9% among participants with an IRH. Conclusions IRH was associated with incident HF but provided negligible change to 10‐year HF risk discrimination. However, among individuals with an IRH, incorporating this information meaningfully improved 10‐year HF risk prediction. Severe infections may serve as a risk‐enhancing factor warranting enhanced preventive measures, particularly in populations where IRH is more common.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

Introduction: Patients with heart failure with preserved ejection fraction (HFpEF) have a high burden of comorbidities. To recognize the complex interplay of obesity, diabetes, and chronic kidney disease (CKD) in patients with cardiovascular disease, the cardiovascular-kidney-metabolic (CKM) syndrome was recently defined, but data on the burden of CKM in HFpEF is limited. Aim: We sought to describe the prevalence of CKM components in HFpEF leveraging data from control participants in clinical trials and NHANES. Methods: We analyzed data presented in publications from four randomized clinical trials that enrolled participants with HFpEF (all of which are available via NHLBI BioLINCC and will be included in the extant HeartShare dataset): TOPCAT, RELAX, NEAT-HFpEF, and INDIE. We abstracted baseline demographic and clinical variables from study publications to define CKM components (e.g., body mass index [BMI], diabetes status, hypertension, CKD status). We compared prevalence of CKM in these trials with a representative sample of US adults with self-reported history of heart failure (HF) from NHANES 2011-2018. Results: We included 1937 patients with HFpEF from four trials with enrollment between 2006-2016 and 715 adults representing 5.6 million adults aged ≥40 years with a self-report of HF between 2011-2018 from NHANES ( Table ). Mean age was similar among enrolled trial participants with HFpEF and those with HF in NHANES (~68-69 years). Mean BMI was in the obesity range and was similar among trial participants with HFpEF and HF in NHANES (31-35 kg/m 2 ). A significant proportion of individuals had hypertension in HFpEF trials (>80%) and in the NHANES sample with HF (89%). The proportion of stage ≥ 3 CKD in HFpEF trials (≥ 37%) was similar to the NHANES sample with HF (37%). Results are shown in Table . Conclusions: Patients with HFpEF enrolled in clinical trials and those with HF in general population are significantly enriched with CKM components that may contribute to morbidity and mortality. Similar prevalence estimates were observed despite variability in trial inclusion criteria and heterogeneity in defining HFpEF and highlight CKM as a central target for HFpEF management.

Background: Inequities in Preeclampsia/Eclampsia (PrE/E) persist. It is unknown if the receipt of cardiology care relates to future risk of major adverse cardiovascular events (MACE) in Black and White patients with PrE/E. We sought to determine the cumulative incidence of MACE by race and whether predelivery cardiology care was associated with the hazard of MACE up to 1-year post-delivery for Black and White patients with PrE/E. Methods: Using Optum’s Clinformatics® Data Mart Database (CDM), we identified Black and White patients with PrE/E who had a delivery between 2008 to 2019. MACE was defined as the composite of heart failure, acute myocardial infarction, stroke, and death. Cumulative incidence functions were used to compare the incidence of MACE by race. Cox regression models were used to assess the hazard of MACE by cardiology care for Black and White patients. Results: Among 29,336 patients (83.4% White, 16.6% Black, mean age of 30.9 years) with PrE/E, 11.2% received cardiology care (10.9% White, 13.0% Black). Black patients had a higher incidence of MACE than White patients at 1-yr post-delivery (2.7% vs 1.4%). After adjusting for age and clinical comorbidities, receipt of cardiology care was associated with lower hazard of MACE for White patients (HR= 0.68, 95%CI: 0.50-0.92 p=0.013) but not Black patients (HR: 1.22, 95% CI: 0.82-1.81; p= 0.328). The interaction effect between race and cardiology care was statistically significant (p=0.013) Conclusions: Among a well-insured population of patients with PrE/E, Black patients had a higher cumulative incidence of MACE up to a year post-delivery. However, cardiology care significantly lowered the hazard of MACE for only White women. This observation does not suggest that cardiology care is detrimental to Black individuals but underscores the necessity to investigate why outcomes are disparate among these racial groups.

BACKGROUND: It is unknown whether predelivery cardiology care is associated with future risk of major adverse cardiovascular events (MACE) in preeclampsia/eclampsia (PrE/E). We sought to determine the cumulative incidence of MACE by race and whether predelivery cardiology care was associated with the hazard of MACE up to 1 year post-delivery for Black and White patients with PrE/E. METHODS: Using Optum’s de-identified Clinformatics Data Mart Database, we identified Black and White patients with PrE/E who had a delivery between 2008 and 2019. MACE was defined as the composite of heart failure, acute myocardial infarction, stroke, and death. Cumulative incidence functions were used to compare the incidence of MACE by race. Regression models were used to assess the hazard of MACE by cardiology care for each race. Separate hazards were calculated for the first 14 days and the remainder of the year. RESULTS: Among 29 336 patients (83.4% White patients, 16.6% Black patients, 99.5% commercially insured, mean age: 30.9 years) with PrE/E, 11.2% received cardiology care (10.9% White patients, 13.0% Black patients). Black patients had higher incidence of MACE than White patients at 1 year post-delivery (2.7% versus 1.4%) with the majority within 14 days of delivery (Black patients: 58.7%; White patients: 67.8%). After adjusting for age and comorbidities, receipt of cardiology care was associated with a lower hazard of MACE for White patients within 14 days after delivery (hazard ratio, 0.31 [95% CI, 0.21–0.46]; P <0.001) but not Black patients (hazard ratio, 1.00 [95% CI, 0.60–1.67]; P =0.999). The effect of the interaction between race and cardiology care was significant in the first 14 days ( P <0.001) but not the remainder of the year ( P =0.56). CONCLUSIONS: Among a well-insured population of patients with PrE/E, Black patients had a higher cumulative incidence of MACE up to a year post-delivery. Cardiology care was associated with a lower hazard of MACE only for White patients during the first 14 days after delivery.

BACKGROUND: Heart failure with preserved ejection fraction is associated with significant functional limitations, yet treatments for improving exercise performance have been elusive. We sought to explore the association between prespecified patient characteristics and changes in 6-minute walk distance that constitute a clinically significant response to dapagliflozin. METHODS: We performed a responder analysis to understand patient characteristics associated with clinically meaningful improvement in 6-minute walk test (6MWT) distance ≥15 m among patients randomized to 12 weeks of dapagliflozin versus placebo in the double-blind PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure). RESULTS: A total of 289 randomized patients had 6MWT distance completed at baseline and 12 weeks. Patients randomized to dapagliflozin improved walking distance by ≥15 m more frequently than those on placebo (n=64, 44% versus n=48, 34%). After adjusting for baseline covariates, patients randomized to dapagliflozin were more likely to experience a clinically meaningful improvement in 6MWT distance compared with those that received placebo (adjusted odds ratio, 1.66 [95% CI, 1.00–2.75]; P =0.05). Dapagliflozin-treated patients were also less likely to have a ≥15 m reduction in 6MWT distance compared with placebo-treated patients (adjusted odds ratio, 0.56 [95% CI, 0.33–0.94]; P =0.03). These results were consistent across all prespecified subgroups (all P values for interaction were not significant). CONCLUSIONS: Compared with those on placebo, patients with heart failure with preserved ejection fraction randomized to dapagliflozin were more likely to experience a clinically meaningful improvement and less likely to experience a deterioration in physical function over 12 weeks as measured by 6MWT distance. Beneficial response to dapagliflozin was consistent across prespecified subgroups. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03030235.

More than 40 years after the 1978 Bethesda Conference on the Declining Mortality from Coronary Heart Disease provided the scientific community with a blueprint for systematic analysis to understand declining rates of coronary heart disease, there are indications the decline has ended or even reversed despite advances in our knowledge about the condition and treatment. Recent data show a more complex situation, with mortality rates for overall cardiovascular disease, including coronary heart disease and stroke, decelerating, whereas those for heart failure are increasing. To mark the 40th anniversary of the Bethesda Conference, the National Heart, Lung, and Blood Institute and the American Heart Association cosponsored the “Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40” symposium. The objective was to examine the immediate and long-term outcomes of the 1978 conference and understand the current environment. Symposium themes included trends and future projections in cardiovascular disease (in the United States and internationally), the evolving obesity and diabetes epidemics, and harnessing emerging and innovative opportunities to preserve and promote cardiovascular health and prevent cardiovascular disease. In addition, participant-led discussion explored the challenges and barriers in promoting cardiovascular health across the lifespan and established a potential framework for observational research and interventions that would begin in early childhood (or ideally in utero). This report summarizes the relevant research, policy, and practice opportunities discussed at the symposium.