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Michael J Cuttica,1 Surya P Bhatt,2 Sharon R Rosenberg,1 Lauren Beussink,3 Sanjiv J Shah,3 Lewis J Smith,1 Mark T Dransfield,2 Ravi Kalhan1 1Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 2Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama-Birmingham, Birmingham, AL, 3Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Background: The ratio of the diameter of the pulmonary artery (PA) to the diameter of the aorta (PA:A) on computed tomography (CT) imaging is associated with both COPD exacerbation and pulmonary hypertension. The mechanisms of PA enlargement in COPD are poorly understood. Methods: In this retrospective, single center study we evaluated pulmonary function, CT scans, right heart catheterizations, and echocardiography in 88 subjects with mild-to-moderately severe COPD. A sensitivity analysis was performed in 43 subjects in whom CT scan and echocardiogram were performed within 50 days of each other. To evaluate the association between PA:A ratio and echocardiographic parameters and hemodynamics, we performed simple correlations and multivariable linear regression analysis adjusting for lung function, age, sex, race, and diastolic function. Results: All subjects had preserved left ventricular (LV) systolic function (LV ejection fraction 62.7%±5.5%). Among them, 56.8% had evidence of diastolic dysfunction. There was no association between PA:A ratio and the presence of diastolic dysfunction. In a multivariable model, PA:A ratio was associated with right ventricular (RV) chamber size (β=0.015; P

ObjectiveThe objective of this study is to determine associations between anthropometry and echocardiographic measures of cardiac structure and function in Hispanic/Latinos.MethodsA total of 1,824 participants from ECHO-SOL were included. We evaluated associations between echocardiographic measures of left ventricular structure and function and anthropometric measures using multivariable-adjusted linear and logistic regression models adjusting for traditional cardiovascular risk factors.ResultsThe mean age was 56 ± 0.17 years, 57% were women. The mean body mass index (BMI) was 30 ± 9.4 kg m-2, waist circumference (WC) was 100 ± 18 cm, and waist-to-hip ratio (WHR) was 0.93 ± 0.15. Adjusted analysis showed that 5-unit increment in BMI and 5-cm increase in WC was associated with 3.4 ± 0.6 and 1.05 ± 0.05 g m-2.7 (p

Context Allergic asthma continues to increase despite new pharmacological advances for both acute treatment and chronic-disease management. Asthma is a multifactorial disease process with genetic, allergic, infectious, environmental, and dietary origins. Researchers are investigating the benefits of lifestyle changes and alternative asthma treatments, including the ability of bromelain to inhibit inflammation. Bromelain is a commonly used, proteolytically active pineapple extract. Objective The present study intended to determine the ability of bromelain to reduce the inflammation of preexisting asthma via an ovalbumin (OVA)-induced murine model of allergic airway disease (AAD). Design The research team designed a study examining the effects of bromelain in a control group of mice that received phosphate buffered saline (PBS) only and in an intervention group that received bromelain in PBS. Setting The study took place in the Department of Immunology at the University of Connecticut's School of Medicine, Farmington. Intervention The research team sensitized female C57BL/6J mice with intraperitoneal OVA/alum and then challenged them with OVA aerosolization for 10 consecutive days. On day 4, the team began administering daily doses of PBS to the control group (n = 10) and bromelain (6mg/kg) in PBS to the bromelain (intervention) group (n = 10). Outcome Measures The primary measures included bronchoalveolar lavage (BAL) cellular differential, cellular phenotype via flow cytometry, and lung histology. Additional outcomes included testing for serum cytokines and immunoglobulin. Results Bromelain treatment of AAD mice (bromelain group) resulted in significant anti-inflammatory activity as indicated by reduced BAL total leukocytes (P < .05), eosinophils (P < .05), and cellular infiltrates via lung pathology (P < .005), as compared to the control group. In addition, bromelain significantly reduced BAL CD4+ and CD8+ T cells without affecting cell numbers in the spleen or hilar lymph node. The study found decreased interleukins IL-4, IL-12, IL-17, as well as IFN-[alpha] in the serum of bromelain-treated animals. Conclusions The results suggest that bromelain has a therapeutic effect in established AAD, which may translate into an effective adjunctive therapy in patients with similar conditions, such as allergic asthma, who have chosen to initiate treatment after the onset of symptoms. (Altern Ther Health Med. 2012;18(5):9-17.). [ABSTRACT FROM AUTHOR]

Background: Electromechanical coupling, a well-described phenomenon in systolic dysfunction, has not been well studied in diastole. We hypothesized that the ECG T-peak to T-end (TpTe) interval, representing transmural dispersion of repolarization, is associated with echocardiographic markers of diastolic dysfunction (DD).Methods and Results: We performed a prospective, cross-sectional study of the association between TpTe and markers of DD in 84 consecutive, unselected patients referred for exercise echocardiography. We systematically measured TpTe on the resting ECG, and we performed comprehensive assessment of DD at rest and at peak stress. ECGs and echocardiograms were analyzed independently, blinded to each other and to all clinical data. By univariable analysis, increased TpTe was associated with older age, increased E/e' ratio, and DD (P<0.05 for all associations after correcting for multiple comparisons). Increased TpTe was inversely associated with reduced tissue Doppler e' velocity, a marker of DD (R=-0.66, P<0.0001). This association persisted after adjusting for age, QTc, exercise-induced wall motion abnormalities, and left ventricular mass index (β=-0.41 [95% confidence interval, -0.70 to -0.12] cm/s per 10-ms increase in TpTe; P=0.006). Baseline TpTe was also independently associated with resting DD (adjusted odds ratio, 3.9 [95% confidence interval, 1.4-10.7]; P=0.009) and peak exercise E/e' ratio (P<0.0001).Conclusions: Increased TpTe is associated with both resting and exercise-induced DD. Electromechanical coupling may represent a pathophysiologic link between electrical transmural dispersion of repolarization and abnormal myocardial relaxation, and may be a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest that Doppler echocardiography (DE)-based estimates of pulmonary artery systolic pressure (PASP) may not be as accurate as previously believed. We sought to determine the accuracy of PASP measurements using DE compared with right-sided heart catheterization (RHC) in patients with pulmonary hypertension (PH).Methods: We compared DE estimates of PASP to invasively measure PASP during RHC in 160 consecutive patients with PH (part one). To account for possible changes in hemodynamics between DE and RHC, we then prospectively determined PASP in an additional 23 consecutive patients undergoing simultaneous RHC and DE (part two). Bland-Altman analyses were performed to evaluate the agreement between RHC and DE measurements of PASP. Accuracy was predefined as 95% limits of agreement within ± 10 mm Hg for PASP estimates.Results: In part one, there was moderate correlation between DE and RHC measurements of PASP (r = 0.68, P < .001). However, using Bland-Altman analysis, the bias for DE estimates of PASP was 2.2 mm Hg with 95% limits of agreement ranging from -34.2 to 38.6 mm Hg. DE estimates of PASP were determined to be inaccurate in 50.6% of patients. In part two, there was moderate correlation between DE and RHC measurements of PASP (r = 0.71, P < .01). However, despite simultaneous DE and RHC measurements, the bias for DE estimates of PASP was 8.0 mm Hg with 95% limits of agreement ranging from -28.4 to 44.4 mm Hg.Conclusions: DE estimates of PASP are inaccurate in patients with PH and should not be relied on to make the diagnosis of PH or to follow the efficacy of therapy. [ABSTRACT FROM AUTHOR]

Background: Although nesiritide is a potent vasodilator, studies using myocytes and isolated muscle strips have shown that recombinant B-type natriuretic peptide (BNP; nesiritide) decreases contractility. We sought to determine whether nesiritide decreases contractility in heart failure patients. Methods and Results: Twenty-five heart failure patients underwent left heart catheterization (using a pressure-volume conductance catheter) and echocardiography at baseline and after a 2 mcg/kg bolus and 30-minute nesiritide infusion (0.01 mcg.kg.min). From invasive and noninvasive measurements, left ventricular (LV) systolic function indices were calculated, including ejection fraction, end-systolic elastance (E(es); single-beat invasive and noninvasive methods) and preload-recruitable stroke work (PRSW; noninvasive, single-beat method). The mean age was 60 +/- 11 years, 48% were male, 56% had coronary disease, and 64% had hypertension. Although nesiritide did not change LV ejection fraction, it did decrease contractility on pressure-volume analysis. Noninvasive E(es) decreased from 2.6 +/- 1.6 to 2.0 +/- 1.4 mm Hg/mL (P = .02). For those with reduced ejection fraction, E(es) decreased by invasive (P = .006) and noninvasive (P = .02) methods. PRSW decreased from 76 +/- 37 to 62 +/- 28 g/cm(2) (P = .003). On tissue Doppler imaging, nesiritide reduced the systolic annular tissue velocity of the mitral annulus from 8.0 +/- 1.9 to 6.9 +/- 1.3 cm/s (P = .04). Conclusions: Nesiritide infusion acutely decreases derived measures of contractility and systolic function in patients with chronic heart failure. [ABSTRACT FROM AUTHOR]

The development of new therapies for heart failure (HF), especially acute HF, has proven to be quite challenging; and therapies evaluated in HF have greatly outnumbered treatments that are eventually successful in obtaining regulatory approval. Thus, the development of therapies for HF remains a vexing problem for pharmaceutical and device companies, clinical trialists, and health care professionals. Nowhere is this more apparent than in the phase II HF clinical trial, in which the goal is to determine whether an investigational agent should move forward to a phase III trial. Recent advancements in noninvasive cardiovascular imaging have allowed a new era of comprehensive phenotyping of cardiac structure and function in phase II HF trials. Besides using imaging parameters to predict success of subsequent phase III outcome studies, it is essential to also use imaging in phase II HF trials in a way that increases understanding of drug or device mechanism. Determination of the patients who would benefit most from a particular drug or device could decrease heterogeneity of phase III trial participants and lead to more successful HF clinical trials. In this review, we outline advantages and disadvantages of imaging various aspects of cardiac structure and function that are potential targets for therapy in HF, compare and contrast imaging modalities, provide practical advice for the use of cardiovascular imaging in drug development, and conclude with some novel uses of cardiac imaging in phase II HF trials. [ABSTRACT FROM AUTHOR]

B-type natriuretic peptide (BNP) is used widely to exclude heart failure (HF) in patients with dyspnea. However, most studies of BNP have focused on diagnosing HF with reduced ejection fraction (EF). The aim of this study was to test the hypothesis that a normal BNP level (≤100 pg/ml) is relatively common in HF with preserved EF (HFpEF), a heterogenous disorder commonly associated with obesity. A total of 159 consecutive patients enrolled in the Northwestern University HFpEF Program were prospectively studied. All subjects had symptomatic HF with EF >50% and elevated pulmonary capillary wedge pressure. BNP was tested at baseline in all subjects. Clinical characteristics, echocardiographic parameters, invasive hemodynamics, and outcomes were compared among patients with HFpEF with normal (≤100 pg/ml) versus elevated (>100 pg/ml) BNP. Of the 159 patients with HFpEF, 46 (29%) had BNP ≤100 pg/ml. Subjects with normal BNP were younger, were more often women, had higher rates of obesity and higher body mass index, and less commonly had chronic kidney disease and atrial fibrillation. EFs and pulmonary capillary wedge pressures were similar in the normal and elevated BNP groups (62 ± 7% vs 61 ± 7%, p = 0.67, and 25 ± 8 vs 27 ± 9 mm Hg, p = 0.42, respectively). Elevated BNP was associated with enlarged left atrial volume, worse diastolic function, abnormal right ventricular structure and function, and worse outcomes (e.g., adjusted hazard ratio for HF hospitalization 4.0, 95% confidence interval 1.6 to 9.7, p = 0.003). In conclusion, normal BNP levels were present in 29% of symptomatic outpatients with HFpEF who had elevated pulmonary capillary wedge pressures, and although BNP is useful as a prognostic marker in HFpEF, normal BNP does not exclude the outpatient diagnosis of HFpEF. [ABSTRACT FROM AUTHOR]

Importance: Treatment with finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), improved outcomes in patients with heart failure with mildly reduced or preserved ejection fraction in FINEARTS-HF, but was associated with increased levels of serum potassium in follow-up., Objective: To investigate the frequency and predictors of serum potassium level greater than 5.5 mmol/L and less than 3.5 mmol/L and examine the treatment effect associated with finerenone, relative to placebo, on clinical outcomes based on postrandomization potassium levels., Design, Setting, and Participants: Secondary analysis of the FINEARTS-HF multicenter, randomized clinical trial, performed between September 14, 2020, and January 10, 2023, with a median follow-up of 32 months (final date of follow-up: June 14, 2024). Patients with heart failure and left ventricular ejection fraction greater than or equal to 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides were included., Intervention: Participants received finerenone or placebo., Main Outcomes and Measures: The primary outcome was a composite of total worsening heart failure events or cardiovascular death., Results: A total of 6001 participants were included (3003 randomized to receive finerenone and 2998 randomized to receive placebo). The increase in serum potassium was greater in the finerenone group than the placebo group at 1 month (median [IQR] difference, 0.19 [0.17-0.21] mmol/L) and 3 months (median [IQR] difference, 0.23 [0.21-0.25] mmol/L), which persisted for the remainder of trial follow-up. Finerenone increased the risks of potassium level increasing to greater than 5.5 mmol/L (hazard ratio [HR], 2.16 [95% CI, 1.83-2.56]; P < .001) and decreased the risks for potassium level decreasing to less than 3.5 mmol/L (HR, 0.46 [95% CI, 0.38-0.56]; P < .001). Both low (< 3.5 mmol/L; HR, 2.49 [95% CI, 1.8-3.43]) and high (>5.5 mmol/L; HR, 1.64 [95% CI, 1.04-2.58]) potassium levels were associated with higher subsequent risks of the primary outcome in both treatment groups. Nevertheless, the risk of the primary outcome was generally lower in patients treated with finerenone compared with placebo, even in those whose potassium level increased to greater than 5.5 mmol/L., Conclusions and Relevance: In patients with heart failure with mildly reduced or preserved ejection fraction, finerenone resulted in more frequent hyperkalemia and less frequent hypokalemia. However, with protocol-directed surveillance and dose adjustment, clinical benefit associated with finerenone relative to placebo was maintained even in those whose potassium level increased to greater than 5.5 mmol/L., Trial Registration: ClinicalTrials.gov Identifier: NCT04435626.

Introduction: The World Health Organization's burn mortality estimate is 180,000 annually. Ninety-five percent of all mortality caused by fire-related burns worldwide occurs in low- and middle-income countries (LMICs). Prior studies have shown that transfer status (direct transfer from an injury scene to a trauma center vs. indirect transfer from another health facility) affects patient outcomes. We evaluated the effect of interhospital transfer on burn mortality., Methods: We analyzed a burn database of pediatric patients admitted to the Kamuzu Central Hospital (KCH) burn unit in Lilongwe, Malawi. We performed a bivariate analysis based on their transfer status and mortality and a logistic regression analysis to determine the effect of transfer status on mortality after burn injury., Results: A total of 2301 patients were analyzed, with 1095 (47.6%) being in the transfer cohort from referring hospitals. The median age was 3 years (IQR 1-4). The transfer cohort had more patients presenting to the hospital more than 48 h after injury. Upon multivariate logistic regression, controlling for pertinent variables, including time to presentation, burn-injured patients in the transfer cohort had increased odds of mortality (OR 2.26, 95% CI 1.22-4.19, and p = 0.01) compared to patients who were not transferred. The predictive probabilities of burn mortality by TBSA showed significant differences in mortality based on transfer status at TBSA between 20% and 80%., Conclusion: Ensuring district hospitals and other primary health care centers in resource-limited settings are sufficiently equipped to provide initial burn resuscitation and care may decrease mortality rates associated with transferred patients., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Background: Current hypertension treatments rely on chronological age, which may not reflect individual differences in aging and its impact on cardiovascular health. This study aimed to determine whether biological age can predict adverse outcomes in older adults with hypertension, independent of traditional risk factors including chronological age., Methods: An analysis of a prospective cohort was conducted using data from the Health and Retirement Study, a longitudinal survey of older adults in the United States. The Klemera-Doubal method was employed to calculate the biological age of the participants with hypertension at the time of enrollment in 2016. Discrete-time survival analysis was conducted to analyze the relationship between accelerated biological aging and the risk of mortality, heart disease, and stroke over four years of follow-up., Results: A total of 4,442 individuals were analyzed. Of these, 2,438 showed decelerated aging, whereas 2,004 experienced accelerated aging (biological age > chronological age). The median age of the patients in both groups was around 70 years. Both groups had similar racial and ethnic distributions and predominantly consisted of non-Hispanic whites. The accelerated aging group had a higher prevalence of chronic diseases, lower education levels, and less wealth than the decelerated aging group. After adjustment for these differences, accelerated aging was associated with a higher risk of a composite outcome of death, heart disease, and stroke, with an adjusted hazard ratio (a-HR) of 1.62 (95% confidence interval: 1.27-2.06, p= 0.001)., Conclusions: Accelerated biological age is a predictor of cardiovascular outcomes and death in patients with hypertension., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest. All authors had access to the data and contributed to the writing of the manuscript., (Copyright © 2024. Published by Elsevier Inc.)

Background: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF., Methods: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points., Results: The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo ( P =0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF ( P interaction >0.10), whereas the ketogenic effect diminished at higher LVEF ( P interaction =0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF., Conclusions: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes., Registration: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT03030235 and NCT02653482., Competing Interests: Dr Selvaraj receives research support from the National Heart, Lung, and Blood Institute (grant K23HL161348), the Doris Duke Foundation (grant 2020061), the American Heart Association (grant 935275), the Mandel Foundation, the Duke Heart Center Leadership Council, the Institute for Translational Medicine and Therapeutics, and the Foundation for Sarcoidosis Research. Dr Selvaraj has participated in advisory boards for AstraZeneca for unrelated work. Dr Sauer performs consulting and advising or receives research funding from Abbott, Boston Scientific, Biotronik, Bayer, Amgen, CSL Vifor, AstraZeneca, Acorai, Story Health, FIRE1, uLink, General Prognostics, Impulse Dynamics, Edwards Lifesciences, 35Pharma, Rivus, and Pfizer, and he owns stock as a senior advisor to ISHI, a private digital health company. Dr McGarrah has been a consultant for AstraZeneca and M3 and received research funding from Eli Lilly. Dr Newgard is a member of the Eli Lilly Global Diabetes Advisory Board. Dr Borlaug receives research support from the National Institutes of Health (NIH) and the US Department of Defense and research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics. Dr Borlaug has served as a consultant for Actelion, Amgen, Aria, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Janssen, Merck, and Novo Nordisk. Dr Borlaug and Shah are named inventors (US Patent 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Kitzman has been a consultant for AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer Ingelheim, Novo Nordisk, Rivus, and St. Luke’s Medical Center; received grant support from Novartis, AstraZeneca, Bayer, Pfizer, Novo Nordisk, Rivus, and St. Luke’s Medical Center; and owns stock in Gilead Sciences. Dr Sanjiv Shah reports support from research grants from the NIH (U54 HL160273, R01 HL140731, and R01 HL149423), Pfizer, and AstraZeneca and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Corvia, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, Ultromics, and United Therapeutics. Dr Margulies reports sponsored research funding from Amgen, Bristol Myers Squibb, and Lexicon Pharmaceuticals and advisory board activities for Amgen and Bristol Myers Squibb. Dr David Lanfear reports support from NIH grants (P50MD017351 and R01HL132154) and Illumina; consulting fees from Janssen, AstraZeneca, and Abbot Laboratories (via ACI clinical); and clinical trial participation with Lilly, Pfizer, AstraZeneca, Bayer, Illumina, and Janssen. Dr Kosiborod reports research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; is on the consultant/advisory board of 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; other research support from AstraZeneca; honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and stock options in Artera Health and Saghmos Therapeutics. Dr Svati Shah reports research funding through sponsored research agreements to Duke University from AstraZeneca, Lilly Inc, Verily Inc, and nference and is a co-inventor of unlicensed patents held by Duke University. The other authors report no conflicts.

Background: Finerenone improves outcomes in patients with heart failure and mildly reduced or preserved ejection fraction. It is important to understand the efficacy and safety of finerenone in these patients according to age., Methods: The aim of this analysis was to evaluate the interaction between age and the efficacy and safety of finerenone in the FINEARTS-HF trial (Finerenone Trial to Investigate Efficacy and Safety Compared to Placebo in Patients With Heart Failure). A total of 6001 patients aged 40 to 97 years were stratified by quartile (Q1-Q4) of baseline age: Q1, 40 to 66 years (n=1581); Q2, 67 to 73 years (n=1587); Q3, 74 to 79 years (n=1421); and Q4, ≥80 years (n=1412). FINEARTS-HF evaluated the impact of age on the efficacy of finerenone with respect to the primary composite outcome of cardiovascular death and total (first and recurrent) heart failure events, including heart failure hospitalization or urgent heart failure event, along with secondary efficacy and safety outcomes., Results: The incidence of primary outcomes increased with age. Finerenone reduced the risk of the primary outcome consistently across all age categories: rate ratio in Q1, 0.70 (95% CI, 0.53-0.92); Q2, 0.83 (95% CI, 0.64-1.07); Q3, 0.98 (95% CI, 0.76-1.26); and Q4, 0.85 (95% CI, 0.67-1.07); P interaction =0.27. Similarly, a consistent effect was observed for the components of the primary outcome. The mean increase in Kansas City Cardiomyopathy Questionnaire-total symptom score from baseline to 12 months was greater with finerenone than placebo, with a consistent effect across all age categories: mean placebo-corrected change in Q1, 2.87 (95% CI, 1.09-4.66); Q2, 1.24 (95% CI, -0.59 to 3.07); Q3, 0.94 (-0.98 to 2.86); and Q4, 1.24 (-0.90 to 3.38); P interaction =0.50. Adverse events were similar across all age categories. The odds of experiencing hypotension, elevated creatinine, or hyperkalemia (increased) or hypokalemia (decreased) related to finerenone did not differ by age., Conclusions: In the FINEARTS-HF trial, finerenone reduced the primary outcome and components of the primary outcome and improved symptoms across a wide age spectrum. In addition, finerenone was safe and well-tolerated, irrespective of age., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT04435626 and EudraCT 2020-000306-29., Competing Interests: Dr Chimura received research grants and personal fees from Otsuka Pharma, Daiwa Foundation, and the Japan Research Foundation for Clinical Pharmacology. Dr Petrie reports, outside of the submitted work, grants or contracts from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; consulting fees from Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, Abbvie, Bayer, Horizon Therapeutics, Foundry, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, and 3R Lifesciences; and is Director of Global Clinical Trials Partners. Dr Schou reports other from Novo Nordisk, Novartis, AstraZeneca, and Boehringer outside the submitted work and reports personal fees from Bayer during the conduct of the study and personal fees from Alleviant, AstraZeneca, Boehringer Ingelheim, Edwards Lifesciences, Janssen, Novartis, Novo Nordisk, and Rivus outside the study. Dr Martinez reports personal fees from Bayer, during the conduct of the study. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb (BMS), Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket and has served on a data safety monitoring board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer, as well as personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. Drs Kolkhof, Lage, and Rohwedder and K. Mueller are employees of Bayer. Dr Viswanathan is a full-time employee of Bayer Pharmaceuticals. Dr Lam has received research support from NovoNordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, BMS, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and nonexecutive director of Us2.ai. Dr Senni has served on advisory boards, consultancy and honoraria for Novartis, Abbott, Merck, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from the National Institutes of Health (NIH; U54 HL160273, X01 HL169712, R01 HL140731, and R01 HL149423), the American Heart Association (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer; and received consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, BMS, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voors’ employer received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, BMS, Boehringer Ingelheim, Corteria, EliLilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. Dr Zannad reports personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, NovoNordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2, having stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical Research, and being the founder of Cardiovascular Clinical Trialists. Dr Pitt is a consultant for Bayer, Astra Zeneca, Boehringer Ingelheim, Lexicon, BMS, KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical; stock/stock options for KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical; and US Patent 9931412-site specific delivery of eplerenone to the myocardium and US Patent pending 63/045,783 Histone modulating agents for the prevention and treatment of organ failure. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Jhund reports speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics. Dr Jhund’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and is the director of GCTP Ltd. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, the NIH/National Heart, Lung, and Blood Institute (NHLBI), Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline (GSK), Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr McMurray reports payments through Glasgow University from work on clinical trials, consulting, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, and Novartis, the British Heart Foundation, the NIH/NHLBI, Boehringer Ingelheim, SQ Innovations, and Catalyze Group; personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; personal lecture fees from Abbott, Alkem Metabolics, Astra Zeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, JB Chemicals and Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; and Data Safety Monitoring Board for WIRB-Copernicus Group Clinical Inc. He is a director of Global Clinical Trial Partners Ltd. All other authors report no conflicts.

Background and Purpose: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H 2 S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H 2 S donor in two preclinical models of cardiometabolic HFpEF was investigated., Experimental Approach: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H 2 S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols., Key Results: SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology., Conclusions and Implications: SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H 2 S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H 2 S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: Prior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer., Methods: EXTEND is a multicenter phase II randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomized 1:1 to MDT (definitive local treatment to all sites of disease, plus SOC systemic therapy) or to SOC systemic therapy only. Primary endpoint was PFS, and secondary endpoints included overall survival (OS), time to subsequent line of systemic therapy, and time to the appearance of new metastases. Exploratory analyses included quality of life (QOL) and systemic immune response measures., Results: From September 2018 through July 2022, 22 and 21 patients were randomized to the MDT and no-MDT arms, respectively. At a median follow-up of 24.8 months, PFS was not improved with the addition of MDT to SOC systemic therapy (median PFS 15.6 months MDT vs 24.9 months no-MDT [hazard ratio {HR} 0.91; 95% CI 0.34-2.48, p=0.86]). Similarly, MDT did not improve OS, time to subsequent line of systemic therapy, or time to the appearance of new metastases (all p>0.05). No significant differences were found in QOL measures, systemic T-cell activation, or T-cell stimulatory cytokine concentration., Conclusion: Among patients with oligometastatic breast cancer, the addition of MDT to SOC systemic therapy did not improve PFS. These findings suggest that MDT may have no systemic benefit in otherwise unselected oligometastatic breast cancer patients, although this trial was limited by a heterogenous and small sample size and overperformance of both treatment arms., Competing Interests: Declaration of competing interest Mr Fellman reported receiving grants from the National Institutes of Health (NIH) to The University of Texas MD Anderson Cancer Center during the conduct of the study. Dr Haymaker reported receiving grants from Avenge Bio, Sanofi, Dragonfly, BTG, Iovance Biotherapeutics, and TriSalus Life Sciences; receiving personal fees from Nanobiotix; receiving speaker honoraria from the Southwest Oncology Group and the Society for Immunotherapy of Cancer; and receiving stock options from BriaCell as a member of the scientific advisory board outside the submitted work. Dr Smith reported receiving salary support from Varian Medical Systems for a strategic alliance between MD Anderson Cancer Center and Varian Medical Systems outside the submitted work and royalty and equity interest in Oncora Medical. Dr Shaitelman reported funding from the Emerson Collective Foundation and contracted research agreements with Alpha Tau, Exact Sciences, TAE Life Sciences, and Artios Pharmaceuticals, outside the submitted work. Dr. Chun declares in the past 36 months support from grants or contracts from NIH R50 CA275822 and MD Anderson; consulting fees from Curio Science, Norton Healthcare, and AstraZeneca; honoraria from Binaytara Foundation, Curio Science, Henry Ford Health Systems, Japanese Society for Radiation Oncology and Hong Kong Precision Oncology society; and support for attending meetings and/or travel from ViewRay, American Board of Radiology, Binaytara Foundation, Japanese Society for Radiation Oncology, and AstraZeneca outside the submitted work. Dr Reuben reported receiving consulting fees and honoraria from Adaptive Biotechnologies outside the submitted work. Dr Ghia reported receiving consulting fees and honoraria from Brainlab outside the submitted work. Dr. Woodward reported personal fees from Exact Sciences and Epic Sciences, outside the submitted work. Dr Gomez reported receiving grants from AstraZeneca, Merck, Varian, and Bristol Myers Squibb and receiving consulting fees and honoraria from Grail, AstraZeneca, Olympus, Johnson & Johnson, Varian, Medtronic, and Med Learning Group outside the submitted work. Dr Tang reported receiving grants from the Cancer Prevention & Research Institute of Texas (CPRIT) and the Andrew Sabin Family Foundation and being an Andrew Sabin Scholar during the conduct of the study and receiving royalties from Wolters Kluwer and consulting fees and honoraria from Bayer, Diffusion Pharmaceuticals, and The Osler Institute Lecture Series outside the submitted work. No other disclosures were reported., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Radiation treatment planning is highly complex and can have significant inter- and intra-planner inconsistency, as well as variability in planning time and plan quality. Knowledge-based planning (KBP) is a tool that can be used to efficiently produce high-quality, consistent, clinically acceptable plans, independent of planner skills and experience. In this study, we created and validated multiple clinically acceptable and fully automatable KBP models, with the goal of creating VMAT plans without user intervention., Methods: Ten KBP models were configured using high quality clinical plans from a single institution. They were then honed to be part of a fully automatable system by incorporating scriptable planning structures, plan creation, and plan optimization. These models were verified and validated using quantitative (model statistics) and qualitative (dose-volume histogram estimation review) analysis. The resulting KBP-generated plans were reviewed by physicians and rated for clinical acceptability., Results: Autoplanning models were created for anorectal, bladder, breast/chest wall, cervix, esophagus, head and neck, liver, lung/mediastinum, prostate, and prostate with nodes treatment sites. All models were successfully created to be part of a fully automated system without the need for human intervention to create a fully optimized plan. The physician review indicated that, on average, 88% of all KBP-generated plans were "acceptable as is" and 98% were "acceptable after minor edits.", Conclusion: KBP models for multiple treatment sites were used as a basis to generate fully automatable, efficient, consistent, high-quality, and clinically acceptable plans. These plans do not require human intervention, demonstrating the potential this work has to significantly impact treatment planning workflows., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed., Methods: In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed., Results: Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P = 0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia., Conclusions: In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.)., (Copyright © 2024 Massachusetts Medical Society.)