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Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease. Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi‐stakeholder, multi‐specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non‐invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies. The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting. [ABSTRACT FROM AUTHOR]

Summary: Obesity is a worsening public health epidemic that remains challenging to manage. Obesity substantially increases the risk of cardiovascular diseases and presents a significant financial burden on the healthcare system. Digital health interventions, specifically telemedicine, may offer an attractive and viable solution for managing obesity. During the COVID‐19 pandemic, the need for a safer alternative to in‐person visits led to the increased popularity of telemedicine. Multiple studies have tested the efficacy of telemedicine modalities, including digital coaching via videoconferencing sessions, e‐health monitoring using wearable devices, and asynchronous forms of communication such as online chatrooms with counselors. In this review, we discuss the available evidence for telemedicine interventions in managing obesity, review current challenges and barriers to using telemedicine, and outline future directions to optimize the management of patients with obesity using telemedicine. [ABSTRACT FROM AUTHOR]

Aim: Left ventricular (LV) global longitudinal strain (GLS) may detect subtle abnormalities in myocardial contractility among individuals with normal LV ejection fraction (LVEF). However, the prognostic implications of GLS among healthy, community‐dwelling adults is not well‐established. Methods and results: Overall, 2234 community‐dwelling adults (56% women, 47% Black) with LVEF ≥50% without a history of cardiovascular disease (CVD) from the Dallas Heart Study who underwent cardiac magnetic resonance (CMR) with GLS assessed by feature tracking CMR (FT‐CMR) were included. The association of GLS with the risk of incident major adverse cardiovascular events (MACE; composite of incident myocardial infarction, incident heart failure [HF], hospitalization for atrial fibrillation, coronary revascularization, and all‐cause death), and incident HF or death were assessed with adjusted Cox proportional hazards models. A total of 309 participants (13.8%) had MACE during a median follow‐up duration of 17 years. Participants with the worst GLS (Q4) were more likely male and of the Black race with a history of tobacco use and diabetes with lower LVEF, higher LV end‐diastolic volume, and higher LV mass index. Cumulative incidence of MACE was higher among participants with worse (Q4 vs. Q1) GLS (20.4% vs. 9.0%). In multivariable‐adjusted Cox models that included clinical characteristics, cardiac biomarkers and baseline LVEF, worse GLS (Q4 vs. Q1) was associated with a significantly higher risk of MACE (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.07–2.24, p = 0.02) and incident HF or death (HR 1.57, 95% CI 1.03–2.38, p = 0.04). Conclusions: Impaired LV GLS assessed by FT‐CMR among adults free of cardiovascular disease is associated with a higher risk of incident MACE and incident HF or death independent of cardiovascular risk factors, cardiac biomarkers and LVEF. [ABSTRACT FROM AUTHOR]

A study published in the European Journal of Heart Failure examined the association between a diabetes-specific heart failure risk score (WATCH-DM) and the presence of subclinical cardiomyopathy in individuals with diabetes. The study included 150 adults with diabetes and found that those with high WATCH-DM scores had a significantly greater prevalence of diabetic cardiomyopathy (DbCM) compared to those with low scores. The study suggests that the WATCH-DM risk score may be a useful tool for identifying individuals with diabetes who are at high risk of developing heart failure. However, the study has limitations, such as a small sample size and the inability to establish causality. The study was supported by a research grant and the authors have disclosed potential conflicts of interest. [Extracted from the article]

This article discusses the complexity of exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Exercise intolerance is a common symptom of HFpEF and is associated with a poor quality of life and increased risk of adverse outcomes. The article highlights a study that characterizes the haemodynamic profiles of HFpEF patients and identifies four clinically defined phenogroups: cardiometabolic, left atrial myopathy, pulmonary vascular disease, and vascular stiffening. The study findings reveal distinct exercise haemodynamic impairments across these phenogroups and provide insights into the physiologic basis of disease progression. The article suggests that personalized treatment approaches based on these phenogroups may improve exercise capacity and quality of life for HFpEF patients. [Extracted from the article]

This article discusses the challenges in diagnosing heart failure with preserved ejection fraction (HFpEF) and the potential of artificial intelligence (AI) and natural language processing (NLP) to improve diagnosis. HFpEF is difficult to diagnose and often underdiagnosed, leading to missed opportunities for treatment and management. The study by Wu et al. applied NLP to a database of patients with a clinical diagnosis of heart failure and found a significant disparity in the diagnosis rates of HFpEF. NLP can aid clinicians in identifying high-risk patients and prompt further investigation for accurate diagnosis and personalized treatment. The incorporation of AI and NLP into HFpEF detection shows promise for enhancing diagnosis, monitoring disease progression, and tailoring treatment regimens. However, further research, validation, and ethical considerations are needed for the full integration of AI and NLP into clinical practice. [Extracted from the article]

Aims: Heart failure with reduced ejection fraction (HFrEF) is treatable but guideline‐directed medical therapy (GDMT) may not be affordable or accessible to people living with the disease. Methods and results: In this cross‐sectional survey, we investigated the price, affordability, and accessibility of four pivotal classes of HFrEF GDMT: angiotensin‐converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or angiotensin‐neprilysin inhibitors (ARNI); beta‐blockers; mineralocorticoid receptor antagonists (MRA); and sodium glucose co‐transporter 2 inhibitors (SGLT2i). We sampled online or community pharmacies in 10 countries across a range of World Bank income groups, assessing mean 30 day retail prescription prices, affordability relative to gross national income per capita per month, and accessibility. We reported median price ratios relative to the International Reference Standard. We performed a literature review to evaluate accessibility to GDMT classes through publicly funded drug programmes in each country. HFrEF GDMT prices, both absolute and relative to the international reference, were highest in the United States and lowest in Pakistan and Bangladesh. The most expensive drug was the ARNI, sacubitril/valsartan, with a mean (standard deviation, SD) 30 day price ranging from $11.06 (0.81) in Pakistan to $611.50 (3.54) in United States. The least expensive drug was the MRA, spironolactone, with a mean (SD) 30 day price ranging from $0.18 (0.00) in Pakistan to $12.32 (0.00) in England. Affordability (SD) of quadruple therapy—ARNI, beta‐blockers, MRA, and SGLT2i—was best in high‐income and worst in low‐income countries, ranging from 1.49 (0.00)% of gross national income per capita per month in England to 232.47 (31.47)% in Uganda. Publicly funded drug programmes offset costs for eligible patients, but ARNI and SGLT2i were inaccessible through these programmes in low‐ and middle‐income countries. Price, affordability, and access were substantially improved in all countries by substituting ARNI for ACEi/ARB. Conclusions: There was marked variation between countries in the retail price of HFrEF GDMT. Despite higher prices in high‐income countries, GDMT was more accessible and affordable than in low‐ and middle‐income countries. Publicly funded drug programmes in lower income countries increased affordability but limited access to newer HFrEF GDMT classes. Pharmaco‐disparities must be addressed to improve HFrEF outcomes globally. [ABSTRACT FROM AUTHOR]

Aims: Sex differences in long‐term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow‐up following an index HF hospitalization event. Methods and results: Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Association's Get With The Guidelines‐Heart Failure registry with available 5‐year follow‐up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5‐year follow‐up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41–49%], and HF with preserved EF [HFpEF, EF >50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5‐year follow‐up, males and females had comparably poor survival post‐discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age‐ and sex‐matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65‐69 years). In adjusted analysis, females (vs. males) had a lower risk of 5‐year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87–0.90, p < 0.0001), and the risk difference was most pronounced among patients with HFrEF (aHR 0.87, 95% CI 0.85–0.89; pinteraction[sex*HF subtype] = 0.04). Females (vs. males) had a higher adjusted risk of HF readmission over 5‐year follow‐up (aHR 1.06, 95% CI 1.04–1.08, p < 0.0001), with the risk difference most pronounced among patients with HFpEF (aHR 1.11, 95% CI 1.07–1.14; pinteraction[sex*HF subtype] = 0.001). Conclusions: While females (vs. males) had lower adjusted mortality, females experienced a significantly greater loss in survival time than the median age‐ and sex‐matched US population and had a greater risk of rehospitalization over 5 years following HF hospitalization. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a heterogeneous syndrome affecting more than 60 million individuals globally. Despite recent advancements in understanding of the pathophysiology of HF, many issues remain including residual risk despite therapy, understanding the pathophysiology and phenotypes of patients with HF and preserved ejection fraction, and the challenges related to integrating a large amount of disparate information available for risk stratification and management of these patients. Risk prediction algorithms based on artificial intelligence (AI) may have superior predictive ability compared to traditional methods in certain instances. AI algorithms can play a pivotal role in the evolution of HF care by facilitating clinical decision making to overcome various challenges such as allocation of treatment to patients who are at highest risk or are more likely to benefit from therapies, prediction of adverse outcomes, and early identification of patients with subclinical disease or worsening HF. With the ability to integrate and synthesize large amounts of data with multidimensional interactions, AI algorithms can supply information with which physicians can improve their ability to make timely and better decisions. In this review, we provide an overview of the AI algorithms that have been developed for establishing early diagnosis of HF, phenotyping HF with preserved ejection fraction, and stratifying HF disease severity. This review also discusses the challenges in clinical deployment of AI algorithms in HF, and the potential path forward for developing future novel learning‐based algorithms to improve HF care. [ABSTRACT FROM AUTHOR]

Natriuretic peptides, brain (B‐type) natriuretic peptide (BNP) and N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor–neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up‐to‐date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptide‐guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions. [ABSTRACT FROM AUTHOR]

Their findings illuminate the potential of these models to improve the early identification of patients at risk of developing HF, particularly stage B HF, which could lead to early intervention strategies and, ultimately, improved patient outcomes. B This article refers to 'Prediction models for heart failure in the community: A systematic review and meta-analysis' by R Nadarajah I et al i ., published in this issue on pages 1724-1738. b Heart failure (HF) is a complex clinical syndrome that represents a significant and growing public health concern worldwide.[1] With an aging population and increasing prevalence of risk factors such as hypertension, diabetes, and obesity, the incidence of HF is only expected to increase. [Extracted from the article]

Aims: To evaluate the contribution of baseline and longitudinal changes in cardiometabolic health (CMH) towards heart failure (HF) risk among adults with type 2 diabetes (T2D). Methods and results: Participants of the Look AHEAD trial with T2D and without prevalent HF were included. Adjusted Cox models were used to create a CMH score incorporating target levels of parameters weighted based on relative risk for HF. The associations of baseline and changes in the CMH score with risk of overall HF, HF with preserved (HFpEF) and reduced ejection fraction (HFrEF) were assessed using Cox models. Among the 5080 participants, 257 incident HF events occurred over 12.4 years of follow‐up. The CMH score included 2 points each for target levels of waist circumference, glomerular filtration rate, urine albumin‐to‐creatinine ratio, and 1 point each for blood pressure and glycated haemoglobin at target. High baseline CMH score (6–8) was significantly associated with lower overall HF risk (adjusted hazard ratio [HR], ref = low score (0–3): 0.31, 95% confidence interval [CI] 0.21–0.47) with similar associations observed for HFpEF and HFrEF. Improvement in CMH was significantly associated with lower risk of overall HF (adjusted HR per 1‐unit increase in score at 4 years: 0.80, 95% CI 0.70–0.91). In the ACCORD validation cohort, the baseline CMH score performed well for predicting HF risk with adequate discrimination (C‐index 0.70), calibration (chi‐square 5.53, p = 0.70), and risk stratification (adjusted HR [high (6–8) vs. low score (0–3)]: 0.35, 95% CI 0.26–0.46). In the Look AHEAD subgroup with available biomarker data, incorporating N‐terminal pro‐B‐type natriuretic peptide to the baseline CMH score improved model discrimination (C‐index 0.79) and risk stratification (adjusted HR [high (8–10) vs. low score (0–4)]: 0.18, 95% CI 0.09–0.35). Conclusions: Achieving target levels of more CMH parameters at baseline and sustained improvements were associated with lower HF risk in T2D. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate the impact of obstructive coronary artery disease (CAD) in patients with acute decompensated heart failure (ADHF), and examine potential differences in prognostic utility for heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF). Methods and results: The Atherosclerosis Risk in Communities study conducted hospital surveillance of ADHF from 2005 to 2014. Obstructive CAD was defined as ≥50% or ≥75% stenosis, respectively, for the left main and other major epicardial arteries. Adjusted associations between obstructive CAD and 30‐, 60‐, and 90‐day mortality were analysed. A total of 934 (4146 weighted) patients admitted with ADHF (mean age 72 years, 46% women, 30% Black, 30% HFpEF) had available angiography (61% performed in hospital). Obstructive CAD was more prevalent with HFrEF than HFpEF, whether at the left main (15% vs. 11%), left anterior descending (LAD) (48% vs. 30%), left circumflex (37% vs. 32%), right coronary (42% vs. 32%), or multiple coronary arteries (45% vs. 33%). In‐hospital revascularization was performed in 25% and 22% of patients with HFrEF and HFpEF, respectively. Obstructive CAD was associated with higher adjusted mortality, particularly with left main or LAD involvement, and had a more pronounced association with 90‐day mortality in HFrEF (odds ratio [OR] 2.77; 95% confidence interval [CI] 1.53–5.02) than HFpEF (OR 0.94; 95% CI 0.36–2.41) (p‐interaction = 0.05). Conclusion: Patients hospitalized with ADHF and coexisting obstructive CAD have higher short‐term mortality, warranting the need for effective interventions and secondary prevention. [ABSTRACT FROM AUTHOR]

Introduction: Texas Health Resources (THR), a large, nonprofit health care system based in the Dallas‐Fort Worth area, has collaborated with the University of Texas Southwestern Medical Center (UTSW) to develop and operate a unique, integrated approach for Learning Health System (LHS) workforce development. This training model centers on academic health system faculty members conducting later‐stage translational research within a partnering regional care delivery organization. Methods: The THR Clinical Scholars Program engages early career UTSW faculty members to conduct studies that are likely to have an impact on care delivery at the health system level. Interested candidates submit formal applications to the program. A joint committee comprised of senior research faculty from UTSW and THR clinical leadership reviews proposals with a focus on the shared LHS needs of both institutions—developing high quality research output that can be applied to enhance care delivery. A key prioritization criterion for funding is the degree to which the research addresses a question relevant to THR as a high‐volume network with multiple channels for consumers to access care. The program emphasis is on supporting embedded research initiatives using health system data to generate knowledge that will improve the quality and efficiency of care for the patient populations served by the participant organizations. Results: We discuss specific strategic and tactical components of the THR Clinical Scholars Program including an overview of the academic affiliation agreement between the collaborating organizations, criteria for successful program applications, data sharing, and funding. We also share project summaries from selected clinical scholars as examples of the LHS research done in the program to date. Conclusion: This experience report provides an implementation framework for other academic health systems interested in adopting similar LHS workforce training models with community partners. [ABSTRACT FROM AUTHOR]

Aims: Sodium‐glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown. Materials and methods: Among participants from VERTIS CV, a trial of patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percentage mediation of ertugliflozin efficacy on the first HHF and kidney composite outcome in 26 potential mediators. Time‐dependent approaches were used to evaluate associations between early (change from baseline to the first post‐baseline measurement) and average (weighted average of change from baseline using all post‐baseline measurements) changes in covariates with clinical outcomes. Results: For the HHF analyses, early changes in four biomarkers (haemoglobin, haematocrit, serum albumin and urate) and average changes in seven biomarkers (early biomarkers + weight, chloride and serum protein) were identified as fulfilling the criteria as mediators of ertugliflozin effects on the risk of HHF. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (glycated haemoglobin, haemoglobin, haematocrit and urate), and average changes in five biomarkers [early biomarkers (not glycated haemoglobin) + weight, serum albumin] mediating the effects of ertugliflozin on the kidney outcome. Conclusions: In these analyses from the VERTIS CV trial, markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF and composite kidney outcomes in the early and average change periods. ClinicalTrials.gov identifier: NCT01986881 [ABSTRACT FROM AUTHOR]

Aims: To assess heart failure (HF) in‐hospital quality of care and outcomes before and during the COVID‐19 pandemic. Methods and results: Patients hospitalized for HF with ejection fraction (EF) <40% in the American Heart Association Get With The Guidelines©‐HF (GWTG‐HF) registry during the COVID‐19 pandemic (3/1/2020–4/1/2021) and pre‐pandemic (2/1/2019–2/29/2020) periods were included. Adherence to HF process of care measures, in‐hospital mortality, and length of stay (LOS) were compared in pre‐pandemic vs. pandemic periods and in patients with vs. without COVID‐19. Overall, 42 004 pre‐pandemic and 37 027 pandemic period patients (median age 68, 33% women, 58% White) were included without observed differences across clinical characteristics, comorbidities, vital signs, or EF. Utilization of guideline‐directed medical therapy at discharge was comparable across both periods, with rates of implantable cardioverter defibrillator (ICD) placement or prescription lower during the pandemic (vs. pre‐pandemic period). In‐hospital mortality (3.0% vs. 2.5%, p <0.0001) and LOS (mean 5.7 vs. 5.4 days, p <0.0004) were higher during the pandemic vs. pre‐pandemic. The highest in‐hospital mortality during the pandemic was observed among patients hospitalized in the Northeast region (3.4%). Among patients concurrently diagnosed with COVID‐19 (n = 549; 1.5%), adherence to ICD placement or prescription, prescription of aldosterone antagonist or angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor at discharge were lower, and in‐hospital mortality (8.2% vs. 3.0%, p <0.0001) and LOS (mean 7.7 vs. 5.7 days, p <0.0001) were higher than those without COVID‐19. Conclusion: Among GWTG‐HF participating hospitals, patients hospitalized for HF with reduced EF during the pandemic received similar care quality but experienced higher in‐hospital mortality than the pre‐pandemic period. [ABSTRACT FROM AUTHOR]

Aims: The effects of inhibition of sodium glucose cotransporter (SGLT)‐1, as opposed to SGLT2, on cardiovascular structure and function are not well known. We assessed the associations of a missense genetic variant of SGLT1 with cardiac structure and function. Methods and results: We evaluated associations of a functionally modifying variant of SLC5A1 (rs17683011 [p.Asn51Ser]), the gene that encodes SGLT1, with cardiac structure and function on echocardiography among middle‐aged adults in the Coronary Artery Risk Development in Young Adults Study. Of 1904 participants (55.3 ± 3.5 years, 57% female, 34% Black), 166 (13%) White participants and 18 (3%) Black participants had at least one copy of rs17683011. There were no significant differences in age, sex, body mass index, glucose, or diabetes status by the presence of the rs17683011 variant. In Black participants, the presence of at least one copy of the rs17683011 variant was significantly associated with better GLS compared with those without a copy of the variant after covariate adjustment (−15.8 ± 0.7% vs. −14.0 ± 0.1%, P = 0.02). Although the direction of effect was consistent, the association between the presence of at least one copy of rs17683011 and GLS was not statistically significant in White participants (−15.1 ± 0.2% vs. −14.8 ± 0.1%, P = 0.16). There were no significant associations between rs17683011 and other measures of LV structure, systolic function, or diastolic function. Conclusions: The rs17683011 variant, a functionally modifying variant of the SGLT1 gene, was associated with higher GLS among middle‐age adults. These exploratory findings require further validation and suggest that SGLT1 inhibition may have beneficial effects upon LV systolic function. [ABSTRACT FROM AUTHOR]

Aims: Hospitalization for heart failure (HF) constitutes a major healthcare and economic burden. Trends and characteristics of hospitalizations for HF for the recent years are not clear. We sought to determine the trends and characteristics of hospitalization for HF in the United States. Method and results: A retrospective analysis of the National Inpatient Sample weighted data between 1 January 2004 and 31 December 2018, which included hospitalized adults ≥ 18 years with primary discharge diagnosis of HF using International Classification of Diseases‐9/10 administrative codes. Main outcomes were trends in hospitalizations for HF (per 1000 person) and inpatient mortality (%) between 2004 and 2018. Conclusions: Hospitalizations for HF have been increasing across both sexes and age groups since 2013, whereas inpatient mortality has been decreasing over the study period. Blacks have the highest risk of hospitalization for HF, and Whites have the highest in‐hospital mortality. There are significant racial and geographic disparities related to hospitalizations for HF. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the performance of the WATCH‐DM risk score, a clinical risk score for heart failure (HF), in patients with dysglycaemia and in combination with natriuretic peptides (NPs). Methods and results: Adults with diabetes/pre‐diabetes free of HF at baseline from four cohort studies (ARIC, CHS, FHS, and MESA) were included. The machine learning‐ [WATCH‐DM(ml)] and integer‐based [WATCH‐DM(i)] scores were used to estimate the 5‐year risk of incident HF. Discrimination was assessed by Harrell's concordance index (C‐index) and calibration by the Greenwood–Nam–D'Agostino (GND) statistic. Improvement in model performance with the addition of NP levels was assessed by C‐index and continuous net reclassification improvement (NRI). Of the 8938 participants included, 3554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5 years. The WATCH‐DM(ml) and WATCH‐DM(i) scores demonstrated high discrimination for predicting HF risk among individuals with dysglycaemia (C‐indices = 0.80 and 0.71, respectively), with no evidence of miscalibration (GND P ≥0.10). The C‐index of elevated NP levels alone for predicting incident HF among individuals with dysglycaemia was significantly higher among participants with low/intermediate (<13) vs. high (≥13) WATCH‐DM(i) scores [0.71 (95% confidence interval 0.68–0.74) vs. 0.64 (95% confidence interval 0.61–0.66)]. When NP levels were combined with the WATCH‐DM(i) score, HF risk discrimination improvement and NRI varied across the spectrum of risk with greater improvement observed at low/intermediate risk [WATCH‐DM(i) <13] vs. high risk [WATCH‐DM(i) ≥13] (C‐index = 0.73 vs. 0.71; NRI = 0.45 vs. 0.17). Conclusion: The WATCH‐DM risk score can accurately predict incident HF risk in community‐based individuals with dysglycaemia. The addition of NP levels is associated with greater improvement in the HF risk prediction performance among individuals with low/intermediate risk than those with high risk. [ABSTRACT FROM AUTHOR]

This editorial comments on the article "Frailty implications for exercise participation and outcomes in patients with heart failure" by Mudge et al. in the current issue. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the association between prefrailty and the risk of heart failure (HF) among older adults. Design, setting, and participants: This prospective, community‐based cohort study included participants from the Atherosclerotic Risk in Communities study who underwent detailed frailty assessment using Fried Criteria and physical function assessment using the Short Performance Physical Battery (SPPB) score. Individuals with prevalent HF and frailty were excluded. Main outcomes and measures: Adjusted association between prefrailty (vs robust), physical function measures (SPPB score, grip strength, and gait speed), and incident HF (overall and HF subtypes, HF with reduced [HFrEF, EF < 50%] and preserved ejection fraction [HFpEF]) were assessed using Cox proportional hazards models. Results: Among 5210 participants (mean age 75 years, 58% women), 2565 (49.2%) were identified as prefrail. In cross‐sectional analysis, prefrail individuals had a higher burden of chronic myocardial injury (troponin, Std β = 0.08 [0.05–0.10]) and neurohormonal stress (NT‐ProBNP, Std β = 0.03 [0.02–0.05]) after adjustment for potential confounders. Over a median follow‐up of 4.6 years, there were 232 (4.5%) HF events (HFrEF: 102; HFpEF: 97). Prefrailty was associated with an increased risk of HF after adjusting for potential clinical confounders and cardiac biomarkers (aHR [95% CI] = 1.65 [1.24–2.20]). Among HF subtypes, prefrailty was associated with an increased risk of HFpEF but not HFrEF (aHR [95% CI] = 1.73 [1.11–2.70] and 1.38 [0.90–2.10], respectively). A lower SPPB score was also associated with an increased risk of overall HF and HFpEF, but not HFrEF. Among individual components, increased gait speed were associated with a lower risk of HFpEF, but not HFrEF. Conclusions and relevance: Subtle abnormalities in physiological reserve (prefrailty) and impairment in physical function (SPPB) were both significantly associated with a higher risk of incident HF, particularly HFpEF. These findings highlight the potential role of routine assessment of geriatric syndromes for early identification of HF risk. [ABSTRACT FROM AUTHOR]

This editorial comments on the article by Dasarathy et al. in this issue. [ABSTRACT FROM AUTHOR]

Aims: We sought to compare the generalizability and prognostic implications of heart failure with preserved ejection fraction (HFpEF) scores (HFA‐PEFF and H2FPEF score) in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) and Phosphodiesterase‐5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial participants and matched controls from the Atherosclerosis Risk in Community (ARIC) study. Methods and results: Based on the respective scores, the study participants from the TOPCAT (N = 356), RELAX (N = 216), and ARIC (N = 379) studies were categorized as having a low, intermediate, or high likelihood of HFpEF. Age, sex, and race matched controls free of cardiovascular disease who had unexplained dyspnoea were used to evaluate the diagnostic performance. The prognostic value of scores was assessed using multivariable‐adjusted Cox regression analyses. The median HFA‐PEFF scores in the TOPCAT, RELAX, and ARIC studies were 5.0 [interquartile range (IQR): 5.0–6.0], 4.0 (IQR: 2.0–4.0), and 3.0 (IQR: 2.0–4.0), respectively. The median H2FPEF scores in the three studies were 5.5 (IQR: 4.0–7.0), 6.0 (IQR: 4.0–7.0), and 3.0 (IQR: 2.0–5.0), respectively. A low HFA‐PEFF and H2FPEF score can rule out HFpEF with high sensitivity (99.5% and 99.6%, respectively) and negative predictive value (95.7% and 98.3%, respectively). A high HFA‐PEFF and H2FPEF score can rule‐in HFpEF with good specificity (82.8% and 95.6%, respectively) and positive predictive value (79.9% and 90.4%, respectively). Among TOPCAT participants, the hazard for adverse cardiovascular events per point increase in HFA‐PEFF and H2FPEF score was 1.26 (95% confidence interval: 0.98–1.63) and 1.01 (95% confidence interval: 0.88–1.15), respectively. A higher H2FPEF score was associated with lower peak oxygen intake in RELAX trial participants (adjusted P = 0.01). Conclusions: The HFA‐PEFF and the H2FPEF scores are reliable diagnostic tools for HFpEF. The prognostic utility of HFpEF scores requires further validation in larger rigorously phenotyped populations. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: Obesity increases with age, is disproportionately prevalent in black populations, and is associated with heart failure with preserved ejection fraction (HFpEF). An "obesity paradox," or improved survival with obesity, has been reported in patients with HFpEF. The aim of this study was to examine whether racial differences exist in the temporal trends and outcomes associated with obesity among older patients with HFpEF. DESIGN: Community surveillance of acute decompensated heart failure (ADHF) hospitalizations, sampled by stratified design from 2005 to 2014. SETTING: Atherosclerosis Risk in Communities Study (NC, MS, MD, MN). PARTICIPANTS: A total of 10,147 weighted hospitalizations for ADHF (64% female, 74% white, mean age 77 years), with ejection fraction ≥50%. MEASUREMENTS: ADHF classified by physician review, HFpEF defined by ejection fraction ≥50%. Body mass index (BMI) calculated from weight at hospital discharge. Obesity defined by BMI ≥30 kg/m2, class III obesity by BMI ≥40 kg/m2. RESULTS: When aggregated across 2005–2014, the mean BMI was higher for black compared to white patients (34 vs 30 kg/m2; P <.0001), as was prevalence of obesity (56% vs 43%; P <.0001) and class III obesity (24% vs 13%; P <.0001). Over time, the annual mean BMI and prevalence of class III obesity remained stable for black patients, but steadily increased for white patients, with annual rates statistically differing by race (P‐interaction =.04 and P =.03, respectively). For both races, a U‐shaped adjusted mortality risk was observed across BMI categories, with the highest risk among patients with a BMI ≥40 kg/m2. CONCLUSION: Black patients were disproportionately burdened by obesity in this decade‐long community surveillance of older hospitalized patients with HFpEF. However, temporal increases in mean BMI and class III obesity prevalence among white patients narrowed the racial difference in recent years. For both races, the worst survival was observed with class III obesity. Effective strategies are needed to manage obesity in patients with HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Non‐alcoholic fatty liver disease leads to progressive liver fibrosis and appears to be a frequent co‐morbid disease in heart failure with preserved ejection fraction (HFpEF). It is well known that liver fibrosis severity predicts future liver‐related morbidity and mortality, but its impact on outcomes in patients with HFpEF remains unknown. This analysis aimed to describe the prevalence of liver fibrosis, as assessed using surrogate biomarkers, in patients with HFpEF and the association of such biomarkers in predicting clinical outcomes in these patients. Methods and results: Patients with HFpEF from TOPCAT Americas were included in the analysis. The non‐alcoholic fatty liver disease fibrosis score (NFS) and fibrosis‐4 (FIB‐4) scores were calculated using a combination of clinical characteristics and laboratory parameters. Risk of advanced fibrosis was classified as low, intermediate, and high. For the 1423 with sufficient data, we used Cox regression analysis to test the association between the risk of fibrosis severity and the combined primary endpoint of all cardiovascular death, aborted cardiac arrest, and hospitalization for heart failure. Advanced fibrosis, as determined by high fibrosis scores, was present in 37.57% by the NFS and 8.02% by the FIB‐4. Higher risk of advanced hepatic fibrosis was associated with older age. In unadjusted models, the risk of advanced fibrosis was associated with the primary cardiovascular outcome [NFS high vs. low, hazard ratio (HR) 1.709 (95% confidence interval, CI 1.238–2.358, P = 0.0011) and FIB‐4 high vs. low, HR 1.561 (95% CI 1.139–2.140, P = 0.0056)]. After multivariable adjustment, this association was diminished [NFS high vs. low, HR 1.349 (95% CI 0.938–1.939, P = 0.1064) and FIB‐4 high vs. low, HR 1.415 (95% CI 0.995–2.010, P = 0.0531)]. Conclusions: Our study suggests that advanced liver fibrosis, as estimated by fibrosis risk scores, may not be uncommon in patients with HFpEF, and there appears to be a limited independent association between liver fibrosis risk scores and clinical outcomes related to heart failure events. [ABSTRACT FROM AUTHOR]

Aims: Patients with obesity and ischaemic heart failure may counter‐intuitively have better outcomes compared with patients with normal body weight due to an 'obesity paradox'. This study sought to determine if body mass index (BMI) impacts the treatment effects or safety outcomes of the treatment of ischaemic heart failure with coronary artery bypass grafting (CABG). Methods and results: We obtained and reviewed the Surgical Treatment of Ischaemic Heart Failure (STICHES) data for 1212 patients. We categorized obesity by the World Health Organization (WHO) classes to define baseline characteristics and test for treatment interactions for the primary and secondary STICHES outcomes by treatment groups. While CABG decreased the risk of death, there was no evidence of treatment interaction by BMI per 5 kg/m2 (P = 0.83) or WHO obesity class. For the overall cohort, there was no interaction by WHO obesity class for the cumulative incidence of death in either the medical therapy or CABG plus medical therapy (P‐interaction = 0.90). There was a non‐significant trend for higher BMI and a lower risk of death [hazard ratio 0.92, 95% confidence interval (CI) 0.85–1.00, P = 0.051]. Increasing body size (per 5 kg/m2) was associated with return to the operating room (odds ratio 2.48, 95% CI 1.45–4.26, P < 0.001) and infectious mediastinitis (odds ratio 2.09, 95% CI 1.10–3.97, P = 0.024) at 30 days but not other 30 day safety outcomes. Conclusions: The benefit of CABG vs. medical therapy for ischaemic heart failure was consistent regardless of BMI or WHO obesity class for death or secondary clinical outcomes. However, higher BMI was associated with some short‐term post‐CABG complications. [ABSTRACT FROM AUTHOR]

Aim: To identify distinct phenotypic subgroups in a highly-dimensional, mixed-data cohort of individuals with heart failure (HF) with preserved ejection fraction (HFpEF) using unsupervised clustering analysis.Methods and Results: The study included all Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) participants from the Americas (n = 1767). In the subset of participants with available echocardiographic data (derivation cohort, n = 654), we characterized three mutually exclusive phenogroups of HFpEF participants using penalized finite mixture model-based clustering analysis on 61 mixed-data phenotypic variables. Phenogroup 1 had higher burden of co-morbidities, natriuretic peptides, and abnormalities in left ventricular structure and function; phenogroup 2 had lower prevalence of cardiovascular and non-cardiac co-morbidities but higher burden of diastolic dysfunction; and phenogroup 3 had lower natriuretic peptide levels, intermediate co-morbidity burden, and the most favourable diastolic function profile. In adjusted Cox models, participants in phenogroup 1 (vs. phenogroup 3) had significantly higher risk for all adverse clinical events including the primary composite endpoint, all-cause mortality, and HF hospitalization. Phenogroup 2 (vs. phenogroup 3) was significantly associated with higher risk of HF hospitalization but a lower risk of atherosclerotic event (myocardial infarction, stroke, or cardiovascular death), and comparable risk of mortality. Similar patterns of association were also observed in the non-echocardiographic TOPCAT cohort (internal validation cohort, n = 1113) and an external cohort of patients with HFpEF [Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial cohort, n = 198], with the highest risk of adverse outcome noted in phenogroup 1 participants.Conclusions: Machine learning-based cluster analysis can identify phenogroups of patients with HFpEF with distinct clinical characteristics and long-term outcomes. [ABSTRACT FROM AUTHOR]

Aims Methods Conclusions Compared with those without obesity, patients with obesity‐related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4‐dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity‐related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose.We describe the rationale and design of HuMAIN‐HFpEF, a Phase 2a randomized, double‐blind, placebo‐controlled, dose‐titration, parallel‐group trial in patients with obesity‐related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials.HuMAIN will test a promising novel agent for obesity‐related HFpEF. [ABSTRACT FROM AUTHOR]

B This article refers to 'Baseline characteristics of patients in the PARALLAX trial: insights into quality of life and exercise capacity in heart failure with preserved ejection fraction' by S.J. Shah I et al i ., published in this issue on pages 1541-1551. b Heart failure with preserved ejection fraction (HFpEF) is growing in prevalence and associated with a high burden of morbidity, mortality, and poor quality of life.1,2 HFpEF is common in older adults and particularly among women, with more than 80% of new-onset heart failure among octogenarian women being due to HFpEF.3 Development of HFpEF involves a complex interplay of multiple pathophysiologic impairments, including adverse physiologic consequences of adiposity, increased comorbidity burden, accelerated decline in exercise capacity with aging, up-regulation of inflammatory pathways, and sarcopenia, that culminates in decreased aerobic physiologic reserve and symptoms of clinical heart failure.2,4-7 Patients with HFpEF have a similar high burden of functional impairment, frailty, and poor quality of life as patients with heart failure with reduced ejection fraction.7-9 Exercise intolerance, characterized by reduced exercise capacity and symptoms of fatigue and dyspnoea with usual daily activities, is one the most common manifestations of HFpEF. Patients with HFpEF have 30-40% lower exercise capacity than healthy age- and sex-matched controls and often perform activities of daily living using near maximal aerobic effort.10-12 Exercise intolerance is associated with higher risk of hospitalization, death, and poor quality of life in HFpEF.12,13 Thus, exercise intolerance and low aerobic capacity are meaningful endpoints that should be targeted for developing effective therapies to improve this patient-centred outcome. Improving exercise tolerance and quality of life in heart failure with preserved ejection fraction - time to think outside the heart. [Extracted from the article]

Are post-influenza vaccine reactions truly "adverse"? Association of post-vaccination adverse reactions after influenza vaccine with mortality and cardiopulmonary outcomes in patients with high-risk cardiovascular disease: the INVESTED trial. B This article refers to 'Association of post-vaccination adverse reactions after influenza vaccine with mortality and cardiopulmonary outcomes in patients with high-risk cardiovascular disease: the INVESTED trial' by A. Peikert I et al i ., published in this issue on pages xxx. b With nearly 10% of the population infected and half a million deaths annually, influenza is an important global cause of hospitalization and death.[1] Apart from its respiratory manifestations, influenza infection leads to cardiovascular morbidity and mortality, with a significant association of influenza with acute myocardial infarction (MI) and acute heart failure (HF) as a result of systemic inflammation and/or direct myocardial damage.[[2], [4]] Influenza vaccination is strongly recommended for patients with cardiovascular disease. [Extracted from the article]