Thomas J, Dagan M, Wang B
… +2 more, Gutman S, Kaye DM
Circ Heart Fail
· 2026 May · PMID 41878820
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Heart failure with preserved ejection fraction is a complex and increasingly prevalent condition often associated with metabolic comorbidities such as obesity, diabetes, and hypertension. Although its burden is substanti...Heart failure with preserved ejection fraction is a complex and increasingly prevalent condition often associated with metabolic comorbidities such as obesity, diabetes, and hypertension. Although its burden is substantial, therapeutic progress has lagged compared with heart failure with reduced ejection fraction. GLP-1RAs (glucagon-like peptide-1 receptor agonists), initially developed for glycemic control in type 2 diabetes, have emerged as promising therapeutic agents for the obese/cardiometabolic heart failure with preserved ejection fraction phenotype. Recent trials, including STEP-HFpEF and SUMMIT, have demonstrated improvements in symptoms, quality of life, and reductions in heart failure events. Beyond inducing substantial weight loss, GLP-1RAs exert a range of metabolic, cardiovascular, and anti-inflammatory effects. In this review, we summarize weight-dependent and weight-independent actions of GLP-1RAs and outline how these mechanisms may influence cardiovascular physiology, myocardial remodeling, cardiac metabolism, renal sodium handling, and systemic inflammation in heart failure with preserved ejection fraction.
Tang AB, Li S, Li Y
… +12 more, Zhao J, Thomas K, Lewsey SC, Heidenreich PA, Greene SJ, Allen LA, Jessup M, Bolles M, Rutan C, Navar N, Yancy CW, Fonarow GC
Circ Heart Fail
· 2026 May · PMID 41874198
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BACKGROUND: The Get With The Guidelines-Heart Failure program is a national quality improvement initiative that was established in 2005 with the goal of improving the quality of care for patients hospitalized with heart...BACKGROUND: The Get With The Guidelines-Heart Failure program is a national quality improvement initiative that was established in 2005 with the goal of improving the quality of care for patients hospitalized with heart failure. METHODS: We examined patient characteristics, adherence to achievement and quality measures, and in-hospital outcomes in patients hospitalized with heart failure among Get With The Guidelines-Heart Failure fully participating hospitals between 2005 and 2024. Measures were applied to eligible patients without documented contraindications. Multivariable regression analysis, adjusting for patient and hospital characteristics, was performed to assess temporal changes in individual measures and outcomes. RESULTS: Over the first 20 years, the Get With The Guidelines-Heart Failure program has grown to include 1 561 093 patient records (median age 73 [62-83], 47.4% women, median ejection fraction 45% [28%-58%]) and 819 participating hospitals. There was significant and sustained improvement in an all-or-none composite achievement metric, with an increase from 76.1% to 88.7% between 2005 and 2024 (adjusted odds ratio, 3.7 [95% CI, 3.5-4.0]; <0.001). Rates of mineralocorticoid receptor antagonist prescriptions among eligible patients also increased substantially from 27.4% to 80.9% (adjusted odds ratio, 22.3 [95% CI, 20.2-24.6]; <0.001). Meanwhile, prescriptions of new therapies such as angiotensin receptor-neprilysin inhibitors and sodium-glucose cotransporter-2 inhibitors reached rates of 67.3% and 78.2% in 2024, respectively. Sustained improvements were also seen for other achievement and quality measures, including postdischarge follow-up and prescription of anticoagulation for patients with atrial fibrillation or atrial flutter. Equity of care by social vulnerability index also improved over time for guideline-based therapies such as evidence-based β-blockers and mineralocorticoid receptor antagonists. In contrast, vaccination rates and use of implantable cardioverter defibrillators saw recent decreases. CONCLUSIONS: The Get With The Guidelines-Heart Failure program was associated with sustained improvements in key achievement and quality measures for patients hospitalized with heart failure during its initial 2 decades, with a notable rise in the prescription of guideline-directed medical therapies and rapid implementation of new medications.
Madsen CT, Refsgaard JC, Voordes GHD
… +8 more, van Essen BJ, Ouwerkerk W, Hoegl A, Grønborg M, Tromp J, Lang CC, Barascuk Michaelsen N, Voors AA
Circ Heart Fail
· 2026 May · PMID 41874184
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BACKGROUND: Peptides such as angiotensin II and brain natriuretic peptide are pivotal in diagnosing and treating heart failure (HF). However, unbiased systematic studies of the peptidome in patients with HF are lacking....BACKGROUND: Peptides such as angiotensin II and brain natriuretic peptide are pivotal in diagnosing and treating heart failure (HF). However, unbiased systematic studies of the peptidome in patients with HF are lacking. Deciphering the plasma peptidome might significantly improve the diagnosis, prognostication, and treatment of patients with HF. METHODS: To systematically explore the low molecular peptidome, we conducted a cross-sectional mass spectrometry analysis from 486 patients with HF and 98 age-matched non-HF controls. We quantified 21 694 unique peptides in plasma, which were ranked according to (1) the relative upregulation in HF versus controls, (2) pattern similarity to bioactive peptides by an adapted machine learning method, and (3) association with clinical outcome. RESULTS: We observed 1924 differentially expressed peptides between patients with HF and non-HF controls. Among high-ranking peptides in patients with HF were angiotensin-related peptides (eg, angiotensin 1-9), propeptides from GIP (gastric inhibitory polypeptide), osteocalcin and cholecystokinin, and peptides mapping to the extracellular part of the natriuretic peptide clearance receptor and integrin alpha-7. Among the regulated peptides, 141 were scored in the top 5% by our machine learning approach, and 65 peptides herein were independently associated with clinical outcome. A hierarchical clustering analysis of patients with HF revealed 3 major patient clusters based on the peptide signature. The patient cluster with the lowest survival probability exhibited a specific peptide degradation pattern with a higher proportion of peptides linked to the acute phase response and increased inflammation. CONCLUSIONS: This study uniquely identifies peptides according to their regulation and likelihood of being a bioactive peptide in patients with HF compared with non-HF controls. The study provides crucial peptide-level information to complement protein-based methodologies. The most promising peptides were related to the renin-angiotensin system, natriuretic peptides, and cardiometabolic regulation. The stepwise ranking highlights the HF peptide signal important for outcome and provides a rich resource for additional exploration.
Belkin MN, Fudim M, Baratto C
… +10 more, Grinstein J, Hollis I, Ijioma N, Kataria R, Lewis GD, Mak S, Tedford RJ, Thibodeau JT, Yaku H, American Heart Association Fellow-In-Training and Early Career Committee of the Council on Clinical Cardiology
Kervella M, Behrens CS, Peccate C
… +11 more, Guesmia Z, Grandi F, Mougenot N, Forand A, Charrabi A, Brochier G, Andriantsitohaina R, Singh SR, Eschenhagen T, Meli AC, Muchir A
Circ Heart Fail
· 2026 Apr · PMID 41841259
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BACKGROUND: Dilated cardiomyopathy caused by mutations is a severe cardiac condition marked by arrhythmias, contractile dysfunction, and excessive myocardial fibrosis, which collectively impair left ventricular function...BACKGROUND: Dilated cardiomyopathy caused by mutations is a severe cardiac condition marked by arrhythmias, contractile dysfunction, and excessive myocardial fibrosis, which collectively impair left ventricular function and increase the risk of heart failure. Although the disease has been well characterized, a lack of insight into the pathogenesis has impeded the development of therapies. METHODS: Here, we employed human induced pluripotent stem cells (hiPSCs) derived from a patient carrying a point mutation (c.665A>C, p.His222Pro), alongside a murine model carrying the same mutation, to investigate the functional and molecular abnormalities driving dilated cardiomyopathy. RESULTS: We demonstrated that patient-derived cardiomyocytes and engineered heart tissues exhibited elevated diastolic calcium levels and reduced sensitivity to external calcium, respectively, as well as hypocontractility. These cells also displayed nuclear shape abnormalities in 2-dimensional and 3-dimensional, a hallmark of -associated dilated cardiomyopathy, associated with disrupted chromosome spatial organization and altered gene expression profiles. Transcriptomic analysis revealed dysregulation of extracellular matrix remodeling and significant upregulation of Loxl2 in mutated hiPSC-cardiomyocytes, hiPSC-engineered heart tissues, and mice. Treatment with Simtuzumab, a Loxl2 inhibitor, effectively prevented cardiac dysfunction and fibrosis in vivo. CONCLUSIONS: Taken together, our findings underscore the crucial role of Loxl2 as a therapeutic target and suggest that its inhibition could be a promising strategy to preserve cardiac function in -associated dilated cardiomyopathy.
Eberly LA, George C, Sandman S
… +20 more, Bex D, Jones K, Yazzie A, Gray L, Morgan L, Tennison A, Williams C, Chandra M, Wickre R, Wickre B, Bolas M, Welbel R, Ignace D, Feliciano B, Damon-Mallette D, Lindsey E, Mora P, Merino M, Schisterman EF, Shin SS
Circ Heart Fail
· 2026 Apr · PMID 41766529
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BACKGROUND: Nutrition insecurity is a major driver of poor cardiovascular health in Indigenous communities. Medically tailored meals may improve heart failure outcomes and quality of life. There is growing momentum among...BACKGROUND: Nutrition insecurity is a major driver of poor cardiovascular health in Indigenous communities. Medically tailored meals may improve heart failure outcomes and quality of life. There is growing momentum among Indigenous communities to reclaim traditional precontact foods to improve cardiovascular health. In this context, utilizing community-based-participatory methods, we designed MUTTON-HF (Medically Utilized Tailored Traditional Foods to Optimize Nutrition in Heart Failure)-an Indigenous culturally and medically tailored meals program that locally sources Native produce and meat and incorporates traditional Diné (Navajo) foods and recipes. METHODS: The MUTTON-HF trial is a 2-center, pragmatic, open-label randomized controlled trial to determine the efficacy and safety of MUTTON-HF among Diné patients with heart failure and hospitalization, or emergency room visit in the last 12 months. Two hundred and four subjects at 2 Indian Health Service sites will be randomized in a 1:1 stratified fashion by sex, age (<65 versus ≥65 years), and left ventricular ejection fraction (<50% versus ≥50%). Study subjects will receive either culturally and medically tailored meals that incorporate traditional Diné recipes and foods or usual dietary advice for 8 weeks. Data analysts will be blinded to group assignment until study completion. RESULTS: The primary efficacy end point is the proportion of patients with a hospitalization or emergency room visit (all-cause) within 90 days. Secondary outcomes will include hospitalizations or emergency room visits for heart failure specifically; Kansas City Cardiomyopathy Questionnaire scores for health-related quality of life; measures of food insecurity; Indigenous nourishment; diet quality; financial strain; and clinical biomarkers from study enrollment to 8 weeks. CONCLUSIONS: Community-based interventions that leverage the protective assets of Indigenous communities are needed to improve cardiovascular health among Native populations. This pragmatic randomized controlled trial will target a rural tribal population and be the first to evaluate the efficacy of an Indigenous food is medicine intervention to improve Indigenous cardiovascular health outcomes for patients with heart failure. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06549699.
Zampieri M, Biagioni G, Del Franco A
… +24 more, Canepa M, Porto I, Zanoletti M, Labate ME, Porcari A, Bordignon L, Merlo M, Sinagra G, Tini G, Musumeci B, Barbato E, Autore C, Biagini E, Longhi S, Sena G, Ponziani A, Saturi G, Fico V, Argirò A, Mazzoni C, Fumagalli C, Olivotto I, Perfetto F, Cappelli F
Circ Heart Fail
· 2026 Mar · PMID 41732853
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BACKGROUND: The tenet of cardiac amyloidosis (CA) as a paradigm of heart failure with restrictive ventricular physiology and preserved systolic function has come under scrutiny. We aimed to evaluate the prevalence and cl...BACKGROUND: The tenet of cardiac amyloidosis (CA) as a paradigm of heart failure with restrictive ventricular physiology and preserved systolic function has come under scrutiny. We aimed to evaluate the prevalence and clinical significance of left ventricular (LV) systolic dysfunction versus restriction in a large real-world cohort with CA, assessed at the time of diagnosis. METHODS: We retrospectively analyzed 540 TTR (transthyretin)-CA and 280 AL (light chain)-CA. Patients were divided into 3 LV phenotypes: (1) preserved LV function: LV ejection fraction >40% associated with grade I diastolic dysfunction; (2) restriction: LV ejection fraction >40% associated with grade II/III diastolic dysfunction; (3) systolic dysfunction: LV ejection fraction ≤40% irrespective of diastolic function. We analyzed the progression from preserved LV function towards the other 2 LV phenotypes and survival free from the composite end point of all-cause mortality and heart transplantation. RESULTS: In TTR-CA, the prevalence of preserved LV function was 32.0%, restriction was 56.1%, and systolic dysfunction was 11.9%. Among patients with preserved LV function, at the last evaluation, the conversion rate to restriction was 16.3% and to systolic dysfunction was 1.8%. The 3-year freedom from the composite end point was 75%, 61%, and 44%, respectively. In AL-CA, the prevalence of preserved LV function was 32.9%, restriction was 58.6%, and systolic dysfunction was 8.5%. Among patients with preserved LV function, at the last evaluation, the conversion rate to restriction was 12.9%, and to systolic dysfunction was none. The 3-year freedom from the composite end point was 46%, 32%, and 21%, respectively. CONCLUSIONS: Restriction was the most common presenting phenotype, while preserved LV function represented approximately one-third. The rate of progression from preserved LV function towards restriction was high, whereas it was limited towards systolic dysfunction. Although patients with preserved LV function presented the best event-free survival, considering all-cause mortality and heart transplantation, compared with restriction or systolic dysfunction, these phenotypes are not independent predictors of this composite end point.
Khurshid S, Friedman SF, Kany S
… +18 more, D'Souza V, Roshandelpoor A, Kosyakovsky LB, Chitsazan M, Cunningham JW, Singh P, Lau ES, Pipilas D, Al-Alusi MA, Rämö JT, Pirruccello JP, Reeder C, Waks JW, Lubitz SA, Philippakis AA, Maddah M, Ellinor PT, Ho JE
Circ Heart Fail
· 2026 Apr · PMID 41730522
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BACKGROUND: ECG-based artificial intelligence may enable efficient prediction of incident heart failure (HF) risk to facilitate preventive efforts. Prior models are proprietary, with modest or inconsistent accuracy. We s...BACKGROUND: ECG-based artificial intelligence may enable efficient prediction of incident heart failure (HF) risk to facilitate preventive efforts. Prior models are proprietary, with modest or inconsistent accuracy. We sought to develop and validate a generalizable and publicly available convolutional neural network to predict incident HF using the 12-lead ECG waveform (ECG-to-HF [ECG2HF]). METHODS: We developed ECG2HF in 94 636 patients receiving longitudinal ambulatory care at Massachusetts General Hospital (MGH), and validated it in 3 test sets: MGH, Brigham and Women's Hospital (BWH), and Beth Israel Deaconess Medical Center (BIDMC), among 93 868 individuals aged 30 to 79 years without HF. HF events at 10 years were identified using a validated electronic health record-based natural language processing model. Discrimination was quantified using the area under the receiver operating characteristic curve. We then compared discrimination and net reclassification (at <10%, 10% to 20%, ≥20% 10-year risk categories) using ECG2HF versus the 15-component Pooled Cohorts Equations to Prevent HF score. RESULTS: The test sets comprised MGH (13 954 individuals, 441 events, age 57±13 years, 48% women), BWH (54 396 individuals, 1809 events, age 57±13 years, 55% women), and BIDMC (25 457 individuals, 901 events, age 57±13 years, 53% women). Over 10 years, the cumulative risk of HF was 4.6% (95% CI, 4.1-5.0) in MGH, 5.0% (4.8-5.2) in BWH, and 4.4% (4.1-4.7) in BIDMC. ECG2HF discriminated 10-year incident HF in each test set (area under the receiver operating characteristic curve: MGH 0.86 [0.84-0.87]; BWH 0.85 [0.84-0.86]; BIDMC 0.84 [0.83-0.86]). Compared with the Pooled Cohorts Equations to Prevent HF, ECG2HF provided favorable discrimination (improvement in area under the receiver operating characteristic curve MGH/BWH 0.061 [0.025-0.097]; BIDMC 0.038 [-0.0096 to 0.086]) and net reclassification (NRI MGH/BWH 0.16 [0.077-0.24]; BIDMC 0.23 [0.10-0.35]) of 10-year HF risk. CONCLUSIONS: ECG2HF is a publicly available 12-lead ECG-based artificial intelligence model that discriminates the risk of future HF with favorable and consistent performance across 3 large health care samples from the northeastern United States. ECG2HF may enable efficient prioritization of high-risk individuals for HF-related preventive measures.
BACKGROUND: Guidelines acknowledge that discordant low-gradient (LG) aortic stenosis (AS) may be severe, but verifying this can be challenging. Right heart catheterization during exercise is considered the gold standard...BACKGROUND: Guidelines acknowledge that discordant low-gradient (LG) aortic stenosis (AS) may be severe, but verifying this can be challenging. Right heart catheterization during exercise is considered the gold standard for evaluating ventricular hemodynamics. No invasive studies have compared the hemodynamic response of discordant LG and severe AS during exercise. The aim of this observational study was to describe exercise hemodynamics in patients with asymptomatic discordant AS and left ventricular ejection fraction ≥50%. METHODS: Patients with aortic valve area ≤1.5 cm underwent right heart catheterization at rest and during maximal exercise, measuring pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and the PCWP/CO-slope. Patients were stratified into 3 groups: discordant LG AS (aortic valve area ≤1.0 cm and mean gradient <40 mm Hg); moderate AS (aortic valve area >1.0 cm); and high-gradient (HG) severe AS (aortic valve area ≤1.0 cm and mean gradient ≥40 mm Hg). RESULTS: Among 86 patients, 17 (20%) had discordant LG, 49 (57%) moderate, and 20 (23%) HG severe AS. The median PCWP/CO-slope was significantly steeper in discordant LG (3.3 [interquartile range, 2.1-4.3] mm Hg/L/min) and HG severe AS (2.7 [1.9-3.4] mm Hg/L per minute) compared with moderate AS (1.9 [0.7-2.8] mm Hg/L per minute), =0.004. In a regression model adjusted for age, sex, and rest PCWP, systemic arterial compliance and AS severity were significantly associated with the PCWP/CO-slope. Furthermore, patients with discordant LG AS had a leftward-upward shift in the PCWP/CO-curve. CONCLUSIONS: Discordant LG and HG severe AS had similar hemodynamic responses to exercise with steeper PCWP/CO-slope than in moderate AS, suggesting that discordant LG AS is a severe form of AS. In addition, the left upwards shift in PCWP/CO-curve for discordant LG compared with HG severe AS indicates that this group also has heart failure with preserved ejection fraction physiology. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04913870 and NCT02395107.
DeFilippis EM, Cheng RK, Donald EM
… +9 more, Dunlay SM, Evangelista LS, Kamdar F, Khazanie P, Mohammed SF, Rossi AP, Van Spall HGC, Verma A, Breathett K
Kidney dysfunction after heart transplantation (HT) is associated with significant morbidity and mortality. Recipient and perioperative factors may all influence the risk of kidney injury. Furthermore, data suggest that...Kidney dysfunction after heart transplantation (HT) is associated with significant morbidity and mortality. Recipient and perioperative factors may all influence the risk of kidney injury. Furthermore, data suggest that the incidence of kidney dysfunction, both acute and chronic, is increasing after the implementation of the United States' 2018 allocation system due to increasing use of temporary mechanical circulatory support and changing recipient characteristics. While data are robust regarding nephroprotective therapies such as renin-angiotensin-aldosterone system inhibition and SGLT2i (sodium-glucose cotransporter 2 inhibitors) to minimize the progression of chronic kidney disease in patients with heart failure, data in HT recipients are beginning to emerge. This state-of-the-art review will critically examine the existing literature regarding the epidemiology of kidney dysfunction after HT, mitigation strategies for acute kidney injury and chronic kidney disease, including pharmacotherapeutics, the need for kidney transplantation after HT, and practical next steps for the larger HT community.
BACKGROUND: There are limited data on the etiology, management, and outcomes of Society for Cardiovascular Angiography and Interventions (SCAI) B cardiogenic shock. METHODS: From 2017 to 2022, adult patients (≥18 years)...BACKGROUND: There are limited data on the etiology, management, and outcomes of Society for Cardiovascular Angiography and Interventions (SCAI) B cardiogenic shock. METHODS: From 2017 to 2022, adult patients (≥18 years) admitted to the medical, intermediate, and critical care units in a 6-hospital system were evaluated. SCAI B cardiogenic shock was defined as hypotension (systolic ≤90/mean ≤65 mm Hg) or hypoperfusion (lactate 2-5 mEq/L). Cardiac arrest, use of circulatory support, and noncardiac etiologies were excluded. The composite primary end point included transfer to a higher level of care, SCAI stage escalation, or in-hospital mortality. Multivariable analysis and mixed-effects regression models were used. RESULTS: During this period, 500 patients (median age, 76 years; 56% men; 79% White) developed SCAI B cardiogenic shock (hypotension 18%, hypoperfusion 82%). The most common etiologies were heart failure (37%), arrhythmia (23%), and acute myocardial infarction (13%). The primary composite end point was noted in 135 patients (deterioration cohort). The deterioration cohort had comparable baseline characteristics to those who recovered, but before the primary outcome, had lower blood pressures, higher rates of renal (60% versus 33%) and hepatic (15% versus 4%) injury, less negative fluid balance (-0.30 versus -0.68 L), and greater diuretic resistance (21% versus 2%; <0.001). In a multivariable analysis, acute kidney injury-adjusted odds ratio 2.17 (95% CI, 1.11-4.22); =0.02-and diuretic resistance-adjusted odds ratio 9.55 (95% CI, 2.61-34.89); =0.001-were independently predictive of clinical deterioration. Patients with isolated hypotension had worse outcomes compared with those with isolated hypoperfusion. CONCLUSIONS: Among patients with SCAI B cardiogenic shock, a quarter of the population experienced clinical deterioration. Acute kidney injury and diuretic resistance in the preceding 24 hours were independently predictive of developing the primary end point.