Search

Introduction: Obesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of heart failure. Few effective therapies exist to control metabolic alterations and lipid homeostasis. Objectives: We aimed to investigate the cardioprotective roles of AdipoRon, the adiponectin receptor agonist, in regulating lipid accumulation in the two-hit HFpEF model. Methods: HFpEF mouse model was induced using 60 % high-fat diet plus L-NAME drinking water. Then, AdipoRon (50 mg/kg) or vehicle were administered by gavage to the two-hit HFpEF mouse model once daily for 4 weeks. Cardiac function was evaluated using echocardiography, and Postmortem analysis included RNA-sequencing, untargeted metabolomics, transmission electron microscopy and molecular biology methods. Results: Our study presents the pioneering evidence that AdipoR was downregulated and impaired fatty acid oxidation in the myocardia of HFpEF mice, which was associated with lipid metabolism as indicated by untargeted metabolomics. AdipoRon, orally active synthetic adiponectin receptor agonist, could upregulate AdipoR1/2 (independently of adiponectin) and reduce lipid droplet accumulation, and alleviate fibrosis to restore HFpEF phenotypes. Finally, AdipoRon primarily exerted its effects through restoring the balance of myocardial fatty acid intake, transport, and oxidation via the downstream AMPKα or PPARα signaling pathways. The protective effects of AdipoRon in HFpEF mice were reversed by compound C and GW6471, inhibitors of AMPKα and PPARα, respectively. Conclusions: AdipoRon ameliorated the HFpEF phenotype by promoting myocardial fatty acid oxidation, decreasing fatty acid transport, and inhibiting fibrosis via the upregulation of AdipoR and the activation of AdipoR1/AMPKα and AdipoR2/PPARα-related downstream pathways. These findings underscore the therapeutic potential of AdipoRon in HFpEF. Importantly, all these parameters get restored in the context of continued mechanical and metabolic stressors associated with HFpEF.

Background: While Reddy proposed the H2FPEF diagnostic algorithm to aid in diagnosing heart failure with preserved ejection fraction (HFpEF), certain parameters like age and obesity are not suitable for Asian population, especially given the increasing incidence of HFpEF in younger individuals. Therefore, this study aimed to develop an easy-to-use nomogram with non-invasive indices that can be used in outpatient clinics in Taiwan to quickly estimate the probability of HFpEF and help decide whether further invasive cardiopulmonary exercise test (CPET) is needed. Methods: Outpatients with unexplained dyspnea and fatigue were recruited divided into HFpEF (n = 64) and non-HFpEF (n = 34) groups based on invasive CPET and echocardiography. Multivariate logistic regression analyses identified independent noninvasive variables for developing an HFpEF nomogram. The nomogram's performance was assessed and validated using the concordance index (C-index), area under the curve (AUC), calibration curves, and decision curve analysis. Results: Multivariate logistic regression analyses identified five independent noninvasive variables for developing an HFpEF nomogram, including dyslipidemia (OR = 5.264, p = 0.010), diabetes (OR = 3.929, p = 0.050), left atrial area (OR = 1.130, p = 0.046), hemoglobin

Objective: A less-invasive left atrial assist device (LAADx) is a novel and implantable, extracardiac blood pump concept, intended for the treatment of diastolic heart failure, represented by heart failure with preserved ejection fraction. Methods: A mixed-flow pump was used as the working LAADx model. Its performance was evaluated at 3 speeds, using an in vitro pulsatile mock circulatory loop, with a pneumatic pump that can simulate diastolic heart failure conditions by adjusting the diastolic drive pressure. The LAADx model was implanted in 4 healthy calves. The pump's inflow and outflow cannulas were inserted into the left atrium (LA) and left ventricle (LV), respectively, without cardiopulmonary bypass. The LAADx was operated at 3 speeds, and diastolic heart failure-like conditions were induced by inflating a balloon, inserted into the LV. Results: With the in vitro study, diastolic heart failure-like conditions were successfully induced, exhibiting decreased cardiac output and aortic pressure as well as increased mean LA pressure both mitigated with the LAADx support. With regard to the in vivo study, simulated diastolic heart failure conditions showed a decrease in aortic pressure and an increase in LA pressure and LV end-diastolic pressure, which were again mitigated by the LAADx. Echocardiography showed good positioning of the outflow cannula and neither cardiac dysfunction nor mitral interference was observed. Conclusions: Initial in vitro and in vivo results confirmed that the LAADx model, a device concept driven by creating an extracardiac route from the LA to LV, has the potential to mitigate high LA pressure and improve LV filling of heart failure with preserved ejection fraction pathology.

Patients with heart failure with preserved ejection fraction (HFpEF) are burdened by multiple diet-sensitive comorbidities, including obesity and malnutrition. Despite this, a low percentage of patients with HFpEF have been enrolled in dietary intervention trials in heart failure and few dietary interventions have been conducted in HFpEF exclusively. This scoping review will examine available evidence regarding dietary interventions in patients with HFpEF, highlight existing gaps in knowledge, and discuss emerging dietary therapies in this population.

Background: The benefit of pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF) is well established; its efficacy in patients with heart failure preserved ejection fraction (HFpEF) is less clear. Objective: The objective of the study was to compare AF and heart failure (HF) rehospitalizations after PVI in patients with HFpEF vs HFrEF. Methods: The IBM MarketScan Database was used to identify patients undergoing PVI for AF. Patients were categorized by HF status: absence of HF, presence of HFrEF, or presence of HFpEF. Primary outcomes were HF and arrhythmia hospitalizations after PVI. Results: A total of 32,524 patients were analyzed: 27,900 with no HF (86%), 2948 with HFrEF (9%), and 1676 with HFpEF (5%). Compared with those with no HF, both patients with HFrEF and HFpEF were more likely to be hospitalized for HF (hazard ratio [HR] 7.27; P < .01 for HFrEF and HR 9.46; P < .01 for HFpEF) and for AF (HR 1.17; P < .01 for HFrEF and HR 1.74; P < .01 for HFpEF) after PVI. In matched analysis, 23% of patients with HFrEF and 24% patients with HFpEF demonstrated a reduction in HF hospitalizations (P = .31) and approximately one-third demonstrated decreased arrhythmia rehospitalizations (P = .57) in the 6 months after PVI. Compared with those with HFrEF in longer-term follow-up (>1 year), patients with HFpEF were more likely to have HF (HR 1.30; P < .01) and arrhythmia (HR 1.19; P < .01) rehospitalizations. Conclusion: Reductions in HF and arrhythmia hospitalizations are observed early after PVI across all patients with HF, but patients with HFpEF demonstrate higher HF rehospitalization and arrhythmia recurrence in longer-term follow-up than do patients with HFrEF.

Background: The pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF) is heterogeneous and incompletely understood. This study evaluated the presence of a ventricular conduction delay (VCD) phenotype in HFpEF through QRS duration and vectorcardiographic QRS area, and their relation to adverse outcomes. Methods: This study included consecutive ambulatory HFpEF patients. Baseline QRS duration was obtained from an electrocardiogram (ECG). QRS area was derived from vectorcardiographic analyses of the ECG. QRS duration and area were assessed and analysed as categorical (43.1 µVs) and continuous variables to determine the relation to the composite outcome of HF hospitalisation and all-cause mortality. Results: 349 HFpEF patients were included of whom 70 % had a QRS duration 43.1 µVs. Only 4 % had a QRS area ≥69µVs, indicating delayed lateral wall activation. After a median of 3 years follow-up, 30 % of the patients had an adverse outcome. Longer QRS duration but not larger QRS area was associated with more adverse outcomes on both categorical and continuous scales (HR per 5 ms increase = 1.06, P = 0.033). This prognostic association was mainly present in males. Conclusion: HFpEF patients have a low prevalence of a VCD phenotype(9 % QRS duration ≥120 ms;4 % a QRS area ≥69 µVs). However, QRS duration >100 ms was present in 30 % and was an independent predictor for adverse outcomes. Future efforts are needed to understand the mechanisms underlying the association of QRS duration and adverse outcomes, and to determine its clinical implications.

Background: Women are at greater risk for heart failure with preserved ejection fraction (HFpEF). Objectives: The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood. Methods: This cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO2) and its determinants. HFpEF was considered likely when the H2FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student’s t-test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression. Results: The cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO2 and its determinants. Overall, women had lower peak VO2 (mean difference −4.4 mL/kg/min [95% CI: −3.7 to −5.1 mL/kg/min]) secondary to a reduced O2 delivery (−0.5 L/min [95% CI: −0.4 to −0.6 L/min]) and less oxygen extraction (−2.9 mL/dL [95% CI: −2.5 to −3.2 mL/dL]). Reduced O2 delivery was due to lower hemoglobin (−1.2 g/dL [95% CI: −0.9 to −1.5 g/dL]) and smaller stroke volume (−15 mL [95% CI: −14 to −17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (−9 mL/m2 [95% CI: −8 to −11 mL/m2]) and mass (−12 g/m2 [95% CI: −9 to −14 g/m2]) and more often iron deficiency (55% vs 33%; P < 0.001). Conclusions: Women with unexplained dyspnea had significantly lower peak VO2, regardless of HFpEF likelihood, attributed to both lower peak exercise O2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness.

Background: Muscle wasting is pronounced in patients with heart failure with preserved ejection fraction (HFpEF). The quadriceps femoris echotexture biomarkers assessed by ultrasound (US) have not been studied in these patients. Objective: To describe echotexture biomarkers assessed by the US and to assess their relationship with sex, age, body mass index (BMI), self-reported outcomes, muscle strength and physical function in older adults with HFpEF. Methods: A cross-sectional study was conducted. Patients 70 years and older with HFpEF were included. The sex, age, BMI, and self-reported outcomes were collected. The US assessed muscle and subcutaneous fat tissue contrast, correlation, energy, homogeneity, and entropy at rest and maximal voluntary isometrical contraction (MVIC). The six-minute walk test (6MWT), the short physical performance battery (SPPB), the timed up and go test (TUG), the usual pace gait speed test (UGS), and the fast pace gait speed test (FGS) were used to assess physical function. The five-repetitions sit-to-stand test (5-STS) was performed to assess muscle strength. Bivariant Pearson correlations and subsequent multivariate linear regression analyses were conducted. Results: Seventy-two older adults with HFpEF [81.06 years, 29.13 BMI, and 55.60% females] were recruited. In women, relaxed and MVIC muscle energy and entropy explained 35.40% of the TUG variance; relaxed muscle entropy and MVIC muscle energy shared 24.00% of the UGS variance; relaxed and MVIC muscle entropy, MVIC muscle contrast and MVIC muscle energy explained 32.60% of the FGS variance, adjusted all the models by age and BMI. Conclusions: Echotexture biomarkers are related to women's muscle strength and physical function, especially muscle energy, contrast, and entropy. Echotexture biomarkers assessed by the US could facilitate the management of older adults with HFpEF, monitor its progression and assess the effectiveness of treatments on the musculoskeletal structure. Trial registration: NCT03909919. April 10, 2019. Retrospectively registered.

Background: Heart failure with preserved ejection fraction (HFpEF) presents a serious risk to human health. The increased prevalence of sarcopenia in the HFpEF population has a negative impact on patient prognosis. Uric acid (UA) is the byproduct of purine metabolism and is harmful to the cardiovascular system. This study aims to establish the potential relationship between sarcopenia and serum UA in HFpEF patients. Methods: Data were obtained from 180 individuals (aged ≥60 years) with HFpEF admitted to the Geriatric Department of Jiangsu Province Hospital between January 2021 and December 2022. The UA values were grouped into 4 quartiles (Q1-Q4). Logistic generalized linear models and restricted cubic spline (RCS) regression were used to analyze the relationship between sarcopenia and UA. Subgroups based on gender were utilised for further analysis. Results: After adjusting for covariates, odds ratios (ORs) and 95 % confidence intervals (CIs) for sarcopenia prevalence in the 2nd, 3rd, and 4th quartiles were 2.56 (0.57–12.65), 4.94 (1.10–24.49), and 6.95 (1.30–44.25), respectively, unlike the 1st quartile (P for trend = 0.022). The RCS plot demonstrated a positive linear relationship between serum UA levels and sarcopenia (P for non-linearity = 0.190). A sex-based subgroup analysis revealed a statistically significant relationship between UA and sarcopenia in males (P

Introduction: The ICAM1 variant rs5491 (p.K56M) is common among Black individuals and has been associated with risk of heart failure with preserved ejection fraction (HFpEF). The pathways by which rs5491 leads to HFpEF are not known. Methods: Among Black individuals within the Multi-Ethnic Study of Atherosclerosis, we evaluated associations of rs5491 with 3 inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], and tumor necrosis factor-α receptor 1 [TNFR-1]). Results: Among 1558 Black participants (mean age 62 ± 10 y, 47 % female), each additional rs5491 allele was associated with higher hsCRP after covariate adjustment (β: 0.15, SE: 0.07, P = 0.02). Each additional rs5491 allele was associated with higher TNFR-1 (β: 0.06, SE: 0.02, P = 0.02), but not IL-6 (β: 0.04, SE: 0.04, P = 0.29). The association between rs5491 and HFpEF remained significant after adjustment for hsCRP. Conclusion: In Black individuals, rs5491 (p.K56M) is associated with higher hsCRP and higher TNFR-1, but not IL-6.

Summary: Background: Whether there is a subset of patients with heart failure with preserved ejection fraction (HFpEF) that benefit from spironolactone therapy is unclear. We applied a machine learning approach to identify responders and non-responders to spironolactone among patients with HFpEF in two large randomized clinical trials. Methods: Using a reiterative cluster allocating permutation approach, patients from the derivation cohort (Aldo-DHF) were identified according to their treatment response to spironolactone with respect to improvement in E/e’. Heterogenous features of response (‘responders’ and ‘non-responders’) were characterized by an extreme gradient boosting (XGBoost) algorithm. XGBoost was used to predict treatment response in the validation cohort (TOPCAT). The primary endpoint of the validation cohort was a combined endpoint of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization. Patients with missing variables for the XGboost model were excluded from the validation analysis. Findings: Out of 422 patients from the derivation cohort, reiterative cluster allocating permutation identified 159 patients (38%) as spironolactone responders, in whom E/e’ significantly improved (p = 0.005). Within the validation cohort (n = 525) spironolactone treatment significantly reduced the occurrence of the primary outcome among responders (n = 185, p log rank = 0.008), but not among patients in the non-responder group (n = 340, p log rank = 0.52). Interpretation: Machine learning approaches might aid in identifying HFpEF patients who are likely to show a favorable therapeutic response to spironolactone. Funding: See Acknowledgements section at the end of the manuscript.

Aims: Anemia is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with exercise intolerance. However, there are limited data on how anemia contributes to reduced exercise capacity in patients with HFpEF. We aimed to characterize exercise capacity, cardiovascular and ventilatory reserve, and the oxygen (O2) pathway in anemic patients with HFpEF. Methods: A total of 238 patients with HFpEF and 248 dyspneic patients without HF underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. Patients with HFpEF were classified into two groups based on the presence of anemia (hemoglobin

Background: Although heart failure with preserved ejection fraction (HFpEF) is a serious disease, only limited options are available for its treatment. Recent studies have analyzed the effects of phosphodiesterase (PDE) inhibitors, especially PDE5 and PDE3 inhibitors, in patients with HFpEF, with mixed outcomes. Methods: We searched PUBMED and EMBASE databases up to August 2021. Randomized controlled trials (RCTs) and clinical trials that tested the effects of PDE inhibitors on patients with HFpEF were included as eligible studies. Indicators of left ventricular (LV) function, pulmonary arterial pressure (PAP), right ventricular (RV) function, exercise capacity, and quality of life (QOL) were used to evaluate the efficacy of PDE inhibitors in HFpEF. Results: Six RCTs that reported in 7 studies were included to evaluate the efficiency of PDE inhibitors on HFpEF patients. In the pooled analysis, PDE inhibitors showed insignificant changes in the ratio of early diastolic mitral inflow to annular velocities, left atrial volume index, pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR), peak oxygen uptake, 6-minute walking test distance, as well as Kansas City Cardiomyopathy Questionnaire score. However, substantial improvement was observed in the tricuspid annular plane systolic excursion (TAPSE). Additionally, the regression analysis showed that PDE inhibitor administration time is a critical factor for the decrease in PASP. Conclusions: PDE inhibitors did not effectively improve LV function, PAP, exercise capacity, and QOL in patients with HFpEF. However, they improved RV function with significant difference, suggesting that PDE inhibitors might be a promising option for HFpEF patients with RV dysfunction.

Background: Sodium glucose co-transporter 2 inhibitors (SGLT2i) have been proven to reduce the combined risk of cardiovascular death and hospitalizations in patients with heart failure (HF), irrespective of the presence or absence of diabetes. Despite class 1 and class 2A recommendations for their usage in HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) respectively by the American College of Cardiology, their prescription rate has remained low. Objective: The aim of this study is to analyze SGLT2i prescription patterns at two academic institutions, with the goal of identifying barriers to implementation. Design: A two-center retrospective analysis was conducted on patients ≥18 years old with a diagnosis of heart failure who were admitted to one of two hospital systems between 5/1/21 and 5/31/22. Patients with an eGFR ≥20 mL/min/1.73m2 and BNP ≥ 100 pg/mL were included. Results: SGLT2i was prescribed in only 19 out of 1081 HFpEF patients (1.8 %) and 51 out of 1596 HFrEF patients (3.2 %). A majority of SGLT2i prescriptions for the HFpEF population came from general medicine services (57.9 %) after obtaining approval from a cardiologist, which was required at our institutions. Adverse effects such as hypoglycemia and urinary tract infections were not significantly associated with SGLT2i use. Conclusions: Despite proven benefits of this class of medications as witnessed in large-scale clinical trials, the implementation of this drug class continues to be low.

Background: Atrial functional mitral regurgitation (AFMR) and heart failure with a preserved ejection fraction (HFpEF) often coexist. However, the clinical impact of HFpEF in patients with AFMR has not been well characterized. This study aimed to determine clinical outcomes and response to mitral valve (MV) intervention or rhythm control therapy in patients with HFpEF and moderate AFMR (HFpEF-AFMR)., Methods: This was a post-hoc analysis of the REVEAL-AFMR, a retrospective observational study involving patients with ≥ moderate AFMR. After excluding patients with severe MR, the presence of HFpEF was defined by the Universal definition., Results: Of 438 patients with moderate AFMR, 352 met the criteria of HFpEF (prevalence: 80 %). Compared to non-HFpEF-AFMR (n = 86), patients with HFpEF-AFMR were older and had greater symptom burden and a higher prevalence of severe tricuspid regurgitation (19 %). During a median follow-up of 33.2 months, a composite outcome of all-cause mortality or HF hospitalization occurred in 130 patients. Patients with HFpEF-AFMR had a 3.6-fold increased risk of the composite outcome compared to non-HFpEF-AFMR. While MV intervention was not associated with outcomes in HFpEF-AFMR, concomitant tricuspid valve (TV) procedures were associated with a better outcome than isolated MV intervention (HR 0.15, 95 %CI 0.04-0.54, p = 0.009). Catheter or surgical rhythm control showed a favorable outcome in HFpEF-AFMR and atrial fibrillation (HR 0.38, 95 %CI 0.17-0.87, p = 0.008)., Conclusion: HFpEF was substantially common in moderate AFMR and was associated with worse clinical outcomes. Simultaneous MV and TV intervention procedures or rhythm control therapy were associated with better clinical outcomes in HFpEF-AFMR., Competing Interests: Declaration of competing interest Dr. Kagiyama was affiliated with a department endowed by grants from Paramount Bed Holdings Co., Ltd., and received research grants from EchoNous. Inc. and AMI Inc., and received speaker fees from Novartis Japan, Otsuka Pharma, Eli Lilly, and Nippon Boehringer Ingelheim outside the submitted work. Dr. Ishii received lecture fees from AstraZeneca Inc., Bayer Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Bristol-Myers Squibb Inc., Daiichi-Sankyo Pharma Inc., MSD K. K., Mitsubishi Tanabe Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Novartis Japan, and Pfizer Japan Inc. Dr. Obokata received speaker honoraria from AstraZeneca, Eli Lily, Novartis, Otsuka pharmaceutical, and Nippon Boehringer-Ingelheim., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Aims: Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent cardiovascular disease, which is often accompanied by kidney dysfunction. Exercise has been recognized as a feasible strategy to improve renal function. The aim of this study was to investigate whether aerobic exercise (AE) could ameliorate HFpEF-induced renal injury by regulating the expression of acyl-coenzyme A: lysocardiolipin acyltransferase-1 (ALCAT1)., Materials and Methods: Eight-week-old C57BL/6 and Alcat1 knockout mice were used to establish a HFpEF induced kidney injury model. Mice in the exercise-intervention group were performed a six-week of AE training. Cardiac function and blood pressure were assessed using echocardiography and a non-invasive intelligent blood pressure monitor. Renal morphology and function were detected by HE, Masson, and PAS staining, as well as biochemical assays using commercial kits. Oxidative stress, inflammation, apoptosis, and renal fibrosis-related proteins were detected by Western Blotting., Key Findings: In the HFpEF induced kidney injury model, ALCAT1 protein expression was upregulated, accompanied by cardiac and renal dysfunction. These pathological changes were reversed by AE. In addition, Alcat1 knockout significantly alleviated HFpEF-induced oxidative stress, inflammation, apoptosis, and fibrosis in the kidneys. Furthermore, Alcat1 knockout further enhanced the protective effects of exercise, ameliorating renal injury and improving renal function in HFpEF mice., Significance: AE significantly improved renal function by alleviating oxidative stress, inflammation, apoptosis, and fibrosis in HFpEF mice. These beneficial effects were further enhanced in the lack of ALCAT1. Thus, ALCAT1 might represent a potential therapeutic target for the treatment of HFpEF-induced kidney injury., 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 © 2025 Elsevier Inc. All rights reserved.)

Background: Accumulating evidences have suggested a pathophysiological link between coronary microvascular dysfunction (CMD) and heart failure with preserved ejection fraction (HFpEF). The clinical relevance and prognostic impact of myocardial blood flow (MBF) using single-photon emission computed tomography (SPECT) among HFpEF patients remain unexplored clearly., Methods: Fifty-five patients with HFpEF and 48 controls were prospectively enrolled. All underwent dynamic myocardial perfusion imaging with (99 m) Tc-sestamibi at rest and a stress test at peak with dipyridamole. MBF and myocardial flow reserve (MFR) parameters were obtained after perfusion and further related to cardiac structural and advanced functional strain measures using echocardiography and clinical outcomes., Results: CMD (defined as global MFR <2.5) was more prevalent in HFpEF than in control (71 % vs 16.7 %). Patients with HFpEF had worse longitudinal strain indices, lower post-stress MBF (2.37 ± 0.78 vs. 3.30 ± 0.94 ml/min/g, p < 0.001), higher global rest MBF (1.11 ± 0.55 vs. 0.89 ± 0.19 ml/min/g, p = 0.008), and lower global MFR (2.34 ± 0.84 vs. 3.68 ± 1.04, p < 0.001) than the controls. These results were similar for the regional MFRs in the vascular-based analysis. Lower MFR correlated with more impaired left ventricular, left atrial, and right ventricular strain measures (r = -0.44, 0.38, and 0.27, respectively, all p < 0.05). Patients with HFpEF and CMD had increased risks of all-cause mortality and hospitalization compared with those without HFpEF nor CMD (adjusted hazard: 6.42, 95 % CI: 1.40-29.43, p = 0.017)., Conclusions: CMD by dynamic SPECT is frequently observed among patients with HFpEF and correlated with more impaired overall cardiac mechanics. HFpEF with comorbid CMD had worse clinical outcome., 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. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Despite increasing awareness in general practice, heart failure with preserved ejection fraction (HFpEF) remains under-diagnosed in the community due to diagnostic difficulties. Dedicated dyspnea clinics are responsible for diagnosing HFpEF and efficient referral from primary care physicians is the key to enhance its role., Methods: This retrospective analysis was performed to assess the effectiveness of a one-year collaborative project between our dyspnea clinic and the Maebashi Medical Association. Primary care physicians were encouraged to screen patients at risk for HFpEF and refer them to the dyspnea clinic, where exercise stress echocardiography was utilized to enhance the identification of HFpEF. To evaluate the clinical value of the project, the data obtained were compared with data from the previous year without collaboration., Results: The collaborative project was conducted between May 2023 and May 2024. The rate of patients referred from the city increased from 47 % during the previous year to 87 % during the collaborative period (p < 0.0001). Most of the patients were referred by non-cardiologists (77 %). The prevalence of HFpEF diagnosis tended to increase from 32 % to 39 % after the collaborative project, while pulmonary causes of dyspnea tended to decrease from 21 % to 12 %. After a thorough evaluation at the dyspnea clinic, 98 % of referred patients were referred back to their referring physicians for further treatment and follow-up., Conclusions: These data suggest the effectiveness of our approach to identify HFpEF in the community through collaboration between the dedicated dyspnea clinic and primary care physicians., Competing Interests: Declaration of competing interest Dr. Obokata received speaker honoraria from Novartis, Otsuka Pharmaceutical, AstraZeneca, Eli Lilly, and Nippon Boehringer-Ingelheim. Dr. Ishii received lecture fees from AstraZeneca Inc., Bayer Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Bristol-Myers Squibb Inc., Daiichi-Sankyo Pharma Inc., MSD K. K., Mitsubishi Tanabe Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Novartis Japan, and Pfizer Japan Inc., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with enhanced response to drug-induced QT interval lengthening. We determined the influence of HFpEF on drug-induced lengthening of dispersion of repolarization, a measure of proarrhythmic risk., Methods: We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched controls without HF. Twelve‑lead electrocardiograms were obtained prior to ibutilide and serially for 8 h post-ibutilide. Tpeak-Tend, a measure of dispersion of ventricular repolarization, and heart rate-corrected J-Tpeak (J-Tpeakc), representing early repolarization, were measured by an investigator blinded to study groups., Results: Baseline (pre-ibutilide) Tpeak-Tend and J-Tpeakc were not significantly different in the HFpEF and control groups. Maximum Tpeak-Tend was longer in the HFpEF group than in the control group (85 ± 10 vs 73 ± 8 ms, p = 0.01). Additionally, % change from baseline in Tpeak-Tend was greater in the HFpEF group [median (IQR) 17 (11) vs 8 (3)%, p = 0.003]. The area under the effect curve from 0 to 8 hours following ibutilide (including the 10-minute infusion) (AUEC 0-8.17 ) for Tpeak-Tend was also larger in the HFpEF group (600 ± 42 vs. 543 ± 49 ms•hr, p = 0.03). Maximum J-Tpeakc, % change from baseline in J-Tpeakc and AUEC 0-8.17 for J-Tpeakc in the two groups were not significantly different., Conclusion: HFpEF is associated with enhanced response to drug-induced increases in dispersion of repolarization., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This review aims to determine if patients who undergo atrial fibrillation (AF) ablation with heart failure with preserved ejection fraction (HFpEF) do better, or worse or the same compared to patients with heart failure with reduced ejection fraction (HFrEF). Methods: A search of MEDLINE and EMBASE was performed using the search terms: “atrial fibrillation”, “ablation” and terms related to HFpEF and HFrEF in order to identify studies that evaluated one or more of i) AF recurrence, ii) periprocedural complications and iii) adverse outcomes at follow up for patients with HFpEF and HFrEF who underwent AF ablation. Data was extracted from included studies and statistically pooled to evaluate adverse events and AF recurrence. Results: 5 studies were included in this review and the sample size of the studies ranged from 91 to 521 patients with heart failure. There was no significant difference in the pooled rate for no AF or symptom recurrence after AF ablation comparing patients with HFpEF vs HFrEF (RR 1.07 95%CI 0.86–1.33, p = 0.15). The most common complications were access site complications/haematoma/bleeding which occurred in similar proportion in each group; HFpEF (3.1%) and HFrEF (3.1%). In terms of repeat ablations, two studies were pooled to yield a rate of 78/455 (17.1%) for HFpEF vs 24/279 (8.6%) for HFrEF (p = 0.001. Conclusions: Heart failure patients with preserved or reduced ejection fraction have similar risk of AF or symptom recurrence after AF ablation but two studies suggest that patients with HFpEF are more likely to have repeat ablations.

Dahl Salt-Sensitive (DSS) rats develop heart failure with preserved ejection fraction (HFpEF) when fed a high-salt (8 % NaCl) diet. Hypertension-induced inflammation and subsequent ventricular fibrosis are believed to underlie the development of HFpEF. We investigated the role of diet modification in the progression of HFpEF using male DSS rats, fed either a high-salt diet from 7 weeks of age to induce HFpEF, or a normal-salt (0.3 % NaCl) diet as controls. After echocardiographic confirmation of diastolic dysfunction at 14–15 weeks of age along with HF manifestations, the HFpEF rats were randomly assigned to either continue a high-salt diet or switch to a normal-salt diet for an additional 4 weeks. HFpEF rats with diet modification showed improved diastolic function (reduced E/E′ ratio in echocardiogram), increased functional capacity (increased treadmill exercise distance), and reduced pulmonary congestions (lung/body weight ratio), compared to high-salt-fed HFpEF rats. Systolic blood pressure remained high (~200 mmHg), and ventricular hypertrophy remained unchanged. Ventricular arrhythmia inducibility (100 % inducible) and corrected QT interval (on ECG) did not change in HFpEF rats after diet modification. HFpEF rats with diet modification showed prolonged survival and reduced ventricular fibrosis (Masson's trichrome staining) compared to high-salt-fed HFpEF rats. Hence, the modification of diet (from high-salt to normal-salt diet) reversed HFpEF phenotypes without affecting blood pressure or ventricular hypertrophy.

Study objective: Half of patients with heart failure have preserved ejection fraction (HFpEF). Over the years, guidelines have recommended or advised against various therapies for HFpEF management. However, there is limited evidence on the trends in utilization of the various medications. The aim of this study was to examine the trends in the use of pharmacotherapies among patients with HFpEF from 2008 through 2020. Design: Retrospective cohort study of patients with HFpEF used MarketScan® Commercial and Medicare Supplemental Databases (2007–2020). Participants: Patients with HFpEF. Outcome measures: Utilization rates for angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), aldosterone receptor antagonists (ARAs), diuretics, β-blockers, calcium channel blockers (CCBs), phosphodiesterase 5 inhibitors (PDE5Is), nitrates, digoxin, and sodium glucose cotransporter-2 inhibitors (SGLT2i) within 90 days of the first HFpEF diagnosis. Results: We identified 156,730 patients with HFpEF (mean [SD] age, 73 [13.4] years; 57 % females). From 2008 to 2020, we found increased utilization rates for ARNIs (0.02 % vs. 0.17 % of all patients, p

Summary: Background: The pathophysiology and subsequent myocardial dysfunction of heart failure with preserved ejection fraction (HFpEF) with comorbid obesity has not been extensively described. This study aimed to investigate the clinical features and cardiovascular magnetic resonance (CMR) derived myocardial strain and tissue characteristics in patients with HFpEF and comorbid obesity phenotype. Methods: In this prospective cohort study, we included consecutive patients admitted to Fuwai hospital in China who underwent CMR. Patients with HFpEF or obesity were diagnosed with demographic data, clinical presentation, laboratory test, and echocardiography or CMR imaging. The key exclusion criteria were cardiomyopathy, primary valvular heart disease, and significant coronary artery disease. Participant data were obtained from the electronic medical records database or inquiry. Comparisons of clinical features and CMR derived structural and functional parameters amongst different groups were made using one-way analysis of variance, or χ2 tests, and post hoc Bonferroni analysis where appropriate. Findings: Between January 1, 2019 and July 31, 2021, 280 participants (108 patients with HFpEF and obesity, 50 patients with HFpEF and normal weight, 72 patients with obesity, and 50 healthy controls) were enrolled. Compared with patients with HFpEF and normal weight, patients with HFpEF and obesity were younger males, and had higher plasma volume, uric acid and hemoglobin levels, yet less often atrial fibrillation, and lower NT-proBNP levels, and had higher left ventricular mass index, end-diastole/systole volume index, lower left atrial volume index, and worse myocardial strains (all p ≤ 0.05), but no remarkable difference in late gadolinium enhancement (LGE) presence and extracellular volume fraction (ECV). After adjusting for age, atrial fibrillation, and coronary artery disease, only global longitudinal strain (GLS, p = 0.031) and early-diastolic global longitudinal strain rate (eGLSR, p = 0.043) were considerably worse in patients with HFpEF and obesity versus patients with HFpEF and normal weight. Furthermore, early-diastolic strain rates showed no linear association with ECV in patients with HFpEF and obesity. Moreover, GLS demonstrated the highest diagnostic ability when compared with traditional CMR structural parameters and ECV to diagnose patients with HFpEF and obesity in the setting of obesity. Interpretation: Higher systemic inflammation, and worse GLS and eGLSR may be the distinct features of obesity-related HFpEF phenotype; strains and ECV may represent different mechanisms of HFpEF with obesity, deserving further study. Funding: The Construction Research Project of Key Laboratory (Cultivation) of Chinese Academy of Medical Sciences (2019PT310025); National Natural Science Foundation of China (81971588); Capital’s Funds for Health Improvement and Research (CFH 2020-2-4034); Youth Key Program of High-level Hospital Clinical Research (2022-GSP-QZ-5).

Among heart failure (HF) patients, the onset of atrial fibrillation (AF) is often associated with a marked worsening of HF symptoms and increased morbidity and mortality. Among AF patients, 30%–40% experience at least 1 HF episode. New data suggest that, in HF patients, AF rhythm control is superior to rate control and that rhythm control by catheter ablation is superior to antiarrhythmic drugs. In recent years, several trials that addressed the impact of AF ablation on morbidity and mortality included HF patients; however, studies also have specifically investigated the growing cohort of patients suffering from both HF and AF. Although the majority of these trials showed a marked benefit of AF ablation, there are hints that not all HF patients benefit equally from AF ablation. AF treatment in HF is challenging because the same cardiac morbidities that lead to HF can also act as risk factors for the development of the arrhythmogenic substrate that causes AF. In many patients, this arrhythmogenic substrate can be successfully treated by antral pulmonary vein isolation pulmonary vein isolation (PVI). However, due to advanced atrial disease, some patients also might require multiple procedures and/or “PVI plus” ablation strategies. In this review, we summarize current data on the effect of AF ablation in HF patients, with a special focus on the beneficial effect of AF ablation in different clinical HF subgroups.

Atrial fibrillation (AF) is associated with exercise intolerance, stroke, and all-cause mortality. However, whether this can be solely attributable to the arrhythmia itself or alternative mechanisms remains controversial. Heart failure with preserved ejection (HFpEF) commonly coexists with AF and may contribute to the poor outcomes associated with AF. Indeed, several invasive hemodynamic studies have confirmed that patients with AF are at increased risk of underlying HFpEF and that the presence of HFpEF may have important prognostic implications in these patients.Mechanistically, AF and HFpEF are closely linked. Both conditions are driven by the presence of common cardiovascular risk factors and are associated with left atrial (LA) myopathy, characterized by mechanical and electrical dysfunction. Progressive worsening of this left atrial (LA) myopathy is associated with both increased AF burden and worsening HFpEF. In addition, there is growing evidence to suggest that worsening LA myopathy is associated with poorer outcomes in both conditions and that reversal of the LA myopathy could improve outcomes. In this review article, we will present the epidemiologic and mechanistic evidence underlying the common coexistence of AF and HFpEF, discuss the importance of a progressive LA myopathy in the pathogenesis of both conditions, and review the evidence from important invasive hemodynamic studies. Finally, we will review the prognostic implications of HFpEF in patients with AF and discuss the relative merits of AF burden reduction vs HFpEF reduction in improving outcomes of patients with AF and HFpEF.

Abstract Background Coronary microvascular dysfunction (CMD) has been proposed as a novel mechanism for the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). Recent studies have suggested the potential utility of coronary flow reserve (CFR) as a marker of CMD in patients with HFpEF. Phase contrast (PC) cine cardiovascular magnetic resonance (CMR) of the coronary sinus has emerged as a non-invasive method to quantify CFR. We aimed to investigate the prognostic value of CMR-derived CFR in patients with HFpEF. Methods Data from 163 HFpEF patients (73 ± 9 years; 86 [53%] female) were retrospectively analyzed. Coronary sinus blood flow was measured in all patients, and myocardial blood flow was calculated as coronary sinus blood flow divided by left ventricular mass. CFR was calculated as the myocardial blood flow during adenosine triphosphate infusion divided by that at rest. Adverse events were defined as all-cause death and hospitalization due to HF exacerbation. Event-free survival stratified according to CFR

Diastolic dysfunction (DD) underlies heart failure with preserved ejection fraction (HFpEF), a clinical syndrome associated with aging that is becoming more prevalent. Despite extensive clinical studies, no effective treatment exists for HFpEF. Recent findings suggest that oxidative stress contributes to the pathophysiology of DD, but molecular mechanisms underpinning redox-sensitive cardiac remodeling in DD remain obscure. Using transgenic mice with mitochondria-targeted NOX4 overexpression (Nox4TG618) as a model, we demonstrate that NOX4-dependent mitochondrial oxidative stress induces DD in mice as measured by increased E/E′, isovolumic relaxation time, Tau Glantz and reduced dP/dtmin while EF is preserved. In Nox4TG618 mice, fragmentation of cardiomyocyte mitochondria, increased DRP1 phosphorylation, decreased expression of MFN2, and a higher percentage of apoptotic cells in the myocardium are associated with lower ATP-driven and maximal mitochondrial oxygen consumption rates, a decrease in respiratory reserve, and a decrease in citrate synthase and Complex I activities. Transgenic mice have an increased concentration of TGFβ and osteopontin in LV lysates, as well as MCP-1 in plasma, which correlates with a higher percentage of LV myocardial periostin- and ACTA2-positive cells compared with wild-type mice. Accordingly, the levels of ECM as measured by Picrosirius Red staining as well as interstitial deposition of collagen I are elevated in the myocardium of Nox4TG618 mice. The LV tissue of Nox4TG618 mice also exhibited increased ICaL current, calpain 2 expression, and altered/disrupted Z-disc structure. As it pertains to human pathology, similar changes were found in samples of LV from patients with DD. Finally, treatment with GKT137831, a specific NOX1 and NOX4 inhibitor, or overexpression of mCAT attenuated myocardial fibrosis and prevented DD in the Nox4TG618 mice.Together, our results indicate that mitochondrial oxidative stress contributes to DD by causing mitochondrial dysfunction, impaired mitochondrial dynamics, increased synthesis of pro-inflammatory and pro-fibrotic cytokines, activation of fibroblasts, and the accumulation of extracellular matrix, which leads to interstitial fibrosis and passive stiffness of the myocardium.Further, mitochondrial oxidative stress increases cardiomyocyte Ca2+ influx, which worsens CM relaxation and raises the LV filling pressure in conjunction with structural proteolytic damage.

Heart failure with preserved ejection fraction is associated with elevated left atrial pressure during exercise. Sodium-glucose cotransporter-2 inhibitors have demonstrated the evidence of benefit in heart failure with preserved ejection fraction, but even with this treatment, heart failure hospitalizations remain high, and improvements in quality of life scores are modest. Thus, there is growing interest in nonpharmacological methods of limiting the rise in left atrial pressure during exertion. Creation of an interatrial shunt (IAS) may unload the left heart during exercise. Multiple implant or nonimplant IAS procedures are under investigation. Implantation of the most studied device results in 3 to 5 mm Hg decreases in pulmonary capillary wedge pressure during exercise, no increase in incidence of stroke, stable increases in Qp/Qs (1.2-1.3), and mild right heart enlargement without change in function out to at least a year after treatment. The findings from the first large randomized controlled trial of an atrial shunt have recently been published. For the population as a whole, implantation of the atrial shunt device appeared to be safe but did not provide clinical benefit. However, prespecified and post-hoc analyses have demonstrated that men, patients with larger right atrial volumes, and those with pulmonary artery systolic pressure >70 mm Hg at 20 W exercise had worse outcomes with IAS therapy, whereas those with peak exercise pulmonary vascular resistance

Background: Heart failure (HF) is a complex clinical syndrome with symptoms and signs that result from any structural or functional impairment of ventricular filling or ejection of blood. Limited data is available regarding the in-hospital outcomes of TAVR compared to SAVR in the octogenarian population with HF. Methods: The National Inpatient Sample (NIS) database was used to compare TAVR versus SAVR among octogenarians with HF. The primary outcome was in-hospital mortality. The secondary outcome included acute kidney injury (AKI), cerebrovascular accident (CVA), post-procedural stroke, major bleeding, blood transfusions, sudden cardiac arrest (SCA), cardiogenic shock (CS), and mechanical circulatory support (MCS). Results: A total of 74,995 octogenarian patients with HF (TAVR-HF n = 64,890 (86.5%); SAVR n = 10,105 (13.5%)) were included. The median age of patients in TAVR-HF and SAVR-HF was 86 (83–89) and 82 (81–84) respectively. TAVR-HF had lower percentage in-hospital mortality (1.8% vs. 6.9%;p

Objectives: Though invasive monitoring is the most accurate to estimate diastolic dysfunction but it has its own risk. The purpose of this study was to find out any standardized correlation between invasive and non -invasive parameters. Methods: It is an observational, descriptive study comprising of a total of 500 patients. The primary objective of the study was to determine the correlation between echocardiographic diastolic parameters and invasively measured left ventricular end diastolic pressure (LVEDP). Results: On studying correlation of different invasive and non-invasive data it was reported that there was a weak correlation between peak E velocity (r = 0.14, p = 0.631), Peak A velocity (r = 0.67, p = 0.59), IVRT (r = −0.35, p = 0.178), Mitral deceleration time (DT) (r = −0.06, p = 0.842), pulmonary venous peak systolic (r = −0.02, p = 0.966) and diastolic flows (r = 0.47, p = 0.201) to LVEDP. There was a good positive correlation between elevated LVEDP and difference in duration of pulmonary venous and mitral flow at atrial contraction (A-Ard) and E/Ea at all four longitudinal segments of the left ventricle. The sensitivity and specificity for detecting an elevated LVEDP of more than 12 mm Hg, using a cut off value of E/Ea< 8, were 89% and 90%.Lateral E/Ea ≥ 12, LAVI ≥34 mL/m2, and Ard–Ad > 30 msec have the greatest diagnostic value for diagnosing diastolic dysfunction in HFpEF patients. Conclusion: Lateral E/Ea ≥ 12, LAVI ≥34 mL/m2, and Ard–Ad > 30 msec have the greatest diagnostic value for diagnosing diastolic dysfunction in HFpEF patients and have good correlation with invasively measured LVEDP.

Background: Despite recent advances in the treatment of heart failure with preserved ejection fraction (HFpEF), the overall outcome is poor and evidence-based therapeutic options are scarce. So far, the only evidence-based therapy in HFpEF, sodium glucose linked transporter 2 inhibitors, has only insignificant effects in patients with a high EF (EF > 60%, HEF) when compared to a normal EF (EF 50%-60%, NEF). This could be explained by different biomechanical and cellular phenotypes of HFpEF across the range of EFs rather than a uniform pathophysiology. We aimed to investigate the concept of different phenotypes in the HEF and NEF using noninvasive single-beat estimations and to observe alterations in pressure-volume relations in both groups following sympathomodulation using renal denervation (RDN). Methods: Patients from a previous study on RDN in HFpEF were stratified by having HFpEF with an HEF or NEF. Single-beat estimations were used to derive arterial elastance (Ea), end-systolic elastance (Ees), and diastolic capacitance (VPED20). Results: Overall, 63 patients were classified as having an HEF, and 36 patients were classified as having an NEF. Ea did not differ between the groups and was reduced at follow-up in both groups (p < 0.01). Ees was higher and VPED20 was lower in the HEF than those in the NEF. Both were changed significantly at follow-up in the HEF but not in the NEF. Ees/Ea was lower in the NEF (0.95 ± 0.22 vs 1.15 ± 0.27, p < 0.01) and was significantly increased in the NEF (by 0.08 ± 0.20, p < 0.05) but not in the HEF. Conclusions: Beneficial effects of RDN were observed in the NEF and HEF, supporting the further investigation of sympathomodulating treatments for HFpEF in future trials.

Cardiac amyloidosis (CA) is an important cause of restrictive cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). At present, 3 bone-seeking tracers, 99mTc-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD), 99mTc-pyrophosphate (99mTc-PYP), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP), have been evaluated for detecting CA, but they are not widely available. In contrast, methylene diphosphate (MDP) is widely available. However, only sporadic case reports have shown that MDP can accumulate in patients with CA. We report an 86-year-old man with multiple medical problems, including hypertension, hyperlipidemia, HFpEF, and a history of treated prostate cancer, who was referred for a 99mTc-MDP bone scan to rule out bone metastasis. The bone scan was negative for bone metastasis, but there was mild tracer accumulation in the heart, suggestive of CA. Subsequently, CA was diagnosed on 99mTc-PYP imaging. MDP may play a role comparable to other bone-seeking tracers in the diagnosis of CA and may be used as a noninvasive adjunct in the diagnosis of CA. Future research should compare MDP with other bone-seeking tracers for the diagnosis of CA. In addition, mechanistic studies on tracer binding to amyloid fibrils may help understand the pathophysiology of CA and facilitate the development of better and more specific tracers for CA.

Abstract Background Left ventricular (LV) diastolic dysfunction is the main cause of heart failure with preserved ejection fraction (HFpEF), and is characterized by LV stiffness and relaxation. Abnormal LV global longitudinal strain (GLS) is frequently observed l in HFpEF, and was shown to be useful in identifying HFpEF patients at high risk for a cardiovascular event. Cardiovascular magnetic resonance (CMR) feature tracking (CMR-FT) enables the reproducible and non-invasive assessment of global strain from cine CMR images. However, the association between GLS and invasively measured parameters of diastolic function has not been investigated. We sought to determine the prevalence and severity of GLS impairment in patients with HFpEF by using CMR-FT, and to evaluate the correlation between GLS measured by CMR-FT and that measured by invasive diastolic functional indices. Methods Eighteen patients with HFpEF and 18 age- and sex-matched healthy control subjects were studied. All subjects underwent cine, pre- and post-contrast T1 mapping and late gadolinium-enhancement CMR. In the HFpEF patients, invasive pressure–volume loops were obtained to evaluate LV diastolic properties. GLS was quantified from cine CMR, and extracellular volume fraction (ECV) was quantified from pre- and post-contrast T1 mapping as a known imaging biomarker for predicting LV stiffness. Results GLS was significantly impaired in patients with HFpEF (− 14.8 ± 3.3 vs.–19.5 ± 2.8%, p

Left bundle branch block (LBBB) causes immediate electrical and mechanical dyssynchrony of the left ventricle (LV) and gradual structural damages in the Purkinje cells and myocardium. Mechanical dyssynchrony reduces the LV ejection fraction (EF) instantly, but only to ≈55% in an otherwise normal heart. Because of the heart's in-built functional redundancy, a patient with LBBB does not always notice the heart's reduced efficiency straightaway. After a variable period of time (which could be from days to decades), the patient may become symptomatic with heart failure (HF), which classifies as HF with preserved EF ≥50% (HFpEF). The LVEF drops further because of continuous adverse remodeling and inefficient cardiac contraction. The patient transits to HF with moderately reduced EF 35%-50% (HFmrEF) and then reduced EF ≤35% (HFrEF) over 5-21 years. Cardiac resynchronization therapy (CRT) is currently only indicated in guidelines for HFrEF and LBBB. LBBB shortens the median survival of patients with HFmrEF by 5.5 years. Randomized controlled trials have shown that CRT improves echocardiographic indices for HFmrEF with LBBB. CRT in HFpEF with LBBB is a promising but underexplored/underused therapy. There have been anecdotal reports that CRT produced symptom relief in patients debilitated by HFpEF with LBBB, who constitute ≈6% of all patients with HF and an adequate pool of potential randomized controlled trial participants. Conduction system pacing in the form of left bundle branch area pacing is an emerging pacing strategy that might reverse and forestall the deleterious effects of LBBB., Competing Interests: Disclosures Open access publishing for this article was supported through a transformative agreement between the DEAL Consortium and Elsevier., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcome in patients with heart failure (HF) and reduce serum uric acid (SUA). The relevance of this metabolic effect in patients with heart failure with preserved ejection fraction (HFpEF) is unclear., Objectives: The authors investigated the effect of empagliflozin on SUA levels in relation to the therapeutic efficacy in patients with HFpEF., Methods: This post hoc analysis of the EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction; NCT03057951) trial assessed the clinical effect of SUA reduction in relation to the outcome endpoints of the trial (composite primary outcome of cardiovascular mortality or hospitalization for HF, its individual components, and all-cause mortality in patients with HFpEF)., Results: Hyperuricemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) was prevalent in 49% of patients. Elevated SUA (highest tertile SUA 8.8 ± 1.4 g/dL) was associated with advanced HF severity and with higher risk of adverse outcome (primary endpoint HR: 1.23 [95% CI: 0.98-1.53]; P = 0.07; HF hospitalization HR: 1.42 [95% CI: 1.08-1.86]; P = 0.01). SUA was reduced early (after 4 weeks vs placebo -0.99 ± 0.03 mg/dL; P < 0.0001) and throughout follow-up, with reduction in all prespecified subgroups. Empagliflozin reduced clinical events of hyperuricemia (acute gout, gouty arthritis, or initiation of antigout therapy) by 38% (HR: 0.62 [95% CI: 0.51-0.76]; P < 0.0001). The treatment benefit on the primary endpoint was not influenced by baseline SUA (HR: 0.79 [95% CI: 0.69-0.90]; P = 0.0004). The change in SUA was an independent correlate of the treatment benefit on the primary endpoint (P = 0.07)., Conclusions: Hyperuricemia is a common complication in HFpEF and is related to advanced disease severity and adverse outcome. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricemia., Competing Interests: Funding Support and Author Disclosures This study was funded by Boehringer Ingelheim and Eli Lilly and Company Alliance. Graphical assistance was provided by 7.4 Ltd, HCG, and was funded by Boehringer Ingelheim. Dr Doehner has received consulting fees from Boehringer Ingelheim related to work on clinical events committee during the conduct of the study and personal fees from Aimediq, Bayer, Boehringer Ingelheim, Medtronic, Vifor Pharma and research support from EU (Horizon 2020), German ministry of Education and Research, German Center for Cardiovascular Research, Vifor Pharma, and ZS Pharma. Dr Anker has received grants and personal fees from Vifor Int and Abbott Vascular; and personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Medtronic, Novartis, Occlutech, Servier, V-Wave, and Vifor Int. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, LivaNova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. Dr Filippatos has received lecture fees and/or committee member contributions in clinical trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, Amgen, and Boehringer Ingelheim; and research support from the European Union. Dr Coats has received fees from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards, Eli Lilly, Menarini, Novartis, Servier, Vifor, Abbott, Actimed, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Impulse Dynamics, Respicardia, and Viatris. Dr Ferreira has received research support from Boehringer Ingelheim, Novartis, and AstraZeneca through the University of Porto. Drs Henrichmoeller and Brueckmann are employees of Boehringer Ingelheim International. Ms Schueler is an employee of mainanalytics GmbH contracted by Boehringer Ingelheim. Dr Pocock has received consultancy fees from Boehringer Ingelheim. Dr Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott, Applied Therapeutics, HeartFlow Inc, Innolife, and Roche Diagnostics; has received consulting fees from Abbott, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Jana Care, Janssen, Novartis, Merck, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Intercept, Pfizer, and Takeda. Dr Packer has received personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, Salamandra, outside of the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although the use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with obesity and heart failure with preserved ejection fraction (HFpEF) has demonstrated improvement in cardiovascular outcomes, the incremental benefits of GLP-1 RA for patients already on sodium-glucose cotransporter 2 inhibitors (SGLT2is) remain underexplored., Objectives: This study aimed to assess the incremental benefits of GLP-1 RA in patients with type 2 diabetes mellitus, overweight/obesity, and HFpEF receiving SGLT2i therapy., Methods: The authors conducted a retrospective cohort study using the TriNetX research database including patients ≥18 years with type 2 diabetes mellitus, body mass index ≥27 kg/m 2 , and HFpEF on SGLT2i. Two cohorts were created based on GLP-1 RA prescription. The outcomes were heart failure exacerbation, all-cause emergency department visits/hospitalizations among others over a 12-month period., Results: A total of 7,044 patients remained in each cohort after propensity score matching. There was a significantly lower risk of heart failure exacerbations, all-cause emergency department visits/hospitalizations, new-onset atrial arrhythmias, new-onset acute kidney injury, and pulmonary hypertension in the GLP-1 RA plus SGLT2i cohort compared with the SGLT2i-only cohort. The associated benefits persisted across different body mass indexes and ejection fractions as well as in patients with elevated natriuretic peptide. The risk of diabetic retinopathy was higher in the combination therapy group than with SGLT2i-only use., Conclusions: GLP-1 RA, in addition to SGLT2i, was associated with a significantly lower risk of heart failure hospitalizations in this patient population, suggesting a potential incremental benefit. This highlights the need for prospective studies to confirm the clinical benefits., Competing Interests: Funding Support and Author Disclosures Dr Bhatt is on the advisory board for Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; he is on the Board of Directors for American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); he is a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene; he is on the Data Monitoring Committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, Rutgers University (for the National Institutes of Health–funded MINT Trial); he has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor, Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee), Clinical Cardiology (Deputy Editor); he is named on a patent for sotagliflozin (assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither he nor Brigham and Women's Hospital receive any income from this patent); he has received research funding for Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; he has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); he is Site Co-Investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; he is trustee for American College of Cardiology; and he has done unfunded research for FlowCo. Dr Butler has been a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim; and has served as a consultant for Alnylam, AstraZeneca, Amgen, Applied Therapeutics, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Sanofi, and Vifor. Dr Fonarow has done consulting for Abbot, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson and Johnson, Medtronic, Merck, Novartis, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The combined effect of left ventricular ejection fraction (LVEF) and atrial fibrillation (AF) on clinical outcomes in heart failure (HF) remains complex., Objective: In this post hoc analysis of the TOPCAT trial, we aimed to evaluate the impact of AF on clinical outcomes in patients with HF stratified by LVEF range., Methods: A total of 3442 patients were included, stratified into 3 groups according to LVEF range-HF with mid-range ejection fraction (HFmrEF), LVEF of 45%-50% (n = 823); HF with preserved ejection fraction (HFpEF), LVEF of 51%-60% (n = 1682); and HF with normal ejection fraction (HFnEF), LVEF >60% (n = 937)-and subdivided according to the presence of AF at enrollment. Cox regression analysis was used to define independent associations between AF and clinical outcomes., Results: AF was prevalent in 38.6% in HFmrEF, 34.6% in HFpEF, and 33.7% in HFnEF (P = .07). AF was associated with worse primary outcome in each subgroup and with HF hospitalizations and worse cardiovascular mortality in HFpEF and HFnEF. The hazard ratio for the primary outcome in those with AF compared with sinus rhythm (SR) was 1.11 (1.01-1.22; P = .03) in HFmrEF, 1.20 (1.11-1.29; P < .001) in HFpEF, and 1.16 (1.05-1.28; P = .004) in HFnEF. When LVEF was treated as a continuous variable, there was a linear negative association between LVEF and the effect of AF vs SR for the primary end point and HF hospitalizations and a linear positive association for cardiovascular mortality., Conclusion: Compared with SR, AF was independently associated with worse outcomes across all LVEF ranges., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The impact of comorbidity burden on outcomes of radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) in patients with heart failure and preserved ejection fraction (HFpEF) remains unclear., Objective: The purpose of this study was to evaluate how comorbidity burden influences the association between RFCA and cardiovascular outcomes in AF patients with HFpEF., Methods: AF patients with HFpEF from the prospective China-AF cohort, recruited between August 2011 and December 2020, were categorized into 2 groups based CHA 2 DS 2 -VASc score: low comorbidity burden (score ≤4) and high comorbidity burden (score >4). The associations between RFCA and cardiovascular outcomes and interaction effects of comorbidity burden on these associations were assessed., Results: Among 1700 patients with median follow-up of 65.9 months, those in the low comorbidity burden group who received RFCA had a lower risk of composite events (cardiovascular death and ischemic stroke/transient ischemic attack [TIA]) (adjusted hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.21-0.59] and all-cause death (adjusted HR 0.31, 95% CI 0.17-0.54) compared to those without RFCA. However, significant associations were not observed in the high comorbidity burden group. The differences between low and high comorbidity burden groups were significant, with interaction effects noted between comorbidity burden and RFCA for cardiovascular death (P interaction = 0.045) and ischemic stroke/TIA (P interaction = 0.010). RFCA was associated with a reduced risk of AF recurrence in both comorbidity burden groups., Conclusion: RFCA for AF is associated with reduced AF recurrence and improved cardiovascular outcomes in patients with HFpEF. However, these benefits may be limited for patients with a CHA 2 DS 2 -VASc score >4 (high comorbidity burden)., Competing Interests: Disclosures Dr Ma has received honoraria for presentations from AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Bristol Myers Squibb, Johnson & Johnson, and Pfizer. Dr Dong has received honoraria for presentations from Johnson & Johnson. All other authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Heart failure is an important cause of mortality and morbidity worldwide. Heart failure with preserved ejection fraction (HFpEF) incidence and prevalence is increasing, and the phenotype associated with obesity is the most frequent. Epicardial adipose tissue (EAT) is directly associated with systemic obesity and several previous studies have shown a clear link between EAT and HFpEF. Moreover, the restriction induced by the pericardium is also linked to HFpEF. In this review we will describe the epidemiological association between the pericardium, EAT and HFpEF, how to quantify EAT, what are the pathophysiological mechanism to explain theses association and how can the pericardium and EAT be a treatment target in patients with HFpEF., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There is an urgent need to develop an efficient therapeutic strategy for heart failure with preserved ejection fraction (HFpEF), which is mediated by phenotypic changes in cardiac macrophages. We previously reported that vitamin B-6 inhibits macrophage-mediated inflammasome activation., Objectives: We sought to examine whether the prophylactic use of vitamin B-6 prevents HFpEF., Methods: HFpEF model was elicited by a combination of high-fat diet and N ω -nitro-l-arginine methyl ester supplement in mice. Cardiac function was assessed using conventional echocardiography and Doppler imaging. Immunohistochemistry and immunoblotting were used to detect changes in the macrophage phenotype and myocardial remodeling-related molecules., Results: Co-administration of vitamin B-6 with HFpEF mice mitigated HFpEF phenotypes, including diastolic dysfunction, cardiac macrophage phenotypic shifts, fibrosis, and hypertrophy. Echocardiographic improvements were observed, with the E/E' ratio decreasing from 42.0 to 21.6 and the E/A ratio improving from 2.13 to 1.17. The exercise capacity also increased from 295.3 to 657.7 min. However, these beneficial effects were negated in downstream of kinase (DOK) 3-deficient mice. Mechanistically, vitamin B-6 increased DOK3 protein concentrations and inhibited macrophage phenotypic changes, which were abrogated by an AMP-activated protein kinase inhibitor., Conclusions: Vitamin B-6 increases DOK3 signaling to lower risk of HFpEF by inhibiting phenotypic changes in cardiac macrophages., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Study objective: This study sought to assess the predictive value of H2FPEF score in patients with COVID-19. Design: Retrospective study. Setting: Rush University Medical Center. Participants: A total of 1682 patients had an echocardiogram in the year preceding their COVID-19 admission with a preserved ejection fraction (≥50%). A total of 156 patients met inclusion criteria. Interventions: Patients were divided into H2FPEF into low (0–2), intermediate (3–5), and high (6–9) score H2FPEF groups and outcomes were compared. Main outcome measures: Adjusted multivariable logistic regression models evaluated the association between H2FPEF score group and a composite outcome for severe COVID-19 infection consisting of (1) 60-day mortality or illness requiring (2) intensive care unit, (3) intubation, or (4) non-invasive positive pressure ventilation. Results: High H2FPEF scores were at increased risk for severe COVID-19 infection when compared intermediate to H2FPEF score groups (OR 2.18 [CI: 1.01–4.80]; p = 0.049) and low H2FPEF score groups (OR 2.99 [CI: 1.22–7.61]; p

This report describes a case of heart failure with preserved ejection fraction in a post-menopausal woman with obesity. The case highlights a metabolic phenotype of heart failure with preserved ejection fraction that commonly manifests in women, with the discussion focusing on pathophysiology, mechanistic pathways, and potential targeted therapeutic strategies. (Level of Difficulty: Intermediate.)

Background: The benefit of catheter ablation for atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFpEF) remains uncertain., Objective: We performed a systematic review and meta-analysis to compare catheter ablation and medical therapy (antiarrhythmics for rhythm or rate control) in patients with AF and HFpEF., Methods: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials. Outcomes were the composite end points of death or heart failure (HF) hospitalization, all-cause death, cardiovascular death, all-cause rehospitalization, and HF hospitalization. Statistical analysis was performed using R statistical software, version 4.3.2 (R Foundation for Statistical Computing). Heterogeneity was assessed with I 2 statistics., Results: We included 20,257 patients from 8 studies. Of those, 3 were derived from RCTs, either through post hoc analysis or subgroup analysis, and 5 were observational studies. The median follow-up ranged from 24.6 to 61.2 months. Compared with medical therapy, catheter ablation was associated with a statistically significant lower risk of death or HF hospitalization (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.47-0.83; P = .001; I 2 = 66%), all-cause death (HR 0.68; 95% CI 0.46-0.99; P = .047; I 2 = 61%), cardiovascular death (HR 0.42; 95% CI 0.21-0.84; P = .014; I 2 = 22%), and HF hospitalization (HR 0.43; 95% CI 0.23-0.82; P = .011; I 2 = 87%)., Conclusion: In this meta-analysis, catheter ablation was associated with a lower risk of all-cause death, cardiovascular death, HF hospitalization, and all-cause rehospitalization in comparison to medical therapy in patients with AF and HFpEF., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: A common genetic variant of ICAM1 among African-American individuals (rs5491; p.K56M) is associated with heart failure (HF) hospitalization, but whether this risk is specific to heart failure with preserved ejection fraction (HFpEF) remains unclear. Older women are at high risk for HFpEF, and the relationship between rs5491 and HFpEF across the age spectrum is unknown., Objectives: This study assessed risk of HF and its subtypes conferred by ICAM1 p.K56M (rs5491)., Methods: Associations of rs5491 with risk of HF and its subtypes were estimated among African American individuals in WHI (Women's Health Initiative). The study evaluated whether the association between rs5491 and HF hospitalizations was modified by baseline age. Subsequently, African-American women in WHI and MESA (Multi-Ethnic Study of Atherosclerosis) were pooled and analyses were repeated., Results: Among 8,401 women in WHI, the minor allele frequency of rs5491 was 20.7%, and 731 HF hospitalizations occurred over 19.2 years. The rs5491 variant was not associated with HF or its subtypes across WHI. Interaction analyses suggested that age as a continuous variable modified the association of rs5491 with HFpEF hospitalization (interaction P = 0.04). Upon categorizing women into age decades, rs5491 conferred increased risk of HFpEF among women ≥70 years (HR per additional rs5491 allele: 1.82 [95% CI: 1.25-2.65]; P = 0.002) but was not associated with HFpEF risk among women <70 years. Pooling African-American women in WHI (n = 8,401) and MESA (n = 856) demonstrated that the effect modification by age on the association of rs5491 with HFpEF became more significant (interaction P = 0.009), with consistent HFpEF risk effect estimates among women ≥70 years., Conclusions: ICAM1 p.K56M (rs5491) is associated with HFpEF among African-American women ≥70 years., Competing Interests: Funding Support and Author Disclosures This work was supported by grants KL2TR001424 from the National Center for Advancing Translational Sciences, U.S. NIH (National Institutes of Health). The WHI program is funded by the NHLBI (National Heart, Lung, and Blood Institute), NIH, U.S. Department of Health and Human Services through 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. The opinions expressed in this manuscript are those of the authors and do not necessarily reflect the views of the Department of Health and Human Services/NIH. MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. Dr Sanjiv Shah has received research grants from the NIH (U54 HL160]]273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer, and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Ravi B. Patel has received consulting fees from ICA, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Although some patients with heart failure (HF) with mildly reduced/preserved ejection fraction have low natriuretic peptide levels, there are no large-scale systematic studies of how common these individuals are or what happens to them., Objectives: The purpose of this study was to examine the proportion of patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction) trial with an N-terminal pro-B-type natriuretic peptide (NT-proBNP) level <125 pg/mL, their clinical characteristics, and outcomes., Methods: I- PRESERVE enrolled patients with symptomatic HF and a LVEF ≥45% but who did not have NT-proBNP or body mass index inclusion/exclusion criteria. Baseline NT-proBNP was measured after enrollment but not reported to investigators. The primary outcome in this analysis was the composite of cardiovascular death or HF hospitalization., Results: Overall, 808 of 3,480 patients (23.2%) had NT-proBNP <125 pg/mL. Patients with a low NT-proBNP were younger (68.6 years vs 72.6 years; P < 0.001), were less often men (36.1% vs 40.9%; P = 0.015), and had a higher body mass index (48.4% vs 38.7% obese; P < 0.001) than those with a higher NT-proBNP level. Patients with a low NT-proBNP had less atrial fibrillation (8.5% vs 35.1%; P < 0.001), myocardial infarction, diabetes, chronic obstructive pulmonary disease, and anemia but better kidney function. Patients with a lower NT-proBNP level had less marked echocardiographic abnormalities and were less likely to experience cardiovascular death or HF hospitalization; adjusted HR: 0.35 (95% CI: 0.27-0.46; P < 0.001). However, health status was similarly impaired in patients with lower and higher NT-proBNP levels (median Minnesota Living with Heart Failure Questionnaire 43 vs 43; P = 0.95)., Conclusions: Almost one-quarter of patients with HF with mildly reduced/preserved ejection fraction had a low NT-proBNP level. Although these patients have a favorable prognosis, compared to those with a high NT-proBNP level, they have similarly impaired health status which should be a target for treatment. (Irbesartan in Heart Failure With Preserved Systolic Function [I- PRESERVE]; NCT00095238)., Competing Interests: Funding Support and Author Disclosures Dr Kondo has received speaker fees from Abbott, Ono Pharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, and Abiomed. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, and Analog Devices Inc; his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and he is a Director of Global Clinical Trial Partners. Drs Jhund and McMurray are supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund. Dr Anand has received consulting fees from Amgen, ARCA Pharma, AstraZeneca, Boehringer Ingelheim, Boston Scientific, LivaNova, and Novartis. Dr Carson has received honoraria as a CEC member from Novartis. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, 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 serves as cofounder and non-executive director of Us2.ai. Dr Shah has received either personal or institutional research support from AstraZeneca. Dr Vadagunathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, 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 Zannad has received consulting fees from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, Cereno Scientific, Cellprothera, CEVA, CVRx, Merck, Novartis, Servier, and Vifor-Pharma; and has been a founder of CardioRenal and CVCT. Dr Zile reports research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. Dr McMurray has received payments through Glasgow University for work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consultancy fees from: Alnylam Pharma, Bayer, Bristol Myers Squibb, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma. Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica health, Intas Pharma, J.B. Chemicals and Pharma. Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma., The Corpus, Translation Research Group, and Translational Medicine Academy; and is a Director of Global Clinical Trial Partners., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)