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Background: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes.Objective: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure.Methods: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days.Results: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group.Conclusions: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purpose of this study was to develop an automated surveillance system, using pressure-based hemodynamic factors that would detect which patients were making the transition from compensated to decompensated heart failure before they developed worsening symptoms and required acute medical care. METHODS AND RESULTS: Intracardiac pressures in 274 patients with heart failure were measured using an implantable hemodynamic monitor (IHM) and were analyzed in a retrospective manner. An automated pressure change detection (PCD) algorithm was developed using the cumulative sum method. The performance characteristics of the PCD algorithm were defined in all patients who developed a heart failure-related event (HFRE); patients without HFRE served as controls. Optimal PCD threshold values were chosen using a receiver operator curve analysis. Each of the pressures measured with the IHM were evaluated using the PCD analysis. All had sensitivities >=80% and false-positive rates <4.7/patient-year; however, estimated pulmonary artery diastolic pressure (ePAD) had the best performance. An ePAD based on the optimized PCD threshold of 6.0 yielded a sensitivity of 83% and a false-positive rate of 4.1/patient-year for detecting patients making the transition from compensated to decompensated heart failure. These performance characteristics were not significantly different for patients with an ejection fraction > vs. <50%, estimated glomerular filtration rate > vs. <60 mL/min/1.73 m(2), or age > vs. <60 years. CONCLUSIONS: The automated PCD algorithm had high sensitivity and acceptable false-positive rates in detecting the development of decompensated heart failure before the patient developed worsening symptoms and required acute medical care. These data support the development of a prospective study to examine the utility of adding an automated PCD algorithm to IHM-based management strategies to prevent decompensated heart failure. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purpose of this study was to determine which pressure-based hemodynamic factor was most closely associated with the transition from chronic compensated to acute decompensated heart failure. METHODS AND RESULTS: Intracardiac pressures were retrospectively examined in 274 heart failure patients using an implantable hemodynamic monitor. The relationship between the development of a heart failure-related event (HFRE) and 3 pressure variables were analyzed: peak estimated pulmonary artery diastolic pressure (ePAD) at the time of an HFRE, change in ePAD from baseline to peak pressure, and the product of ePAD pressure and time (PxT) calculated as the area under the pressure-versus-time curve from baseline to peak pressure. Patients without an HFRE served as control subjects. Peak ePAD and change in ePAD were not closely associated with the development of an HFRE. In patients with an HFRE, PxT was 221 ± 130 mm Hg·days with only 4% of the PxT values <60 mm Hg·days. In contrast, in patients without an HFRE, the PxT was 5 ± 23 with only 4% of the PxT values >60 mm Hg·days. CONCLUSIONS: The product of small increases in pressure that occur over an extended period of time (PxT) is the pressure-based hemodynamic factor most closely associated with the transition to acute decompensated heart failure. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DbCM), which consists of cardiac hypertrophy and failure in the absence of traditional risk factors, is a major contributor to increased heart failure risk in type 2 diabetes patients. In rodent models of DbCM, cardiac hypertrophy and dysfunction have been shown to depend upon saturated fatty acid (SFA) oversupply and de novo sphingolipid synthesis. However, it is not known whether these effects are mediated by bulk SFAs and sphingolipids or by individual lipid species. In this report, we demonstrate that a diet high in SFA induced cardiac hypertrophy, left ventricular systolic and diastolic dysfunction, and autophagy in mice. Furthermore, treatment with the SFA myristate, but not palmitate, induced hypertrophy and autophagy in adult primary cardiomyocytes. De novo sphingolipid synthesis was required for induction of all pathological features observed both in vitro and in vivo, and autophagy was required for induction of hypertrophy in vitro. Finally, we implicated a specific ceramide N-acyl chain length in this process and demonstrated a requirement for (dihydro)ceramide synthase 5 in cardiomyocyte autophagy and myristate-mediated hypertrophy. Thus, this report reveals a requirement for a specific sphingolipid metabolic route and dietary SFAs in the molecular pathogenesis of lipotoxic cardiomyopathy and hypertrophy. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is common and is associated with increased mortality in heart failure (HF). However, it is unknown whether the effect of CKD on mortality varies by left ventricular ejection fraction (LVEF). We evaluated the effect of CKD on mortality in patients with systolic (LVEF 45%) HF. Of the 7,788 patients in the Digitalis Investigation Group trial, 3,527 (45%) had CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2). We calculated the propensity score for CKD for each patient, using a multivariate logistic regression model (c statistic 0.76, postmatch absolute standardized differences <5% for all 32 co-variates). We matched 2,399 pairs of patients with and without CKD with similar propensity scores. There were 757 (rate 1,049/10,000 person-years) and 882 (rate 1,282/10,000 person-years) deaths, respectively, in patients without and with CKD (hazard ratio 1.22, 95% confidence interval 1.09 to 1.36, p <0.0001). CKD-associated mortality was higher in those with diastolic HF (371 extra deaths/10,000 person-years, hazard ratio 1.71, 95% confidence interval 1.21 to 2.41, p = 0.002) than in systolic HF (214 extra deaths/10,000 person-years, hazard ratio 1.19, 95% confidence interval 1.07 to 1.32, p = 0.001), which was significant (adjusted p for interaction = 0.034). A graded association was found between CKD-related deaths and LVEF. The hazard ratios for CKD-associated mortality for the LVEF subgroups of <35%, 35% to 55%, and >55% were 1.15 (95% confidence interval 1.02 to 1.29), 1.35 (95% confidence interval 1.11 to 1.64), and 2.33 (95% confidence interval 1.34 to 4.06). In conclusion, CKD-associated mortality was higher in those with diastolic than systolic HF. Patients with diastolic HF should be evaluated for CKD, and the role of inhibitors of the renin-angiotensin system in these patients needs to be investigated. [ABSTRACT FROM AUTHOR]

Aims: Beta-blockers may inhibit neprilysin activity and conversely, neprilysin inhibition may have a sympatho-inhibitory action. Consequently, sacubitril/valsartan may have a greater effect in patients not receiving a beta-blocker compared to those treated with a beta-blocker., Methods and Results: We examined the effect of sacubitril/valsartan compared to enalapril on outcomes according to background beta-blocker treatment in the 8399 patients with heart failure with reduced ejection fraction enrolled in PARADIGM-HF. The primary outcome was time to first heart failure hospitalization or cardiovascular death. Compared to the 7811 patients taking a beta-blocker, the 588 patients not receiving a beta-blocker were older, more frequently female, but had a similar mean left ventricular ejection fraction and New York Heart Association class distribution, with little difference in N-terminal pro-B-type natriuretic peptide. Patients not taking beta-blockers had a higher rate of the primary endpoint than those taking beta-blockers. The benefit of sacubitril/valsartan on the primary endpoint was evident in both the no beta-blocker subgroup (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.45-0.82) and the beta-blocker subgroup (HR 0.82, 95% CI 0.75-0.90; p-interaction = 0.06). The respective HRs for cardiovascular death were 0.47 (95% CI 0.32-0.69) versus 0.84 (95% CI 0.75-0.95; p-interaction <0.01) and for HF hospitalization 0.76 (95% CI 0.51-1.12) versus 0.80 (95% CI 0.71-0.90; p-interaction = 0.73). For all-cause death, the HR in the no beta-blocker group was 0.50 (95% CI 0.36-0.71) compared to 0.89 (95% CI 0.80-0.99) in the beta-blocker group (p-interaction <0.01). Safety outcomes related to sacubitril/valsartan versus enalapril did not differ according to background beta-blocker use., Conclusion: Sacubitril/valsartan may be more effective than enalapril in reducing the risk of death in patients not treated with a beta-blocker compared to those treated with a beta-blocker, but is effective regardless of beta-blocker use., Clinical Trial Registration: ClinicalTrials.gov NCT01035255., (© 2024 European Society of Cardiology.)

Background: Patients with heart failure, a preserved ejection fraction (HFpEF), and obesity have significant disability and suffer frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical endpoints, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden in these patients., Methods: 731 patients in class II-IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m 2 were randomized(double-blind) to tirzepatide(titrated up to 15mg subcutaneously weekly)(n=364) or placebo(n=367), added to background therapy for a median of 104 weeks (Q1=66, Q3=126 weeks)., Primary Endpoints: tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score(KCCQ-CSS). The current expanded analysis included sensitivity analyses of the primary endpoints, 6-minute walk distance(6MWD), EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health(PGIS), NYHA class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in KCCQ-CSS and 6MWD., Results: Patients were aged 65.2±10.7, 53.8%(n=393) were female; BMI 38.2±6.7kg/m 2 , KCCQ-CSS 53.5±18.5, 6MWD 302.8±81.7meters, and 53%(n=388) had a worsening heart failure event in the prior 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time-to-first-event (hazard ratios 0.41-0.67). At 52 weeks, tirzepatide increased KCCQ-CSS 6.9 points (95%CI, 3.3, 10.6, P<0.001), 6MWD 18.3 meters (95%CI, 9.9, 26.7, P<0.001) and EQ-5D-5L 0.06 (95%CI, 0.03, 0.09, P<0.001). The tirzepatide group shifted to a more favorable PGIS (proportional odds ratio 1.99 (95%CI, 1.44, 2.76) and NYHA class (proportional odds ratio 2.26 (95%CI, 1.54, 3.31), both P<0.001 and required less heart failure medications (P=0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio 1.63, 95%CI, 1.17, 2.28;P=0.004)., Conclusions: Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance and well-being; and reduced symptoms and medication burden in patients with HFpEF and obesity.

Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) display circulatory volume expansion and pressure overload contributing to cardiovascular-kidney end-organ damage. In the SUMMIT trial, patients with HFpEF and obesity were randomized to the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide (n = 364, 200 women) or placebo (n = 367, 193 women). As reported separately, tirzepatide decreased cardiovascular death or worsening heart failure. Here, in this mechanistic secondary analysis of the SUMMIT trial, tirzepatide treatment at 52 weeks, as compared with placebo, reduced systolic blood pressure (estimated treatment difference (ETD) -5 mmHg, 95% confidence interval (CI) -7 to -3; P < 0.001), decreased estimated blood volume (ETD -0.58 l, 95% CI -0.63 to -0.52; P < 0.001) and reduced C-reactive protein levels (ETD -37.2%, 95% CI -45.7 to -27.3; P < 0.001). These changes were coupled with an increase in estimated glomerular filtration rate (ETD 2.90 ml min -1  1.73 m -2  yr -1 , 95% CI 0.94 to 4.86; P = 0.004), a decrease in urine albumin-creatinine ratio (ETD 24 weeks, -25.0%, 95% CI -36 to -13%; P < 0.001; 52 weeks, -15%, 95% CI -28 to 0.1; P = 0.051), a reduction in N-terminal prohormone B-type natriuretic peptide levels (ETD 52 weeks -10.5%, 95% CI -20.7 to 1.0%; P = 0.07) and a reduction in troponin T levels (ETD 52 weeks -10.4%, 95% CI -16.7 to -3.6; P = 0.003). In post hoc exploratory analyses, decreased estimated blood volume with tirzepatide treatment was significantly correlated with decreased blood pressure, reduced microalbuminuria, improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and increased 6-min walk distance. Moreover, decreased C-reactive protein levels were correlated with reduced troponin T levels and improved 6-min walk distance. In conclusion, tirzepatide reduced circulatory volume-pressure overload and systemic inflammation and mitigated cardiovascular-kidney end-organ injury in patients with HFpEF and obesity, providing new insights into the mechanisms of benefit from tirzepatide. ClinicalTrials.gov registration: NCT04847557 ., Competing Interests: Competing interests B.A.B. receives research support from the National Institutes of Health (NIH) and the US Department of Defense, as well as research grant funding from AstraZeneca, Axon, Corvia, Novo Nordisk and Tenax Therapeutics. B.A.B. has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT and VADovations and is named inventor (US patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat HF. M.R.Z. receives research support from the Department of Veterans Affairs and serves as a consultant for Abbott, Adona Medical, Aria CV, Avery Therapeutics, Inc., Boehringer Ingelheim, Boston Scientific, Cardiovascular Research Foundation (CRF) Clinical Trials Center, CVRx, DIASTOL Therapeutics, LLC, EBR, Edwards, Lilly, GenKardia, Innoventric, Kestra Medical, Medtronic, Merck, Morphic Therapeutics, Novartis, Pulnovo, Salubris Biotherapeutics, Sonata, sRNAlytics Inc., V-WAVE and Vectorious. C.M.K. has served as a consultant for Eli Lilly. S.J.B. has served as consultant for Altimmune, Amgen, Beren Therapeutics, Boehringer Ingelheim, Lilly, Esperion, Ionis Pharmaceuticals, Madrigal Pharmaceuticals, Merck, Novartis and Regeneron. S.E.L. reported being on the patient selection committee for Corvia and Axon and being a consultant for Novo Nordisk and Lilly. K.H., M.M., Y.O. and N.U. are employed by Eli Lilly and Company. M.P. has served as a consultant for 89bio, AbbVie, Actavis, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, ARMGO, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Imara, Medtronic, Moderna, Novartis, Pharmacocosmos, Reata, Regeneron, Roche and Salamandra., (© 2024. The Author(s).)

Background: Obesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes., Methods: In this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 30 to receive tirzepatide (up to 15 mg subcutaneously once per week) or placebo for at least 52 weeks. The two primary end points were a composite of adjudicated death from cardiovascular causes or a worsening heart-failure event (assessed in a time-to-first-event analysis) and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life)., Results: A total of 364 patients were assigned to the tirzepatide group and 367 to the placebo group; the median duration of follow-up was 104 weeks. Adjudicated death from cardiovascular causes or a worsening heart-failure event occurred in 36 patients (9.9%) in the tirzepatide group and in 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P = 0.026). Worsening heart-failure events occurred in 29 patients (8.0%) in the tirzepatide group and in 52 patients (14.2%) in the placebo group (hazard ratio, 0.54; 95% CI, 0.34 to 0.85), and adjudicated death from cardiovascular causes occurred in 8 patients (2.2%) and 5 patients (1.4%), respectively (hazard ratio, 1.58; 95% CI, 0.52 to 4.83). At 52 weeks, the mean (±SD) change in the KCCQ-CSS was 19.5±1.2 in the tirzepatide group as compared with 12.7±1.3 in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 23 patients (6.3%) in the tirzepatide group and in 5 patients (1.4%) in the placebo group., Conclusions: Treatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure than placebo and improved health status in patients with heart failure with preserved ejection fraction and obesity. (Funded by Eli Lilly; SUMMIT ClinicalTrials.gov number, NCT04847557.)., (Copyright © 2024 Massachusetts Medical Society.)

Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV K c ) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs ( n = 9) by sequential ascending aortic cuff and age- and weight-matched pigs ( n = 6) served as controls. LV function was measured by echocardiography and LV K c by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed ( n = 10, n = 9, respectively). LV samples from LVPO and controls ( n = 6, respectively) were subjected to RNA sequencing. LV mass and K c increased by over 40% with LVPO ( P < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV K c ( P < 0.05) that mapped to functional domains relevant to K c such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold ( P < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets. NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is an ever-growing cause for the HF burden. HFpEF is particularly difficult to treat as the mechanisms responsible for this specific form of HF are poorly understood. Using a relevant large animal model, this study uncovered a unique molecular signature with the development of HFpEF that regulates specific biological pathways relevant to the progression of this ever-growing cause of HF.

Importance: Sacubitril/valsartan is indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalizations in patients with chronic HF. However, many of these patients are older and have multiple comorbidities that increase the risk of hospitalization for causes other than HF., Objective: To assess the effects of sacubitril/valsartan on hospitalizations of any cause across the spectrum of left ventricular ejection fraction (LVEF)., Design, Setting, and Participants: This post hoc, participant-level, pooled analysis of the PARADIGM-HF (in patients with an LVEF ≤40%) and PARAGON-HF (in patients with an LVEF ≥45%) randomized clinical trials was conducted from February 5, 2024, to April 5, 2024. Participants with chronic HF, New York Heart Association classes II through IV symptoms, and elevated natriuretic peptides were randomized to treatment with either sacubitril/valsartan or a renin-angiotensin system inhibitor (RASi)-enalapril in the PARADIGM-HF trial or valsartan in the PARAGON-HF trial., Intervention: Sacubitril/valsartan vs RASi (enalapril or valsartan)., Main Outcomes and Measures: The effects of sacubitril/valsartan on time to first investigator-reported all-cause and cause-specific hospitalizations were examined using Cox proportional hazards models, stratified by geographic region and trial. Effect modification by LVEF as a continuous function was examined., Results: Among 13 194 participants in the PARADIGM-HF and PARAGON-HF trials, mean (SD) patient age was 67 (11) years, 8883 patients (67.3%) were male, and mean (SD) LVEF was 40% (15%). Sacubitril/valsartan significantly reduced the risk of all-cause hospitalization (ACH) compared with RASi over a median (IQR) follow-up period of 2.5 (1.8-3.1) years (hazard ratio [HR], 0.92; 95% CI, 0.88-0.97; P = .002). The incidence rate of first ACH was 25 (95% CI, 24-26) per 100 patient-years in the sacubitril/valsartan arm and 27 (95% CI, 26-28) per 100 patient-years in the RASi arm. The absolute risk reduction (ARR) was 2.1 per 100 patient-years, corresponding to a number needed to treat (NNT) of 48 patient-years of treatment exposure to prevent 1 ACH. Reductions in overall hospitalizations seemed primarily driven by lower rates of cardiac and pulmonary hospitalizations with sacubitril/valsartan. Patients in the 2 treatment arms had similar rates of composite noncardiac hospitalizations. Treatment heterogeneity on ACH by LVEF was observed (P for interaction = .03), with benefits most apparent in patients with an LVEF less than 60% (HR, 0.91; 95% CI, 0.86-0.96), but not in patients with an LVEF of 60% or more (HR, 0.97; 95% CI, 0.86-1.09)., Conclusions and Relevance: In this post hoc pooled analysis of 13 194 patients with chronic HF in the PARADIGM-HF and PARAGON-HF randomized clinical trials, sacubitril/valsartan significantly reduced hospitalization for any reason, with benefits most apparent in patients with an LVEF below normal. This reduction appeared to be principally driven by lower rates of cardiac and pulmonary hospitalizations., Trial Registrations: ClinicalTrials.gov Identifiers: NCT01035255 (PARADIGM-HF) and NCT01920711 (PARAGON-HF).

Background: Hypotension is an important clinical problem in heart failure (HF)., Objectives: This study sought to examine the association between asymptomatic vs symptomatic hypotension and outcomes in PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure)., Methods: In a post hoc analysis of PARADIGM-HF, the efficacy and safety of sacubitril/valsartan compared to enalapril were estimated using time-updated Cox proportional hazards models. The primary outcome was cardiovascular death or HF hospitalization., Results: Among 8,399 patients in PARADIGM-HF, 1,343 (16.0%) experienced only asymptomatic hypotension, and 936 (11.1%) experienced symptomatic hypotension at least once after randomization. Patients with symptomatic hypotension were older and more frequently had cardiovascular comorbidities compared to those developing only asymptomatic hypotension. By contrast, left ventricular ejection fraction was lower in those with asymptomatic hypotension. Patients who experienced either type of hypotension were at higher risk for all outcomes examined. However, the effect of sacubitril/valsartan on the primary outcome was not diminished in patients experiencing hypotension compared to those who did not: the HR for sacubitril/valsartan vs enalapril was 0.80 (95% CI: 0.72-0.89) for no hypotension, 0.87 (95% CI: 0.70-1.08) for asymptomatic hypotension, and 0.51 (95% CI: 0.38-0.69) for symptomatic hypotension (P interaction  = 0.01), and this was also true for cardiovascular and all-cause deaths. The safety of sacubitril/valsartan vs enalapril was also maintained regardless of the occurrence of hypotension. Discontinuation of randomized treatment was less common with sacubitril/valsartan vs enalapril in patients experiencing asymptomatic and symptomatic hypotension., Conclusions: Although both asymptomatic and symptomatic hypotension during treatment with sacubitril/valsartan or enalapril were associated with worse outcomes, the benefits of sacubitril/valsartan were maintained (or even enhanced) in patients experiencing hypotension., Competing Interests: Funding Support and Author Disclosures The PARADIGM-HF trial was sponsored by Novartis. Dr Matsumoto has received research grants and personal fees from Abbott, Bayer Pharma, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Novartis, Ono Pharma, Orbus Neich, Otsuka Pharma, and the Uehara Memorial Foundation. Dr Böhm has received lecture fees from Amgen, Bayer, Servier, Medtronic, Boehringer Ingelheim, ReCor, Vifor Pharma, and Bristol Myers Squibb; has received grant support and lecture fees from AstraZeneca; and has received grant support from Deutsche Forschungsgemeinschaft. Dr Desai has received grants and personal fees from AstraZeneca during the conduct of the study; has received personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; has received grants and personal fees from Alnylam and Novartis; and has received personal fees from Amgen, outside the submitted work. Dr Køber has received speaker fees from Novartis, Novo Nordisk, and AstraZeneca. Dr Lefkowitz is an employee of Novartis. Dr Packer has received consulting fees from 89bio, AbbVie, Actavis, Alderlyx, Amarin, Amgen, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra. Dr Rouleau has received grants and consulting fees from Novartis; and has received consulting fees from AstraZeneca. 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 Swedberg has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novartis. Dr Vaduganathan has received research grant support from or served on Advisory Boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; has had speaker engagements with AstraZeneca, Novartis, and Roche Diagnostics; and participates on Clinical Trial Committees for studies sponsored by AstraZeneca, Occlutech, Impulse Dynamicx, Galmed, and Novartis. Dr Vardeny has received research support from AstraZeneca, Bayer, and Cardurion; and has received personal consulting fees from Bayer, Cytokinetics, Moderna, AstraZeneca, and Cardior. The employer of Dr Voors (University Medical Center Groningen) has received consultancy and/or research fees from Adrenomed, Anacardio, BMS, Boehringer Ingelheim, Bayer, Cardurion, Corteria, Cytokinetics, Eli Lilly, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and Salubrisbio. Dr Zile has received fees for serving on a Steering Committee from Abbott and Ironwood Pharma; has received consulting fees from Boston Scientific and MyoKardia; has received grant support and fees for serving on a Steering Committee from CVRx and Medtronic; has received fees for serving on an Eligibility Committee from EBR Systems and V-Wave; has received fees for serving on a Clinical Events Committee from Endotronics; and has received fees for serving on a Data and Safety Monitoring Board from Merck. 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; Dr Jhund’s employer (University of Glasgow) has been remunerated for clinical trial work by AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and is a director of Global Clinical Trial Partners Ltd. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; has received personal consultancy fees from Alnylam Pharma, Bayer, BMS, 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 & 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 Ltd. 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.)

Aims: Resting heart rate (HR) is a strong risk marker in patients with heart failure (HF), but the clinical implications of visit-to-visit changes in HR (ΔHR) are less well established. We aimed to explore the association between ΔHR and subsequent outcomes in a pooled dataset of two well-characterized cohorts of patients with HF across the full range of left ventricular ejection fraction (LVEF)., Methods and Results: PARADIGM-HF and PARAGON-HF were randomized trials testing sacubitril/valsartan versus enalapril or valsartan, respectively, in patients with HF and LVEF ≤40% (PARADIGM-HF) or LVEF ≥45% (PARAGON-HF). We analysed the association between ΔHR from the preceding visit with the primary endpoint of HF hospitalization (HFH) or cardiovascular death using covariate-adjusted Cox proportional hazards models. A total of 13 194 patients (mean age 67 ± 11 years, 67% men, mean LVEF 40 ± 15%) were included. Over a median follow-up of 2.5 years, 3114 patients experienced a first HFH or cardiovascular death event (10.4 events per 100 patient-years). An increase in HR from the preceding visit, compared with no change, was associated with a higher risk (hazard ratio 1.12; 95% confidence interval [CI] 1.10-1.15; p < 0.001 per 5 bpm increase). Conversely, a drop in HR was associated with a lower risk (hazard ratio 0.97; 95% CI 0.94-1.00; p = 0.044 per 5 bpm drop). The prognostic implications of ΔHR were consistent across the range of LVEF and observed regardless of β-blocker use or presence of a permanent pacemaker. Visit-to-visit increases in HR were especially prognostic in patients without atrial fibrillation (p interaction  = 0.006)., Conclusion: Across a broad spectrum of patients with chronic HF, increases in HR from a preceding visit independently predicted clinical outcomes. The detection of notable increases in HR between outpatient visits may help identify patients at heightened risk of adverse events. Clinical Trial Registration; ClinicalTrials.gov NCT01035255 (PARADIGM-HF), NCT01920711 (PARAGON-HF)., (© 2024 European Society of Cardiology.)

Background: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood., Methods: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide)., Results: At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death., Conclusions: In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.