BACKGROUND AND AIMS:The use of the Kidney Failure Risk Equation (KFRE) is guideline recommended in patients with chronic kidney disease (CKD) to predict risk of kidney failure, however, this has not been well studied in patients with heart failure (HF). METHODS:The KFRE score incorporates baseline urine albumin-creatinine ratio (UACR), age, sex, and estimated glomerular filtration rate (eGFR). Among patients with HF and reduced EF (HFrEF) and CKD in PARADIGM-HF, we explored the association of the 2- and 5-year KFRE score continuously, risk-based categories, and in quartiles with subsequent cardiovascular and kidney outcomes. RESULTS:Among 794 patients with HFrEF and eGFR<60 ml/min/1.73m2 with all KFRE variables available, median 5-year KFRE score was 0.63% [0.28%-1.67%]. Patients with higher KFRE baseline score had higher systolic blood pressure and NT-proBNP levels and were more likely to have a history of diabetes or atrial fibrillation, or to be treated with diuretics at baseline. The KFRE 5-year score was not significantly associated with the composite of ESKD or 50% decline in eGFR (HR 1.45; 95% CI 0.93-2.25; P=0.10), although confidence limits were wide in light of few events. Continuous KFRE 5-year score was associated with cardiovascular death or HF hospitalization (HR 1.22; 95% 1.09-1.36; P<0.001) and all-cause mortality (HR 1.24; 95% CI 1.10-1.39; P<0.001). CONCLUSIONS:These data suggest that the KFRE is associated with risk of cardiovascular events in patients with HFrEF. However, as the median KFRE was low in PARADIGM-HF, these data require validation in HF populations with more advanced CKD.

Background The importance of nutritional status is underappreciated in patients with heart failure (HF). This study aimed to describe the range of the prognostic nutrition index (PNI), and the clinical characteristics and outcomes according to PNI, in patients with HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). The primary outcome was the composite of HF hospitalization or cardiovascular death.Methods and Results Individual patient data from the PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in HF) trials were used to examine patient characteristics and outcomes according to quartiles of PNI. Cox regression was used to analyze clinical outcomes, and multivariable fractional polynomial interaction analysis to examine the effects of sacubitril-valsartan, according to PNI. Patients with lower PNI (poorer nutrition) were older, frailer, and had more comorbidities and worse HF status, with greater congestion. Patients with lower PNI had biomarker abnormalities indicating inflammation, bone marrow suppression, and increased collagen turnover, among other physiologic perturbations. Lower PNI was associated with worse outcomes; that is, the rate of the primary end point among patients in the first quartile was 11.31 (10.20-12.54) compared with 7.09 (6.17-8.14) per 100 person-years in the fourth quartile. These associations persisted after adjustment for other prognostic variables. PNI did not modify the effects of sacubitril-valsartan in HFrEF although sacubitril/valsartan seemed to have a greater benefit in patients with HFpEF with a higher PNI.Conclusions Nutritional status, assessed using PNI, is an independent predictor of poor outcomes in HF. Evaluation of nutritional status in clinical practice, the causes of undernutrition, and whether undernutrition should be a therapeutic target, are all worthy of further investigation in HF.

BACKGROUND The novel win ratio statistic has emerged as a promising alternative end point for the comparison of 2 treatment groups on multiple end points simultaneously, but it has not been used for cardiac resynchronization therapy (CRT) trials. RE-synchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE; ClinicalTrials.gov identifier: NCT00271154) was the first multicenter, randomized CRT trial in mild heart failure (HF). The primary result was a nonsignificant reduction in the proportion of CRT patients with worsened clinical composite score compared with control. However, CRT did improve reverse remodeling measures and delayed time to first HF hospitalizations. OBJECTIVE To demonstrate the value of the win ratio for the evaluation of CRT using data from REVERSE. METHODS Individual patient data were analyzed using the win ratio on a hierarchical end point at 12 months that included the following clinical composite score components: all-cause death, HF hospitalization, crossover or exit because of HF, change in New York Heart Association class from baseline, and the Patient Global Assessment. All pairs of a CRT and a control patient were compared. The win ratio is the number of CRT wins divided by the number of losses. Reverse remodeling and quality of life were assessed as alternative end points. RESULTS REVERSE included 610 patients randomized between treatment (CRT-ON, n = 419) and control (CRT-OFF, n = 191). Comparison of all 80,029 treatment/control pairs resulted in 53.5% wins, 36.9% losses, and 9.5% ties. The win ratio was 1.45 (95% confidence interval, 1.17-1.80), showing CRT superiority (P = .0009). CONCLUSION Win ratio analysis confirms the benefits of CRT beyond a single primary end point and holds promise for analysis of combined end points in CRT and other arrhythmia studies.

Background Myocardial fibrosis is prevalent in cardiomyopathies that result in heart failure with reduced ejection fraction. Heart failure with reduced ejection fraction treated with a left ventricular assist device (LVAD) yields hemodynamic unloading and may provide partial cardiomyocyte recovery, but contemporary studies reveal no consistent reductions in fibrosis. This study tested the hypothesis that, despite normalization of hemodynamic overload by LVAD, fibrosis and fibroblast activation persist resulting in sustained increases in myocardial stiffness. Methods and Results Tissues from subjects with heart failure with reduced ejection fraction undergoing LVAD implantation (pre‐LVAD), from transplanted hearts with LVAD (post‐LVAD) or without cardiac pathology (control) were collected. Quantification of myocardial stiffness and collagen content revealed significant increases in pre‐LVAD versus control that remained elevated in post‐LVAD. Myocardial fibroblast populations increased in pre‐ and post‐LVAD hearts versus control. Control, pre‐LVAD, and post‐LVAD fibroblasts were isolated and plated on substrates with mechanical stiffnesses reflective of normal (≈2 kPa) or fibrotic (≈8 kPa) myocardium. Quantification of collagen I and α‐smooth muscle actin production demonstrated that control fibroblasts were responsive to substrate stiffness, whereas pre‐ and post‐LVAD fibroblasts were unresponsive and exhibited no significant differences on either substrate. Bulk‐RNA sequence analysis revealed changes in gene expression in pre‐LVAD versus control fibroblasts including mechano‐sensitive pathways that appear to be uncoupled, resulting in increased expression of genes implicated in proliferation, whereas mechano‐sensing genes were decreased. Conclusions These data support that sustained cardiac hemodynamic overload leads to a phenotypic conversion in fibroblasts in which the capacity to detect changes in mechanical input is muted, thus contributing to retention of collagen content and stiffness in both pre‐ and post‐LVAD hearts.

BACKGROUND:Recent trials of new heart failure (HF) treatments suggest the effect of therapy may vary by N-terminal pro-B type natriuretic peptide (NT-proBNP) level. OBJECTIVES:The authors examined the efficacy of sacubitril/valsartan according to NT-proBNP levels in patients with reduced, mildly reduced, and preserved left ventricular ejection fraction (LVEF) enrolled in PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) and PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Receptor Blockers Global Outcomes in HF with Preserved Ejection Fraction). METHODS:Individual patient data from PARADIGM-HF and PARAGON-HF were pooled and participants were divided into categories defined by quintiles of NT-proBNP level. The primary outcome examined was the composite of HF hospitalization or cardiovascular death. RESULTS:Among the 13,195 patients enrolled in both trials, 13,142 (99.6%) had a baseline NT-proBNP level measured. The rate of the primary outcome (per 100 person-years) increased with NT-proBNP levels: quintile 1, 5.9 (95% CI: 5.3-6.5); quintile 2, 7.5 (95% CI: 6.9-8.2); quintile 3, 9.0 (95% CI: 8.2-9.7); quintile 4, 12.0 (95% CI: 11.1-12.9); and quintile 5, 20.8 (95% CI: 19.6-22.2). The relative risk reduction in the primary outcome with sacubitril/valsartan was consistent across NT-proBNP levels: the HR in quintile 1 was 0.79 (95% CI: 0.65-0.96); quintile 2, 0.87 (95% CI: 0.72-1.04); quintile 3, 0.79 (95% CI: 0.66-0.93); quintile 4, 0.85 (95% CI: 0.73-0.99); and quintile 5, 0.86 (95% CI: 0.76-0.97; P for interaction = 0.86). The absolute risk reduction was greatest in NT-proBNP quintile 5; the number needed to treat for the primary outcome over the median follow-up of 31 months was 16 in quintile 5 vs 37 in quintile 1. CONCLUSIONS:The relative risk reductions with sacubitril/valsartan were consistent irrespective of NT-proBNP level in HF patients across the range of LVEF. Consequently, the absolute risk reductions were greatest in patients with higher NT-proBNP levels. (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial]; NCT01035255; and PARAGON-HF [Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Receptor Blockers Global Outcomes in HF with Preserved Ejection Fraction]; NCT01920711).

Introduction Sympathetic activation and parasympathetic withdrawal are hallmarks of the pathophysiology of heart failure (HF), associated with HF symptoms, disease progression, morbidity, and mortality. Baroreflex activation therapy (BAT), using the Barostim Neo device, is designed to rebalance the autonomic nervous system to improve symptoms and quality of life in patients with HF with reduced ejection fraction (HFrEF). The Baroreflex Activation Therapy for Heart Failure (BeAT-HF) randomized controlled trial showed Barostim was safe, improved quality of life, exercise capacity, and functional status, and lowered NT-proBNP levels in HFrEF patients with NT-proBNP <1,600 pg/mL. However, BeAT-HF and the ongoing post-market observational Real-world Experience - Barostim Advancing the Level of Clinical Evidence (REBALANCE Registry) both enrolled patients with NT-proBNP levels >1,600 pg/mL. Since NT-proBNP is a strong predictor of clinical outcomes in HFrEF, we analyzed clinical outcomes by baseline NT-proBNP levels in patients treated with BAT in a combined cohort from the BeAT-HF and REBALANCE studies. Hypothesis Analyzing mortality data in relation to baseline NT-proBNP will determine if patients are inappropriate for BAT based on their baseline NT-proBNP. Methods Patients implanted with BAT from BeAT-HF and REBALANCE were analyzed based on pre-implant NT-proBNP (pg/mL) levels and subsequent survival status. Patients were split into 3 groups based on baseline NT-proBNP (<1,600, 1,600-5,000, and >5,000 pg/mL). Results A total of 392 Barostim implanted patients were evaluated: 272 patients (69%) had a pre-implant NT-proBNP < 1,600, 86 (22%) patients were between 1,600-5,000, and 34 (9%) patients were ≥ 5,000. At 1-year post-implant, in NT-proBNP pre-implant levels <1,600, 1,600-5,000, and >5,000, there were 98%, 88%, and 60% of patients still alive, respectively. Conclusions There may be patients with a NT-proBNP of >1600 but less than <5000 that would be appropriate for BAT. While mortality generally increases with increasing NT-proBNP values, there is a clear decrease in survival with NT-proBNP values >5000. Physicians should be cautious when considering Barostim implantation in patients with an NT-proBNP of >5000, as expected mortality rates at 1-year or 2-years may not warrant such device therapies.

Introduction Subcutaneous insertable cardiac monitors (ICM) have the capability to detect tachycardia episodes which mostly includes supraventricular tachycardias (SVT) and occasionally ventricular tachycardia and fibrillation (VT/VF). Hypothesis We investigated the incidence of spontaneous VT/VF in NYHA class II/III heart failure (HF) patients with reduced and preserved ejection fraction using cardiac arrhythmia diagnostics measured by an ICM. Methods Patients with a recent history of HF events were implanted with an ICM equipped with tachycardia detection capability in the LINQ-HF and ALLEVIATE-HF phase-1 studies. ICMs detect tachycardia if 30 of 40 recent intervals are shorter than 260 ms or if 16 consecutive intervals are shorter than the tachycardia interval (nominally 340 ms) which is adjusted with age. Episodes are rejected if there is a large amount of baseline noise using a noise rejection algorithm. Tachycardia episodes that were detected by the ICM were first classified as VT/VF, SVT, or oversensing using an artificial intelligence (AI) model that was pre-trained using over 50,000 manually adjudicated ICM detected tachycardia episodes. If the AI model output probability for VT/VF was greater than 0.2, then those episodes were manually adjudicated for true incidence of non-induced spontaneous VT/VF. The Kaplan-Meier incidence curves for VT/VF incidence are reported as a function of reduced vs. preserved ejection fraction. Results The two studies had a combined 163 patients implanted with an ICM and followed for an average of 14.7±8.3 months. The baseline characteristics include average age of 67.2±11.2 years, 62.6% males, 55.2% with LVEF ≥ 50% (143 patients had LVEF measurements prior to implant), 16.6%% class-II and 83.4% class-III, and 55.2% with a clinical history of AF. There were 13 deaths and 14 device upgrades in the studies. There were 4 spontaneous polymorphic VT/VF episodes in 3 patients and 52 sustained monomorphic VT episodes in another 9 patients. The Kaplan-Meier incidence of VT/VF in the overall patient cohort was estimated to be 14% at 24 months. Patients with reduced and preserved EF had estimated incidence of 20% and 10%, respectively, at 24 months (Figure). Conclusion Incidence of VT/VF, as detected by an ICM and after manual adjudication of episodes after screening by an AI model over 2 years of follow-up, was estimated to be more than 14% in Class II/III HF patients with a history of HF events. VT/VF incidence was higher in HF patients with reduced vs. preserved LVEF in these study cohorts.

BACKGROUND Hypertension is common in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), and current guidelines recommend treating systolic blood pressure (SBP) to a target <130 mm Hg. However, data supporting treatment to this target are limited. Additionally, pulse pressure (PP), a marker of aortic stiffness, has been associated with increased risk of cardiovascular events, but its prognostic impact in HFpEF has not been extensively studied. OBJECTIVES This study aimed to explore the impact of baseline SBP and PP on cardiovascular outcomes in patients with HFmrEF or HFpEF. METHODS The I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction), TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist)-Americas, PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blocker Global Outcomes in HF With Preserved Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials were global, randomized clinical trials testing irbesartan, spironolactone, sacubitril/ valsartan, and dapagliflozin, respectively, against either a placebo or an active comparator (valsartan, in PARAGON-HF), in patients with heart failure and a left ventricular ejection fraction >= 40% (in DELIVER) or >= 45% (in the other trials). The relationship between continuous baseline SBP and PP, and the primary endpoint (first heart failure hospitalization or cardiovascular death) was analyzed with restricted cubic splines. We further evaluated the prognostic impact of SBP categories (<120, 120-129, 130-139, and >= 140 mm Hg) and PP quartiles on the primary endpoint. RESULTS A total of 16,950 patients (mean age 71 f 9 years; 49% male; mean SBP 131 f 15 mm Hg; mean PP 55 f 14 mm Hg) were included. The relationship between SBP and the primary endpoint was J-shaped, with the lowest risk at 120 to 130 mm Hg. A similar pattern was found for PP, with the lowest risk at 50 to 60 mm Hg. The highest SBP category (reference: 120-129 mm Hg) and PP quartile (reference: 46-54 mm Hg) were associated with a higher risk of the primary outcome (HR: 1.22; 95% CI: 1.10-1.34 and HR: 1.22; 95% CI: 1.11-1.34, respectively). Higher PP was associated with greater cardiovascular risk, regardless of SBP. CONCLUSIONS Our analysis of a large pooled dataset from 4 clinical trials, including >16,900 patients with HFmrEF/ HFpEF, indicates a J-shaped relationship between both SBP and PP and cardiovascular risk. The lowest risk was observed at SBP levels between 120 and 130 mm Hg and PP values between 50 and 60 mm Hg (I-PRESERVE [Irbesartan in Heart Failure With Preserved Systolic Function], NCT00095238; TOPCAT [Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist], NCT00094302; PARAGON-HF [Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction], NCT01920711; DELIVER [Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure], NCT03619213) (JACC. 2025;85:710-722) (c) 2025 Published by Elsevier on behalf of the American College of Cardiology Foundation.

BACKGROUND Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF). OBJECTIVES The authors aimed to examine the safety and efficacy of sacubitril/valsartan among patients with HF by self-reported race. METHODS PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) were global, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor (RASi) (enalapril or valsartan, respectively) in patients with HF and left ventricular ejection fraction <= 40% (PARADIGM-HF) or left ventricular ejection fraction >= 45% (PARAGON-HF). Patients with self-reported race were categorized as White, Asian, or Black. We assessed the composite of first HF hospitalization or cardiovascular death, its components, and angioedema across races. RESULTS Among 12,097 participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Over a median follow-up of 2.5 years, Black (adjusted HR: 1.68; 95% CI: 1.42-1.98) and Asian patients (adjusted HR: 1.32; 95% CI: 1.18-1.47) experienced higher risks of the primary outcome compared with White patients. Treatment effects of sacubitril/valsartan vs RASi on the primary endpoint were consistent among White (HR: 0.84; 95% CI: 0.77-0.91), Asian (HR: 0.92; 95% CI: 0.78-1.10), and Black patients (HR: 0.79; 95% CI: 0.58-1.07; Pinteraction 1/4 0.58). Rates of severe angioedema were higher with sacubitril/valsartan vs RASi (White: 0.2% vs 0.1%; Black: 1.5% vs 0.0%; Asian: 0.1% vs 0.1%). CONCLUSIONS In a pooled experience of 2 global trials, Black and Asian patients exhibited a higher risk of cardiovascular events than White patients. The benefits of sacubitril/valsartan were consistent across races. Risks of severe angioedema were low but numerically higher with sacubitril/valsartan. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255; Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711) (JACC Heart Fail. 2025;13:58-71) (c) 2025 by the American College of Cardiology Foundation.

Introduction Sudden death (SD) is common in patients with heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF). However, there are limited data describing risk factors for SD in this population. Methods We pooled patient-level data for patients with HFmrEF/HFpEF from 5 randomized clinical trials (CHARM Preserved, I-Preserve, TOPCAT Americas, PARAGON-HF, and DELIVER). Patients with SD, adjudicated by the clinical endpoint committee of each trial, were included. Clinical risk factors independently associated with risk for SD were identified using a Cox regression model with stepwise backward selection (p<0.001 for retention) in patients without missing data. The association of baseline NT-proBNP with risk for SD was assessed alone and together with clinical risk factors. Differences in the C-statistic were calculated using Somers’ D method. The continuous associations between ejection fraction (EF) or NT-proBNP with incidence of SD were examined using restricted cubic splines models adjusted for age, sex, and prior myocardial infarction (MI). Results SD occurred in 804 of 19,977 patients (4%), which represented 23% of all deaths and 39% of cardiovascular (CV) deaths. The incidence rate of SD was 1.4 events/100 patient-years. In 14,812 patients without missing data, age (hazard ratio [HR] 1.13, per 5-year increase), male sex (HR 1.73), prior MI (HR 1.52), diabetes (HR 1.42), NYHA functional class (HR 1.52), and lower EF (HR 1.20, per 5% decrease) were independent predictors of SD with p<0.001 and collectively predicted SD with C-statistic 0.66. NT-proBNP alone predicted SD with C-statistic 0.65 and adding NT-proBNP to the top clinical risk factors improved the C-statistic to 0.70 (p<0.001). These risk factors remained significant after accounting for competing risk of non-sudden death using the method of Fine and Gray. Higher NT-proBNP was continuously associated with higher SD risk in HFmrEF/HFpEF (Figure 1). Conclusion SD accounted for 39% of CV deaths among patients with HFmrEF/HFpEF, especially in males and patients with ischemic heart disease. Combining clinical risk factors and NT-proBNP may be an efficient strategy for identifying HFmrEF/HFpEF patients with high risk of SD.

BACKGROUND:Obesity is highly prevalent among individuals with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) and is associated with increased risk of disability and death. OBJECTIVES:The purpose of this study is to explore the association between different adiposity-related anthropometrics and clinical outcomes in this population. METHODS:In this participant-level pooled analysis of 5 international randomized trials that enrolled adults with HFmrEF/HFpEF, the association between adiposity-related anthropometrics (body mass index [BMI], waist circumference [WC], and waist-to-height ratio [WHtR]) and heart failure (HF) and mortality outcomes was evaluated, overall and by age and sex. Independent and combined associations between BMI and/or WHtR and outcomes were also assessed. RESULTS:At baseline, BMI was available in 21,479 participants, and WC and WHtR were available in 7,827. Overall, 46% had BMI ≥30 kg/m2 and 95% had elevated WC or WHtR. Among those with BMI <30 kg/m2, 89% had excess abdominal adiposity, especially older and female participants. Sex (Pinteraction = 0.003) and race (Pinteraction = 0.046) modified the association between BMI and WHtR, such that women vs men had higher WHtR at higher BMI, and Asian and Black participants had higher WHtR at lower BMI. Although BMI exhibited complex J- and U-shaped associations with clinical outcomes, higher WHtR was linearly associated with increased risk of HF and mortality events. Younger participants exhibited the steepest associations between BMI or WHtR and cardiovascular death or HF hospitalization (Pinteraction <0.001 for both). Independent of BMI, higher WHtR was associated with adverse outcomes. Independent of WHtR, higher BMI was associated with HF hospitalization. Participants with elevated BMI and WHtR experienced higher rates of cardiovascular death or HF hospitalization vs those with elevated BMI or WHtR alone. CONCLUSIONS:These data from 5 large-scale HFmrEF/HFpEF clinical trials further question the utility of BMI as the sole measure to define obesity. WC or WHtR assessment identifies a substantial number of individuals with abdominal obesity despite BMI <30 kg/m2, and may enhance risk stratification beyond BMI alone in HFmrEF/HFpEF. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213; Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711; Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve] (NCT00095238); Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM-Preserved] (NCT00634712).

Background and Aims An expansion of fat mass is an integral feature of patients with heart failure and preserved ejection fraction (HFpEF). While body mass index (BMI) is the most common anthropometric measure, a measure of central adiposity-the waist-to-height ratio (WHtR)-focuses on body fat content and distribution; is not distorted by bone or muscle mass, sex, or ethnicity; and may be particularly relevant in HFpEF. Methods The PARAGON-HF trial randomized 4796 patients with heart failure (HF) and ejection fraction >= 45% to valsartan or sacubitril/valsartan. The current work characterizes the association of BMI and WHtR with clinical features, outcomes, and the response to neprilysin inhibition. Results About half (49%) of the participants were considered obese by BMI (>= 30 kg/m(2)), but nearly every patient (96%) had central adiposity (WHtR >=.5). Among patients who were not obese (BMI <30 kg/m(2)), 860 (37%) had marked central adiposity (WHtR >=.6). Higher BMI and WHtR were both associated with higher risk of total HF hospitalizations, but as compared with BMI, WHtR was linearly associated with HF outcomes and identified a higher proportion of patients who had a particularly elevated risk (i.e. 30% or greater). An obesity-survival paradox (i.e. improved outcomes in those with greater adiposity) was apparent with BMI in unadjusted analyses, but it was not observed with WHtR. Although neprilysin inhibition appeared to have greater effects on HF outcomes in patients with higher BMI and WHtR, analyses of interaction with obesity metrics did not show significant heterogeneity across the range of values for adiposity. Conclusions In PARAGON-HF, in contrast with BMI, nearly every patient with HFpEF had central adiposity (as assessed by WHtR), and the risks of adverse HF events were more robustly related to WHtR. These data challenge the current reliance on BMI as an appropriate metric of adiposity, and they suggest that-rather than obesity-related HFpEF being regarded as a select HFpEF subgroup-central adiposity is a ubiquitous feature of HFpEF.

BACKGROUND:The RELIEVE-HF (REducing Lung congestion symptoms using the v-wavE shunt in adVancEd Heart Failure) trial randomized 508 patients with heart failure (HF) to interatrial shunt treatment vs placebo procedure. Randomization was stratified into 2 patient groups: heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] ≤40%); and heart failure with preserved ejection fraction (HFpEF) (LVEF >40%). HF event rates (all-cause death, transplantation or left ventricular (LV) assist device, HF hospitalization or outpatient worsening) after shunt treatment during 2-year follow-up were directionally opposite: decreased by 51% in HFrEF, increased by 69% in HFpEF. OBJECTIVES:This study aims to examine differences in cardiac structure and function before and after interatrial shunt placement in patients with HFrEF vs HFpEF that could underlie these discordant clinical outcomes. METHODS:Serial changes from baseline to 12 months in 17 transthoracic echocardiographic parameters in shunt-treated vs control patients in HFrEF vs HFpEF were assessed and compared by ANCOVA (analysis of covariance). RESULTS:In shunt-treated vs control patients with HFrEF, there were reductions in median LV end-diastolic volumes (-11.9 mL/m2 [Q1-Q3: -21.3 to -2.5 mL/m2]; P = 0.01) and LV end-systolic volumes (-8.9 mL/m2 [Q1-Q3: -17.2 to -20.7 mL/m2]; P = 0.01) indicative of reverse LV remodeling. There were no significant changes in right ventricular (RV), right atrial, or inferior vena cava sizes or pulmonary artery systolic pressure (PASP). In contrast, shunt-treated vs control patients with HFpEF did not have LV remodeling, but they had increased RV, right atrial, and inferior vena cava dimensions, and PASP also increased (4.7 mm Hg [Q1-Q3: 0.9-8.5 mm Hg]; P = 0.02). LV and RV diastolic compliance were decreased in HFpEF vs HFrEF at baseline and decreased further after shunt treatment in HFpEF. CONCLUSIONS:Differential changes in left-sided and right-sided heart remodeling and PASP following interatrial shunt placement in patients with HFrEF vs HFpEF provide a mechanistic basis for the variable effects on clinical outcomes observed in RELIEVE-HF. (REducing Lung congestion symptoms using the v-wavE shunt in adVancEd Heart Failure [RELIEVE-HF]; NCT03499236).

Introduction Patients with heart failure and preserved ejection fraction (HFpEF) have a marked increase in morbidity and mortality. Despite recent seminal advances in medical therapy for HFpEF, there is substantial residual risk and symptomatic burden. Cardiosphere-derived progenitor cells (CDCs), which are in phase 3 testing for Duchenne muscular dystrophy (DMD) and its cardiomyopathy, may be one therapeutic option. Hypothesis Based on data from a rodent model of HFpEF, we hypothesized that treatment with allogeneic human CDCs would result in regression of interstitial fibrosis (by actions on the extracellular matrix, ECM) and reversal of diastolic dysfunction in patients with HFpEF. Methods We performed a single-center, randomized, placebo - infusion (placebo group) vs. CDCs (CDC group) trial, with non-occlusive, sequential, intracoronary delivery of 25 million CDCs (or placebo) in each of the three coronary arteries. HFpEF patients 69.4±9.5 years, New York Heart Association (NYHA) class II-IV, treated with guideline directed therapy (present during period of randomization) plus diuretics. Baseline echocardiogram, cardiac magnetic resonance imaging (MRI), 6-minute hall walk distance (6MHWD), Minnesota Living with Heart Failure quality of life (QOL) questionnaire, left and right heart catheterization with exercise were compared to studies performed 6 or 12 months post infusion. Results Twenty-seven HFpEF patients (13 randomized to placebo, 14 to CDCs) had clinical and structure/function characteristics typical of HFpEF. There were no statistically significant differences between the placebo vs CDC groups at baseline, 6 or 12 months in any variable measured (Table 1). There were no imbalances in any serious adverse event metric between groups. Conclusion Intracoronary infusion of allogeneic human CDCs at a single point in time did not significantly alter any structural, functional, clinical or ECM variable measured. Since the design of this trial, the preferred dosing and delivery for CDCs has evolved from single-dose intracoronary delivery to repeated (q 3 months), intravenous delivery, as is being used in DMD. Further studies with repeated intravenous dosing of CDCs may be warranted to fully elucidate therapeutic potential of this intervention.

BACKGROUND:Obesity leads to both heart failure with a preserved ejection fraction (HFpEF) and to chronic kidney disease (CKD); CKD may both influence the clinical course of obesity-related HFpEF; and incretin-based drugs may influence renal function. OBJECTIVES:This analysis had dual objectives: 1) to evaluate the influence of CKD on the clinical responses to tirzepatide in patients with obesity-related HFpEF; and 2) to investigate the complexity of tirzepatide-related changes in renal function. For both objectives, we focused on discrepancies between creatinine-based and cystatin C-based estimates of the estimated glomerular filtration rate (eGFR). METHODS:The SUMMIT trial randomly assigned 731 patients with HFpEF and a body mass index ≥30 kg/m2, who were enriched for participants with CKD. Patients received either placebo or tirzepatide for a median of 104 weeks and were followed for cardiovascular death or worsening heart failure events and for changes in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) after 52 weeks. Because of the confounding produced by obesity and changes in muscle mass, eGFR was assessed at randomization and after 12, 24, and 52 weeks by both creatinine-based and cystatin C-based formulae. RESULTS:Patients with CKD (based on creatinine or cystatin C) had greater severity of heart failure, as reflected by: 1) worse functional class, KCCQ-CSS scores, and 6-minute walk distance; 2) higher levels of NT-proBNP and cardiac troponin T; and 3) a 2-fold increase in the risk of worsening heart failure events. CKD did not influence the effect of tirzepatide to reduce the relative risk of major adverse heart failure events and to improve KCCQ-CSS, quality of life, and functional capacity, but the absolute risk reduction in the primary events was numerically greater in patients with CKD. Regarding renal function assessments, baseline eGFR-cystatin C was consistently ≈9 mL/min/1.73 m2 lower than that eGFR-creatinine, with significant individual variance. Furthermore, tirzepatide increased eGFR at 52 weeks, assessed by both creatinine-based and cystatin C-based formulae, but with considerable discordance in individual patients. Tirzepatide produced a decline in eGFR at 12 weeks with eGFR-creatinine (but not eGFR-cystatin C), and it led to an improvement in eGFR at 52 weeks in all patients (when assessed by cystatin C), but only in patients with CKD (when assessed by eGFR-creatinine). CONCLUSIONS:The triad of obesity, HFpEF, and CKD identifies patients with considerable functional impairment and an unfavorable prognosis, who nevertheless respond favorably to tirzepatide. Long-term tirzepatide improves renal function (both by cystatin C and creatinine), but the measurement of eGFR in patients with obesity receiving incretin-based drugs is likely to be skewed by the effects of fat and muscle mass (and by changes in body composition) on the synthesis of both cystatin C and creatinine. (A Study of Tirzepatide [LY3298176] in Participants With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity: The SUMMIT Trial; NCT04847557).