Mineralocorticoid Antagonism in Heart Failure: Established and Emerging Therapeutic Role.

The pathophysiology of heart failure (HF) is related to the overactivation of the mineralocorticoid receptor, leading to fluid retention and adverse myocardial remodeling. Although mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of heart failure with reduced ejection fraction (HFrEF), they remain underused due to adverse effects such as hyperkalemia; and their efficacy is controversial in heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF). Recent trials in people with diabetes and kidney disease have supported the use of nonsteroidal MRAs in reducing HF-related morbidity and mortality and have fewer side effects than their steroidal counterparts. The efficacy and safety of nonsteroidal MRAs have not been tested in HF and are currently being evaluated in additional clinical trials. This review comprehensively examines the current data regarding MRAs for HF and the future direction of nonsteroidal MRA research while exploring the causes of MRA underutilization.

Metabolic dysfunction and incidence of heart failure subtypes among Black individuals: The Jackson Heart Study.

AIMS: The extent to which metabolic syndrome (MetS) severity influences subclinical myocardial remodelling, heart failure (HF) incidence and subtypes, remains unclear. We assessed the association of MetS with incident HF (including ejection fraction subtypes) among Black individuals. METHODS AND RESULTS: We included 4069 Jackson Heart Study participants (mean age 54.4 years, 63.8% women, 37.2% with MetS) without HF. We categorized participants based on MetS status and MetS severity scores (based on waist circumference [MetS-Z-WC] and body mass index [MetS-Z-BMI]). We assessed the associations of MetS indices with echocardiographic parameters, biomarkers of myocardial damage (high-sensitivity cardiac troponin I [hs-cTnI] and B-type natriuretic peptide [BNP]) and incident HF hospitalizations including HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). MetS severity was associated with subclinical cardiac remodelling (assessed by echocardiographic measures and biomarkers of myocardial damage). Over a median of 12 years, 319 participants developed HF (157 HFpEF, 149 HFrEF and 13 HF of unknown type). MetS was associated with a twofold greater risk of HF (hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.64-2.61). Compared to the lowest quartile (Q1) of MetS-Z-WC, the highest quartile (Q4) conferred a higher risk of HF (HR 2.35, 95% CI 1.67-3.30), with a stronger association for HFpEF (Q4 vs. Q1: HR 4.94, 95% CI 2.67-9.14) vs. HFrEF (HR 1.69, 95% CI 1.06-2.70). CONCLUSIONS: Metabolic syndrome severity was associated with both HF subtypes among Black individuals, highlighting the importance of optimal metabolic health for preventing HF.

Trajectory of C-Reactive Protein and Incident Heart Failure in Black Adults: The Jackson Heart Study.

BACKGROUND: Increased hsCRP (high-sensitivity C-reactive protein), a marker of inflammation, is associated with incident cardiovascular events. We aim to determine whether the baseline or trajectory of hsCRP levels over time predicts incident heart failure (HF) hospitalization. METHODS: JHS (Jackson Heart Study) participants' (n=3920 Black adults) hsCRP levels were measured over 3 visits (from 2000 to 2013). We assessed the association of hsCRP at baseline (visit 1) with incident HF hospitalization using Cox proportional hazards models. Furthermore, we assessed the association of the trajectory of hsCRP over repeated measurements (visits 1-3) with incident HF using joint models. Hazard ratios are reflective of an increase in hsCRP by 1 SD on a log2 scale. We also assessed the association of change in hsCRP between visit 1 and visit 3 with Cox proportional hazards models by grouping patients by low (<2 mg/L) and high (≥2 mg/L) hsCRP levels. The 4 groups were low-to-low (referent), low-to-high, high-to-low, and high-to-high. RESULTS: Mean baseline age of participants was 54±13 years, and 63.8% were women. Over a median follow-up of 12 years, 308 (7.9%) participants were hospitalized with incident HF. Baseline hsCRP was not associated with incident HF (adjusted hazard ratio, 1.08 [95% CI, 0.96-1.22]). However, increasing hsCRP levels over repeated measures were associated with a higher risk of incident HF overall (adjusted hazard ratio, 1.22 [95% CI, 1.03-1.44]) and HF with preserved ejection fraction (adjusted hazard ratio, 1.30 [95% CI, 1.02-1.65]) but not HF with reduced ejection fraction (P>0.05). Furthermore, changes in hsCRP from low-to-high and high-to-low levels were associated with incident HF (P<0.05). CONCLUSIONS: While baseline hsCRP was not associated with incident HF, an increasing trajectory of hsCRP over time was associated with increased risk for incident HF (particularly HF with preserved ejection fraction). Temporal change in hsCRP may be an important marker of risk for incident HF with preserved ejection fraction in Black adults.

Neighborhood Socioeconomic Disadvantage and 30-Day Outcomes for Common Cardiovascular Conditions.

BACKGROUND: Understanding the relationship between neighborhood environment and cardiovascular outcomes is important to achieve health equity and implement effective quality strategies. We conducted a population-based cohort study to determine the association of neighborhood socioeconomic deprivation and 30-day mortality and readmission rate for patients admitted with common cardiovascular conditions. METHODS AND RESULTS: We examined claims data from fee-for-service Medicare beneficiaries aged ≥65 years between 2017 and 2019 admitted for heart failure, valvular heart disease, ischemic heart disease, or cardiac arrhythmias. The primary exposure was the Area Deprivation Index; outcomes were 30-day all-cause death and unplanned readmission. More than 2 million admissions were included. After sequential adjustment for patient characteristics (demographics, dual eligibility, comorbidities), area health care resources (primary care clinicians, specialists, and hospital beds per capita), and admitting hospital characteristics (ownership, size, teaching status), there was a dose-dependent association between neighborhood socioeconomic deprivation and 30-day mortality rate for all conditions. In the fully adjusted model for death, estimated effect sizes of residence in the most disadvantaged versus least disadvantaged neighborhoods ranged from adjusted odds ratio 1.29 (95% CI, 1.22-1.36) for the heart failure group to adjusted odds ratio 1.63 (95% CI, 1.36-1.95) for the valvular heart disease group. Neighborhood deprivation was associated with increased adjusted 30-day readmission rates, with estimated effect sizes from adjusted odds ratio 1.09 (95% CI, 1.05-1.14) for heart failure to adjusted odds ratio 1.19 (95% CI, 1.13-1.26) for arrhythmia. CONCLUSIONS: Neighborhood socioeconomic disadvantage was associated with 30-day mortality rate and readmission for patients admitted with common cardiovascular conditions independent of individual demographics, socioeconomic status, medical risk, care access, or admitting hospital characteristics.

Embracing an era of targeted combination therapy for heart failure with preserved ejection fraction.

The concept of quadruple therapy as a "one-size-fit-all" approach is effective among all eligible patients with heart failure with reduced ejection fraction, with consistent and significant clinical benefits including reduced mortality across various subgroups. However, with exception of sodium-glucose cotransporter 2 inhibitors, the consistency of benefit with therapies does not extend to patients with heart failure with preserved ejection fraction. The clinical benefits of other promising medical therapies, such as angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have been demonstrated only in certain phenotypes of the highly heterogenous heart failure with preserved ejection fraction population. This variability can confuse frontline practicing cardiologists, potentially leading to the under-implementation of these medications. Therefore, we propose a simple approach: "targeted" combination therapy. This strategy aims to optimize evidence-based medications in heart failure with preserved ejection fraction by tailoring treatments to specific subgroups within the heart failure with preserved ejection fraction population where significant benefits are most evident.

Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction: The AMETHYST Randomized Clinical Trial.

Importance: Elevated serum uric acid (SUA) level may contribute to endothelial dysfunction; therefore, SUA is an attractive target for heart failure with preserved ejection fraction (HFpEF). However, to the authors' knowledge, no prior randomized clinical trials have evaluated SUA lowering in HFpEF. Objective: To investigate the efficacy and safety of the novel urate transporter-1 inhibitor, verinurad, in patients with HFpEF and elevated SUA level. Design, Setting, and Participants: This was a phase 2, double-blind, randomized clinical trial (32-week duration) conducted from May 2020 to April 2022. The study took place at 59 centers in 12 countries and included patients 40 years and older with HFpEF and SUA level greater than 6 mg/dL. Data were analyzed from August 2022 to May 2024. Interventions: Eligible patients were randomized 1:1:1 to once-daily, oral verinurad, 12 mg, plus allopurinol, 300 mg; allopurinol, 300 mg, monotherapy; or placebo for 24 weeks after an 8-week titration period. Allopurinol was combined with verinurad to prevent verinurad-induced urate nephropathy, and the allopurinol monotherapy group was included to account for allopurinol effects in the combination therapy group. All patients received oral colchicine, 0.5 to 0.6 mg, daily for the first 12 weeks after randomization. Main Outcomes and Measures: Key end points included changes from baseline to week 32 in peak oxygen uptake (VO2), Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), and SUA level; and safety/tolerability (including adjudicated cardiovascular events). Results: Among 159 randomized patients (53 per treatment group; median [IQR] age, 71 [40-86] years; 103 male [65%]) with median (IQR) N-terminal pro-brain natriuretic peptide level of 527 (239-1044) pg/mL and SUA level of 7.5 (6.6-8.4) mg/dL, verinurad plus allopurinol (mean change, -59.6%; 95% CI, -64.4% to -54.2%) lowered SUA level to a greater extent than allopurinol (mean change, -37.6%; 95% CI, -45.3% to -28.9%) or placebo (mean change, 0.8%; 95% CI, -11.8% to 15.2%; P < .001). Changes in peak VO2 (verinurad plus allopurinol, 0.27 mL/kg/min; 95% CI, -0.56 to 1.10 mL/kg/min; allopurinol, -0.17 mL/kg/min; 95% CI, -1.03 to 0.69 mL/kg/min; placebo, 0.37 mL/kg/min; 95% CI, -0.45 to 1.19 mL/kg/min) and KCCQ-TSS (verinurad plus allopurinol, 4.3; 95% CI, 0.3-8.3; allopurinol, 4.5; 95% CI, 0.3-8.6; placebo, 1.2; 95% CI, -3.0 to 5.3) were similar across groups. There were no adverse safety signals. Deaths or cardiovascular events occurred in 3 patients (5.7%) in the verinurad plus allopurinol group, 8 patients (15.1%) in the allopurinol monotherapy group, and 6 patients (11.3%) in the placebo group. Conclusions and Relevance: Results of this randomized clinical trial show that despite substantial SUA lowering, verinurad plus allopurinol did not result in a significant improvement in peak VO2 or symptoms compared with allopurinol monotherapy or placebo in HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT04327024.

Mechanistic Differences between Torsemide and Furosemide.

BACKGROUND: Torsemide is proposed to have clinically important pharmacokinetic and pharmacodynamic advantages over furosemide. However, clinical outcomes did not differ in the Torsemide Comparison with Furosemide for Management of Heart Failure (TRANSFORM-HF) randomized trial. METHODS: We conducted a multicenter mechanistic substudy of patients with heart failure randomized to oral furosemide or torsemide (TRANSFORM-Mechanism). At baseline and 30 days, participants underwent detailed assessments of pharmacokinetic and pharmacodynamic parameters. RESULTS: TRANSFORM-Mechanism enrolled 88 participants. Kidney bioavailability, or the proportion of dose delivered to the tubular site of action, was significantly less with torsemide compared to furosemide [median 17.1%, (IQR 12.3, 23.5%) vs. 24.8% (16.6, 34.1%), p < 0.001]. Furosemide had a longer duration of kidney drug delivery and duration of natriuresis (p≤0.004 for both). Prescribed doses of furosemide and torsemide in TRANSFORM-Mechanism were similar to TRANSFORM-HF, with providers on average using a 2:1 dose equivalence conversion between drugs. However, these doses resulted in a substantially greater natriuresis with torsemide (p<0.001). A dose equivalence of ∼4:1 resulted in similar natriuresis. Higher diuretic doses in the torsemide group resulted in mild perturbations in kidney function and significant increases in renin, aldosterone, and norepinephrine (p<0.05 for all). Plasma volume (p=0.52) and body weight (p=0.89) did not improve with torsemide vs. furosemide. CONCLUSIONS: We observed no meaningful pharmacokinetic/pharmacodynamic advantages for torsemide vs. furosemide. The greater natriuresis from higher diuretic doses in the torsemide group was offset by greater neurohormonal activation and kidney dysfunction.

Patiromer-Facilitated Renin-Angiotensin-Aldosterone System Inhibitor Utilization in Patients With Heart Failure With or Without Comorbid Chronic Kidney Disease: Subgroup Analysis of DIAMOND Randomized Trial.

INTRODUCTION: Renin-angiotensin-aldosterone system inhibitor (RAASis; including mineralocorticoid receptor antagonists [MRAs]) benefits are greatest in patients with heart failure with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD); however, the risk of hyperkalemia (HK) is high. METHODS: The DIAMOND trial (NCT03888066) assessed the ability of patiromer to control serum potassium (sK+) in patients with HFrEF with/without CKD. Prior to randomization (double-blind withdrawal, 1:1), patients on patiromer had to achieve ≥50% recommended doses of RAASi and 50 mg/day of MRA with normokalemia during a run-in period. The present analysis assessed the effect of baseline estimated glomerular filtration rate (eGFR) in subgroups of ≥/<60, ≥/<45 (prespecified), and ≥/<30 mL/min/1.73 m2 (added post hoc). RESULTS: In total, 81.3%, 78.9%, and 81.1% of patients with eGFR <60, <45, and <30 mL/min/1.73 m2 at screening achieved RAASi/MRA targets. A greater efficacy of patiromer vs placebo to control sK+ in patients with more advanced CKD was reported (p-interaction ≤ 0.027 for all eGFR subgroups). Greater effects on secondary endpoints were observed with patiromer vs placebo in patients with eGFR <60 and <45 mL/min/1.73 m2. Adverse effects were similar between patiromer and placebo across subgroups. CONCLUSION: Patiromer enabled use of RAASi, controlled sK+, and minimized HK risk in patients with HFrEF, with greater effect sizes for most endpoints noted in patient subgroups with lower eGFR. Patiromer was well tolerated by patients in all eGFR subgroups.

Carbon emissions and air pollution savings among telehealth visits for cardiology appointments.

Background: Climate change has been associated with adverse cardiovascular health, prompting interest in climate mitigation strategies while improving access for cardiovascular patients. We estimated greenhouse gas and air pollution savings from telehealth use in cardiology. Methods: Using cardiology telehealth visits at a large academic medical center from July 2020 to March 2024, carbon dioxide (CO2), nitrogen oxides (NOx), carbon monoxide (CO), and particulate matter (PM2.5) emissions saved were calculated using U.S. Environmental Protection Agency modeling software. Savings were converted into real-world comparators and differences were assessed by cardiology subspecialty and patient insurance status. Results: Over 45 months, 14,828 telehealth visits among 9942 patients resulted in savings of 484,152 kg of CO2, 5225 kg of CO, 243,491 g of NOx, and 9091 g of PM2.5 with the total carbon saved equivalent to planting 9070 tree saplings over ten years. CO2 emissions saved per visit (kg) differed significantly by payor (Self-pay 24.99, Medicare 19.67, Medicaid 19.54, Private 17.85, Other 17.37, p = 0.004) and by subspecialty (Interventional 23.79, General 19.08, Heart Failure 18.86, Electrophysiology 17.81, Adult Congenital 16.59, p < 0.001). Conclusions: Carbon emission and air pollution savings from telehealth in cardiology were substantial, with an estimated 19.06 kg of CO2 saved per visit and total savings over 45 months equivalent to planting over nine thousand trees.

Management of Iron Deficiency in Heart Failure: Practical Considerations and Implementation of Evidence-Based Iron Supplementation.

Iron deficiency (ID) is present in approximately 50% of patients with heart failure (HF) and even higher prevalence rate up to 80% in post-acute HF setting. The current guidelines for HF recommend intravenous (IV) iron replacement in HF with reduced or mildly reduced ejection fraction and ID based on clinical trials showing improvements in quality of life and exercise capacity, and an overall treatment benefit for recurrent HF hospitalization. However, several barriers cause challenges in implementing IV iron supplementation in practice due, in part, to clinician knowledge gaps and limited resource availability to protocolize routine utilization in appropriate patients. Thus, the current review will discuss practical considerations in ID treatment, implementation of evidence-based ID treatment to improve regional health disparities with toolkits, inclusion/exclusion criteria of IV iron supplementation, and clinical controversies in ID treatment, as well as gaps in evidence and questions to be answered.

Time from admission to randomization and the effect of empagliflozin in acute heart failure: A post-hoc analysis from EMPULSE.

AIMS: Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization. METHODS AND RESULTS: The EMPULSE population was dichotomized by median time from hospital admission to randomization (1-2 days vs. 3-5 days). The primary outcome was a hierarchical composite endpoint of time to all-cause death, number of HF events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3-5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1-2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3-5 days: WR 1.69, 95% confidence interval [CI] 1.26-2.25) but was attenuated in patients randomized earlier (1-2 days: WR 1.04, 95% CI 0.74-1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all-cause hospitalizations (interaction p < 0.1 for both). The reduction of N-terminal pro-B-type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004). CONCLUSIONS: Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3-5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1-2 days). These findings should be confirmed in future studies before clinical application.

Beyond quadruple therapy: the potential roles for ivabradine, vericiguat, and omecamtiv mecarbil in the therapeutic armamentarium.

Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro-B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval.

Peripheral artery disease, chronic kidney disease, and recurrent admissions for acute decompensated heart failure: The ARIC study.

BACKGROUND AND AIMS: Peripheral artery disease (PAD) has not only been associated with recurrent hospitalization for acute decompensated heart failure (ADHF) but is also associated with chronic kidney disease (CKD), a known risk factor for worse heart failure outcomes. The interaction of CKD with PAD in post-discharge ADHF outcomes is not well known. METHODS: Since 2005, hospitalizations for ADHF were sampled from 4 US regions by the Atherosclerosis Risk in Communities (ARIC) study and classified by physician review. We examined the adjusted association of PAD with 1-year ADHF readmissions, in patients with and without CKD (defined by glomerular filtration rate [GFR] ≤60 mL/min/1.73 m2 [stage 3a or worse]). RESULTS: From 2005 to 2018, there were 1049 index hospitalizations for patients with ADHF (mean age 77 years, 66 % white) with creatinine data, who were discharged alive. Of these, 155 (15 %) had PAD and 66 % had CKD. In comparison to those without PAD, patients with PAD had more comorbid conditions and higher 1-year ADHF readmission rates, irrespective of CKD status. After adjustment, PAD was associated with a greater risk of 1-year ADHF readmissions, both for patients with concomitant CKD (HR, 1.70; 95 % CI: 1.29-2.24) and those without CKD (HR, 1.97; 95 % CI: 1.14-3.40); p-interaction = 0.8. CONCLUSION: Among patients hospitalized with ADHF, those with concurrent PAD have more prevalent cardiovascular comorbidities and higher likelihood of 1-year ADHF readmission, irrespective of CKD status. Integrating a more holistic approach in management of patients with concomitant heart failure, PAD and CKD may be an important strategy to improve the prognosis in this vulnerable population.