# Acute Heart Failure: Transitioning From Symptom-Based Care to Remission

Gad Cotter, Beth Davison, Douglas Mann, Jan Biegus, Jozine Termaaten, Matteo Pagnesi, Yonathan Freund, Adriaan Voors, Piotr Ponikowski, Marco Metra, et al.

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To cite this version:

Gad Cotter, Beth Davison, Douglas Mann, Jan Biegus, Jozine Termaaten, et al. Acute Heart Failure: Transitioning From Symptom-Based Care to Remission. Journal of Cardiac Failure, 2025, S1071-9164 (25), pp.00046-00056. 10.1016/j.cardfail.2024.12.016. inserm-05399853

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https://inserm.hal.science/inserm-05399853v1

Submitted on 5 Dec 2025

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JCF
Journal of Cardiac Failure

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Review Article

Acute Heart Failure: Transitioning From Symptom-Based Care to Remission

GAD COTTER, MD<sup>1,2,3</sup> BETH A. DAVISON, PhD<sup>1,2,3</sup> DOUGLAS L. MANN, MD<sup>4</sup>

JAN BIEGUS, MD, PhD<sup>5</sup> JOZINE M. TERMAATEN, MD, PhD<sup>6</sup> MATTEO PAGNESI, MD, PhD<sup>7</sup>

YONATHAN FREUND, MD, PhD<sup>8,9</sup> ADRIAAN A. VOORS, MD, PhD<sup>6</sup>

PIOTR PONIKOWSKI, MD, PhD<sup>5</sup> MARCO METRA, MD<sup>7</sup> and ALEXANDRE MEBAZAA, MD, PhD<sup>1,10</sup>

Paris, France; Durham, North Carolina, USA; St. Louis, Missouri, USA; Wroclaw, Poland; Groningen, The Netherlands; and Brescia, Italy

A B S T R A C T

During the past century, the characteristics of patients with heart failure (HF) and acute HF (AHF) have shifted from patients with severe pump failure due to rheumatic, hypertensive and ischemic heart disease to older and more obese patients with multiple severe comorbidities. The pathophysiology of AHF has shifted, in parallel, from that of advanced, end-stage pump failure caused by severe left ventricular dysfunction to age, obesity and comorbidity-related cardiovascular dysfunction combined with neurohormonal and inflammatory dysregulation or "inflammaging." With the advent of neurohormonal blockers leading to improved outcomes of patients with chronic HF, the focus of AHF therapy has also changed from care directed at early symptom improvement to therapies directed toward longer-term improvements in quality of life and outcomes. Studies conducted in the past 5 years suggest that the beneficial effects seen with the 4 pillars of guideline-directed medical therapy for HF, mostly comprising neurohormonal blockade, can be extended to AHF when these therapies are initiated and rapidly uptitrated during admission and after discharge. A recent pilot study, CORTAHF (Effect of Short-Term Prednisone Therapy on CRP Change in Emergency Department Patients With Acute Heart Failure and Elevated Inflammatory Markers), has suggested that these benefits can be extended by treating patients with AHF and markers of inflammatory activation with anti-inflammatory therapies. Future studies should further examine whether combined anti-inflammatory therapy and neurohormonal blockade can lead to the reversal of disrupted underlying pathophysiology and remission in patients with AHF. (J Cardiac Fail 2025;00:1–9)

**Key Words:** Acute heart failure, neurohormonal blockade, anti-inflammatory therapy.

© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

At the beginning of the 20th century heart failure (HF) had a malignant course and prognosis, particularly in patients

who suffered from HF exacerbation (ie, acute HF [AHF])
due to the combined lack of cardiovascular perfusion

From the ¹Université Paris Cité, INSERM UMR-S 942 (MASCOT), Paris, France; ²Heart Initiative, Durham, NC, USA; ³Momentum Research, Durham, NC, USA; ⁴Cardiovascular Division, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO, USA; ⁵Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland; ⁶Department of Cardiology, University Medical Centre Groningen, Groningen, The Netherlands; ⁷Cardiology, ASST Sedale Civili and Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy; ⁸Sorbonne Université, Improuvant Emergency Care FHU, Paris, France; ⁹Emergency Département and Service Mobile d'Urgence et de Réanimation (SMUR), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France and ¹⁰Department

of Anesthesiology and Critical Care and Burn Unit, Saint-Louis and Labissière Hospitals, FHU PROMICE, DMU Parabola, APHP Nord, Paris, France.

Manuscript received November 25, 2024; revised manuscript received December 6, 2024; revised manuscript accepted December 10, 2024.

Reprint requests: Gad Cotter, MD, Momentum Research, Inc., 1426 East NC Highway 54, Suite B, Durham, NC 27713, USA. Tel: 1 919 599 0949 E-mail: gadcotter@momentum-research.com

1071-9164/$ - see front matter

© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

https://doi.org/10.1016/j.cardfail.2024.12.016
("forward failure") and pulmonary congestion ("backward failure").¹ Since then, the characteristics of patients with AHF have changed. Three articles authored by Dr. Eugene Braunwald in 1956, 1968 and 1983 described the etiology of HF in individual patients enrolled in clinical studies, and they illustrate this shift. In the 1950s, HF was typically due to rheumatic or hypertensive diseases. By the 1980s, ischemic heart diseases and left ventricular systolic dysfunction were predominant.²⁻⁵ In recent years, patients with HF have been older and more commonly have preserved left ventricular (LV) function and diastolic dysfunction (Fig. 1). The treatment of AHF has also evolved from a focus on symptom relief to the induction of remission.

## AHF Treatment, Late 1910s–1990s

Given the high rates of morbidity and mortality in HF and AHF,² treatments for AHF were developed mostly to improve symptoms as a form of palliative care. The first drugs to be used for the treatment of HF and AHF were digoxin derivatives, which had already been discovered in the 12th century and were described in detail by William Withering in his groundbreaking work, titled *An Account of the Foxglove*.⁶ Diuretics were first discovered in 1919, when mercury was administered first to a patient with syphilis and then to a patient with anasarca due to rheumatic heart disease.⁷ In the early 1950s, the treatment of AHF consisted of digoxin, mercurial diuretics, morphine, rotating tourniquets, and phlebotomy of 350–1000 mL of blood⁸ (probably as a way to reduce preload). To that, Paul Dudley White added the importance of psychological comfort: "Last but not least is the spirit of cheerfulness that should surround the patient."⁹ It was not until 1949,

when sulfanilamide, the first carbonic anhydrase inhibitor, was discovered,¹⁰ followed by the discovery of the more potent acetazolamide, thiazides and the synthesis of furosemide in 1959 by Konrad Strum.¹¹ These discoveries led to a better ability to substantially improve symptoms and reduce adverse outcomes related to the immediate effects of pulmonary congestion.⁴ Later, during the 1970s and 1980s, the importance of nitrates for the treatment of HF and AHF was established,¹² and inotropes were introduced.⁵ This era of rapid evolution in AHF therapy, from the late 1950s to the late 1990s, saw an improved ability to stabilize patients with AHF during the first few hours and days of admission and to reduce early adverse outcomes and mortality. However, beyond the first hours after presentation, when combined treatment with oxygen, intravenous loop diuretics, nitrates, and inotropes, when needed, helped to stabilize the patients' conditions¹³ and provide symptomatic relief, no treatment has been shown to improve either in-hospital outcomes beyond the first hours of emergency stabilization or post-discharge outcomes, or to improve quality of life (QoL).

## Late 1990s–2020: the Hemodynamic and Enhanced Diuretic Phase of AHF Drug Development

In the 1990s and early 2000s, with the introduction of renin-angiotensin system inhibitors (RASIs), beta-blockers (BBs) and mineralocorticoid receptor antagonists (MRAs), the outcomes of patients with chronic HF were improved substantially, while the 30-day outcomes after an AHF admission had not changed.¹⁴ These advancements were driven

<figure><img src="image_4.png" /><figcaption>Fig. 1. Acute heart failure (AHF) patients' profiles evolution over the past few decades as therapies for rheumatic and ischemic heart disease improved, but the population became older and more obese.</figcaption></figure>
mostly by the understanding that neurohormonal-adrenergic activation in patients with chronic HF is deleterious and, therefore, its blockage may lead to substantial improvements in outcomes. However, even though data existed that showed that similar or even more pronounced neurohormonal, adrenergic and inflammatory activation occurred in patients with AHF,¹⁵⁻¹⁸ the focus of AHF treatment remained diuretic and hemodynamically active medications administered during the index hospital admission.

Although right-heart catheterization was first introduced in the 1700s,¹⁹ it came into more general use only in the late 1940s.²⁰ With the availability of such metrics as cardiac output, pulmonary artery pressure and pulmonic and systemic resistance, the perception of AHF shifted to that of a disease that is driven by core hemodynamic processes (reduced cardiac output, increase vascular resistance, increased pulmonary pressures) leading to hypoperfusion, congestion and edema. The symptoms and signs of AHF were then divided into those caused by "forward" failure (hypoperfusion) and those due to "backward" failure (congestion). Such logic dictates that effective medications to address the core hemodynamic-congestive pathophysiology of AHF would be medications targeting decongestion, positive inotropy and vasodilation (Fig. 1). Indeed, from the mid-1990s to 5 years ago, most efforts of drug development in AHF were focused on either evolving decongestive therapies beyond loop diuretics (such as natriuretic peptides, aquaretic drugs, adenosine blockers, combined thiazides/acetazolamide and loop diuretics, mechanical ultrafiltration, etc.) or introducing new vasoactive/inotropic drugs (such as levosimendan, tezosentan, nesiritide, sere-laxin, etc).²¹ Regretfully, these efforts did not lead to the development of any new therapy or therapeutic strategy that improves patients' symptoms, QoL or outcomes beyond the first few hours after hospital presentation. These repeated failures have led to some questioning about whether AHF is, indeed, an entity separate from chronic HF and have led to a complete halt in the development of new interventions for AHF.²²

Despite these failures, one must remember that diuretics and hemodynamically active medications still maintain a key role in the initial stabilization of patients presenting with AHF. As described above, those medications revolutionized the ability to control patients' symptoms and reduced immediate mortality dramatically. Therefore, their failure to improve outcomes beyond the immediate period should not detract from their immense utility in early symptom relief. Moreover, for patients who cannot be fully stabilized, and whose symptoms cannot be reasonably controlled within a few hours or days after presentation, enhanced diuretic therapy (ie, addition of second-line diuretics to loop diuretics), vasodilators and inotropes still have a crucial role in further improving patients' symptoms; those treatments should continue to be administered. Indeed, those and potentially other new therapies are desperately needed for patients with AHF

complicated by either cardiogenic shock²³,²⁴ or the development of significant diuretic resistance.²⁵

## Last 5 years: Neurohormonal Blockade to Treat AHF

As described above, the importance of neurohormonal activation in predicting the outcomes of HF and AHF has been well described. In chronic HF, neurohormonal blockade has been shown, since the late 1980s, to improve patients' outcomes and, therefore, the role of neurohormonal and adrenergic activation has been established as a key modifiable pathophysiological pathway in chronic HF.²⁶ However, only in the recent 5 years did this understanding extend to AHF. This was achieved by the advent of small, mostly investigator-initiated studies that included approximately 500–1000 patients each and were, therefore, believed to be underpowered for "harder" endpoints, such as HF readmission and death.

In the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) study, patients with diabetes mellitus and a recent admission for AHF were randomized up to 72 hours from discharge to receive placebo or the sodium-glucose linked transporter (SGLT)-1 and -2 blocker, sotagliflozin.²⁷ Despite the study's being discontinued (due to financial constraints) after 1222 patients had been enrolled, the study showed large reductions in the occurrence of cardiovascular death, HF readmissions and urgent visits due to HF (revised primary endpoint) and improvements in QoL. In the Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode (PIONEER-HF) study,²⁸ patients with AHF and reduced ejection fraction (EF) were randomized to either sacubitril-valsartan or enalapril. With only 881 patients enrolled and follow-up of only 8 weeks, a 39% relative risk reduction of cardiovascular death or readmission due to HF was observed in the risk of cardiovascular death or HF readmission compared to enalapril (16.3% enalapril vs 9.8% sacubitril/valsartan). In the EMPagliflozin 10 mg Compared to Placebo, Initiated in Patients Hospitalised for Acute Heart Failure (EMPULSE) study,²⁹ the SGLT2 inhibitor empagliflozin was studied in 530 patients with diagnoses of AHF, regardless of EF. The study showed that patients treated with empagliflozin experienced significant clinical benefit compared with placebo, driven by both a 35% relative reduction in 90-day cardiovascular death or HF event and improvement in the Kansas City Cardiomyopathy Questionnaire-12 total symptom score at 90 days. Empagliflozin therapy was also associated with improvements in congestion.³⁰ Finally, the Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testing, of Heart Failure Therapies (STRONG-HF³¹) study was a randomized, prospective clinical trial designed to assess the safety and efficacy of a rapid up-titration of Guideline-
Directed Medical Therapy (GDMT) before and after discharge from an admission due to AHF. Patients were randomly assigned to either usual care—discharge and follow-up according to the local practice until day 90 after randomization—or high-intensity care. Under high-intensity care, patients were administered 50% of maximally recommended dosages of BBs, RASIs and MRAs before discharge and full dosages at 2 weeks after discharge under strict safety follow-up that included 4 post-discharge visits within 6 weeks. At 180 days, the risk of HF readmission or all-cause death was lower in the high-intensity-care group (15.2%) compared to the usual-care group (23.3%). The secondary endpoint of change from baseline to day 90 in the EuroQol-5 Dimension (EQ-5D) visual analog scale score was markedly improved in the high-intensity-care group, as were markers of congestion; patients treated with high-intensity care had lower levels of NT-proBNP and more weight loss.³² The benefits of the high-intensity-care strategy were consistent across age, sex, ejection fraction, estimated glomerular filtration rate, NT-proBNP levels, blood pressure, and the occurrence of safety indicators.³³⁻³⁹

Taken together, the results of these studies suggest that rapid institution and up titration of therapies that block the neurohormonal and adrenergic systems has large beneficial effects in patients with AHF that are similar to or even greater than those observed in chronic HF.⁴⁰,⁴¹ These studies have led to substantial changes in the recommended approach to patients with AHF.⁴²

## Inflammatory Activation and AHF

Inflammatory activation has been shown to be present in patients with HF, to be associated with HF disease

severity, to improve during times of recompensation, and to worsen before death in the seminal description by Elster, Braunwald and Wood in 1956.³ Myriad studies followed, confirming these results by using a plethora of biomarkers (Table 1).¹⁵⁻¹⁷,⁴³⁻⁴⁶ After the neutral results of 2 large studies assessing the effects of tumor necrosis factor alpha (TNF-α) blockers in chronic HF more than 20 years ago,⁴⁷ no large studies have been conducted to assess the potential effects of anti-inflammatory therapies in patients with AHF. Only a few small studies have been conducted in AHF. Van Tassel⁴⁸ showed reduced C-reactive protein (CRP) in 30 patients with AHF, EF < 40% and CRP ≥ 5 mg/dL treated with anakinra,⁴⁹ an interleukin (IL)-1 receptor antagonist, and in 60 randomized patients with AHF, EF < 50% and CRP > 2 mg/L; treatment with anakinra showed some improvement in peak VO₂ at 12 weeks and a trend toward reduced death or rehospitalization due to HF at 24 weeks. Interestingly, indirect evidence from the randomized Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) trial, which enrolled 10,061 patients with previous myocardial infarction and high-sensitivity CRP ≥ 2 mg/L, showed that canakinumab, a monoclonal antibody targeting IL-1β, was associated with a dose-dependent reduction in HF hospitalizations and in the composite of HF-related mortality or HF-related hospitalizations, as compared to placebo.⁵⁰ The composite of HF-related hospitalizations and heart failure-related mortality was also reduced by canakinumab, with unadjusted hazard ratios of 1.00 (95% CI, 0.78–1.29) for 50 mg, 0.88 (95% CI, 0.68–1.13) for 150 mg and 0.78 (95% CI, 0.60–1.02) for 300 mg (P for trend = 0.042). In the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) study, steroid therapy was

<table><caption>**Table 1** Potential inflammatory targets for AHF studies</caption><thead><tr><th>The Inflammation Biomarker</th><th>Study Population (AHF/CHF) n</th><th>Outcomes, if Applicable</th></tr></thead><tbody><tr><td rowspan="4">hsCRP</td><td>CHF<sup>1</sup></td><td>Prognostic information in HFpEF but not in HFrEF</td></tr><tr><td>CHF<sup>2</sup></td><td>hsCRP in CHF is associated with more congestion and worse prognosis</td></tr><tr><td>CHF (TOPCAT)<sup>3</sup></td><td>Elevated hsCRP identifies patients at higher risk of poor outcomes</td></tr><tr><td>AHF population (ASCEND-HF)<sup>4</sup></td><td>hsCRP are elevated in AHF patients. Increasing levels at 30 days after discharge are associated with higher 180-day mortality.</td></tr><tr><td></td><td>AHF population<sup>5</sup></td><td>Independent prognostic factor</td></tr><tr><td>IL-1</td><td>CHF<sup>6</sup></td><td>Marker of disease progression and potential target of the therapy</td></tr><tr><td>IL-6</td><td>CHF BIOSTAT-CHF<sup>7</sup> study</td><td>In a heterogeneous cohort of HF patients, elevated IL-6 levels were found in more than 50% of patients and were associated with poor outcomes.</td></tr><tr><td></td><td>CHF<sup>1</sup></td><td>Prognostic information in HFpEF but not in HFrEF</td></tr><tr><td></td><td>DM population<sup>8</sup></td><td>Associated with HF development</td></tr><tr><td></td><td>CHF<sup>9</sup></td><td>IL-6 levels are elevated in HFpEF and are associated with greater symptom severity, poorer exercise capacity and more upper-body fat accumulation.</td></tr><tr><td></td><td>AHF population (ASCEND-HF)<sup>10</sup></td><td>IL-6 at baseline was not an independent risk factor of long-term outcomes.</td></tr><tr><td></td><td>AHF population<sup>11</sup></td><td>IL-6 elevated in AHF</td></tr><tr><td>IL-17</td><td>CHF<sup>12</sup></td><td>Associated with HF severity</td></tr><tr><td rowspan="2">Tumor necrosis factor (TNF)-α</td><td>CHF<sup>13</sup></td><td>Related to mortality</td></tr><tr><td>CHF<sup>14</sup></td><td>Related to HF progression and outcomes</td></tr><tr><td>Soluble ST2</td><td>AHF<sup>15,16</sup></td><td>Prognostic importance</td></tr></tbody></table>

AHF, acute heart failure; CHF, congestive heart failure; DM, diabetes mellitus; hsCRP, high-sensitivity C-reactive protein.
shown to improve diuresis, reduce creatinine at day 7 and reduce the risk of 30-day cardiovascular death.⁵¹,⁵² In a retrospective analysis, Miro et al. found trends toward improved outcomes in patients with AHF and high CRP who were given corticosteroids in the emergency department.⁵³ In the CORTAHF (Effect of Short-Term Prednisone Therapy on CRP Change in Emergency Department Patients With Acute Heart Failure and Elevated Inflammatory Markers) pilot study,⁵⁴ 100 patients with AHF and inflammatory activation, as evidenced by a CRP level > 20 mg/L at screening, were enrolled. The results of the study suggest that a short "burst" course of steroid therapy (40 mg prednisone daily orally for a week) leads to suppression of inflammatory markers during the period of steroid administration. In addition, the short course of steroid therapy resulted in greater improvement in QoL (at day 7) and a significantly reduced risk of a worsening HF event through day 91. These results were equally significant in a predetermined group of patients with IL-6 levels > 13 pg/dL at baseline, measured blindly at the end of the study by a core laboratory. Steroid therapy was also associated with trends toward less congestion and lower doses of loop diuretics at day 31.

These results stand in contrast to the simultaneously published study of Colchicine in AHF (COLICA).⁵⁵ In that study, patients with milder AHF (about half did not require admission to the hospital and were treated as outpatients) and no requirement for inflammatory activation at baseline were given low-dose colchicine for 8 weeks. The study found small decreases in inflammatory markers (CRP and IL-6) but no effects on natriuretic peptide levels or worsening HF events, although the number of events was small, because the patients were not selected on the basis of increased inflammation at baseline. There was a trend toward less outpatient IV diuretic administration and significantly lower dosages of furosemide.

The disparate results of various studies highlight that these studies should include patients who have clear evidence of inflammatory activation (high levels of IL-6/CRP) and have sufficiently severe disease to ensure that enough events will be registered to detect effects on clinical outcomes and/or quality of life. Of note, in none of the above-mentioned studies⁴⁸⁻⁵⁵ was an excess in significant infections detected; hence, we believe that the anti-inflammatory therapy to be studied is given at dosages that will lead to a large, significant reduction in inflammation, enabling significant reduction of inflammatory activation. A placebo-controlled study of a monoclonal antibody against IL-6, ziltivekimab, is being conducted in patients with HFmEF and HFpEF for the endpoint of CV death and HF hospitalization. However, no such study is currently being conducted in patients with AHF.

Cross-talk Between the Neurohormonal and
Inflammatory Systems in HF

Over the years, it has been well established that activation of the renin-angiotensin and adrenergic systems, as well as high levels of aldosterone, have significant pro-inflammatory effects.⁵⁶,⁵⁷ Prior studies have shown that there is a reciprocal relationship between activation of the renin angiotensin aldosterone system (RAAS) and inflammatory signaling pathways, which creates a forward feedback loop that exacerbates both processes.⁵⁸ This reciprocal relationship is driven, at least in part, at the transcriptional level, because $\kappa\beta$ elements for the transcription factor nuclear factor-kappa B (NF-$\kappa\beta$) are found in RAAS components (eg, angiotensinogen⁵⁹) and various inflammatory genes, including those encoding proinflammatory cytokines (eg, TNF⁶⁰), chemokines and adhesion molecules. Pro-inflammatory cytokines, such as TNF and IL-6, can stimulate renin release, enhancing RAAS activity. Inflammatory mediators can upregulate the expression of angiotensinogen and angiotensin converting enzyme (ACE), leading to increased production of angiotensin II, which further promotes inflammation by stimulating the production of more pro-inflammatory cytokines.⁵⁹,⁶¹ Mice with cardiac-restricted overexpression of TNF had increased activation of myocardial RAAS, as shown by an increase in ACE mRNA levels and ACE activity and increased angiotensin II peptide levels.⁶¹ Moreover, inflammasome activation can increase the production of reactive oxygen species (ROS), which can enhance the activity of angiotensin II. ROS can amplify the effects of angiotensin II on blood vessels, promoting vasoconstriction. This oxidative stress further perpetuates RAAS activation and inflammatory responses. Angiotensin II, the central effector molecule of RAAS, has profound effects on inflammation in the cardiovascular system. Angiotensin II activates various signaling pathways that result in the production of ROS, as well as the activation of NF-$\kappa\beta$, which provokes the expression of pro-inflammatory genes in the heart. Indeed, pathophysiological concentrations of angiotensin II detected in patients with HF are sufficient to provoke increased mRNA and protein expression of TNF in the mammalian heart in an NF-$\kappa\beta$-dependent manner.⁶⁰ Angiotensin II also induces the expression of adhesion molecules on endothelial cells, facilitating the recruitment of inflammatory cells to vascular tissues. Aldosterone promotes inflammation through increased expression of pro-inflammatory cytokines and adhesion molecules. Further, chronic activation of RAAS and persistent inflammation lead to renal fibrosis and kidney disease, which can also exacerbate HF. These findings were recently extended to SGLT inhibitors.⁶²,⁶³ Therefore, blocking these systems may have significant anti-inflammatory effects. Indeed, several studies have shown that all 4 pillars of GDMT therapy for HF can have significant anti-inflammatory effects.⁶⁴,⁶⁵
Importantly, recent studies have shown that glucagon-like peptides receptor agonists (GLP-1-RAs) have substantial anti-inflammatory effects.⁶⁶⁻⁶⁸ These findings were recently extended to patients with HF; a large retrospective analysis found GLP-1-RA to have effects on HF readmission or death in patients with obesity-related HF and preserved ejection fraction (HFpEF).⁶⁹ Importantly, there was a trend for those effects to be more pronounced in patients with more significant inflammation at the time of recruitment.⁷⁰ Therefore, it is possible that treatment with GLP-1-RA inhibitors may improve inflammation in AHF and that those reductions may translate into better QoL and reduced adverse outcomes.

On the other hand, there is little evidence of the opposite (ie, that anti-inflammatory therapy has effects on neurohormonal activation in patients with HF and AHF). Studies conducted in the 1970s and 1980s suggest that steroids may reduce plasma renin activity and aldosterone and norepinephrine levels.⁷¹⁻⁷³ In the CORTAHF study,⁵⁴ levels of plasma renin concentration (PRC) and neprilysin (NEP) were measured centrally and blindly after the conclusion of enrolment. The results show a strong trend toward a reduction in the levels of PRC and NEP by 20%–30% in the prednisone arm 30 days after steroid initiation. The numeric reductions in PRC and NEP at day 31 in the prednisone arm are similar to those described as induced by BBs (PRC)⁷⁴ and ARNis (NEP)⁷⁵ in previous studies.

Taken together, these data suggest a possible "cross-talk" between neurohormonal and inflammatory activation in patients with HF and AHF. This cross-talk may lead to signal amplification (ie, when 1 system is activated, it may induce activation in the other). Conversely, a blockage of 1 system (as has been shown with GDMT therapies for HF) may lead to reduced activity of the other.

## Shifts in Characteristics of Patients With HF Over the Past Century

The first patient ever to receive a diuretic treatment for HF using mercury-based drugs had anasarca due to rheumatic heart disease.⁷ In studies from the 1950s (Fig. 1), most patients with HF and AHF were young and suffered from rheumatic heart disease, followed by hypertension. Studies performed later have shown a shift in the patient population toward more patients with ischemic heart disease.⁸,⁹ Recent results from the large ADHERE (Acute Deco compensated HEart Failure National REgistry) and the RELAX-AHF-2 (Relaxin in Acute Heart Failure) study⁷⁶⁻⁷⁸ suggest that currently, patients with AHF are older (in their 70s), about half are women, most have relatively preserved EF (40% have EF > 40%), and there is a high prevalence of noncardiac comorbidities, such as hypertension, diabetes and kidney disease, among these patients. Obesity has also become a major characteristic of patients with AHF. In some studies, about 50% of patients are obese, and 20% are severely obese.⁷⁹ This shift from patients with severe pump failure to

older, more obese patients with more noncardiac comorbidities and preserved cardiac function may have significant implications for the pathophysiology and treatment of AHF.

Aging has profound effects on all the components that lead to HF. Aging has obvious effects on blood vessels and the heart that make them stiffer, worsening both vascular function and cardiac function and, most importantly, leading to diastolic dysfunction.⁸⁰ But age also has a direct effect on neurohormonal and inflammatory activation. Aging increases the activation of the sympathetic nervous system⁸¹ and reduces the activity of the renin system but increases angiotensin II.⁸² Most importantly, aging is associated with a very substantial activation of the inflammatory system, which has been termed "inflammaging."⁸³ This inflammaging can be further advanced by the presence of clonal hematopoiesis of indeterminate potential, which can lead to further activation of the inflammatory system.⁸⁴ Obesity has also been associated with significant neurohormonal and inflammatory activation and more preserved EF.⁸⁵ As stated above, these patients may be the target of treatment by GLP-1-RA, especially when they present with more inflammation,⁶⁹,⁷⁰ which is common in patients with AHF. Indeed, in studies examining the effects of GLP-1-Ras, significant improvement in markers of inflammation and reduction in HF events have been observed with 2 different GLP-1-RAs.⁸⁶,⁸⁷

Finally, cardiorenal syndrome has frequently been recognized as an important amplifier of the AHF process. Beyond contributing to worsening congestion and outcomes, cardiorenal syndrome may also play a pivotal role in inflammatory activation.⁸⁸ New therapies that improve renal function in patients with AHF may improve both congestion and inflammation and, hence, outcomes.

Thus, there is (so far) an unmet need for HF therapeutic interventions to keep up with the changes in our understanding of HF pathophysiology and to target its key mechanisms. The filling of this therapeutic gap may lead to further improvements in HF outcomes.

## Putting it all Together: a New Paradigm Emerges for the Pathophysiology and Treatment of AHF

With the advent of newer diuretics, nitrates and inotropes, from the 1950s to 1980s, it has become possible to stabilize patients with AHF during the first hours and days of admission, reducing the early in-hospital mortality to < 5% (Fig. 2). However, these types of medications, neither their older forms nor their more modern versions, have not been able to improve the outcomes of patients further after the initial stabilization, particularly given the changing profile of the typical patient with HF. Studies done with many such medications and/or approaches all showed no further benefit in patients' QoL or outcomes.²¹ At the same time, in patients with chronic HF, neurohormonal therapies, including RASIs, BBs, MRAs, and SGLT2
<figure><img src="image_5.png" /><figcaption>Fig. 2. The leading conceptualization of the pathophysiology of acute heart failure (AHF) (a) in the 1950s–2000s, and (b) today.</figcaption></figure>

inhibitors, have shown substantial effects in dramatically improving patients' outcomes and QoLs.²¹

The medications we use most commonly to treat AHF are diuretics, but reducing congestion does not improve AHF outcomes. These therapies have negative effects on neurohormonal activation and kidney function, which may amplify rather than reduce the core mechanism leading to AHF (Central Illustration).

In the past 5 years, studies in AHF have shifted from interventions that increase diuresis or cause vasodilation and/or inotropy to neurohormonal modulation and have shown, for the first time, that those therapies can lead to improved short- and medium-term changes in QoL and can reduce the adverse outcomes of HF readmission and death.²⁷⁻³⁰ (Central Illustration). The results of the COR-TAHF⁴⁴ study suggest that possibly adding anti-inflammatory therapy to the treatment of patients with AHF and activated inflammatory systems can extend those benefits further, improving QoL and reducing worsening HF events (Central Illustration). These results should lead to further exploration in larger trials that determine whether early complete blockage of both the neurohormonal and inflammatory systems in patients with AHF and significant inflammatory activation may lead to remission in the HF process.

## Conclusions

During the past century the etiology of HF and AHF has shifted from severe pump failure, due to rheumatic, valvular, hypertensive, and ischemic heart disease, to age- and obesity-related neurohormonal and inflammatory activation (such as “inflammaging”). With the demonstration that neurohormonal blockers lead to improved outcomes of patients with HF, the focus of AHF therapy has also changed from early symptom relief to longer-term

improvements in QoL and outcomes. Studies conducted in the past 5 years suggest that the beneficial effects seen with the 4 pillars of GDMT for HF, mostly directed at neurohormonal blockade, can be extended to patients with AHF when those therapies are initiated and rapidly uptitrated during admission and early after discharge. A recent pilot study (CORTAHF) has suggested that these benefits can be expanded by treating patients with AHF and markers of inflammatory activation with anti-inflammatory therapies. Future studies will need to examine further whether combined anti-inflammatory therapy and therapy directed at neurohormonal blockade can lead to remission in patients with AHF.

## Lay summary

In patients with acute heart failure who come to the hospital due to shortness of breath, congestion and fatigue, treatment until 10 years ago was mostly diuretics to improve their symptoms. However, in recent years, studies have shown that blocking multiple pathways of the neurohormonal system can reduce their rates of mortality and hospital readmission. It has been shown that the inflammatory system is highly activated in those patients and possibly, in the future, inflammatory blockers may further reduce deaths and readmissions in patients with acute heart failure.

<figure><img src="image_6.png" /></figure>
CRediT authorship contribution statement

GAD COTTER: Writing – review & editing, Project administration. BETH A. DAVISON: Writing – review & editing, Formal analysis. DOUGLAS L. MANN: Project administration. JAN BIEGUS: Project administration. JOZINE M. TERMAATEN: Project administration. MATTEO PAGNESI: Project administration. YONATHAN FREUND: Project administration. ADRIAAN A. VOORS: Project administration. PIOTR PONIKOWSKI: Project administration. MARCO METRA: Project administration. ALEXANDRE MEBAZAA: Project administration.

Disclosures

GC and BD are directors of Heart Initiative, a nonprofit organization, and are employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. DLM is on the scientific advisory board for Tenaya therapeutics, HAYA therapeutics and Cardurion Therapeutics and is a consultant to Novo Holdings and Tourmaline Therapeutics. JB has received honoraria from Bayer, Boehringer Ingelheim, and AstraZeneca for lectures. JMtM reports speaker and/or consultancy fees to his institution from Novartis, Boehringer Ingelheim, Moderna, Roche, and Novo Nordisk, and receiving grants from Netherlands Heart Foundation and Netherlands Organization for Scientific Research (NWO) outside of the submitted work. MP has received personal fees from Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Novartis, Roche Diagnostics, and Vifor Pharma. The employer of AAV received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, BMS, Boehringer Ingelheim, Corteria, EliLilly, Merck, Moderna, Novartis, Novo Nordisk, Roche diagnostics, and SalubrisBio. MM has received personal fees since January, 2021, from Actelion, Amgen, Livanova, and Vifor Pharma as a member of executive or data-monitoring committees of sponsored clinical trials and from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, and Novartis for participation in advisory boards or for speaking at sponsored meetings. AM has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics and honoraria for lectures from Roche Diagnostics and Bayer. YF and PP have nothing to disclose.

References

1. Ferrari R, Balla C, Fucili A. Heart failure: a historical perspective. Eur Heart J Suppl 2016;18:G3–10.

2. Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397–402.

3. Elster SK, Braunwald E, Wood HF. A study of C-reactive protein in the serum of patients with congestive heart failure. Am Heart J 1956;51:533–41.

4. Stampfer M, Epstein SE, Beiser GD, Braunwald E. Hemodynamic effects of diuresis at rest and during intense upright exercise in patients with impaired cardiac function. Circulation 1968;37:900–11.

5. Baim DS, McDowell AV, Chemiles J, Monrad ES, Parker JA, Edelson J, et al. Evaluation of a new bipyridine inotropic agent—milrinone—in patients with severe congestive heart failure. N Engl J Med 1983;309:748–56.

6. Medical Transactions, vol. 3. 1785. College of Physicians, London. Transaction XVI, 255–86.

7. Vogl A. The discovery of the organic mercurial diuretics. Am Heart J 1950;39:881–3.

8. Silverman ME. A view from the millennium: the practice of cardiology circa 1950 and thereafter. J Am Coll Cardiol 1999;33:1141–51. https://doi.org/10.1016/s0735-1097 (99)00027-3. PMID: 10193710.

9. White PD. Heart Disease, 4th ed. New York, NY: MacMillan, 1951.

10. Lang HJ, Hropot M. 1995. Discovery and development of diuretic agents. In: Greger RF, Knauf H, Mutschler E (eds.) Diuretics. Handbook of Experimental Pharmacology, vol 117. Berlin, Heidelberg, Germany: Springer.

11. Sturm K, Siedel W, Weyer R, Ruschig H. Zur Chemie des Furosemids. I. Synthesen von 5-sulfamoyl-antraniläsure-Derivaten. Chem Ber 1966;99:328–44.

12. Cotter G, Metzkor E, Kaluski E, Faigenberg Z, Miller R, Simovitz A, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998;351:389–93.

13. Cotter G, Moshkovitz Y, Milovanov O, Salah A, Blatt A, Krakover R. Acute heart failure: a novel approach to its pathogenesis and treatment. Eur J Heart Fail 2002;4:227–34.

14. Lee DS, Mamdani MM, Austin PC, Gong Y, Liu PP, Rouleau JL, Tu JV. Trends in heart failure outcomes and pharmacotherapy: 1992 to 2000. Am J Med 2004;116:581–9.

15. Milo-Cotter O, Cotter-Davison B, Lombardi C, Sun H, Bettari L, Bugatti S, et al. Neurohormonal activation in acute heart failure: results from VERITAS. Cardiology 2011;119:96–105.

16. Milo O, Cotter G, Kaluski E, Brill A, Blatt A, Krakover R, et al. Comparison of inflammatory and neurohormonal activation in cardiogenic pulmonary edema secondary to ischemic versus nonischemic causes. Am J Cardiol 2003;92:222–6.

17. Markousis-Mavrogenis G, Tromp J, Ouwerkerk W, Devalaraja M, Anker SD, Cleland JG, et al. The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. Eur J Heart Fail 2019;21:965–73.

18. Davison BA, Senger S, Sama IE, Koch GG, Mebazaa A, Dickstein K, et al. Is acute heart failure a distinctive disorder? An analysis from BIOSTAT-CHF. Eur J Heart Fail 2021;23:43–57.

19. Nossaman BD, Scruggs BA, Nossaman VE, Murthy SN, Kadowitz PJ. History of right heart catheterization: 100 years of experimentation and methodology development. Cardiol Rev 2010;18:94–101.

20. Courand A, Riley RL, Breed ES, et al. Measurement of cardiac output in man using the technique of catheterization of the right auricle or ventricle. J Clin Invest 1945;24:106–16.

21. Cotter G, Davison BA, Lam CSP, Metra M, Ponikowski P, Teerlink JR, Mebazaa A. Acute heart failure is a malignant process: but we can induce remission. J Am Heart Assoc 2023;12:e031745.

22. Packer M. Acute heart failure is an event rather than a disease: plea for a radical change in thinking and in therapeutic drug development. JACC Heart Fail 2018;6:73–5.

23. Riccardi M, Pagnesi M, Chioncel O, Mebazaa A, Cotter G, Gustafsson F. Medical therapy of cardiogenic shock: contemporary use of inotropes and vasopressors. Eur J Heart Fail 2024;26:411–31.

24. Metra M, Chioncel O, Cotter G, Davison B, Filippatos G, Mebazaa A, et al. Safety and efficacy of istaroxine in patients with acute heart failure-related pre-cardiogenic shock: a multicentre, randomized, double-blind, placebo-controlled, parallel group study (SEISMIC). Eur J Heart Fail 2022;24:1967–77.

25. Cox ZL, Hung R, Lenihan DJ, Testani JM. Diuretic strategies for loop diuretic resistance in acute heart failure: the 3T trial. JACC Heart Fail 2020;8:157–68.

26. Bozkurt B. Contemporary pharmacological treatment and management of heart failure. Nat Rev Cardiol 2024;21:545–55.

27. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117–28.

28. Morrow DA, Velazquez EJ, Devore AD, Desai AS, Duffy CI, Ambrosy AP, et al. clinical outcomes in patients with acute decompensated heart failure randomly assigned to sacubitril/valsartan or enalapril in the PIONEER-HF trial. Circulation 2019;139:2285–8.

29. Voors AA, Angermann CE, Teerlink JR, Collins SP, Kosiborod M, Biegus J, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med 2022;28:568–74.

30. Biegus J, Voors AA, Collins SP, Kosiborod MN, Teerlink JR, Angermann CE, et al. Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial. Eur Heart J 2023;44:41–50.

31. Mebazaa A, Davison B, Chioncel O, Cohen-Solal A, Diaz R, Filippatos G, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial. Lancet 2022;400:1938–52.

32. Biegus J, Mebazaa A, Davison B, Cotter G, Edwards C, Čelutkiënje J, et al. Effects of rapid uptitration of neurohormonal blockade on effective, sustainable decongestion and outcomes in STRONG-HF. J Am Coll Cardiol 2024;84:323–36.

33. Arrigo M, Biegus J, Asakage A, Mebazaa A, Davison B, Edwards C, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure in elderly patients: a sub-analysis of the STRONG-HF randomized clinical trial. Eur J Heart Fail 2023;25:1145–55.

34. Cerlinskaite-Bajorė K, Lam CSP, Sliwa K, Adamo M, Ter Maaten JM, Léopold V, et al. Sex-specific analysis of the rapid up-titration of guideline-directed medical therapies
after a hospitalization for acute heart failure: insights from the STRONG-HF trial. Eur J Heart Fail 2023;25:1156-5.

35. Pagnesi M, Metra M, Cohen-Solal A, Edwards C, Adamo M, Tomasoni D, et al. Uptitrating treatment after heart failure hospitalization across the spectrum of left ventricular ejection fraction. J Am Coll Cardiol 2023;81:2131-44.

36. Ter Maaten JM, Mebazaa A, Davison B, Edwards C, Adamo M, Arrigo M, et al. Early changes in renal function during rapid up-titration of guideline-directed medical therapy following an admission for acute heart failure. Eur J Heart Fail 2023;25:2230-42.

37. Adamo M, Pagnesi M, Mebazaa A, Davison B, Edwards C, Tomasoni D, et al. NT-proBNP and high-intensity care for acute heart failure: the STRONG-HF trial. Eur J Heart J 2023;44:2947-62.

38. Pagnesi M, Vilamajó OAG, Meirino A, Dumont CA, Mebazaa A, Davison B, et al. Blood pressure and intensive treatment up-titration after acute heart failure hospitalization: insights from the STRONG-HF trial. Eur J Heart Fail 2024;26:638-51.

39. Tomasoni D, Davison B, Adamo M, Pagnesi M, Mebazaa A, Edwards C, et al. Safety indicators in patients receiving high-intensity care after hospital admission for acute heart failure: the STRONG-HF trial. J Card Fail 2024;30:525-37.

40. Cotter G, Davison B. POINT: Should new drug development in heart failure focus on patients discharged from an acute heart failure admission? Lessons from recent studies. J Card Fail 2023;29:1210-3.

41. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M. ESC Scientific Document Group. 2023 focused update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2023;44:3627-39.

42. Markousis-Mavrogenis G, Tromp J, Ouwerkerk W, et al. The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. Eur J Heart Fail 2019;21:965-73.

43. Habibi D, Daneshpour MS, Asgarian S, et al. Effect of C-reactive protein on the risk of heart failure: a Mendelian randomization study. BMC Cardiovasc Disord 2023;23:112. https://doi.org/10.1186/s12872-023-03149-3.

44. Kalogeropoulos AP, Tang WHW, Hsu A, et al. High-sensitivity C-reactive protein in acute heart failure: insights from the ASCEND-HF trial. J Card Fail 2014;20:319-26.

45. Boulogne M, Sadoune M, Launay JM, Baudet M, Cohen-Solal A, Logart D. Inflammation versus mechanical stretch biomarkers over time in acutely decompensated heart failure with reduced ejection fraction. Int J Cardiol 2017;226:53-9.

46. Garofalo M, Corso R, Tomasoni D, et al. Inflammation in acute heart failure. Front Cardiovasc Med 2023;10:1235178. https://doi.org/10.3389/FCVM.2023.1235178.

47. Coletta AP, Clark AL, Banarjee P, Cleland JGF. Clinical trials update: RENEWAL (RENAISSANCE AND RECOVER) and ATTACH. Eur J Heart Fail 2002;4:559-61.

48. Van Tassell BW, Abouzaki NA, Oddi Erdle C, Carbone S, Trankle CR, Melchior RD, et al. Interleukin-1 blockade in acute decompensated heart failure: a randomized, double-blinded, placebo-controlled pilot study. J Cardiovasc Pharmacol 2016;67:544-51.

49. Van Tassell BW, Canada J, Carbone S, et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (Recently Decompensated Heart Failure Anakirna Response Trial). Circ Heart Fail 2017;10:e004373. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004373.

50. Everett BM, Cornel JH, Lainscak M, Anker SD, Abbate A, Thuren T. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation 2019;139:1289-99.

51. Liu C, Liu K. Cardiac outcome prevention effectiveness of glucocorticoids in acute decompensated heart failure: COPE-ADHF study. J Cardiovasc Pharmacol 2014;63:333-8.

52. Liu C, Liu G, Zhou C, Ji Z, Zhen Y, Liu K. Potential diuretic effects of prednisone in heart failure patients with refractory diuretic resistance. Can J Cardiol 2007;23:865-8.

53. Miró Ó, Takagi K, Davison BA, et al. Effect of systemic corticosteroid therapy for acute heart failure patients with elevated C-reactive protein. ESC Heart Fail 2022;9:2225-32.

54. Cotter G, Davison BA, Freund Y, Voors AA, Edwards C, Novosadova M, et al. Burst steroid therapy for acute heart failure: the CORTAHF randomized, open-label, pilot trial. Eur J Heart Fail 2024;26:2282-92. https://doi.org/10.1002/ejhf.3452.

55. Pascual-Figal D, Núñez Villota J, Pérez-Martínez MT, González-Juanatey JR, Taiboa-Urquía M, Llácer Iborra P. On behalf of the COLICA Investigators. Colchicine in acute heart failure: rationale and design of a randomized double-blind placebo-controlled trial (COLICA). Eur J Heart Fail 2024;26:1999-2007. https://doi.org/10.1002/ejhf.3300.

56. Mann DL. Angiotensin II as an inflammatory mediator: evolving concepts in the role of the renin angiotensin system in the failing heart. Cardiovasc Drugs Ther 2002;16:7-9.

57. Messaoudi S, Azibani F, Delcayre C, Jaisher F. Aldosterone, mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol 2012;350:266-72.

58. Sekiguchi K, Li X, Coker ML, Flesch M, Barger PM, Sivasubramanian N, Mann DL. Cross-regulation between the renin angiotensin system and inflammatory mediators in cardiac hypertrophy and failure. Cardiovasc Res 2004;63:433-42.

59. Takase O, Marumo T, Imai N, Hirahashi J, Takayanagi A, Hishikawa K, et al. NF-kappaB-dependent increase in intrarenal angiotensin II induced by proteinuria. Kidney Int 2005;68:464-73.

60. Kalra D, Sivasubramanian N, Mann DL. Angiotensin II induces tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C-dependent pathway. Circulation 2002;105:2198-205.

61. Flesch M, Hoper A, Dell'Italia L, Evans K, Bond R, Peshock R, et al. Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor. Circulation 2003;108:598-604.

62. Wang D, Naumova A, Isquith D, Sapp J, Huynh KA, Tucker I, et al. Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure. Cardiovasc Diabetol 2024;23:197. https://doi.org/10.1186/s12933-024-02294-z. rs.3-v4.132581.

63. Guo W, Zhao L, Huang W, Chen J, Zhong T, Yan S, et al. Sodium-glucose cotransporter 2 inhibitors, inflammation, and heart failure: a two-sample Mendelian randomization study. Cardiovasc Diabetol 2024;23:118.

64. De Angelis E, Pecoraro M, Rusciano MR, Ciccarelli M, Popolo A. Cross-talk between neurohormonal pathways and the immune system in heart failure: a review of the literature. Int J Mol Sci 2019;20:1698.

65. Markousis-Mavrogenis G, Baumhove L, Al-Mubarak AA, et al. Immunomodulation and immunopharmacology in heart failure. Nat Rev Cardiol 2024;1:211-99.

66. Wong CK, McLean BA, Baggio LL, Koehler JA, Hammoud R, Rittig N, et al. Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation. Cell Metab 2024;36:130-43.

67. McLean BA, Wong CK, Kabir MG, Drucker DJ. Glucagon-like peptide-1 receptor Tie2 + cells are essential for the cardioprotective actions of liraglutide in mice with experimental myocardial infarction. Mol Metab 2022;66:101641.

68. Lee YS, Jun HS. Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. Mediat Inflam 2016;2016:3094642.

69. Butler J, Shah SJ, Petrie MC, Borlaug BA, Abildstrøm SZ, Davies MJ. STEP-HFpEF Trial Committees and Investigators. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet 2024;403:1635-48.

70. Verma S, Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW. STEP-HFpEF Trial Committees and Investigators. Inflammation in obesity-related HFpEF: the STEP-HFpEF program. J Am Coll Cardiol 2024. https://doi.org/10.1016/j.jacc.2024.08.028. S0735-1097(24)08234-2 Epub ahead of print.

71. Katz FH, Popovitzer MM, Pinggera WF, Halgrimsom CG, Starzl TE. Acute alteration of plasma renin activity by large doses of intravenous prednisolone. Proc Soc Exp Biol Med 1972;141:887-9.

72. Naslijti A, Masson GM. Effects of corticosteroids on plasma angiotensinogen and renin activity. Am J Physiol 1969;217:1396-400.

73. Kelsch RC, Light GS, Luciano JR, Oliver WJ. The effect of prednisone on plasma normepinephrine concentration and renin activity in salt-depleted man. J Lab Clin Med 1971;77:267-77.

74. Fung JWH, Yu CM, Yip G, et al. Effect of beta blockade (carvedilol or metoprolol) on activation of the renin-angiotensin-aldosterone system and natriuretic peptides in chronic heart failure. Am J Cardiol 2003;92:406-10.

75. Nougué H, Pezel T, Picard F, Sadoune M, Arrigo M, Beauvais F, et al. Effects of sacubitril/valsartan on nephrilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study. Eur J Heart Fail 2019;21:598-605.

76. Adams Jr KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT. ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am J Heart Fail 2005;14:209-16.

77. Atherton JH, Hayward CS, Wan Ahmad WA, Kwok B, Jorge J, Hernandez AF. ADHERE International-Asia Pacific Scientific Advisory Committee. Patient characteristics from a regional multicenter database of acute decompensated heart failure in Asia Pacific (ADHERE International-Asia Pacific). J Card Fail 2012;18:82-8.

78. Metra M, Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G. RELAX-AHF-2 Committees Investigators. Effects of serelaxin in patients with acute heart failure. N Engl J Med 2019;381:716-26.

79. Joyce E, Lala A, Stevens SR, Cooper LB, Abou-Ezzedidine OF, Groarke JD. Heart Failure Apprentice Network. Prevalence, profile, and prognosis of severe obesity in contemporary hospitalized heart failure trial populations. JACC Heart Fail 2016;4:923-31.

80. Singam NSV, Fine C, Fleg JL. Cardiac changes associated with vascular aging. Clin Cardiol 2020;43:92-8.

81. de Lucia C, Eguchi A, Koch WJ. New Insights in Cardiac β-Adrenergic Signaling During Heart Failure and Aging. Front Pharmacol 2018;9:904.

82. Miller AJ, Arnold AC. The renin-angiotensin system and cardiovascular autonomic control in aging. Peptides 2022;150:170733.

83. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 2018;14:576-90.

84. Sikking MA, Stroeks SLVM, Waring OJ, Henkens MTHM, Riksen NP, Hoischen A. Clonal hematopoiesis of indeterminate potential from a heart failure specialist's point of view. J Am Heart Assoc 2023;12:e030603. https://doi.org/10.1161/JAHA.123.030603. Epub 2023 Jul 25.

85. Packer M. Derangements in adrenergic-adipokine signalling establish a neurohor-monal basis for obesity-related heart failure with a preserved ejection fraction. Eur J Heart Fail 2018;20:873-8.

86. Verma S, Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW. STEP-HFpEF Trial Committees and Investigators. Inflammation in obesity-related HFpEF: the STEP-HFpEF program. J Am Coll Cardiol 2024;84:1646-62. https://doi.org/10.1016/j.jacc.2024.08.028. Epub Aug 30, 2024. PMID: 39217564.

87. Borlaug BA, Zile MR, Kramer CM, Baum SJ, Hurt K, Litwin SE, et al. Effects of tирzepa-tetan on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nat Med 2025;31:544-51. https://doi.org/10.1038/s41591-024-03374-z. PMID: 39551891.

88. Colombo PC, Ganda A, Lin J, Onat D, Harxhi A, Iyasere JE, et al. Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome. Heart Fail Rev 2012;17:177-90. https://doi.org/10.1007/s10741-011-9261-3. PMID: 21688186; PMCID: PMC3876739.