Rampant Inflammation in Heart Failure: Can Anything Be Done About It?

PHOENIX — Cardiovascular inflammation was highly prevalent among U.S. heart failure (HF) patients, a registry study found, illustrating the unmet need for good inflammation-targeting pharmacotherapy.

In a subanalysis of POSEIDON — the largest global registry of inflammation in patients with atherosclerotic cardiovascular disease (ASCVD) or HF — elevated high-sensitivity C-reactive protein (hsCRP; ≥2 mg/L) was detected in about half the American participants — 50.8% in those with heart failure with preserved ejection fraction (HFpEF), 44.7% with mildly reduced ejection fraction (HFmrEF), and 50.3% with reduced ejection fraction (HFrEF).

That makes the U.S. cohort at disproportionately high cardiovascular inflammatory risk compared with the global POSEIDON study as a whole, where elevated hsCRP in HFpEF came out to 38.8%, in HFmrEF 38.1%, and in HFrEF 38.2% across 18 countries, reported Marat Fudim, MD, MHS, of Duke University Medical Center in Durham, North Carolina, at the Heart Failure Society of America annual conference.

“Now, what does that mean? I don’t know how to address it, but all I can tell you is that we are very inflamed as a nation of HF patients … Of course, comorbidities are the key drivers … obesity, diabetes, and CKD [chronic kidney disease] being key drivers,” he said.

In Fudim’s presentation, residual inflammatory risk persisted despite use of guideline-directed medical therapy. He stressed that hsCRP is a “practical” biomarker to identify HF patients with persistent residual inflammatory risk. “Of course, it starts with lifestyle and exercise that we know can reduce inflammatory risk, weight loss therapy, and you know, addressing key risk factors of CKD. So I use [hsCRP] as a jumping board to motivate my patients and inform me of the risk category,” he said.

“Of course, we don’t have actually a dedicated treatment,” said Fudim, alluding to the “disappointing story” of anti-inflammatory drug development that has left his enthusiasm “a little bit stifled.”

In September, Novo Nordisk announced that it had two trials of the interleukin (IL)-6 inhibitor ziltivekimab stopped early for futility. The two placebo-controlled trials, HERMES and ATHENA, had been designed to assess a range of hard and soft endpoints in HF patients with high hsCRP. Prior to the premature stop of these studies, ziltivekimab already showed it was unable to reduce major adverse cardiovascular events in the ZEUS trial of people with ASCVD, CKD, and inflammation.

“A bit of a tricky field to navigate at the moment,” commented session discussant Amanda Vest, MBBS, MPH, of Cleveland Clinic, who recalled the long history of neutral, if not outright negative studies that had tried to establish HF drugs that target specific inflammatory pathways.

“How do you put it together? This discrepancy between the demonstration of high inflammatory burden, what we know from other cohorts about its mortality implications, and yet these disappointing interventional trials over the recent years?” Vest posed.

Fudim’s answer was to go forward with a broader approach that eradicates multiple inflammatory pathways at once.

He cited GLP-1 drugs as an example. “GLPs reduce inflammation, but they do it differently, right? … It’s going to be a whole array of inflammatory environments, not just IL-6 … I would probably not put my money right on IL-6 again. I think that door has closed in this moment.”

“If you have an agent that can target multiple pathways, you might be OK. But at the same time, be careful how much you suppress or interfere with the immune system. It was given to us for a reason,” he cautioned.

Fudim’s report was a cross-sectional analysis of the POSEIDON study that prospectively enrolled 18,904 adults with ASCVD and/or HF undergoing routine care. Individuals were recruited in 18 countries from 2023 to 2025.

The U.S. HF subset was further spit into HFpEF (n=315), HFmrEF (n=94), and HFrEF (n=392) cohorts.

Besides the typical characteristics associated with these populations, Fudim noted that there were few distinctive features that made some people more likely to have high inflammation; of note, there did appear to be higher insulin and diuretic use in those with high hsCRP across HF phenotypes.

Elevated hsCRP ≥2 mg/L was linked to higher IL-6 and NT-proBNP across all HF phenotypes.