Inflammation and the Heart: Why the Field Is Asking a Different Question

In September 2025, the American College of Cardiology published a Scientific Statement on Inflammation and Cardiovascular Disease . It was only the second such statement in the ACC’s history. Its conclusion was unambiguous: the evidence linking inflammation with cardiovascular disease “is no longer exploratory, but is compelling and clinically actionable.”

The statement, published in JACC and co-authored by a writing committee that included Dr. Paul M. Ridker of Harvard Medical School (one of the world’s leading researchers in cardiovascular inflammation and a member of Cardiol Therapeutics’s Scientific Advisory Board) confirmed the central role of chronic, low-grade inflammation in heart failure, atherosclerosis and pericarditis. It also identified HFpEF as one of the specific conditions where novel anti-inflammatory therapies are now being evaluated in active clinical trials.

For much of the history of cardiovascular medicine, inflammation was understood primarily as a response to cardiac injury. The heart was damaged (by a blocked artery, a viral infection or sustained mechanical stress) and inflammation was the body’s attempt to respond. Treatment followed accordingly: address the structural problem, manage the downstream consequences and let the inflammatory response resolve on its own.

A growing body of research is revising that picture. In many forms of cardiac disease, chronic low-grade inflammation appears to be an active driver of disease progression rather than a consequence of it. The ACC Scientific Statement places this shift at the center of a new clinical consensus, one that has direct implications for how heart failure (and HFpEF in particular) needs to be approached therapeutically.

The Inflammatory Biology of HFpEF

In HFpEF specifically, the evidence supporting an inflammatory mechanism has been building steadily. A 2025 review in Current Heart Failure Reports concluded that chronic low-grade inflammation underlies the heterogeneous pathophysiology of HFpEF, with comorbidities including hypertension, obesity, diabetes and chronic kidney disease driving distinct immune profiles through dysregulated cytokine signalling. Circulating inflammatory markers (including interleukin-6, interleukin-1β, TNF-α and C-reactive protein) reflect this comorbidity-driven immune activation and are associated with adverse outcomes.

These cardiometabolic conditions do not merely increase the mechanical load on the heart. They create a chronic pro-inflammatory environment that contributes to myocardial fibrosis, impaired relaxation and the progressive stiffening of cardiac tissue that is the hallmark of HFpEF. Patients with higher inflammatory burden tend to have worse outcomes. Inflammation is now considered one of the central mechanistic threads connecting the overlapping comorbidities these patients carry to the cardiac dysfunction they experience.

The therapeutic implication follows directly: a treatment that meaningfully reduces systemic inflammation in HFpEF patients may attenuate the processes driving disease progression rather than simply managing its consequences. Previous approaches have worked on the downstream effects. An anti-inflammatory approach works on a cause.

The Mechanism: NLRP3 and the Inflammasome Pathway

Much of the relevant inflammatory activity in cardiac disease involves activation of the NLRP3 inflammasome, a multiprotein complex that drives the production of pro-inflammatory cytokines including interleukin-1 and interleukin-18 (IL-1 then induces/ amplifies IL-6 which increases levels of the pro-inflammatory marker CRP). These cytokines promote fibrosis, impair myocardial function and contribute to the adverse remodeling seen across a range of inflammatory cardiac conditions. Selective inhibition of this pathway (reducing inflammatory signalling without broadly suppressing immune function) represents a potentially important category of intervention in conditions where chronic inflammation plays a driving role.

Preclinical studies have demonstrated that NLRP3 inhibition reduces cardiac inflammation, fibrosis and diastolic dysfunction in animal models of HFpEF. The ACC’s 2025 Scientific Statement highlights that large-scale clinical trials testing novel anti-inflammatory agents are now underway specifically in HFpEF, reflecting the field’s growing conviction that the mechanism is a legitimate therapeutic target.

Cannabidiol, the active compound in Cardiol’s lead therapeutic CardiolRx , has demonstrated inhibitory effects on NLRP3 inflammasome activation in preclinical models. Cardiol’s ARCHER trial was designed to test whether that mechanism translates meaningfully in human cardiac tissue.

What ARCHER Demonstrated

ARCHER was a Phase II, randomized, double-blind, placebo-controlled study in 109 patients with acute myocarditis, conducted across 34 sites in the United States, France, Brazil and Israel. Myocarditis is an acute inflammatory disease of the heart muscle for which no approved disease-specific therapies exist. The trial was not designed as a registration study. It was designed to determine whether CardiolRx could produce measurable reductions in inflammation-driven structural damage in human cardiac tissue, using cardiac MRI as the assessment tool.

The results, presented at the European Society of Cardiology’s Working Group on Myocardial and Pericardial Disease in November 2025 and subsequently published in ESC Heart Failure , showed a statistically significant reduction in left ventricular mass (a marker closely linked to myocardial edema and inflammatory burden) alongside improvements across multiple other cardiac MRI measures of structural recovery. The safety and tolerability profile was strong throughout. Dr. Leslie Cooper of the Mayo Clinic, co-chair of the ARCHER steering committee, described the findings as demonstrating that CardiolRx can attenuate myocardial inflammation and edema.

Myocarditis and HFpEF are distinct conditions, but they share a central feature: inflammation as a driver of cardiac structural change.

The ARCHER findings do not establish efficacy in HFpEF. They establish that CardiolRx reduces inflammation-driven structural damage in human cardiac tissue – evidence that is relevant to any condition in which that biology plays a role. Cardiol is also developing CRD-38, a novel subcutaneous formulation of cannabidiol intended specifically for heart failure, including HFpEF. A subcutaneous formulation is designed to deliver sustained systemic anti-inflammatory activity, which may be particularly important in conditions where the inflammatory burden is chronic rather than acute.

Whether targeting upstream inflammatory processes can meaningfully alter the course of HFpEF remains an open scientific question. The ACC’s 2025 Scientific Statement and the body of research it consolidates make clear that this is the question the field is now organized around answering. ARCHER provides one piece of clinical evidence that the approach has biological merit in human cardiac tissue. Building a complete answer requires the kind of staged program that takes years and demands rigorous results at each step.

Related reading:

Heart Failure Is Getting Worse. Understanding Why Is the First Step.

Why the Most Common Form of Heart Failure Is Also the Hardest to Treat

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