Linking To And Excerpting From “Inflammation and Cardiovascular Disease: 2025 ACC Scientific Statement: A Report of the American College of Cardiology”

Today, I review, link to, and excerpt from Inflammation and Cardiovascular Disease: 2025 ACC Scientific Statement: A Report of the American College of Cardiology [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. J Am Coll Cardiol. 2025 Sep 29:S0735-1097(25)07555-2. doi: 10.1016/j.jacc.2025.08.047. Online ahead of print.

All that follows is from the above resource.

Abstract

The crucial role of inflammation in the pathogenesis and clinical outcomes of cardiovascular disease (CVD) has recently gained increased attention. In particular, residual inflammation, measured with high-sensitivity C-reactive protein (hsCRP) remains strongly predictive of recurrent events, even in statin-treated patients. Similarly, elevated hsCRP in apparently healthy individuals identifies a higher-risk group in whom statin therapy significantly reduces the risk of first major CVD events even if LDL-cholesterol is normal. This report provides an updated understanding of the role of chronic, low-grade inflammation in CVD and highlights new seminal research findings, especially in atherosclerosis, myocardial infarction, heart failure, and pericarditis. Consensus recommendations are summarized for screening, evaluation, and CVD risk assessment; inflammatory biomarkers in cardiovascular imaging; inflammation inhibition in behavioral and lifestyle risks; and anti-inflammatory approaches in primary and secondary prevention as well as in heart failure and other CVDs. This report also addresses current challenges and future opportunities. For example, it cautions that not all trials of anti-inflammatory therapy in secondary prevention have been successful and such trial evidence is needed before broad recommendations for other agents can be made. Additionally, in successful trials, the interplay between inflammation and key physiological systems often remains incompletely examined. Another promising area of research is the role that novel special pro-resolving bioactive lipid molecules play in promoting the resolution of inflammation and CVD risk reduction. In aggregate, the evidence linking inflammation with atherosclerotic CVD is no longer exploratory but is compelling and clinically actionable. The time for taking action has now arrived.

Introduction

The American College of Cardiology (ACC) has a long history of developing documents to complement clinical practice guidelines. Among these documents, scientific statements represent a novel approach to inform clinicians about areas where the scientific evidence is new and evolving or where sufficient data are more limited. Recently, the role of inflammation in cardiovascular disease (CVD) has gained significant attention, prompting a reevaluation of traditional paradigms of the pathogenesis and clinical outcomes of CVD. This scientific statement provides clinicians with an updated understanding of the role inflammation plays in CVD. The statement’s scope includes new research findings on the role of inflammation in atherosclerosis, myocardial infarction, heart failure (HF), and pericarditis. It also emphasizes primary and secondary prevention and inflammatory pathways in behavioral and lifestyle risks.

Definitions and Classifications

Adaptive immune cell: A specialized immune cell that provides a specific, long-lasting immune response to pathogens. It recognizes unique antigens and can form immune memory, enabling faster and stronger response upon re-exposure.

Augmented immunoinflammatory response: A heightened immune and inflammatory reaction that goes beyond what is necessary to protect the body, often leading to tissue damage, chronic inflammation, or exacerbation of disease. These responses have been linked with increased mortality and morbidity in chronic HF.

Cardioimmunology: An emerging interdisciplinary field that studies the interactions between the immune system and the cardiovascular system, with a focus on how immune cells, molecules, and inflammatory processes influence cardiovascular function in health and disease.

Clonal hematopoiesis of indeterminate potential: A condition characterized by the presence of somatic mutations in blood-forming (hematopoietic) stem cells, leading to the expansion of genetically identical blood cell clones, without evidence of blood cancer or other hematological disease.

Efferocytosis: A specialized form of phagocytosis where apoptotic cells are cleared by immune cells—primarily macrophages and dendritic cells—without triggering inflammation, thus maintaining tissue homeostasis and promoting resolution of inflammation.

Immune checkpoint inhibitor: A class of cancer immunotherapy drug that blocks inhibitory pathways (“checkpoints”) used by tumors to evade immune detection, thereby releasing the brakes on T cells and enhancing its ability to attack cancer cells.

Immune dysregulation: An abnormally functioning immune system—one that is either overactive, underactive, or inappropriately responding to stimuli.

Immunomodulatory strategy: A therapeutic approach that aims to alter or regulate the immune system’s activity—by enhancing, suppressing, or restoring balance—to treat diseases or promote health.

Innate immune cell: The first line of defense in the immune system. It responds rapidly and nonspecifically to invading pathogens or tissue injury, without prior exposure or memory formation.

Janus kinase inhibitor: A targeted small-molecule drug that blocks the activity of a family of intracellular tyrosine kinases (Janus kinases) involved in cytokine signaling. By inhibiting Janus kinases, this drug reduces the activity of proinflammatory and immune-related pathways.

Parainflammation: A state of low-grade, chronic, subclinical inflammation that occurs when tissues are under mild or persistent stress—not enough to trigger full immune activation, but enough to disrupt normal cellular function. Tissue macrophages are important drivers of this response.

Plasminogen activator inhibitor-1: A serine protease inhibitor that functions as the principal inhibitor of tissue-type plasminogen activator and urokinase-type plasminogen activator, the enzymes responsible for converting plasminogen to plasmin, the key enzyme in fibrinolysis.

Perivascular fat attenuation index: A quantitative imaging marker derived from computed tomography scans that measures the density (attenuation) of fat surrounding blood vessels, especially coronary arteries.

Perivascular fat phenotyping: The process of analyzing the characteristics of the fat tissue surrounding blood vessels to understand its biological behavior and impact on cardiovascular health and disease.

Residual inflammatory risk: Persistent, elevated risk of cardiovascular events that manifest as chronic, low-grade inflammation in some individuals despite optimal management of traditional risk factors. This risk is most commonly measured with high-sensitivity C-reactive protein (hsCRP).

Specialized pro-resolving lipid mediator (SPM): A bioactive lipid molecule derived from polyunsaturated fatty acids—mainly omega-3 fatty acids—that actively promote the resolution of inflammation without causing immunosuppression.

Vulnerable plaque: A type of atherosclerotic plaque that has a high risk of rupturing and triggering a thrombus formation that may lead to an acute cardiovascular event, such a myocardial infarction or stroke.

Abbreviations

Abbreviation	Meaning/Phrase
ASCVD	atherosclerotic cardiovascular disease
CHD	coronary heart disease
CHIP	clonal hematopoiesis of indeterminate potential
CVD	cardiovascular disease
DHA	docosahexaenoic acid
EPA	eicosapentaenoic acid
HF	heart failure
HFpEF	heart failure with preserved ejection fraction
hsCRP	high-sensitivity C-reactive protein
IL	interleukin
LDL	low-density lipoprotein
LV	left ventricular
SMuRF	standard modifiable risk factor
SPM	specialized pro-resolving lipid mediator

Background

In March 2002, the Centers for Disease Control and Prevention and the American Heart Association convened a workshop to assess the state of the science on inflammation and provide guidance on the use of inflammatory markers for predicting CVD risk in clinical and public health practice.¹ The resulting scientific statement identified hsCRP as the analyte of choice in specific clinical settings, such as in persons at intermediate CVD risk, where hsCRP might guide further evaluation and therapy; however, the 2002 statement discouraged inflammatory marker use in widespread population screening due to insufficient evidence. The statement further called for rigorous randomized clinical trials to clarify the utility of inflammatory markers in CVD treatment planning.

Since that workshop, substantial progress has been made in the basic, clinical, and population science research in inflammation and CVD. It is now well established that chronic, silent, low-grade inflammation, together with key mediators like cytokines, chemokines, and acute-phase reactants, plays a pivotal role in atherosclerotic plaque formation, progression, rupture, and thrombogenesis that lead to acute coronary syndrome. Additionally, inflammatory pathways, driven by immunoregulatory influences, contribute to endothelial dysfunction, leukocyte infiltration of the subendothelial space, foam cell formation, and apoptosis that further contribute to atherogenesis. These advances have paved the way for several novel therapeutic avenues focused on modulating inflammation to reduce CVD burden and risk. In the following sections of this scientific statement, insights from seminal publications on these topics are discussed and consensus recommendations for clinical practice are summarized in Table 1.

Evaluation and Risk Assessment Biomarkers ▪ Because clinicians will not treat what they do not measure, universal screening of hsCRP in both primary and secondary prevention patients, in combination with cholesterol, represents a major clinical opportunity and is therefore recommended. ▪ Other inflammatory biomarkers such as serum amyloid A, IL-6, fibrinogen, white blood cell count, neutrophil-to-lymphocyte ratio, and EPA/AA ratio also predict cardiovascular risk; however, routine evaluation of these adds little to hsCRP and only hsCRP is recognized by regulatory agencies and has consistently been used in major cardiovascular outcome trials.

Imaging biomarkers ▪ Imaging biomarkers to detect vascular inflammation are promising in research but should not be used in routine clinical settings.

hsCRP screening and inflammation inhibition in primary prevention ▪ A single measurement of hsCRP (>3 mg/L) can be used in routine clinical practice to identify individuals at increased inflammatory risk if the patient is not acutely ill. ▪ In individuals with increased inflammatory burden, an early initiation of lifestyle interventions is recommended to reduce inflammatory risk. ▪ In primary prevention, the finding of a persistently elevated hsCRP level should lead to consideration of initiation or intensification statin therapy, irrespective of LDL cholesterol.

hsCRP screening and anti-inflammatory approaches in secondary prevention ▪ Among individuals with known cardiovascular disease both treated and not treated with statins, hsCRP is at least as powerful a predictor of recurrent vascular events as that of LDL cholesterol, demonstrating the importance of “residual inflammatory risk” in contemporary practice. ▪ Among individuals taking statin therapy, consideration should be given to increase dosage into the higher intensity range if hsCRP levels remain >2 mg/L, irrespective of LDL cholesterol. ▪ Low-dose colchicine reduces cardiovascular events among individuals with chronic stable atherosclerosis and is the first FDA approved anti-inflammatory agent for this purpose. ▪ Low-dose colchicine is intended to be used as an adjunct to lipid lowering; however, colchicine has not proven effective when initiated at the time of acute ischemia and should be avoided among individuals with significant liver or renal disease. ▪ Several novel anti-inflammatory agents, including IL-6 inhibitors, are now being evaluated in ongoing randomized trials in the settings of chronic kidney disease, dialysis, HFpEF, and acute coronary syndrome.

Inflammatory pathways in behavioral and lifestyle risks ▪ Focus on anti-inflammatory patterns like the Mediterranean or DASH diet. ○ Emphasize consumption of fruits, vegetables, whole grains, legumes, nuts, and olive oil. ○ Increase dietary intake of omega-3 fatty acids; 2-3 fish meals/wk are recommended—preferably fatty fish high in EPA+DHA. ○ Minimize red and processed meats, refined carbohydrates, and sugary beverages. ▪ Engage in ≥150 min/wk of moderate exercise or 75 min/wk of intense exercise. ▪ Quit smoking to reduce chronic low-grade inflammation. ▪ Maintain a healthy weight to attenuate systemic inflammation.

Inflammation in HF and other CVD ▪ Inflammatory and immune markers such as  hsCRP and IL-6 may be used as risk predictors in chronic HF. ▪ EPA+DHA may be considered as part of the management of patients with NYHA functional class II-IV HF, irrespective of etiology or LVEF. ▪ Statins may be considered as a part of management for patients with ischemic HF and >60 years of age.

Anti-inflammatory therapy for recurrent pericarditis ▪ IL-1 blockade may be considered among select patients with multiple recurrent episodes of colchicine- and steroid-resistant pericarditis, with hsCRP levels >10 mg/L, in the absence of tuberculosis. ▪ Novel anti-inflammatory therapies for recurrent pericarditis represent an important therapeutic advance for high-risk patients.

AA = arachidonic acid; CVD = cardiovascular disease; DASH = Dietary Approaches to Stop Hypertension; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; FDA = U.S. Food and Drug Administration; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; hsCRP = high-sensitivity C-reactive protein; IL-1 = interleukin-1; IL-6 = interleukin-6; LDL = low-density lipoprotein; LVEF = left ventricular ejection fraction.

Based on these biological advances on consistent epidemiological replications in both primary and secondary prevention, and a series of robust, high-quality randomized clinical trials, near-universal screening for hsCRP along with targeted chronic low-grade inflammation inhibition is today warranted in the prevention and clinical management of CVD.^2,3 There is now compelling evidence of adverse CVD outcomes in the setting of elevated markers of inflammation and that targeting inflammation significantly reduces recurrent CVD events. This is true in the setting of cardiovascular health promotion in apparently healthy individuals, in primary prevention among persons with CVD risk factors, and in secondary prevention strategies in individuals with established CVD. Inflammation also plays a pivotal role in the lifestyle choices and behavioral risks, as well as the social and environmental determinants that predispose to CVD.

Although most of the compelling clinical trial evidence for the role of inflammation in CVD originates from coronary atherosclerosis and myocardial infarction, there is emerging evidence in several other CVDs that provides hope for improved therapeutic targeting for CVD prevention and treatment. For example, evidence from preclinical and clinical studies in both HF and recurrent pericarditis have increased our understanding of the role of inflammation and immune dysregulation in specific treatment strategies.^4-7 Emerging evidence also exists for other CVD and cardiovascular imaging. Additional supporting clinical trials are summarized in Table 2.^2,3 Remaining gaps in knowledge that present opportunities for research in basic, clinical, and population science are identified, and a call to action is highlighted for clinical practice and research.

Table 2 Major Clinical Trials

Evaluation and risk assessment

Biomarkers

In clinical practice, silent vascular inflammation is commonly evaluated through blood measurement of hsCRP, which adds prognostic information about cardiovascular risk comparable with that of blood pressure and cholesterol. In general, levels of hsCRP <1, 1 to 3, and >3 mg/L connote lower, average, and higher relative cardiovascular risk, respectively, when interpreted in the context of other traditional factors (Figure 1).^23,24 hsCRP levels >10 mg/L may reflect a transient infectious process or other acute-phase response and thus should be repeated in 2 to 3 weeks with the lower value, not the average, used for risk prediction;^23,25 however, persistently high hsCRP values may be seen and do not necessarily represent false-positive findings, because many individuals with chronic autoinflammatory disorders also suffer from premature atherosclerosis.²⁶

When measured in stable outpatients, the long-term stability and variability of hsCRP is comparable with that of low-density lipoprotein (LDL) cholesterol and blood pressure. Moreover, the long-term information content implicit in hsCRP appears to be at least as large as that associated with LDL cholesterol. For example, in a recent prospective study inclusive of 27,939 initially healthy U.S. women, a single random assessment of hsCRP provided a greater spread of risk for future cardiovascular events during the next 30 years when directly compared with either LDL cholesterol or lipoprotein(a) (Figure 2).²⁷ Similar contemporary data demonstrating the independent and additive clinical utility of LDL, hsCRP, and lipoprotein(a) have recently been presented from the EPIC (European Prospective Investigation into Cancer)-Norfolk study inclusive of 17,087 men and women followed for 20 years.²⁸

Alternative inflammatory biomarkers, including fibrinogen, lipoprotein-associated phospholipase-A2, myeloperoxidase, serum amyloid A, total white blood cell count, neutrophil-to-lymphocyte ratio, eicosapentaenoic acid (EPA)/arachidonic acid ratio, and interleukin-6 (IL-6), have also found predictive value but generally have not proven superior to hsCRP and often are not widely available in standardized commercial formats. As will be described in the following text, several novel approaches to inflammation imaging hold promise for the detection of silent vascular inflammation. Further, imaging for coronary artery calcium is an efficient method to detect underlying atherosclerotic disease and the strongest risk predictor. Yet, although coronary artery calcium can tell clinicians who to treat, it cannot tell clinicians what to use for treatment. As such, universal screening for hsCRP, along with LDL cholesterol and lipoprotein(a), among individuals suspected to have atherosclerotic risk is becoming a common approach to vascular disease evaluation and risk assessment.²⁹ hsCRP screening should be done when patients are stable and not during an acute infection or during other acute clinical events.

Consensus recommendations: evaluation and risk assessment, biomarkers

▪ Because clinicians will not treat what they do not measure, universal screening of hsCRP in both primary and secondary CVD prevention represents a major clinical opportunity and is therefore recommended.

▪ Whereas several other inflammatory biomarkers, such as IL-6, fibrinogen, and neutrophil-to-lymphocyte ratio, also predict risk, routine evaluation of these adds little to hsCRP.

Imaging biomarkers

Noninvasive imaging techniques for assessing local vascular inflammation might represent a valuable approach to enhance risk prediction and even guide the management of patients with residual inflammatory risk in the future. To date, there are several imaging modalities, including computed tomography, cardiac magnetic resonance, ultrasound, and positron emission tomography imaging with fluorodeoxyglucose (Figure 3),³⁰ that might help to identify inflamed atherosclerotic plaques and perivascular inflammation. Both conditions are known to drive the progression of atherosclerosis and plaque rupture.³⁰ These modalities, however, have unique advantages and limitations^29-31 and currently are mainly used in research. A recently introduced and promising noninvasive computed tomography–derived imaging biomarker may directly identify both inflamed coronary arteries without atherosclerosis and vulnerable atherosclerotic plaques prone to rupture by using perivascular fat phenotyping.³² Named perivascular “fat attenuation index,” this method has been already shown to predict future coronary events independently of the calcium score and traditional cardiovascular risk factors.³³ Although imaging biomarkers might represent a promising research tool for the integration of vascular inflammation into personalized cardiovascular risk stratification, there are several issues to be addressed, such as a better understanding of the interplay with circulating inflammatory biomarkers, effects of anti-inflammatory treatment on plaque progression, and local arterial inflammation. Although preliminary, results of the small EKSTROM (Effect of Colchicine on Progression of Known Coronary Atherosclerosis in Patients With Stable Coronary Artery Disease Compared to Placebo) trial³⁴ showed that low-dose colchicine therapy modestly reduced total plaque volume in stable patients with coronary heart disease (CHD) compared with those taking placebo after 1 year are of interest and consistent with trial data demonstrating efficacy of low-dose colchicine in patients with established atherosclerotic cardiovascular disease (ASCVD).

Consensus recommendation: imaging biomarkers

▪ Imaging biomarkers to detect vascular inflammation are promising in research but should not be used in routine clinical settings.

hsCRP screening and inflammation inhibition in primary prevention

The seminal Physician’s Health Study³⁵ in 1997 initiated a series of epidemiological studies in primary prevention, providing unequivocal evidence that elevated hsCRP concentration might serve as a robust predictor of future ASCVD events among apparently healthy individuals, independent of conventional risk factors. A comprehensive meta-analysis of 54 studies that included 160,309 individuals without a history of ASCVD has further supported these findings, showing that a 1-SD increase in hsCRP concentration was associated with a 37% increased risk of CHD and a 55% increased risk of cardiovascular death.³⁶ Interestingly, the magnitude of association between elevated hsCRP (per 1-SD increase) and incident CVD was largely comparable with that found for systolic blood pressure³⁶ and appeared to be stronger than the associations observed for conventional lipids (total, non–high-density lipoprotein, or LDL cholesterol)^26,36 or lipoprotein(a).^26,37 Elevated hsCRP also predicts incident CHD among individuals without standard modifiable risk factors (SMuRFs) at baseline, thereby extending its utility beyond traditional risk categories.^38,39

In general, the prevalence of a moderate to higher risk hsCRP levels ≥2 mg/L in adults in the primary prevention setting may vary from approximately 30% to 35% in Europe^37,40 to 50% in the United States.^41,42 This could become an important public health issue in the near future, especially due to the obesity epidemic, because body mass index (in combination with smoking) is currently considered an important determinant of longitudinal hsCRP changes.⁴³ More importantly, already 15% of U.S. adolescents aged 12 to 19 years have reported increased hsCRP concentrations.⁴⁴ Considering that treatment of lifestyle risk factors such as increased body weight, smoking, physical inactivity, and unhealthy diet have a strong anti-inflammatory effect,^45,46 hsCRP is an easily measurable clinical biomarker that should be broadly used as a tool to identify and monitor those with an inflammatory burden, especially in the case of primordial prevention (Figure 4).⁴⁶