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ACC SCIENTIFIC STATEMENT
Inflammation and Cardiovascular 
Disease: 2025 ACC Scientific Statement
A Report of the American College of Cardiology
Writing 
Committee 
Members
George A. Mensah, MD, FACC, Chair
Natalie Arnold, MD
Sumanth D. Prabhu, MD, FACC
Paul M Ridker, MD, MPH, FACC
Francine K. Welty, MD, PHD, FACC
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 athero-
sclerosis, 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 pri-
mary and secondary prevention and inflammatory pathways 
in behavioral and lifestyle risks.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2025.08.047
This document was approved by the American College of Cardiology Clinical Policy Approval Committee in September 2025.
The American College of Cardiology requests that this document be cited as follows: Mensah GA, Arnold N, Prabhu SD, Ridker PM, Welty FK. 
Inflammation and cardiovascular disease: 2025 ACC scientific statement: a report of the American College of Cardiology. J Am Coll Cardiol. 2025;XX: 
XXX-XXX.
Copies: This document is available on the website of the American College of Cardiology (www.acc.org). For copies of this document, please contact 
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© 2 0 2 5 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N 
P U B L I S H E D B Y E L S E V I E R 
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To accomplish this work, the ACC constituted a writing 
committee that convened in March 2025 via a confidential 
conference call attended only by writing committee 
members and ACC staff. A review of seminal publications 
and outstanding questions was facilitated. Writing as-
signments were configured according to each committee 
member’s area of expertise. E-mail correspondence was 
used to provide critical review of contributed content. 
Clinical recommendations were made where sufficient 
rigorous evidence existed. Differences were resolved by 
consensus among the writing committee. The commit-
tee’s work was supported only by the ACC without any 
commercial input. Writing committee members were all 
unpaid volunteers. In accordance with the ACC’s policy on 
relationships with industry and other entities, relevant 
disclosures for the writing committee and comprehensive 
disclosures for external peer reviewers can be found in 
Appendixes 1 and 2.
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 height-
ened 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—pri-
marily macrophages and dendritic cells—without 
triggering inflammation, thus maintaining tissue ho-
meostasis 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, underac-
tive, 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,well as large-scale clinical 
trials testing the therapeutic modulation of potential 
immune targets already identified.85 As with other types 
of CVD, knowledge gaps remain about the timing of 
immunomodulatory interventions in HF and the specific 
disease endotypes that might derive greater benefit from 
such therapies. This will need more precise definition in 
future work. Clinically relevant biochemical and imaging 
biomarkers that can be used to track inflammatory and 
immune system activity will also need to be better char-
acterized for feasible implementation of anti- 
inflammatory therapeutics.
The good news is that several recent reviews have 
provided a comprehensive view of novel therapeutics 
and clinical trials in progress that directly explore the role 
of inflammatory markers and anti-inflammatory agents in 
CVD.125-127 For example, Potere et al125 have summarized 
the main characteristics, major challenges, and future 
perspectives of novel therapeutics and upcoming ran-
domized controlled trials in this arena with emphasis on 
the increasing role of dysregulated immunity. These 
include $14 trials in ASCVD and thrombosis, 9 in pe-
ripheral vascular disease, 12 in HF, 6 in inflammatory 
cardiomyopathy, and 4 in cardiac arrhythmia.125 Findings 
from these clinical trials will go a long way to improve our 
understanding of the role of inflammation in CVD and 
provide novel opportunities for the prevention, detec-
tion, evaluation, and treatment of CVD. Other avenues 
for further research are identified in the following 
recommendations.
Recommendations for research
Evaluation and risk assessment
n A deeper insight into interaction between circulatory 
and imaging inflammatory biomarkers is needed.
n Would the combination of both circulating and imaging 
inflammatory biomarkers improve CVD prediction in 
primary and secondary prevention?
n There is a need for additional large randomized clinical 
trials of novel agents to reduce coronary inflammation.
Primary prevention
n Large, randomized, placebo-controlled trials are 
needed to evaluate the potential benefit and risks of 
selective anti-inflammatory therapy in primary ASCVD 
prevention.
n Which patients would benefit most from anti- 
inflammatory treatment in the primary prevention; 
for example, those with residual inflammatory risk 
(suboptimal control of traditional risk factors)? 
Conversely, are there patient groups such as those with 
increased risks for infection who should avoid anti- 
inflammatory strategies?
n When would be the optimal timing to initiate anti- 
inflammatory treatments?
n What is the role of anti-inflammatory treatment in 
primary prevention? Is early intervention preferable? 
What is the recommended overall treatment duration?
n Would length of exposure to elevated hs-CRP affect 
future CVD risk?
Inflammation in HF and other CVD
n Identify disease endotypes in human HF that may 
derive benefit from immunomodulation.
n Define biochemical and imaging markers of cardiac 
tissue inflammation in humans that are of high speci-
ficity and serially measurable.
n Identify the specific immune cell populations (and the 
mechanisms of activation) that are obligatory for the 
progression of adverse cardiac remodeling at different 
stages of HF.
n Define the mechanistic links (and interorgan commu-
nication) between the hematopoietic and lymphoid 
systems and the failing heart.
n Delineate the necessary components of the immunofi-
brotic axis in HF.
n Define the specific arrhythmogenic mechanisms linked 
with different innate and adaptive immune cell pop-
ulations in the heart.
Call to action: inflammation and CVD
The evidence linking chronic, low-grade inflammation to 
the initiation and progression of ASCVD is robust, and 
several seminal randomized controlled clinical trials 
demonstrate that targeting inflammation reduces car-
diovascular risk independent of lipid lowering. We have 
thus entered an era when the evidence linking inflam-
mation with ASCVD is no longer exploratory but is 
compelling and clinically actionable. Yet, clinicians will 
not treat what they do not measure. Therefore, the time 
has come for clinical practice guidelines to implement 
broad screening of primary and secondary prevention 
patients for hsCRP, in combination with LDL cholesterol, 
and to embrace anti-inflammatory interventions in pa-
tients with established ASCVD and evidence of residual 
inflammatory risk, regardless of LDL cholesterol level. 
J A C C V O L . ■ , N O . ■ , 2 0 2 5 Mensah et al 
■ , 2 0 2 5 : ■ – ■ Inflammation and Cardiovascular Disease
19
The time is also ripe for the development of strategies to 
promote increased physician awareness of the crucial 
role of inflammation in CVD and accelerate the adoption 
of evidence-based, guideline-directed anti-inflammatory 
therapy through dissemination and implementation 
research. Because weight reduction, exercise, and 
smoking cessation can reduce hsCRP, endorsement of 
inflammation biology will further promote primordial 
and primary prevention. Inflammation is also strongly 
implicated in diverse cardiovascular conditions, 
including pericarditis, HF, and acute coronary ischemia; 
there is strong need for further research into the inflam-
matory and immune mechanisms underlying these 
conditions so that new anti-inflammatory or 
immunomodulatory treatment strategies can be identi-
fied and developed for translation to humans. The time 
for action has arrived.
PRESIDENT AND STAFF
Christopher M. Kramer, MD, FACC
Cathleen C. Gates, Chief Executive Officer
Richard J. Kovacs, MD, MACC, Chief Medical Officer
Justine Varieur Turco, MA, Divisional Vice President, 
Scientific Publications and Guidelines
Mindy Saraco, MHA, Director, Clinical Policy and 
Guidelines
Rachel Barish, NP, AACC, Scientific Documents Associate
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KEY WORDS ACC Scientific Statement, 
inflammation, high-sensitivity C-reactive 
protein, prevention, cardiovascular disease, 
omega-3 fatty acids
Mensah et al J A C C V O L . ■ , N O . ■ , 2 0 2 5 
Inflammation and Cardiovascular Disease ■ , 2 0 2 5 : ■ – ■
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Committee 
Member Employment Consultant
Speakers 
Bureau
Ownership/ 
Partnership/ 
Principal Personal Research
Institutional, 
Organizational, 
or Other 
Financial 
Benefit
Expert 
Witness
George A. 
Mensah, 
Chair
National Heart, Lung, and Blood 
Institute, National Institutes of Health— 
Director of the Center for Translation 
Research and Implementation Science
None None None None None None
Natalie 
Arnold
Department of Cardiology, University 
Heart and Vascular Center Hamburg, 
University Medical Center Hamburg- 
Eppendorf
n Apontis 
Pharma
n Arrowhead
n Amgen
n Novartis 
Corporation
n Sanofi- 
Aventis
None n Novartis 
Corporation*
None None
Sumanth D. 
Prabhu
Washington University School of 
Medicine—Tobias and Hortense Lewin 
Distinguished Professor of 
Cardiovascular Diseases 
Chief, Division of Cardiology
None None n BioThera†‡ None None None
Paul M 
Ridker
Harvard Medical School—Eugene 
Braunwald Professor of Medicine; 
Center for Cardiovascular Disease 
Prevention—Director; Brigham and 
Women’s Hospital—Physician
n Agepha*
n AstraZeneca
n Cardiol 
Therapeutics*
n Caristo
n Lilly*
n Merck
n New 
Amsterdam*
n Nodthera*
n Novartis 
Corporation*
n Novo Nordisk 
Inc.*
n Pfizer Inc*
n Tourmaline 
Bio*
None None n Amarin*
n Kowa 
Pharmaceuticals*
n NHLBI*
n NCI
n Novo Nordisk
n Novo Nordisk 
Foundation
n Novartis*
n Angiowave, 
Inc†
n Uppton, Ltd†
None
Francine K. 
Welty
University of Massachusetts; Division of 
Nutrition, Harvard Medical School
None None None None None None
This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were 
reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily 
reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of $5% of the voting 
stock or share of the business entity or ownership of $$5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of 
the person’s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are 
modest unless otherwise noted. According to the ACC, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual 
property or asset, topic, or issue addressed in the document; b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the 
document or makes a competing drug or device addressed in the document; or c) the person or a member of the person’s household has a reasonable potential for financial, 
professional, or other personal gain or loss as a result of the issues/content addressed in the document. For the purposes of full transparency, the authors’ comprehensive disclosure 
information is available in a Supplemental Appendix.
*Significant relationship.
†No financial benefit.
‡Spousal relationship. The ACC requires authors to report relationships with industry and other entities for themselves as well as members of their household. This relationship of a 
household member arose after the document was sent for peer review and did not influence document development.
ACC = American College of Cardiology; DSMB = data and safety monitoring board; NHLBI = National Heart, Lung, and Blood Institute; NIH = National Institutes of Health. 
APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (RELEVANT)— 
INFLAMMATION AND CARDIOVASCULAR DISEASE: 2025 ACC SCIENTIFIC STATEMENT
J A C C V O L . ■ , N O . ■ , 2 0 2 5 Mensah et al 
■ , 2 0 2 5 : ■ – ■ Inflammation and Cardiovascular Disease
23
https://doi.org/10.1016/j.jacc.2025.08.047
Reviewer Employment Consultant
Speakers 
Bureau
Ownership/ 
Partnership/ 
Principal
Personal 
Research
Institutional, 
Organizational, or 
Other Financial 
Benefit
Expert 
Witness
Martha Gulati Smidt Heart Institute, Cedars-Sinai 
Medical Center—Director of Prevention 
and Associate Director of the Barbra 
Streisand Women’s Heart Center
n Boehringer 
Ingelheim
n Eli Lilly and Co.
n Medtronic*
n Merck & Co.
n New Amsterdam 
Pharma
n Zoll Medical
None None None n American Soci-
ety for Preven-
tive Cardiology 
(Officer/ 
Director)†
None
Lara C. Kovell University of Massachusetts, Associate 
Professor of Medicine
None None None None None None
Robert Rosenson Mount Sinai Health System—Director, 
Metabolism and Lipids; Professor of 
Medicine
n Avilar 
Therapeutics
n GlaxoSmithKline
n Intercept 
Pharmaceuticals*
n Life Extensionn Lipigon 
Pharmaceuticals
n New Amsterdam 
Pharma
n Novartis 
Corporation
n Rona 
Therapeutics
None n MediMergent 
(stock)*
None n Amgen (ARO)
n Wolters 
Kluwer*
None
*Significant relationship.
†No financial benefit.
ACC = American College of Cardiology; ARO = academic research organization. 
APPENDIX 2. REVIEWER RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (COMPREHENSIVE)— 
INFLAMMATION AND CARDIOVASCULAR DISEASE: 2025 ACC SCIENTIFIC STATEMENT
Mensah et al J A C C V O L . ■ , N O . ■ , 2 0 2 5 
Inflammation and Cardiovascular Disease ■ , 2 0 2 5 : ■ – ■
24
	Inflammation and Cardiovascular Disease: 2025 ACC Scientific Statement
	Introduction
	Definitions and Classifications
	Background
	Evaluation and risk assessment
	Biomarkers
	Imaging biomarkers
	hsCRP screening and inflammation inhibition in primary prevention
	hsCRP screening and anti-inflammatory approaches in secondary prevention
	Inflammatory pathways in behavioral and lifestyle risks
	Inflammation in HF and other CVD
	Anti-inflammatory therapy for recurrent pericarditis
	Evidence gaps and future directions
	Call to action: inflammation and CVD
	President and Staff
	References
	Appendix 1. Author Relationships With Industry and Other Entities (Relevant)—Inflammation and Cardiovascular Disease: 2025 ACC Scientif ...
	Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive)—Inflammation and Cardiovascular Disease: 2025 ACC S ...this drug reduces 
the activity of proinflammatory and immune-related 
pathways.
Parainflammation: A state of low-grade, chronic, sub-
clinical inflammation that occurs when tissues are under 
mild or persistent stress—not enough to trigger full im-
mune 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 sur-
rounding 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 cardio-
vascular event, such a myocardial infarction or stroke.
Mensah et al J A C C V O L . ■ , N O . ■ , 2 0 2 5 
Inflammation and Cardiovascular Disease ■ , 2 0 2 5 : ■ – ■
2
Background
In March 2002, the Centers for Disease Control and Pre-
vention and the American Heart Association convened a 
workshop to assess the state of the science on inflam-
mation and provide guidance on the use of inflammatory 
markers for predicting CVD risk in clinical and public 
health practice.1 The resulting scientific statement iden-
tified 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 estab-
lished 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 syn-
drome. 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, in-
sights from seminal publications on these topics are dis-
cussed and consensus recommendations for clinical 
practice are summarized in Table 1.
T A B L E 1 Table of Consensus Recommendations 
Evaluation and Risk Assessment Biomarkers
n 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.
n 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
n 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
n 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.
n In individuals with increased inflammatory burden, an early initiation of 
lifestyle interventions is recommended to reduce inflammatory risk.
n In primary prevention, the finding of a persistently elevated hsCRP level 
should lead to consideration of initiation or intensification statin ther-
apy, irrespective of LDL cholesterol.
hsCRP screening and anti-inflammatory approaches in secondary prevention
n 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.
n 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.
n Low-dose colchicine reduces cardiovascular events among individuals 
with chronic stable atherosclerosis and is the first FDA approved anti- 
inflammatory agent for this purpose.
n 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.
n 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
n 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.
n Engage in $150 min/wk of moderate exercise or 75 min/wk of intense 
exercise.
n Quit smoking to reduce chronic low-grade inflammation.
n Maintain a healthy weight to attenuate systemic inflammation.
Inflammation in HF and other CVD
n Inflammatory and immune markers such as hsCRP and IL-6 may be used 
as risk predictors in chronic HF.
n EPA+DHA may be considered as part of the management of patients 
with NYHA functional class II-IV HF, irrespective of etiology or LVEF.
n 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
n 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.
n 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.
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
J A C C V O L . ■ , N O . ■ , 2 0 2 5 Mensah et al 
■ , 2 0 2 5 : ■ – ■ Inflammation and Cardiovascular Disease
3
T A B L E 2 Major Clinical Trials 
Trial Name Drug
Sample 
Size (n)
Population/NYHA 
Functional Class Follow-Up Primary Endpoint Treatment Outcome
ATTACH8 Infliximab 
(TNF inhibitor)
150 NYHA III-IV HF 7 mo Clinical status (composite score) 
at 14 wks
No improvement or worsening 
(with high doses) of clinical 
condition
ACCLAIM9 Celacade 2,426 NYHA II-IV HF 10.2 mo Composite: all-cause mortality 
and CV hospitalization
No difference in primary endpoint; 
improved outcomes in 
subjects with prior MI and 
NYHA II HF
CANTOS3,10 Canakinumab 
(anti–IL-1)
10,061 Prior MI; hsCRP 
$2 mg/L
3.7 y Nonfatal MI, nonfatal stroke, or 
CV death (main study3) 
HHF; composite of HHF and 
HF-related mortality (HF 
outcomes study10)
Dose-dependent reduction in 
primary endpoint events
CIRT11 Methotrexate 4,786 Previous MI stable 
CAD
2.3 y (median) CV event rates No reduction in CV event rates; 
did not lower IL-1, IL-6, or 
hsCRP
CLEAR- 
SYNERGY12
Colchicine 3,528 Acute MI plus PCI 3 y Death from CV causes, recurrent 
MI, stroke, or unplanned 
ischemia-driven coronary 
revascularization
Colchicine did not reduce primary 
endpoint when started soon 
post-MI
COLCOT13 Colchicine 4,745 Stable post-MI 
patients
22.6 mo CV event reduction Significantly lower risk of ischemic 
CV events than placebo
CORONA14 Rosuvastatin 5,011 NYHA II-IV HF 32.8 mo Composite of CV death, nonfatal 
MI, or nonfatal stroke
No difference in primary endpoint; 
reduction in CV 
hospitalizations
GISSI-HF15 Rosuvastatin 4,574 NYHA II-IV HF 3.9 y All-cause mortality; composite of 
all-cause mortality and CV 
hospitalization
No difference in primary endpoint
GISSI-HF15 Omega-3 PUFA 6,975 NYHA II-IV HF 3.9 y All-cause mortality; composite of 
all-cause mortality and CV 
hospitalization
Modest reduction in all-cause 
mortality (HR: 0.91; 95% CI: 
0.833-0.998), and composite 
endpoint (HR: 0.92; 99% CI: 
0.849-0.999)
JUPITER16 Rosuvastatin 17,802 No CVD (LDL 
cholesterollevels of hsCRP 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, persis-
tently high hsCRP values may be seen and do not neces-
sarily 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 car-
diovascular 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 avail-
able 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 coro-
nary artery calcium is an efficient method to detect un-
derlying 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 evalu-
ation 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
n 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.
n Whereas several other inflammatory biomarkers, such 
as IL-6, fibrinogen, and neutrophil-to-lymphocyte ra-
tio, 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 
J A C C V O L . ■ , N O . ■ , 2 0 2 5 Mensah et al 
■ , 2 0 2 5 : ■ – ■ Inflammation and Cardiovascular Disease
5
management of patients with residual inflammatory risk 
in the future. To date, there are several imaging modal-
ities, including computed tomography, cardiac magnetic 
resonance, ultrasound, and positron emission tomogra-
phy 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 limitations29-31 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 athero-
sclerotic 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 under-
standing 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 estab-
lished atherosclerotic cardiovascular disease (ASCVD).
FIGURE 1 Clinical Interpretation of hsCRP for Cardiovascular Risk Prediction 
The relationship of inflammation to cardiovascular (CV) risk is linear across a wide range of high-sensitivity C-reactive protein (hsCRP) values. Blue bars represent 
crude relative risks; red bars represent relative risks adjusted for traditional Framingham Risk Score factors. Data from Ridker et al.28 Reproduced from Ridker et al.23
Mensah et al J A C C V O L . ■ , N O . ■ , 2 0 2 5 
Inflammation and Cardiovascular Disease ■ , 2 0 2 5 : ■ – ■
6
Consensus recommendation: imaging biomarkers
n 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 comprehen-
sive meta-analysis of 54 studies that included 160,309 
individuals without a history of ASCVD has further sup-
ported 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 
FIGURE 2 Cumulative Incidence of First Major Cardiovascular Events According to Baseline Levels of hsCRP and LDL-C 
30-year HRs and cumulative incidence for first major adverse cardiovascular events among 27,939 initially healthy American women, according to increasing 
quintiles of baseline level of low-density lipoprotein cholesterol (LDL-C) (bottom) and high-sensitivity C-reactive protein (hsCRP) (bottom). As shown, the 
magnitude of risk is greater for inflammation than for cholesterol. Data are adjusted for age, smoking status, diabetes, blood pressure, estimated 
glomerular filtration rate, and body mass index. Adapted with permission from Ridker et al.26
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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 conventionallipids (total, non– 
high-density lipoprotein, or LDL cholesterol)26,36 or li-
poprotein(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 
Europe37,40 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 longi-
tudinal 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 pri-
mordial prevention (Figure 4).46
The initial evidence that inflammation might become a 
valuable therapeutic drug target came from statin trials, 
which showed that statin administration reduces both 
LDL cholesterol and hsCRP, with reductions in both pa-
rameters contributing to beneficial effects on outcomes. 
A post hoc analysis of AFCAPS/TexCAPS (Air Force/Texas 
Coronary Atherosclerosis Prevention Study)47 revealed 
that the reduction in major adverse cardiovascular events 
observed in subjects treated with lovastatin was not 
limited to those with elevated LDL cholesterol levels 
($149.1 mg/dL): similar risk reduction was also seen in 
individuals with normal LDL cholesterol but elevated 
hsCRP (>1.6 mg/L) levels (47% and 42% relative risk 
reduction for 5 years, respectively).47 The subsequent 
JUPITER (Rosuvastatin to Prevent Vascular Events in Men 
and Women With Elevated C-Reactive Protein) study16
was the first randomized placebo-controlled trial to 
investigate the effect of 20 mg of rosuvastatin in in-
dividuals with LDL cholesterol levels 3 mg/L) can be used in 
routine clinical practice to identify primary prevention 
individuals at increased inflammatory risk as long as 
the patient is not acutely ill.
n In individuals with increased inflammatory burden, an 
early initiation of lifestyle interventions is recom-
mended to reduce inflammatory risk.
FIGURE 5 Cumulative Incidence of Cardiovascular Events in the JUPITER Primary Prevention Trial of Patients With Low Levels of LDL Cholesterol But 
Elevated hsCRP 
Panel A shows the cumulative incidence of the primary endpoint (nonfatal myocardial infarction, nonfatal stroke, arterial revascularization, hospitalization for unstable 
angina, or confirmed death from cardiovascular causes). The HR for rosuvastatin, as compared with placebo, was 0.56 (95% CI: 0.46-0.69; PDeath 
(Top) Following statin therapy, risks of cardiovascular death are greater for individuals with increasing levels of high-sensitivity C-reactive protein (hsCRP) 
(black) than for individuals with increasing levels of low-density lipoprotein (LDL) cholesterol (white). (Bottom) Following statin therapy, risks of 
cardiovascular death are high among those with elevated hsCRP and low LDL cholesterol, but conversely low among those with low hsCRP and elevated 
LDL cholesterol. Reproduced with permission from Ridker et al.51
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n 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
As described previously for primary prevention, there are 
abundant contemporary data in secondary prevention 
that measurement of hsCRP effectively identifies in-
dividuals at high risk for recurrent cardiovascular events. 
In a contemporary overview inclusive of 31,245 statin- 
treated patients participating in the PROMINENT 
(Pemafibrate to Reduce Cardiovascular Outcomes by 
Reducing Triglycerides in Diabetic Patients), REDUCE-IT 
(Evaluation of the Effect of AMR101 on Cardiovascular 
Health and Mortality in Hypertriglyceridemic Patients 
With Cardiovascular Disease or at High Risk for Cardio-
vascular Disease: Reduction of Cardiovascular Events 
With EPA - Intervention Trial), and STRENGTH (Effect of 
High-Dose Omega-3 Fatty Acids vs Corn Oil on Major 
Adverse Cardiovascular Events in Patients at High Car-
diovascular Risk) trials, hsCRP proved to be a stronger 
predictor of recurrent myocardial infarction, stroke, and 
cardiovascular death than that of LDL cholesterol 
(Figure 6A).51 Moreover, risks for recurrent events 
were quite high for those with hsCRP >2 mg/L despite 
having LDL cholesterol levels 2 mg/L despite 
aggressive contemporary care and again experienced 
poor clinical outcomes.53
Broad screening of almost all secondary prevention 
patients for hsCRP and “residual inflammatory risk” rep-
resents a major clinical opportunity.29 As demonstrated in 
CANTOS (Canakinumab Anti-Inflammatory Thrombosis 
Outcomes Study),3 targeted inhibition of the interleukin-1 
(IL-1) to IL-6 to CRP pathway of innate immunity reduced 
recurrent vascular events among stable statin-treated 
patients by 15% to 17%, an effect as large as that antici-
pated from proprotein convertase subtilisin/kexin type 
9 (PCSK9) inhibition,54,55 yet a benefit achieved without 
any change in LDL cholesterol or apolipoprotein(b) 
concentration. Although additional benefits of canakinu-
mab in CANTOS were observed for anemia, gout, large- 
joint arthritis, and lung cancer, adverse effects included 
small but statistically significant reductions in neutro-
phils and a small increase in risk of infections. Whereas 
CANTOS provided proof of principle for the inflammation 
hypothesis of atherothrombosis, canakinumab is not 
available for cardiovascular use, because its primary role 
remains as an orphan drug used for rare individuals with 
IL-1 overexpression syndromes and its experimental role 
has shifted to the treatment and “interception” of lung 
cancer.56
Fortunately, the inexpensive anti-inflammatory agent 
low-dose colchicine (0.5 mg daily) has now been shown 
in COLCOT (Colchicine Cardiovascular Outcomes Trial)13
and the LoDoCo2 (Low Dose Colchicine) for secondary 
prevention of CVD17 randomized trials to reduce recur-
rent cardiovascular events among patients with chronic 
stable atherosclerosis by 25%. A comparable 16% reduc-
tion in recurrent cardiovascular events has been observed 
with colchicine in a recent trial of those with prior stroke, 
although that effect was not statistically significant.57 By 
contrast, in the CLEAR-SYNERGY (Colchicine and Spi-
ronolactone in Patients with MI/SYNERGY) Stent Regis-
try, which was a 2×2 factorial trial of colchicine and 
spironolactone, colchicine was not effective when initi-
ated in the setting of acute STEMI.12 Interpretation of 
CLEAR-SYNERGY, however, has proven to be complex. 
First, acute STEMI is a time where proven therapies 
largely relate to reperfusion and restoration of blood flow 
suggesting that the “timing of taming of inflammation” 
will be important in clinical practice.58 Second, the 
COVID-19 pandemic markedly impacted trial results; 
prior to COVID-19, the hazard ratio for colchicine in 
CLEAR-SYNERGY indicated a 22% reduction in cardio-
vascular risk (HR: 0.78; 95% CI: 0.60-1.02), data consis-
tent with the preceding COLCOT and LoDoCo2 trials. Yet, 
after the onset of COVID—a time of global inflammation 
when access to care changed radically and clinical trials 
were difficult to monitor and conduct—no benefit of 
colchicine was observed raising concern about study drug 
adherence and compliance during the pandemic. This 
issue may help explain why the spironolactone arm of 
CLEAR-SYNERGY also failed to show benefit. Third, 
although 120 global sites participated in CLEAR- 
SYNERGY, more than a third of the total trial partici-
pants (2,589 patients) were enrolled from 4 sites in 1 
small Eastern European country. Although extensive 
commentary has been made regarding these limita-
tions,59-63 it is important to recognize that CLEAR- 
SYNERGY is also the largest colchicine trial conducted 
to date. On the other hand, updated meta-analyses 
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inclusive of the neutral CLEAR-SYNERGY data indicate an 
overall 25% relative risk reduction in major adverse car-
diovascular events (HR: 0.75; 95% CI: 0.56-0.93).64
Currently, low-dose colchicine (0.5 mg daily) is 
approved by the U.S. Food and Drug Administration to 
reduce the risk of myocardial infarction, stroke, coronary 
revascularization, and cardiovascular death in adult pa-
tients with established atherosclerotic disease or with 
multiple risk factors for CVD. Because colchicine is 
renally and hepatically metabolized, use should be 
limited to those with preserved renal and hepatic func-
tion and temporarily stopped if concomitant therapies 
that may alter colchicine metabolism are being used, 
such as clarithromycin, ketoconazole, fluconazole, or 
cyclosporin.65 Despite significant evidence of efficacy and 
safety, the use of inexpensive low-dose colchicine in the 
Unites States and globally remains infrequent.66
It is important to recognize that not all trials of anti- 
inflammatory therapy in secondary prevention have 
been successful and such trial evidence is needed before 
recommendations for other agents can be made. For 
example, the National Institutes of Health–funded CIRT 
(Cardiovascular Inflammation Reduction Trial) found no 
benefit for low-dose methotrexate in the setting of chronic 
atherosclerosis, but also found that this therapy—widely 
used to treat rheumatoid arthritis—did not reduce levels of 
either IL-6 or hsCRP.11 Based upon evidence from the 
CANTOS IL-1β inhibition trial suggesting that the greatest 
benefits of anti-inflammatory therapy accrued among 
those with the greatest reduction in IL-6, a series of 
large-scale trials testing the novel IL-6 ligand inhibitor 
ziltivekimab have been initiatedin the settings of chronic 
kidney disease, heart failure with preserved ejection 
fraction (HFpEF), and acute coronary ischemia.67 In 
addition, the novel IL-6 ligand inhibitor clazakizumab is 
being tested for atherosclerotic event reduction in the 
setting of dialysis.68 It is anticipated that results from the 
earliest of these trials will be available in late 2026 or 
early 2027.
Consensus recommendations: hsCRP screening and 
anti-inflammatory approaches in secondary prevention
n 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.
n Among individuals taking statin therapy, consideration 
should be given to increase dosage into the higher in-
tensity range if hsCRP levels remain >2 mg/L, irre-
spective of LDL cholesterol.
n Low-dose colchicine reduces cardiovascular events 
among individuals with chronic stable atherosclerosis 
and is the first U.S. Food and Drug Administration– 
approved anti-inflammatory agent for this purpose.
n Low-dose colchicine is intended to be used as an 
adjunct to lipid lowering; however, it has not proven 
effective when initiated at the time of acute ischemia 
and should be avoided among individuals with signif-
icant liver or renal disease.
n Several novel anti-inflammatory agents 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
Recent evidence from 3 prospective cohorts, including 
>200,000 participants, indicates that proinflammatory 
dietary patterns are associated with increased risk of 
CVD.69 Conversely, the PREDIMED (Primary Prevention 
of Cardiovascular Disease With a Mediterranean Diet 
Supplemented With Extra-Virgin Olive Oil or Nuts) ran-
domized controlled trial showed that adherence with a 
calorie-restricted Mediterranean diet supplemented with 
extra-virgin olive oil or nuts reduced inflammation and 
major cardiovascular events compared with a low-fat diet 
in high-risk patients.19 Furthermore, lifelong intake of 
fish has been associated with a lower risk of CVD events 
in 24 prospective studies with 714,526 individuals from 
several countries.70,71 Plasma levels of EPA and docosa-
hexaenoic acid (DHA), the polyunsaturated fatty acids in 
fish, may account for the benefit.
In the prospective Cardiovascular Health Study of 
2,692 U.S. adults free of coronary artery disease in 
1992, higher plasma levels of omega-3 fatty acids were 
associated with a 27% lower rate of total mortality due to 
fewer CVD deaths at 16-year follow-up (HR: 0.73; 95% CI: 
0.61-0.86; P-trend = 0.008).72 In the prospective MESA 
(Multi-Ethnic Study of Atherosclerosis) trial, the highest 
quartiles of plasma EPA and DHA levels were associated 
with HRs of 0.49 and 0.39, respectively, for incident CVD 
compared with the lowest quartile at 8 to 10 years of 
follow-up.73 In 19 international studies of 45,637 in-
dividuals free of CHD, the highest quintiles of EPA and 
DHA were associated with 29% and 23% lower rates of 
nonfatal myocardial infarction (relative risk: 0.71; 95% CI: 
0.56-0.90) and fatal CHD (relative risk: 0.77; 95% CI: 
0.64-0.89), respectively.74 Moreover, total mortality was 
18% lower in 17 prospective studies (P 1 g/d (HR: 1.49 [95% CI: 1.04- 
2.15]; P = 0.042) and the risk rose by 11% for each addi-
tional gram per day compared with those using #1 g/d 
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(HR: 1.12 [95% CI: 1.03-1.22]; P = 0.024; P for 
interactionin HF.91 Spe-
cific cell types have unique functional, spatial, and tem-
poral profiles in the failing heart and systemically, linked 
with disease stage and acuity.86 Interestingly, immune 
cells such as macrophages also contribute to atrial and 
ventricular arrhythmias in HF through direct coupling 
with cardiomyocytes and indirect effects on the micro-
environment.92,93 The observations that specific immune 
cells, and their inflammatory profiles, can play causal 
roles in the pathogenesis of HF and CVD have led to rapid 
expansion of the field of cardioimmunology, which pro-
vides a broader understanding of the links between the 
immune system and heart disease, and helps identify 
therapeutic targets to suppress detrimental inflammatory 
and immune responses.87,94
Phase 3 clinical trials (reviewed by Adamo et al85 and 
Mann87) that have targeted inflammation in ischemic and 
nonischemic HF can be categorized as anti-cytokine ap-
proaches (ATTACH [Anti–Tumor Necrosis Factor (TNF) 
With Infliximab])8 and etanercept (RENEWAL [Random-
ized Etanercept Worldwide Evaluation]),21 anti–IL-1β
with canakinumab (CANTOS),10 pleotropic anti- 
inflammatory therapies (prednisone,20,22 rosuvastatin in 
CORONA [Controlled Rosuvastatin Multinational Study in 
Heart Failure] and rosuvastatin and omega-3 
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FIGURE 7 Incidence of Hospitalization for Heart Failure (A) and Hospitalization for Heart Failure or Heart Failure–Related Mortality (B) Among 
Participants in the CANTOS Trial 
Incidence of hospitalization for heart failure (A) and hospitalization for heart failure or heart-failure related mortality (B) among participants in the CANTOS 
Trial. The number at risk for each year is in the table below each figure. Reproduced with permission from Everett et al.10 CANTOS = Canakinumab Anti- 
Inflammatory Thrombosis Outcomes Study.
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polyunsaturated fatty acids in GISSI-HF [Effect of Rosu-
vastatin in Patients With Chronic Heart Failure],14,15,95
oxypurinol in OPT-HF18 [Oxypurinol in Patients With 
Symptomatic Heart Failure]), and immunomodulatory 
strategies (celacade in ACCLAIM9 [Advanced Chronic 
Heart Failure CLinical Assessment of Immune Modula-
tion Therapy]).
To date, most of these trials have not demonstrated 
improvements in primary clinical endpoints such as car-
diovascular death or HF hospitalizations, although sig-
nificant improvements in left ventricular (LV) remodeling 
(improved LV ejection fraction, smaller LV volume) were 
observed in the TIMIC (Immunosuppressive Therapy in 
Patients With Virus-Negative Inflammatory Cardiomy-
opathy) trial in subjects with chronic postmyocarditis HF 
treated with prednisone and azathioprine for 6 months,22
and reductions in cardiovascular hospitalizations were 
observed in older subjects (>60 years of age) with 
ischemic cardiomyopathy in the CORONA trial.14 More-
over, the omega-3 polyunsaturated fatty acid arm of the 
GISSI-HF trial demonstrated that 1 g daily of EPA+DHA 
modestly reduced both all-cause mortality and the com-
posite of all-cause mortality and cardiovascular hospi-
talization in subjects with NYHA functional class II-IV 
HF, irrespective of cause or LV ejection fraction.95 A 
meta-analysis of 19 randomized controlled anti- 
inflammatory trials with 1,341 subjects with HF with 
reduced ejection fraction also indicated that immuno-
modulation improved LV ejection fraction and reduced 
LV size, albeit with a nonsignificant decrease in all-cause 
mortality.96 Most recently, a prespecified, exploratory 
analysis of the CANTOS trial indicated that canakinumab, 
a monoclonal antibody against IL-1β, resulted in a dose- 
dependent reduction in hospitalization for HF and 
FIGURE 8 Time to Pericarditis Recurrence in Anti–Interleukin-1 Agents Randomized Withdrawal Trials 
Time to recurrent pericarditis in anti–interleukin-1 agent randomized withdrawal trials. Reproduced with permission from Klein et al.112
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composite of HF hospitalization and HF mortality in 
subjects with prior myocardial infarction and hsCRP >2 
mg/L (Figure 7).10 This was the first trial to indicate po-
tential benefit for anticytokine therapy in HF.
Blood hsCRP and IL-6 are commonly elevated in pa-
tients with HF and, especially in HFpEF where it portends 
a poorer clinical status and higher risk outcomes.98-102 
Although not directly immunomodulatory, incretin ago-
nists such as semaglutide and tirzepatide consistently 
reduced hsCRP while improving health status and exer-
cise tolerance in obesity-related HFpEF (STEP-HF [Effect 
of Semaglutide 2.4 mg Once Weekly on Function and 
Symptoms in Subjects with Obesity-related Heart Failure 
with Preserved Ejection Fraction] trial and SUMMIT [A 
Study of Tirzepatide in Participants With Heart Failure 
With Preserved Ejection Fraction (HFpEF) and 
Obesity]).103,104 These observations raise the possibility 
that directly targeting inflammatory mediators may also 
be of clinical benefit in HFpEF. The ongoing HERMES 
(Effects of Ziltivekimab Versus Placebo on Morbidity and 
Mortality in Patients With Heart Failure With Mildly 
Reduced or Preserved Ejection Fraction and Systemic 
Inflammation) trial of ziltivekimab is evaluating the po-
tential efficacy of IL-6 inhibition in subjects with HFpEF 
and hsCRP >2 mg/L.97
Beyond proinflammatory cytokines, several preclinical 
studies have raised consideration for directly targeting 
specific immune cell populations in HF. Nonetheless, the 
choice of specific immune-cell population; timing, dura-
tion, and approach of intervention; and appropriate 
biochemical and imaging markers needed for follow-up 
are currently unclear and the focus of intense study. Po-
tential approaches include blocking the CC-chemokine 
receptor or ligand 2 axis to prevent the infiltration of 
proinflammatory monocytes into the failing myocardium, 
and the CXC-motif chemokine receptor 3–CXC motif che-
mokine ligand 9–CXC motif chemokine ligand 10 signaling 
axis to prevent the recruitment of T cells.85 Although not 
being currently trialed in HF, T-cell activation blockade 
with abatacept, which binds cluster of differentiation 80/ 
cluster of differentiation 86 costimulatory molecules on 
antigen-presenting cells, and ruxolitinib, a Janus kinase 
inhibitor, is being tested in patients with steroid-resistant 
immune checkpoint inhibitor–induced myocarditis.105,106
Whether similar approaches can be used in chronic HF 
remains to be determined.
Consensus recommendations: inflammation in HF and 
other CVD
n Inflammatory and immune markers such as hsCRP and 
IL-6 may be used as risk predictors in chronic HF.
n EPA+DHA may be considered as part of the manage-
ment of patients with NYHA functional class II-IV HF, 
irrespective of etiology or LV ejection fraction.
n Statins may be considered as a part of management for 
patients with ischemic HF and age >60 years.
Anti-inflammatory therapy for recurrent pericarditis
Anti-inflammatory therapy is standard of care for acute 
and recurrent pericarditis. For most patients, pericarditis 
of idiopathic or viral cause can be effectively treated with 
a short course of high-dose nonsteroidal anti- 
inflammatory drugs with doses tapered as C-reactive 
protein levels normalize. Based upon the ICAP (Investi-
gation on Colchicine for Acute Pericarditis) trial6 where 
systemic anti-inflammatory therapy reduced recurrent 
pericarditis by 50%, a 3-month course of daily low-dose 
colchicine is recommended in current guidelines.107,108
Similarly, the COPPS-2 (Colchicine for Prevention of the 
Post-Pericardiotomy Syndrome and Post-Operative Atrial 
Fibrillation) randomized trial of patients undergoing 
cardiac surgerydemonstrated a reduction in post-
operative pericarditis from 29.4% to 19.4% with use of 1 
month of low-dose colchicine initiated 48 to 72 hours 
before surgery.109
Until recently, the only pharmacological option for 
high-risk patients with persistent and recurrent pericar-
ditis was corticosteroids; however, randomized trial data 
have demonstrated considerable efficacy for IL-1 
blockade among selected patients with multiple recur-
rent episodes of pericarditis who are resistant to colchi-
cine and steroids and who have hsCRP levels >10 mg/L. In 
the AIRTRIP (Anakinra Treatment of Recurrent Idiopathic 
Pericarditis) trial of patients with idiopathic 
corticosteroid-dependent pericarditis and $3 prior re-
currences, IL-1 blockade reduced recurrent event rates 
from 90% to 18%.110 In RHAPSODY (Study to Assess the 
Efficacy and Safety of Rilonacept Treatment in Partici-
pants With Recurrent Pericarditis) patients with $2 epi-
sodes of recurrent pericarditis, 6.7% had a recurrence on 
continuation of rilonacept as compared with a recurrence 
rate of 74% among those who discontinued therapy.7 In a 
third small trial, allocation to goflikicept resulted in a 
90% reduction in recurrent pericarditis compared with 
those randomly allocated to drug withdrawal111
(Figure 8).
These randomized trial data for the prevention and 
treatment of recurrent pericarditis demonstrate that 
targeted anti-inflammatory therapy has a clearly estab-
lished role in cardiovascular medicine. It is not recom-
mended to use any of these novel therapies in regions 
where tuberculosis is the most common cause of 
pericarditis.
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Consensus recommendations: anti-inflammatory therapy 
for recurrent pericarditis
n 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.
n Novel anti-inflammatory therapies for recurrent peri-
carditis represent an important therapeutic advance 
for high-risk patients.
Evidence gaps and future directions
Several recent seminal clinical trials support the recom-
mendations summarized in Table 2.2,3 Nevertheless, sig-
nificant gaps remain in the evidence needed to fully inform 
comprehensive detection, evaluation, and clinical man-
agement of CVD. The underlying molecular and cellular 
mechanisms for these findings often remain incompletely 
elucidated. The interplay between inflammation and key 
systems, such as the immunomodulatory, neuroendo-
crine, cardiometabolic, and vascular endothelial, remain 
incompletely examined. Several gaps also persist in our 
understanding of the interactions between inflammation 
and genetic predisposition, environmental factors, social 
determinants, and behavioral and lifestyle risks.113 These 
gaps highlight opportunities for future research.
There is a need to explore the comparative effective-
ness of alternative inflammatory markers. Rigorous 
biomarker validation as well as studies eliciting insights 
on their role in early-stage atherosclerosis, plaque sta-
bility and vulnerability, and other manifestation of CVD 
would be invaluable. Similarly, future proteomics 
research may hold significant promise for advancing our 
understanding of how chronic low-grade inflammation 
contributes to CVD by uncovering novel inflammation- 
related proteins linked with adiposity and immune dys-
regulation.114 Additionally, the development of multi-
biomarker panels combining traditional risk factors with 
novel inflammatory markers could enhance risk predic-
tion. Critical insights are also needed in future studies 
that enhance the ability of imaging modalities, such as 
coronary computed tomography angiography and optical 
coherence tomography,115 to characterize the inflamma-
tory features of noncalcified coronary plaque in early- 
stage inflammation with high sensitivity and specificity, 
and to help identify and quantify subclinical atheroscle-
rosis. Similarly, future studies are needed in the assess-
ment of the independent predictive value of perivascular 
fat phenotyping.
Another area of increasing research interest in 
inflammation and CVD is clonal hematopoiesis of inde-
terminate potential (CHIP). CHIP has been independently 
associated with a 2-fold increased risk of CVD in the 
general population,116 adverse outcomes in patients with 
established ASCVD,117 >3-fold increased risk of death in 
ischemic HF,118 and incident cardiovascular events in 
clinical trial populations.119 Future research on the mo-
lecular underpinnings of how CHIP mutations in genes 
such as Ten-Eleven Translocation-2 (TET2) and DNA 
methyltransferase 3 alpha (DNMT3A)120 promote chronic 
low-grade inflammation and which CHIP-specific muta-
tions best inform CVD risk stratification and therapeutic 
strategies would be invaluable. In 1 secondary prevention 
trial of patients with coronary artery disease and residual 
inflammatory risk, treatment with canakinumab resulted 
in a 62% relative risk reduction for major adverse car-
diovascular events in individuals carrying TET2 muta-
tions compared with those without CHIP.121
In primary and secondary prevention of CVD where the 
most compelling evidence exists for the role of anti- 
inflammatory strategies in clinical practice, there 
remains an important gap in dissemination and imple-
mentation research. For example, strategies are needed 
to boost the sustained uptake of hsCRP measurement in 
routine clinical practice to identify individuals at 
increased inflammatory risk. Large, randomized trials are 
further needed to evaluate the benefit of anti- 
inflammatory therapies in primary prevention. Other 
strategies are needed to inform sustained adoption of 
guideline-directed care that incorporates anti- 
inflammatory agents in primary and secondary preven-
tion. Studies that clarify the best time to initiate anti- 
inflammatory therapies will be crucial.
The role of inflammation in lifestyle and behavioral 
risks has implications for cardiovascular health promo-
tion as well as CVD prevention. Further elucidation of the 
molecular and cellular pathways linking behavioral and 
lifestyle factors, including smoking, physical inactivity, 
and diet, will be needed. For example, exploring the role 
of diet and the gut microbiome in modulating inflam-
mation and determining the optimal exercise regimens 
for mitigating chronic inflammation in chronic conditions 
such as obesity and diabetes would be invaluable. Simi-
larly, a greater understanding of the mechanisms by 
which tobacco toxins trigger inflammatory responses in 
atherogenesis is needed.
Another important area of research is the role that 
novel SPM pathways play in cardioprotection,73 and cor-
onary plaque regression.122 There is also increasing in-
terest in exploring SPM-based therapeutics in peripheral 
artery disease (PAD) and other settings of vascular 
injury.123 One double-blind, randomized, placebo- 
controlled clinical trial of fish oil supplementation The 
Effects of Omega-3 Fatty Acids on Peripheral Arterial 
Disease II (OMEGA-PAD II) demonstrated increased SPM 
levels following fish oil supplementation in PAD pa-
tients.124 However, it remains to be determined whether 
such increases in SPM levels in patients with PAD lead to 
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improved clinical outcomes such as walking distance, 
ulcer healing, or amputation risk.
Whereas the role of inflammation in chronic HF is well 
recognized, there are no specifically targeted anti- 
inflammatory or immunomodulatory therapies currently 
approved for clinical practice. Overcoming this large gap 
in clinical translation will require more preclinical 
studies to expand our understanding of the inflammatory 
and immune basis for HF, as