Inflammation and Cardiovascular Disease: 2025 ACC Scientific Statement: A Report of the American College of Cardiology

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.

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.

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

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 parameters 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 individuals with LDL cholesterol levels <130 mg/dL who also had hsCRP concentrations of ≥2 mg/L. The study was prematurely terminated, showing a 47% reduction in the primary endpoint (Figure 5).¹⁶ Further analyses from the JUPITER study demonstrate considerable efficacy of rosuvastatin compared with that of placebo among trial participants who had no SMuRFs but who were only at risk due to elevated hsCRP, a group described as “SMuRF-less but inflamed.”⁴⁸ Recent studies have further indicated that bempedoic acid might also possess anti-inflammatory properties, with a reported 20% to 30% reduction in hsCRP, which was comparable with the extent of LDL cholesterol lowering seen with this treatment.⁴⁹ Although a potentially larger overall cardiovascular benefit has been seen in the primary prevention cohort of the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Outcomes trial,⁴⁹ it is still unknown whether the reduction of hsCRP in individuals without ASCVD taking bempedoic acid would result in a favorable outcome.

Taken together, the contribution of low-grade inflammation to the pathogenesis of ASCVD in primary prevention is well established; however, despite the existence of a comprehensive database, no study that directly targets inflammatory pathways has yet to be conducted in ASCVD-free subjects, although efficacy has been shown for colchicine among those with elevated coronary artery calcium¹⁷ and among patients with gout.⁵⁰ Thus, further research is needed to demonstrate the benefit of anti-inflammatory therapy on cardiovascular outcomes in adequately powered clinical trials in the setting of primary prevention.

As described previously for primary prevention, there are abundant contemporary data in secondary prevention that measurement of hsCRP effectively identifies individuals 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 Cardiovascular 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 Cardiovascular 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 <70 mg/dL, demonstrating the unmet clinical need for anti-inflammatory approaches in contemporary practice (Figure 6B).⁵¹ The strongest association for hsCRP was for the endpoint of cardiovascular death, suggesting that untamed inflammation is indicative of major life-threatening events. Very similar data have been reported in a contemporary study of 13,970 high-risk individuals with statin intolerance.⁵² In a 2024 prospective registry inclusive of 84,399 patients with atherosclerosis undergoing hsCRP testing in Sweden, 60% had hsCRP >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” represents 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 anticipated 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 canakinumab in CANTOS were observed for anemia, gout, large-joint arthritis, and lung cancer, adverse effects included small but statistically significant reductions in neutrophils 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 recurrent cardiovascular events among patients with chronic stable atherosclerosis by 25%. A comparable 16% reduction 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 Spironolactone in Patients with MI/SYNERGY) Stent Registry, which was a 2×2 factorial trial of colchicine and spironolactone, colchicine was not effective when initiated 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 cardiovascular risk (HR: 0.78; 95% CI: 0.60-1.02), data consistent 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 participants (2,589 patients) were enrolled from 4 sites in 1 small Eastern European country. Although extensive commentary has been made regarding these limitations,^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 inclusive of the neutral CLEAR-SYNERGY data indicate an overall 25% relative risk reduction in major adverse cardiovascular 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 patients 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 function 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 initiated in 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.

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) randomized 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 docosahexaenoic 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 individuals 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 < 0.003).⁷⁵ It should be noted that a meta-analysis of 7 randomized controlled trials involving 81,210 subjects found that long-term marine omega-3 fatty acid supplementation was associated with an increased risk of atrial fibrillation.⁷⁶ In analyses stratified by dose, the risk was greater in trials that used doses >1 g/d (HR: 1.49 [95% CI: 1.04-2.15]; P = 0.042) and the risk rose by 11% for each additional gram per day compared with those using ≤1 g/d (HR: 1.12 [95% CI: 1.03-1.22]; P = 0.024; P for interaction <0.001); however, no increased risk of atrial fibrillation was noted in the long-term prospective studies of dietary intake of fish.

A 2021 meta-analysis of 40 randomized controlled trials reported a dose-dependent effect of EPA+DHA for CVD events and myocardial infarction.⁷⁷ It was estimated that every 1 g/d EPA+DHA corresponded with a 9% and 7% lower risk of myocardial infarction and total CHD, respectively, and to a 5.8% lower risk of CVD events. The dose-response benefit may explain why randomized controlled trials with low or moderate doses of omega-3 fatty acids found no significant CHD risk reduction. The benefit from fish consumption may be attributed to SPMs, the downstream products of EPA and DHA that help resolve acute inflammation by halting neutrophil recruitment to inflamed tissues. Additionally, SPMs promote the efferocytosis of apoptotic neutrophils and debris, which is crucial for resolving and preventing chronic inflammation.^78,79 SPM levels have also been shown to predict regression and progression of coronary plaque in the setting of low levels of hsCRP.⁷⁴

Other behaviors and lifestyles, including smoking and physical activity, have effects on inflammation. Chronic physical activity reduces resting C-reactive protein levels by multiple mechanisms, including a decrease in cytokine production by adipose tissue, skeletal muscles, endothelial and blood mononuclear cells: improved endothelial function, and insulin sensitivity.⁸⁰ Regular exercise also reduces inflammation by increasing SPM production in humans and stimulating the catabolism of inflammatory lipid mediators, leukotrienes, and prostaglandins,^81-83 and is associated with a reduction in CVD events.⁸⁴ Smoking is a major source of inflammation in the body, leading to an increase in proinflammatory cytokines and reduced production and function of resolvins, making them less effective at resolving inflammation.⁸¹ Implementing these lifestyle interventions can lead to significant reduction in inflammatory burden and lower CVD risk.

HF is characterized by systemic and local activation of the noncellular and cellular components of the immune system that lead to pathological tissue remodeling and disease pathogenesis.^5,85-87 Immune system activation occurs as a chronic low-grade inflammatory response to ongoing tissue injury (ie, parainflammation⁸⁸) induced by factors such as excessive neurohormonal activation and ongoing mechanical load.⁸⁵ In chronic HF, this parainflammatory response is marked by increased elaboration of inflammatory cytokines and chemokines, expansion of resident and infiltrating innate immune cells (eg, macrophages), and adaptive immune cells (eg, T cells). Augmented immunoinflammatory responses have been linked with increased mortality and morbidity in chronic HF.^89,90

Hematopoietic factors that augment inflammatory responses, such as clonal hematopoiesis of indeterminate potential, have been shown to predict risk in HF.⁹¹ Specific cell types have unique functional, spatial, and temporal 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 microenvironment.^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 provides 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 approaches (ATTACH [Anti–Tumor Necrosis Factor (TNF) With Infliximab])⁸ and etanercept (RENEWAL [Randomized 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 polyunsaturated fatty acids in GISSI-HF [Effect of Rosuvastatin 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 Modulation Therapy]).

To date, most of these trials have not demonstrated improvements in primary clinical endpoints such as cardiovascular death or HF hospitalizations, although significant 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 Cardiomyopathy) 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 Moreover, 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 composite of all-cause mortality and cardiovascular hospitalization 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 immunomodulation 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 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 potential benefit for anticytokine therapy in HF.

Blood hsCRP and IL-6 are commonly elevated in patients with HF and, especially in HFpEF where it portends a poorer clinical status and higher risk outcomes.^98-102 Although not directly immunomodulatory, incretin agonists such as semaglutide and tirzepatide consistently reduced hsCRP while improving health status and exercise 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 potential 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, duration, and approach of intervention; and appropriate biochemical and imaging markers needed for follow-up are currently unclear and the focus of intense study. Potential 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 chemokine 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.

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 (Investigation 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 surgery demonstrated a reduction in postoperative 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 pericarditis was corticosteroids; however, randomized trial data have demonstrated considerable efficacy for IL-1 blockade among selected patients with multiple recurrent episodes of pericarditis who are resistant to colchicine 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 recurrences, 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 Participants With Recurrent Pericarditis) patients with ≥2 episodes 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 established role in cardiovascular medicine. It is not recommended to use any of these novel therapies in regions where tuberculosis is the most common cause of pericarditis.

Several recent seminal clinical trials support the recommendations summarized in Table 2.^2,3 Nevertheless, significant gaps remain in the evidence needed to fully inform comprehensive detection, evaluation, and clinical management 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, neuroendocrine, 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 effectiveness of alternative inflammatory markers. Rigorous biomarker validation as well as studies eliciting insights on their role in early-stage atherosclerosis, plaque stability 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 dysregulation.¹¹⁴ Additionally, the development of multibiomarker panels combining traditional risk factors with novel inflammatory markers could enhance risk prediction. 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 inflammatory features of noncalcified coronary plaque in early-stage inflammation with high sensitivity and specificity, and to help identify and quantify subclinical atherosclerosis. Similarly, future studies are needed in the assessment of the independent predictive value of perivascular fat phenotyping.

Another area of increasing research interest in inflammation and CVD is clonal hematopoiesis of indeterminate 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 molecular 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 mutations 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 cardiovascular events in individuals carrying TET2 mutations 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 implementation 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 prevention. 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 promotion 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 inflammation and determining the optimal exercise regimens for mitigating chronic inflammation in chronic conditions such as obesity and diabetes would be invaluable. Similarly, 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 coronary plaque regression.¹²² There is also increasing interest 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 patients.¹²⁴ However, it remains to be determined whether such increases in SPM levels in patients with PAD lead to 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 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 characterized 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 randomized controlled trials in this arena with emphasis on the increasing role of dysregulated immunity. These include ≥14 trials in ASCVD and thrombosis, 9 in peripheral 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, detection, evaluation, and treatment of CVD. Other avenues for further research are identified in the following recommendations.

Inflammation in HF and other 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 cardiovascular risk independent of lipid lowering. We have thus entered an era when the evidence linking inflammation 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 patients with established ASCVD and evidence of residual inflammatory risk, regardless of LDL cholesterol level. 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 inflammatory and immune mechanisms underlying these conditions so that new anti-inflammatory or immunomodulatory treatment strategies can be identified and developed for translation to humans. The time for action has arrived.