Acute coronary syndrome (ACS) is a major cause of acute death worldwide. Both innate and adaptive immunity regulate atherosclerosis progression, plaque stability, and thrombus formation. Immune and inflammation dysfunction have been indicated in the pathogenesis of ACS. The imbalance in the proatherogenic and antiatherogenic immune networks promotes the transition of plaques from a stable to unstable state and results in the occurrence of acute coronary events. The residual inflammatory risk (RIR) has received increasing attention in recent years, and lowering RIR has been expected to improve the outcomes of ACS patients. The CANTOS, COLCOT, and LoDoCo trials verified the benefits of reducing cardiovascular events using anti-inflammation therapies; however, most of the other studies focusing on lowering RIR produced negative or contradicting results. Therefore, restoring the balance in autoimmune regulation is essential because proatherogenic and antiatherogenic immunomodulatory effects are equally important in the complex human immune network. In this review, we summarized the recent evidence of the roles of proatherogenic and antiatherogenic immune networks in the pathogenesis of ACS and discussed how immune and inflammation contribute to atherosclerosis progression, plaque instability, and adverse cardiovascular events. We also provide a “from bench to bedside” perspective of a novel and promising personalized strategy in RIR intervention and therapeutic approaches for the treatment of ACS.
Acute coronary syndrome (ACS) refers to a complex clinical syndrome that includes a spectrum of entities including unstable angina, ST segment elevation myocardial infarction (STEMI), and non-ST segment elevation myocardial infarction (NSTEMI). The accumulating evidence has implicated an inflammatory process in the pathogenesis of ACS that involves local immune cells in coronary arteries generating inflammatory factors that promote thrombus formation [
The molecular mechanisms of atherosclerosis are cholesterol deposition and immune cell aggregation in the arterial wall. Innate and adaptive immune cells with both proinflammatory and anti-inflammatory effects regulate subsequent atherosclerosis progression. The transition from stable to unstable plaques with subsequent rupture or erosion and thrombus formation contribute to ACS [
Immune-mediated inflammatory disorders, including rheumatic diseases, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and systemic lupus erythematosus, are also closely related to acute cardiovascular events independent of traditional cardiovascular risk factors. ACS is very common in young women with IBD who often show a high level of CRP [
The CANTOS trial showed that canakinumab was associated with a 15% reduction in major adverse cardiovascular events (MACEs), indicating the importance of anti-inflammatory therapy in the management of ACS residual risks [
The accumulating evidence has demonstrated that vascular inflammation plays pivotal roles in the pathogenesis of ACS, and thus ACS is considered an inflammation-related disease. Following systemic or local inflammatory activation, endothelial cells enhance the attachment and migration of T lymphocytes and macrophages into the arterial wall via upregulated adhesion molecules. During this process, both the proatherogenic and antiatherogenic immune networks are activated (Figure
Immune and inflammation pathways in the pathogenesis of acute coronary syndrome.
The innate immune system is the first barrier for human self-protection that activates nonspecific immune cells to respond to pathogens [
A thin fibrous cap is common in unstable plaques [
The adaptive immune system also contributes to plaque rupture. T lymphocyte subsets with distinct effector roles have multiple inflammatory functions [
The nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 (NLRP3) inflammasome is a critical component of the innate immune system and triggers the immune cell release of inflammatory cytokines [
Unlike plaque rupture, macrophages, and T lymphocytes are seldom associated with plaque erosion [
Antiatherogenic immune networks counteract the progressive proatherogenic infiltrates in the pathogenesis of ACS, which mediates a waxing and waning inflammatory environment. Some macrophages differentiate into antiatherogenic subsets (M2 type) to eliminate excessive autoimmune attacks [
Recently, adaptive immunosuppressed cells have received great attention. Regulatory T (Treg) cells are a subtype of immunosuppressed T cells with positive FOXP3, CD20, and CTLA4 expressions that suppress antigen-presenting cells, naive and effector T cells, and natural killer (NK) cells [
Given that a large part of ACS is a systemic inflammation-related disease in which both innate and adaptive immune systems are involved, RIR may be even common besides cholesterol risk [
Regarding the lack of currently available methods for RIR identification, it is difficult to identify the ACS patients that require adjuvant anti-inflammatory treatment. Therefore, it is necessary to propose a novel, efficient, and cost-effective predictive model that does not only focus on the narrow degree of the regional lumen [
The imbalance between the proatherogenic and antiatherogenic immune networks is an essential component in the pathogenesis of ACS, although controversies regarding the contribution of inflammation to plaque erosion still exist. In addition to potent lipid-lowering manipulations, efforts to eliminate this imbalance may be a promising therapeutic strategy for ACS. Currently, although some clinical trials on anti-inflammatory treatments in ACS have obtained satisfactory endpoints; most of them have failed to complete the translation from the theoretical insight into quantifiable benefits (Table
Major published and ongoing clinical studies targeting inflammation therapies in coronary artery disease.
Study | Subjects | Inflammatory target | Therapeutic agent | Median follow-up duration | Primary outcome | Benefit achieved |
---|---|---|---|---|---|---|
LoDoCo | Patients with stable CAD | Broad spectrum | Colchicine | 3 years | Cardiac arrest, ACS, stroke | Yes [ |
CANTOS | Post-ACS patients with high level of hsCRP | IL-1 | Canakinumab | 48 months | Cardiovascular death, nonfatal myocardial infarction or stroke | Yes [ |
CIRT | Type 2 diabetes or metabolic syndrome patients with recent ACS | Broad spectrum | Methotrexate | 2.3 years | Cardiovascular death, nonfatal myocardial infarction or stroke, hospitalization for emergency revascularization | No [ |
COLCOT | Post-ACS patients | Broad spectrum | Colchicine | 22.6 months | Cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, hospitalization for emergency revascularization | Yes [ |
CLEAR-SYNERGY | ACS patients with STEMI/SYNERGY stent | Broad spectrum | Colchicine and spironolactone | 2 years | Cardiovascular death, stroke, recurrent myocardial infarction | Ongoing [ |
LoDoCo2 | Patients with stable CAD | Broad spectrum | Colchicine | 3 years | Cardiovascular death, ACS, stroke | Ongoing [ |
ASSAIL-MI | Patients with first STEMI | IL-6 | Tocilizumab | 6 months | Myocardial salvage index assessed by CMR 1 week after administration | Ongoing [ |
LATITUDE-TIMI 60 | Patients with ACS | Mitogen-activated protein kinase | Losmapimod | 12 weeks | Cardiovascular death, myocardial infarction, recurrent angina requiring emergency revascularization | No [ |
VCU-ART3 | Patients with ACS | IL-1Ra | Anakinra | 12 months | 14-day changes in CRP levels, new-onset heart failure, long-term improvement of left ventricular ejection fraction | Ongoing [ |
Footnote. ACS: acute coronary syndrome; CRP: C-reactive protein; CMR: cardiovascular magnetic resonance; LoDoCo: Low-Dose Colchicine; CANTOS: Canakinumab. Anti-Inflammatory Thrombosis Outcome Study; CIRT: Cardiovascular Inflammation Reduction Trial; COLCOT: Colchicine Cardiovascular Outcomes Trial; CLEAR-SYNERGY: Colchicine and Spironolactone in Patients with STEMI/SYNERGY Stent Registry; LoDoCo2: Low Dose Colchicine After Myocardial Infarction; ASSAIL-MI: ASSessing the Effect of Anti-IL-6 Treatment in MI; LATITUDE-TIMI 60: LosmApimod To InhibiT p38 MAP kinase as a therapeUtic target and moDify outcomes after an acute coronary syndrome; VCU-ART3: Virginia Commonwealth University-Anakinra Remodeling Trial-3.
Given that proatherogenic immune networks dominate the pathogenesis of ACS, targeting proatherogenic immune modulation to inhibit inflammation in ACS is promising in this regard. The most successful study in targeting anti-inflammatory therapy in ACS was the CANTOS trial, which randomized 10,061 patients with previous MI and
TNF-
Other therapies targeting inflammation have also been investigated. The phospholipase A2 (PLA2) enzymes are key contributors to lipid metabolism and inflammatory activation and are strongly correlated with plaque burden [
Due to limited atheroprotective autoimmunity, it is often difficult to prevent excessive proatherogenic immune responses. An improvement in the antiatherogenic ability is expected to affect immune homeostasis. Anakinra, an IL-1Ra antagonist, blocks endogenous IL-1
Recently, Treg cell-based treatments have received great attention. Treg cells induced by specific antigens restored the internal immune environment and reversed atherosclerosis in mice [
Although several studies targeting immune and inflammation in ACS showed improved outcomes of atherosclerosis, the future in this field is full of unknowns. Certain inflammatory pathways or specific immune cells are not the perfect equivalents of systemic inflammatory responses. Fleming et al. proposed the fixed distinction between the “surrogate” and “correlate” of a disease [
To date, studies on targeting proatherogenic inflammation have outnumbered those targeting antiatherogenic inflammation. The clinical benefits observed in most trials investigating the regulation of proatherogenic mechanisms alone were suboptimal. Furthermore, the overwhelming suppression of proatherogenic immunomodulatory effects attenuates systemic immunocompetence and results in multiple infections and malignant tumors [
ACS has been referred to as an inflammation-related disease regarding its pathogenesis. Understanding the mechanisms of immune and inflammation in ACS will transform risk evaluations and treatment paradigms. The management of RIR beyond traditional guideline-based therapy leads to positive cardiovascular outcomes. Efforts targeting the immune system and inflammation to alleviate the ACS burden have provided promising results. Although they are still being developed, therapies based on anti-inflammation and immune modulation will promote a personalized medicine in the future. Finally, cooperation among cardiologists, oncologists, and rheumatologists is needed to achieve precise prevention and therapy for ACS patients.
The authors declare that they have no conflict of interest regarding the publication of this article.
Haiming Wang and Zifan Liu contributed equally to this work.
We thank Birth Defect Intervention and Rescue Foundation of China for professional advice on project design. This work was supported by the National Natural Science Foundation of China (81871516, 81571841) and Open Research Fund of National Clinical Research Center for Geriatric Diseases (NCRCG-PLAGH-2018001).