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Maidana, D.; Arroyo-Álvarez, A.; Arenas-Loriente, A.; Barreres-Martín, G.; Muñoz-Alfonso, C.; Bompart Berroteran, D.; Esteve Claramunt, F.; Blanco Del Burgo, R.; Cepas-Guillén, P.; Garcia-Blas, S.; et al. Anti-Inflammation Strategies in Ischemic Heart Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/53908 (accessed on 07 July 2024).
Maidana D, Arroyo-Álvarez A, Arenas-Loriente A, Barreres-Martín G, Muñoz-Alfonso C, Bompart Berroteran D, et al. Anti-Inflammation Strategies in Ischemic Heart Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/53908. Accessed July 07, 2024.
Maidana, Daniela, Andrea Arroyo-Álvarez, Andrea Arenas-Loriente, Guillermo Barreres-Martín, Carles Muñoz-Alfonso, Daznia Bompart Berroteran, Francisca Esteve Claramunt, Regina Blanco Del Burgo, Pedro Cepas-Guillén, Sergio Garcia-Blas, et al. "Anti-Inflammation Strategies in Ischemic Heart Disease" Encyclopedia, https://encyclopedia.pub/entry/53908 (accessed July 07, 2024).
Maidana, D., Arroyo-Álvarez, A., Arenas-Loriente, A., Barreres-Martín, G., Muñoz-Alfonso, C., Bompart Berroteran, D., Esteve Claramunt, F., Blanco Del Burgo, R., Cepas-Guillén, P., Garcia-Blas, S., & Bonanad, C. (2024, January 16). Anti-Inflammation Strategies in Ischemic Heart Disease. In Encyclopedia. https://encyclopedia.pub/entry/53908
Maidana, Daniela, et al. "Anti-Inflammation Strategies in Ischemic Heart Disease." Encyclopedia. Web. 16 January, 2024.
Anti-Inflammation Strategies in Ischemic Heart Disease
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This entry is adapted from the peer-reviewed paper 10.3390/jcm13020363

Cardiovascular (CV) diseases remain a global health challenge, with ischemic heart disease (IHD) being the primary cause of both morbidity and mortality. Despite optimal pharmacological therapy, older patients with IHD exhibit an increased susceptibility to recurrent ischemic events, significantly impacting their prognosis. Inflammation is intricately linked with the aging process and plays a pivotal role in the evolution of atherosclerosis. Emerging anti-inflammatory therapies have shown promise in reducing ischemic events among high-risk populations.

ischemic heart disease inflammation cardiovascular disease

1. Introduction

Cardiovascular (CV) diseases remain as a global health challenge, representing the leading cause of mortality and loss of health [1]. Among them, ischemic heart disease (IHD) is the predominant cause of morbidity and mortality [2]. It is expected that its incidence will continue to increase primarily due to the aging of the population [3]. Current research goals in the CV field focus on identifying and addressing modifiable CV risk factors to guide the development of population health strategies and establish new therapeutic targets. The critical role of inflammation in atherogenesis, plaque instability, and subsequent cardiac events is now well known. While the importance of inflammation in atherosclerosis is well established [4], its specific implications in the context of older patients with IHD remain an area of active investigation. In this population, managing IHD presents distinctive challenges, requiring a comprehensive understanding of the underlying pathophysiology along with an integral approach to balance benefits and risks due to a high burden of comorbidities and frailty [5][6]. With the increase in the aging population, it is crucial to consider new approaches to reduce the burden of CV diseases, especially IHD.
The role of inflammation in atherosclerosis and IHD has garnered increased attention in recent years, given the latest research revealing a complex interplay between this process and cardiovascular pathophysiology. The acknowledgment of inflammation’s role has prompted researchers and clinicians to explore targeted interventions aimed at mitigating the inflammatory cascade associated with IHD. Consequently, recent trials have tested the hypothesis that anti-inflammatory drugs can reduce the incidence of MACE in patients with IHD [7][8].

2. Pharmacological Anti-Inflammatory Therapy

2.1. Traditional Pharmacological Anti-Inflammatory Therapy

The benefits of low-dose aspirin (100 mg/day) in the secondary prevention of MACE in IHD patients is well documented, although the mechanisms of this effect are unclear [9]. The two primary hypotheses that could explain its benefits are its antiplatelet and anti-inflammatory effects, with the former being better understood than the latter. Nevertheless, several clinical studies have demonstrated that the administration of low-dose aspirin is associated with a decrease in proinflammatory biomarkers such as IL-6, IL-1, and C-reactive protein among patients IHD [10][11]. Moreover, a sub-analysis from The Physicians’ Health Study showed the reduction associated with the use of aspirin in the risk of a first myocardial infarction appears to be directly related to the level of C-reactive protein [12]. In this study, healthy participants were randomly assigned to receive aspirin or placebo. The level of CRP was measured at the beginning of the study. Patients in the quartile with the highest CRP values had higher risk of myocardial infarction or stoke compared to those in the lowest quartile. The use of aspirin was associated with significant reductions in those participants in the highest quartile (55% of reduction) but with only small, nonsignificant reductions in those in the lowest quartile (13.9% of reduction). This study demonstrated that the greater the risk patients face, the greater the benefits of using aspirin in CV prevention, with inflammation (measured through CRP) playing a central role in the pathogenesis of atherosclerosis. This approach, detecting high-risk patiens, is supported by the results of ASPREE trial where the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among healthy older adults [13].
On the other hand, the benefits of lipid lower therapy such as statins or novel PCSK9 inhibitors extends beyond the isolated reduction in LDL levels. The pleiotropic effect of statins in the context of IHD is widely documented with evidence showing that statins could have favorable and clinically relevant anti-inflammatory effects independent of lipid lowering [7]. Data from the CARE (Cholesterol and Recurrent Events) [14] and PRINCE (Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation) [15] trials showed that the administration of pravastatin reduced C-reactive protein levels in a largely LDL-C-independent manner. This effect was observed in both primary (PRINCE trial) and secondary prevention (CARE trial). Similar results were observed in PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis In Myocardial Infarction 22) study, which suggested dual mechanisms of benefit of statin therapy: LDL-lowering, and a direct anti-inflammatory effect independent of LDL-lowering.
Given the important role of inflammation in the CV setting, this effect of statins might explain, in addition to LDL reduction, their reduction in MACE. On the other hand, recent studies have demonstrated the capability of the new PCSK9 inhibitors to reduce atherosclerotic burden by regressing vulnerable plaques in patients following ACS [16][17][18] and patients with familiar hypercholesterolemia [19]. It is important to emphasize that the notable reduction in MACE observed in the pivotal trials of these pharmaceutical families primarily arises from their capacity to decrease LDL levels. However, further exploration is required to fully elucidate the extent and significance of their anti-inflammatory effects [20].

2.2. Novel Pharmacological Anti-Inflammatory Therapy

Canakinumab

The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) was a randomized, double-blind, placebo-controlled trial involving stable patients with previous myocardial infarction; this study evaluated whether canakinumab could prevent recurrent vascular events among those who have a persistent proinflammatory response (high-sensitivity CRP ≥ 2 mg/L) [21]. Canakinumal is a fully human monoclonal antibody targeting interleukin-1β. As previously cited, interleukin-1β has been involved in the proinflammatory cascade leading to atherosclerosis [22]. This was the first study to evaluate the role of a direct anti-inflammatory therapy in cardiovascular events. A total of 10,061 patients were included and were randomly assigned in a 1:1:1 ratio to receive placebo, canakinumab at a dose of 150 mg, or canakinumab at a dose of 300 mg. At a median follow-up of 3.7 years, the incidence rate for the primary end point (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) was 4.50 events per 100 person-years in the placebo group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group—these differences were statistically significant. No difference was observed in all-cause mortality between canakinumab and placebo groups. In the canakinumab groups, a higher percentage of fatal infections/sepsis was observed than in the placebo group (incidence rate, 0.31 vs. 0.18 events per 100 person-years; p = 0.02). On the other hand, cancer mortality was significantly lower with canakinumab than with placebo.
Regarding the role of this therapy among older patients, a post hoc analysis of the CANTOS trial evaluated the effect of canakinumab in frailty [23]. In a total of 9942 participants’ baseline frailty index were calculated. Of those, 13% of participants were classified as frail. In this sub-analysis, the primary findings of CANTOS trial in terms of canakinumab-associated cardiovascular event reduction were unchanged in analyses stratified by baseline frailty, showing the effective and safety of this therapy in frail patients. It is notable that a higher percentage of fatal sepsis was detected among older patients with diabetes, indicating that neutropenia should be monitored among those patients under this therapy to prevent infections.

Colchicine

Colchicine is an immunomodulator that suppresses inflammation by inhibiting neutrophil migration and degranulation and promotes collagen degradation by stimulating collagenase activity [24]. Its use is approved in different inflammatory diseases such as gout, familiar Mediterranean fever, and pericarditis, among others. In recent years, there has been an increasing interest in evaluating its role in CV disease, especially in IHD. Several reasons make colchicine an attractive molecule to evaluate its anti-inflammatory effect in patients with IHD: wide availability, low cost, and tolerable side-effect profile. Thus, Colchicine has emerged as a novel CV prevention treatment. Several clinical trials have evaluated the effectiveness and safety of colchicine among patients with different types of IHD (acute and chronic coronary syndrome). A summary of the main results of these studies is presented in Table 1 [25][26][27][28][29][30].
Table 1. Main elements contributing to inflamm-ageing [25][26][27][28][29][30].

Study

Population

Control

Main Results

LoDoCo trial

CCS

n = 532

Conventional treatment

Follow-up 3 years

Primary endpoint (ACS, cardiac arrest, stroke): 5.3% vs. 16%; p < 0.001

GI intolerance (2.5%) in Colchicine group

LoDoCo2 trial

CCS

n = 5522

Placebo

Follow-up 28.5 months

Primary endpoint (CV death, MI, stroke, ischemia-driven coronary revascularization): 6.8% vs. 9.6%; p < 0.001

Trend to ↑ rate of non-CV death (1.9%; HR, 1.51 [95% CI, 0.99–2.31])

Myalgia 21.2% and GI intolerance 15.4%

COPS trial

ACS

n = 795

Placebo

Follow-up 12 years

Primary endpoint (death, ACS, stroke, ischemia-driven coronary revascularization): 6.1% vs. 9.5%; p = 0.09

Significant higher rate of non-cardiovascular death (5 vs. 0; p = 0.024)

COLCOT trial

ACS

n = 4745

Placebo

Follow-up 22.6 months

Primary endpoint (CV death, ACS, cardiac arrest, stroke, coronary revascularization): 5.5% vs. 7.1%; p = 0.02

Significant higher rate of Pneumonia (0.9% vs. 0.4%; p = 0.03)
CCS = chronic coronary syndrome; ACS = acute coronary syndrome; GI = gastrointestinal; CV = cardiovascular; MI = myocardial infarction. A colchicine dose of 0.5 mg/24 h was used in all studies.
In a prespecified analysis included in the LoDoCo2 (Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease) trial [25], patients aged above 65 years showed greater benefits with colchicine compared to those below 65 years. No data regarding this subgroup of patients are available in the rest of the studies. These studies have contributed valuable insights into the potential benefits of colchicine in managing cardiovascular conditions, particularly in reducing adverse events and inflammation in patients with IHD. The last European Society of Cardiology on CV prevention in clinical practice publication suggested that high-risk CV disease patients could benefit from treatment with colchicine (0.5 mg daily) as secondary prevention if other risk factors are not controlled [31]. However, these results should be used with caution. Adverse effects (digestive intolerance, myalgias, and pneumonia) associated with the use of colchicine are not negligible. Considering the higher burden of associated comorbidities among older patients, its benefits and risks should be evaluated individually for each patient.

Methotrexate

After the CANTOS trial, the research in this field moved to find other drugs with a similar anti-inflammatory profile which might be inexpensive and more available. Low-dose methotrexate was proposed and evaluated in the CIRT (Cardiovascular Inflammation Reduction Trial) [32]. This was a randomized, double-blind, placebo-controlled, investigator-initiated trial that included patients with previous history of IHD and type 2 diabetes mellitus or the metabolic syndrome. The participants were randomly assigned to receive either low-dose methotrexate (with an initial dose of 15 mg) or a placebo. A total of 4786 participants were finally included in the study. After a median follow-up of 2.3 years, first occurrence after randomization of a final primary end-point event (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death, or hospitalization for unstable angina that led to urgent revascularization) was reported in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16; p = 0.67). There were no differences in any other prespecified CV end point or in any individual component of these end points. Rates of serious adverse events, including bleeding and infection, were similar in the two groups. Thus, low-dose methotrexate failed to decrease CV events at the follow-up in patients with IHD. Moreover, the administration of low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or CRP.

Ziltivekimab

Ziltivekimab, a novel IL-6 ligand inhibitor, has emerged as a potential therapeutic option for atherosclerotic disease. IL-6, a key cytokine in innate immunity, plays a pivotal role in the NLRP3 inflammasome pathway, linking to IL-1 and IL-6 and ultimately leading to the production of the inflammatory biomarker CRP (10). Ziltivekimab aims to disrupt these inflammatory pathways, particularly in the context of cardiovascular diseases. In the RESCUE trial, a randomized, double-blind, placebo-controlled phase 2 study, ziltivekimab demonstrated significant efficacy in reducing biomarkers of inflammation and thrombosis, including high-sensitivity CRP, fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein (a). The trial, conducted among individuals with chronic kidney disease and elevated CRP, showed dose-dependent reductions in these biomarkers over 24 weeks, with no significant adverse effects observed [33]. Importantly, the reduction in high-sensitivity CRP was notably larger than that achieved in the CANTOS trial using an upstream IL-1β inhibitor. These promising results have paved the way for the ZEUS trial. This large-scale cardiovascular outcome study aims to investigate the impact of ziltivekimab in patients with chronic kidney disease, elevated high-sensitivity CRP, and established cardiovascular disease. If confirmed in larger long-term trials, the safety and efficacy profile of ziltivekimab may position it uniquely among commercially available IL-6 inhibitors, offering a potential breakthrough in addressing residual inflammatory risk in atherosclerotic cardiovascular disease [34].

Others

Several other anti-inflammatory drugs have undergone clinical trials to assess their potential in preventing CV events in high-risk patients. However, none have succeeded in demonstrating significant CV benefits. Table 2 provides a summary of these trials [35][36][37][38][39][40].
Table 2. Summary of failed trials with other anti-inflammatory therapies [35][36][37][38][39][40].

Study

Drug

Population

Main Results

ARISE

Succinobucol

ACS

n = 6144

Failure to reduce fatal and non-fatal cardiovascular events in patients with recent ACS.

MRC-ILA Heart

Anakinra

ACS

n = 182

Reduction in inflammatory markers 14 days after ACS.

Excess of MACE events 1 year after the treatment.

SOLID-TIMI-52

Darapladib

ACS

n = 13,026

Failure to reduce major coronary events in patients with recent ACS.

STABILITY

Darapladib

CCS

n = 15,828

Failure to reduce fatal and non-fatal cardiovascular events in patients with CCS.

CCS = chronic coronary syndrome; ACS = acute coronary syndrome; GI = gastrointestinal; CV = cardiovascular; MI = myocardial infarction. A colchicine dose of 0.5 mg/24 h was used in all studies.

3. Lifestyle Modifications and Dietary Interventions

Not only have pharmacological therapies demonstrated efficacy in reducing inflammation, but lifestyle modifications and dietary interventions have also shown considerable promise [41][42]. These interventions hold substantial potential in mitigating the risks associated with IHD, and their benefits extend notably to older patients, positively impacting other associated conditions.
A sedentary lifestyle significantly contributes to several CV risk factors, such as type 2 diabetes mellitus, arterial hypertension, and metabolic syndrome, among others. The accumulation of visceral fat associated with overweight and obesity has been proposed as a proinflammatory source, leading to activation of inflammatory pathways though adipokines [43]. The prevalence of overweight/obesity continues to rise worldwide, and older people are also affected [44]. Among older adults, obesity not only impacts the CV system but also is associated with a higher prevalence of cancers, osteoarticular diseases, dementia, and depression [45]. It is mandatory for health professionals to be aware of this disease and fight to overcome its fatal complications.
Engaging in regular physical activity has proven to be a potent anti-inflammatory tool. Several mechanisms might explain the anti-inflammatory effect of exercise, such as the reduction in visceral fat mass and the increased production and release of anti-inflammatory cytokines from contracting skeletal muscle [46]. A recent metanalysis involving 1250 participants evaluated the effect of aerobic exercise on inflammatory markers in middle-aged and older adults [47]. Aerobic exercise had a positive effect on reduction in CRP, TNF-α, and IL-6 among older participants. On the other hand, a simple activity like walking has a positive impact on CV health. A recent study found that walking at least 3867 steps a day started to reduce the risk of dying from any cause, and 2337 steps a day reduced the risk of dying from CV diseases [48]. The more you walk, the greater the health benefits: an increase of 500 steps a day was associated with a 7% reduction in dying from cardiovascular disease. The positive effects of exercise are not only explained by a reduction in systemic inflammation but also by improvements in blood lipid profiles, endothelial function, and myocardial regeneration [46]. Thus, encouraging older patients with IHD to adopt a tailored exercise regimen, combining aerobic activities, resistance training, and flexibility exercises, can significantly improve overall CV health. Cardiac rehabilitation plays a central role in addressing this question. Evidence from randomized controlled trials and meta-analyses supports the efficacy of cardiac rehabilitation on clinically relevant outcomes such as reduced long-term morbidity and mortality [49]. However, older patients are frequently under-referred to cardiac rehabilitation due to clinical, social, or cultural barriers. This fact occurs despite evidence demonstrating the effectiveness of cardiac rehabilitation in the elderly [50][51][52].
Nevertheless, cardiac rehabilitation moves further exercise therapy, integrating other lifestyle modifications, such as dietary and stress management. Diets wield immense influence over individuals’ inflammatory status [41]. A Mediterranean-style diet that is rich in fruits, vegetables, whole grains, fish, and healthy fats (such as olive oil and nuts) has exhibited anti-inflammatory properties [53] and it has been associated with CV benefits in both primary and secondary prevention [54][55]. The PREDIMED (Prevención con Dieta Mediterránea) trial showed that the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet [54]. Similar results were observed in the CORDIOPREV (Coronary Diet Intervention with Olive oil and Cardiovascular Prevention study) trial in secondary prevention [55]. Encouraging older adults with IHD to embrace a Mediterranean diet can effectively lower inflammatory markers, reduce the risk of recurrent cardiac events, and improve long-term prognosis. Moreover, stress management techniques and sufficient sleep are integral components of lifestyle modifications that impact inflammation in IHD [56][57]. Chronic stress contributes to systemic inflammation, exacerbating CV risk [58]. Implementing stress-reduction techniques like mindfulness meditation, yoga, or deep breathing exercises can mitigate stress-induced inflammation [59][60].

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Subjects: Cardiac & Cardiovascular Systems
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Daniela Maidana
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Andrea Arroyo-Álvarez
,
Andrea Arenas-Loriente
,
Guillermo Barreres-Martín
,
Carles Muñoz-Alfonso
,
Daznia Bompart Berroteran
,
Francisca Esteve Claramunt
,
Regina Blanco del Burgo
,
Pedro Cepas-Guillén
,
Sergio Garcia-Blas
,
Clara Bonanad
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Update Date: 17 Jan 2024
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