Inflammation, anti-inflammatory agents, and the role of colchicine in carotid artery stenosis
Abstract
Summary: Cardiovascular disease is a major cause of morbidity and mortality worldwide. In the last few years, the role of inflammation and inflammatory modulatory medications is investigated for the optimal treatment of coronary artery disease. It can be hypothesized that since inflammation is also involved in carotid artery stenosis development and progression, the same class of medication could be useful. Our objective with this review is to present the available evidence, published studies and promising ongoing trials on the role of anti-inflammatory medications – with a special emphasis on the most commonly used drug of this class: colchicine – in patients with carotid artery stenosis.
Introduction
Cardiovascular disease and its main acute manifestations, acute coronary syndrome and stroke are the leading causes of mortality, morbidity, and disease burden globally [1]. Despite efforts to reduce the incidence of cardiovascular disease, recent epidemiological data reveal that the prevalence has doubled over the past three decades, affecting close to 523 million people. The risk factors for cardiovascular disease are well established and include aging, smoking, diabetes mellitus, hypertension, metabolic syndrome, and chronic inflammatory states [2, 3]. These factors have also been associated with an increased risk for carotid artery stenosis and subsequent ipsilateral cerebrovascular events.
Carotid artery stenosis encompasses the degenerative atherosclerotic changes of the vessel wall of the common and internal carotid artery resulting in turbulent flow, intima media thickening and increased carotid stiffness, which has been regarded as an independent risk factor associated with stroke [4]. It is well documented that unstable atherosclerotic plaques of the carotid arteries – especially in the internal common carotid arteries – can be a source of arterial embolization in up to 20% of ischemic stroke events, even in asymptomatic patients with the 15-year risk ranging from 5.7–16%, depending on the degree of the stenosis [5, 6, 7, 8]. For symptomatic carotid stenosis, (when there is strong evidence of clinical symptoms attributable to carotid artery stenosis within the past 6 months) the guidelines of the European Society of Cardiology suggest a threshold of 70% for revascularization, with either carotid endarterectomy or carotid artery stenting, while promising results have also been reported with the transcervical method and preoperative statin administration [9, 10, 11]. Moreover, for symptomatic stenosis >50% and for asymptomatic carotid stenosis >60% and with a life expectancy more than 5 years, revascularization could prove beneficial, even in radiation-induced cases, given that ≥50% stenosis has a reported annual risk of cerebrovascular accidents of 0.34% and an annual transient ischemic attack risk of 1.78% [11, 12, 13, 14, 15].
Strong evidence from recent studies suggests that atherosclerosis is orchestrated by the action of the inflammatory cytokines produced by immune cells and that the inhibition of these signaling pathways can lead to a reduction in cardiovascular events [16, 17]. This has led to increasing interest in the use of anti-inflammatory medications for the prevention of ischemic cardiac disease [18, 19]. The same class of medications have also been proposed for carotid artery stenosis, a different manifestation of atherosclerosis, when the carotid arteries are affected and become stenotic, albeit with a different outcome, manifesting as ischemic stroke rather than myocardial infarction. Colchicine, a medication that was traditionally used to treat acute gout flares and now has a known beneficial effect in coronary artery disease, as part of its anti-inflammatory properties, has also shown promise in slowing the progression of carotid artery stenosis and potentially reducing the overall stroke risk [20].
Our objective in this review is to examine the existing literature regarding the inflammatory process of atherosclerosis in carotid artery stenosis and overview available medications with an emphasis on the tubulin polymerization inhibitor, colchicine.
Carotid artery stenosis and inflammation
Carotid artery stenosis pathophysiology is intertwined with atherosclerosis. Contemporary evidence supports the fact that inflammation has a critical role in almost every stage of atherosclerosis from endothelial dysfunction to enzymatic degradation of the fibrous cap [21, 22, 23]. In more detail, chronic endothelial stress (e.g. frictional force of turbulent flow stemming from chronic hypertension) damages the endothelium in lesion-prone areas and eventually induce a state of dysfunction. The secreted chemokines recruit monocytes, which infiltrate and undergo differentiation into macrophages, while also the PDGF secreted by adhered platelets induces a smooth muscle cell recruitment. Macrophages and smooth muscle cell ingest cholesterol from the oxidized LDL and become foam cells. This leads to a marked increase in the thickness of the inner arterial wall due to a cellular component from the infiltration of immune cells, smooth cells, and an inorganic component from protein, lipid and calcium deposits, forming the “fatty streak” a hallmark of an early atherosclerotic lesion [24].
Furthermore, the inflammatory mediators from the activated endothelium, platelets and lipid-laden macrophages interact with the smooth muscle cells and both activate intracellular pathways to produce extracellular matrix. All these components constitute to the reduction of the arterial caliber and the development of the fibrous plaque (or atheroma) with two main components: the fibrous cap (constituted by cellular components and extracellular matrix) and a necrotic core which includes oxidized and free lipid crystals, cellular debris and foam cells [25]. Subsequent, matrix metalloproteinases secreted by activated inflammatory cells in the atheroma, in combination with smooth muscle cell apoptosis, weaken the fibrous cap by extracellular matrix breakdown [2, 26]. Prone to rupture plaques, also known as “unstable or vulnerable plaques,” have a thin fibrous cap in combination with an increased intraplaque inflammatory process [27]. On the other hand, stable plaques are the ones with a thicker fibrous cap, little to none intraplaque inflammation and diffuse calcification of the intima.
Unstable plaques are prone to the catastrophic event of rupture even at sites of mild to moderate degree of stenosis of <50% which releases highly thrombogenic materials to the circulation and starts a cascade that leads to thrombotic occlusion or even thromboembolic sequela [28]. The ultimate end road of atherosclerotic diseases is myocardial infarction, sudden death and stroke [29].
Nevertheless, the identification of asymptomatic patients with vulnerable plaques, at early stages would aid in the tailoring of individualized treatment plan, evaluate the response to therapy and pave the way towards personalized medicine. For this reason, several inflammatory biomarkers have been recently proposed (hs-CRP, IL-6, pentraxin 3, etc.) for disease progression and follow-up, albeit with mixed results [30, 31, 32]. In addition, after articles highlighted their prognostic value in systemic inflammatory diseases and major surgeries, new studies have underlined the positive association between admission hematologic parameters: neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with sub-clinical atherosclerosis, carotid intima-media thickness (the area of tissue starting at the luminal edge of the artery and ending at the boundary between the media and adventitia, in B-mode ultrasound), atheromatous plaque vulnerability and worse outcomes in carotid stenting and carotid endarterectomy [33, 34, 35, 36, 37].
Furthermore, detection and quantification of the degree of inflammation has also been attracting attention with the usage of novel imaging techniques such as 18F-FDG PET/CT [38]. A higher FDG tracer uptake has been observed for actively metabolic plaques (unstable plaques), in accordance with the extent of the intra-plaque inflammatory processes. This differentiation could evaluate the risk in patients with a vulnerable plaque and stratify it with the risk of available treatment options. However, large scale studies are still required to solidify these findings [39].
Anti-inflammatory medications in coronary artery disease
It is evident that inflammation plays a pivotal role in atherosclerosis. In patients with systemic inflammatory diseases, such as rheumatoid Arthritis (RA), the classic risk factors for cardiovascular disease (smoking, reduced physical activity, dyslipidemia, high blood pressure, diabetes, body weight and composition) cannot fully explain the observed cardiovascular morbidity and mortality [16]. This could be due to the increased inflammatory load and circulating cytokines in such states that could further exacerbate the already existing endothelial dysfunction, resulting in aggressive atherosclerosis progression, increased carotid intima-media thickness and plaque destabilization [40, 41]. This results in higher risk for cardiovascular diseases in such populations [42, 43].
The landmark Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS trial) was designed to assess the inflammatory hypothesis of atherosclerosis. IL-1β inflammatory pathway inhibition with a monoclonal antibody (canakinumab) produced 15% reduction of cardiovascular risk, however the incidence rate per 100 person-years for any stroke events was non-significant in comparison to placebo [17]. Many novel targeted therapies ensued, such as the Cardiovascular Inflammation Reduction Trial (CIRT), which in patients with stable atherosclerosis, tested low dose methotrexate versus placebo. The study was halted at a median 2.3 years of follow-up since preliminary results found there was no reduction in IL-1β, IL-6 and C-reactive protein and cardiovascular events. In addition, there was no difference of non-fatal stroke incidence between the two groups [18].
Colchicine and coronary artery disease
In the light of these conflicting results as well as in combination with the fact that canakinumab has not been approved for cardiovascular diseases, researchers have turned their attention to alternative, inexpensive, thorough studied and relatively well tolerated anti-inflammatory drugs, such as colchicine. Colchicine is an alkaloid, derived from the plant Colchicum autumnale (Autumn Crocus) with the earliest report of its usage as a medication dating as far back as 1.500 B.C. to treat joint inflammation. Today, colchicine has been approved by the Food and Drug Administration (FDA) for autoinflammatory diseases like Behçet’s disease, pericarditis and Familial Mediterranean Fever (FMF) and for gout arthritis flare ups. Colchicine exerts its anti-inflammatory actions in the immune cells through multiple pathways (Figure 1). Firstly, it disrupts the microtubule assembly dynamics and thus inhibits movement, phagocytic and mitotic properties of the immune cells [44]. Secondly, it has been shown to downregulate the expression of E-Selectin on endothelial cells, and L-Selectin in the cytoplasmic membrane of neutrophils preventing their attachment, invasion at the site of inflammation and subsequent release of cytokines, proteolytic enzymes and reactive oxygen species [45]. Lastly, it indirectly inhibits the release of IL-1β by interfering with the formation of NLRP3 inflammasome, which may further explain its anti-atheromatic properties when considering the results of the CANTOS trial [46].
Several studies have tested the efficacy of colchicine as an additional regimen post myocardial infarction. The largest of them all was the Colchicine Cardiovascular Outcomes Trial (COLCOT) in which 4.575 patients were randomized to either receive colchicine or placebo in a post-acute MI setting, including ischemic stroke events [47]. Of note, colchicine treatment was associated with a significant risk reduction of ischemic cardiovascular events. Furthermore, its effect on chronic cardiac disease was tested in the Low-Dose Colchicine 2 (LoDoCo-2) trial which included 5.500 patients. The study replicated the results of COLCOT, underscoring a reduction of the risk for cardiovascular events in the colchicine group, but the risk reduction for ischemic stroke events was non-significant [48].
The comparison of colchicine vs. placebo administration was evaluated in a meta-analysis by Koefler et al., which included 13.125 patients from 13 RCTs [49]. The study underlined the association of colchicine with reduced odds for myocardial infarction (OR: 0.64; 95% CI: 0.46–0.90, p-value <0.05) and ischemic cerebrovascular events (OR: 0.50, 95% CI: 0.31–0.81, p-value <0.05) with low study heterogeneity. However, it was also associated with an increased risk for gastrointestinal drug adverse effects (DAEs), mainly diarrhea, which was mitigated with a reduction of the dosage. The meta-analysis results were confirmed by subsequent studies of Andreis et al. and Xu et al., who also reported no significant difference of the pooled risk ratio for all-cause mortality, with the latter reporting no difference in the risk of drug adverse effects in the colchicine group in comparison to placebo [50, 51]. The results were replicated in another meta-analysis by Wan et al. which underscored that in patient with gout treated with colchicine the odds for MI were significantly lower in the intervention arm than placebo (OR: 0.35, 95% CI: 0.23–0.55, p-value <0.05) [52] (Table I).
Anti-inflammatory medication in carotid artery stenosis
Anti-inflammatory medications have been also tested in specific populations for carotid artery stenosis progression. In more detail, an RCT with patients with active RA evaluated the effect of puerarin, an isoflavoid glycoside carotid intima-media thickness progression. After 2 years of follow up, puerarin was found to halt cIMT progression and was even associated with improved insulin resistance [53].
Furthermore, results of colchicine in coronary artery disease have fueled the research interest to assess whether they can also translate to the carotid artery disease as well, since they share a common pathophysiological background in the face of atherosclerosis. A population that has been well studied is patients with FMF in which there is an indication for administration colchicine. FMF patients have increased carotid intima media thickness and are at an increased risk for cardiovascular events, due to the inflammatory nature of the disease [54]. Sgouropoulou et al. observed a normal carotid-femoral pulse-wave velocity in a cohort of FMF patients, possibly due to colchicine treatment [55]. Vampertzi et al. in a study with pediatric population observed no difference in the vascular parameters between FMF and healthy control group, which was also attributed to the cardioprotective role of regular colchicine [56]. Furthermore, in a retrospective study by Yilmaz et al., which included patients with chronic diseases who were on colchicine for gout vs. non-colchicine group, colchicine was associated with reductions in the carotid intima-media thickness and CRP in comparison to the control group [20] (Table II).
Additionally, the effect of colchicine in cerebrovascular accidents (a devastating sequalae of carotid artery stenosis) has also been a matter of research interest. In cerebrovascular infarction, the abrupt reduction of blood flow in combination with release of damage associated molecular patterns from the lysed cells, may trigger inflammatory pathways that may exacerbate the brain damage [57]. In an animal-based study by Wilkinson et al. the anti-inflammatory properties of colchicine were tested for its effect on post intracerebral hemorrhage inflammation. The study underscored a reduction of the post-hematoma zone without increasing bleeding risk [58]. Moreover, Goh et al. conducted a meta-analysis of patients with coronary artery disease, evaluating the pooled result of 5 RCTs estimating the effect of daily 0.5 mg of colchicine in the incidence of stroke. The results highlighted significant reduction of stroke in the intervention group vs. control (OR: 0.47, 95% CI: 0.27–0.81, p-value <0.01), without increase in gastrointestinal irritation incidence or myopathy due to statin coadministration [59]. The results were consistent with a subsequent meta-analysis by Bao et al., which however pointed a significance of DAE in the colchicine group [60].
The role of colchicine regarding the incidence of stroke, irrespective of coronary artery disease status is currently being investigated in the Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE trial) [61]. This multicenter trial investigates the potential protective role of colchicine in the secondary prevention of major adverse cardiovascular and cerebrovascular events, in patient who suffered from an ischemic stroke or transient ischemic attack which was not caused by a heart related embolus (Table III).
Upcoming trials
It is without doubt that the current fund of knowledge concerning the effects of colchicine in cardiovascular disease is indeed promising, since it has been consistently shown to reduce the risk for cardiovascular events. Nevertheless, apart from the CONVINCE trial, further randomized studies, tailored to the research question regarding its role in carotid artery stenosis and subsequent cerebrovascular accident events are still needed to assess whether these results can be replicated. In this context, there are several ongoing studies that could shed some light regarding its implacability.
Moreover, the pilot study Colchicine for the Prevention of Vascular Events After an Acute Intracerebral Hemorrhage (CoVasc-ICH trial) is designed based on the hypothesis that perihematomal inflammation has a key role in the risk for additional cerebrovascular events and that colchicine may mitigate it (ClinicalTrials.gov Identifier: NCT05159219). The trial will randomize 100 patients to receive 0.5 mg/day of colchicine (P.O.) or placebo to assess for major cardiovascular events and brain injury. Lastly, the Colchicine in High-risk Patients With Acute MiNor-to-moderate IschemiC Stroke or TransiEnt Ischemic Attack (CHANCE-3) trial is an ongoing multicenter randomized controlled trial aiming to investigate the effect of colchicine in stroke recurrence in patients with history of acute minor-to-moderate ischemic stroke or transient ischemic attack (ClinicalTrials.gov Identifier: NCT05439356).
Limitations
This narrative review is not without certain limitations. Despite efforts to conduct a comprehensive literature search, there is a possibility of selection bias, as the inclusion and exclusion of studies may introduce a certain degree of subjectivity. However, to minimize this limitation, the MEDLINE, EMBASE and the Central Library were searched for studies evaluating the role of colchicine in cardiovascular and cerebrovascular disease. Primary, secondary, and tertiary articles were retrieved from these results and evaluated for inclusion based on relevance.
Conclusions
The promising results of colchicine administration for cardiovascular diseases has been getting a lot of traction and has advanced it into a potential candidate for the prevention of coronary artery disease. Nonetheless, before its translation in the current clinical setting for the additional indication in prevention of carotid artery stenosis and stroke incidence, further information from specifically designed randomized studies is still required.
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