Effect of short-term colchicine treatment on endothelial function in patients with coronary artery disease.
Kajikawa Masato,Higashi Yukihito,Tomiyama Hirofumi,Maruhashi Tatsuya,Kurisu Satoshi,Kihara Yasuki,Mutoh Akiko,Ueda Shin-Ichiro
International journal of cardiology
BACKGROUND:Inflammation is associated with endothelial dysfunction and plays an important role in the pathogenesis and development of cardiovascular diseases. It has been shown that colchicine, an anti-inflammatory drug, improves the cardiovascular outcome in patients with cardiovascular disease. The purpose of this study was to evaluate the short-term effect of low-dose colchicine on endothelial function in patients with coronary artery disease (CAD). METHODS:This was a double-blind, randomized, placebo-controlled, crossover-within-subject clinical trial. A total of 28 patients with CAD received low-dose colchicine (0.5 mg/day) or a placebo for 7 days with a washout period of at least 14 days. Flow-mediated vasodilation (FMD) and serum concentrations of high-sensitivity C-reactive protein (hs-CRP) were measured after the 7-day treatment with colchicine or the placebo. RESULTS:The serum concentration of hs-CRP was significantly decreased after administration of colchicine compared with that after administration of the placebo [median (interquartile range): 0.04 (0.02-0.08) mg/dL vs. 0.07 (0.04-0.11) mg/dL, P = 0.003], while there was no significant difference in FMD between the treatments [median (interquartile range): 3.1% (1.5-5.3%) vs. 3.3% (1.9-5.2%), P = 0.384]. Colchicine, however, significantly improved FMD in coronary artery disease patients with white blood cell (WBC) counts of ≥7500 WBC/mm [median (interquartile range): 3.3% (2.1-6.6%) vs. 2.0% (1.4-3.8%), P = 0.043]. CONCLUSIONS:Administration of low-dose colchicine did not improve endothelial function in patients with CAD, but exploratory analysis suggested that endothelial function is significantly improved in patients with leukocyte activation.
Evaluation of the mean platelet volume in children with familial Mediterranean fever.
Arıca Seçil,Ozer Cahit,Arıca Vefik,Karakuş Ali,Celik Tanju,Güneşaçar Ramazan
To evaluate the Mean Platelet Volume (MPV) levels in children diagnosed with familial Mediterranean fever (FMF), during attack and attack-free periods. The records of a total of 117 children with FMF, diagnosed using the Tel-Hashomer criteria, have been scanned. The study consisted of 53 patients during an attack (group 1), 64 patients in attack-free period (group 2), and 57 healthy controls (group 3). Erythrocyte sedimentation rate, C-reactive protein, white blood cell count, platelet count, and MPV levels were retrospectively recorded. The MPV and platelet values in FMF patients during attack (group 1) and FMF patients during attack-free periods (group 2) have been found to be significantly higher than those of the health control group (group 3). Positive correlation has been found between the MPV and platelet values in Group 1 and the disease's severity score (r = 0.224, and r = 0.268, respectively). Positive correlation (r = 0.528, and r = 0.485, respectively) has been also identified between MPV and blood platelet count in patients in Group 1 and 2. No correlation was found between the Colchicine treatment period and MPV (r = -0.005). The MPV values in the complete group of FMF diagnosed children have been found to be much higher compared to those in healthy children. As a consequence, we consider the MPV value as a useful marker that demonstrates the risk of early stage atherosclerosis in children with FMF.
Targeting the unstable plaque in acute coronary syndromes.
Thompson Peter L,Nidorf S Mark,Eikelboom John
BACKGROUND:Rupture or erosion of an unstable atherosclerotic plaque is the typical pathology and usual cause of acute coronary syndromes. Despite detailed understanding of the processes of lipid accumulation, thinning of the fibrous cap, and inflammation leading to plaque instability, there are no strategies in clinical use that uniquely target the unstable plaque. OBJECTIVE:A critical review of recent publications on potential therapies that could be used to stabilize unstable plaque. METHODS:We searched PubMed, other literature databases, drug development sites, and clinical trial registries to retrieve clinical studies on anti-inflammatory and lipid-modulating therapies that could be used to stabilize unstable atherosclerotic plaque. RESULTS:Multiple experimental targets involving lipid and inflammatory pathways have the potential to stabilize the plaque and expand the armamentarium against coronary artery disease. Randomized clinical trials of darapladib, methotrexate, canakinumab, and colchicine are well advanced to establish if plaque stabilization is feasible and effective in patients with acute coronary syndromes. CONCLUSIONS:Although there are still no agents in clinical use for plaque stabilization, there are important advances in understanding plaque instability and several encouraging approaches are being evaluated in Phase III clinical trials.
Prominent inhibitory effects of tranilast on migration and proliferation of and collagen synthesis by vascular smooth muscle cells.
Tanaka K,Honda M,Kuramochi T,Morioka S
To obtain some ideas about prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA), we examined the effects of transilast (anti-allergic agent) on migration and proliferation of, and collagen synthesis by, cultured vascular smooth muscle cells (VSMC) from the thoracic aorta of WKY rats. Tranilast was added to culture medium containing 10% fetal calf serum (FCS). The cultures were pulse-labeled with 3H-thymidine (TdR) or 3H-proline (Pro). TdR and Pro uptake into VSMC were measured. The effect of tranilast on migration of VSMC was examined by using culture dishes of an original design. We also examined the inhibitory effects of various drugs, such as a Ca antagonist, an angiotensin converting enzyme (ACE) inhibitor, a phosphodiesterase inhibitor, elastase, colchicine, and mitomycin C, on proliferation and migration of VSMC. Our data showed that the inhibitory effects of tranilast on migration and proliferation of, and collagen synthesis by, VSMC were prominent. Maximal percentage inhibition of proliferation, migration and collagen synthesis was 60.8 +/- 2.3%, 52.7 +/- 14.7% and 62.1 +/- 8.1%, respectively. On the other hand, the inhibitory effects of other drugs, with the exception of colchicine and mitomycin C, on proliferation and/or migration of VSMC were not very strong. Although the inhibitory effects of colchicine and mitomycin C were strong in vitro, their clinical usefulness may be limited by systemic side-effects. These results indicate the potential usefulness of tranilast for prevention of restenosis of coronary arteries after PTCA.
Anti-inflammatory agents in peripheral arterial disease.
Antonopoulos Alexios S,Papanikolaou Evi,Vogiatzi Georgia,Oikonomou Evangelos,Tousoulis Dimitris
Current opinion in pharmacology
Inflammation is pivotally involved in coronary and peripheral atherosclerotic disease. This established concept is based on both experimental animal models of vascular inflammation and Mendelian randomization studies demonstrating a causal relationship between pro-inflammatory cytokines (e.g. interleukin-6) and cardiovascular disease risk. More recently, the reduction of cardiovascular events by use of an interleukin-1β inhibitor (canakinumab) has revived interest in the use of anti-inflammatory agents for the treatment of atherosclerotic disease, including peripheral arterial disease. In this mini review article we provide an update on the pleiotropic anti-inflammatory properties of approved drugs for use in cardiovascular disease (e.g. antiplatelets, statins, PCSK9 inhibitors) and discuss the role of targeted or untargeted anti-inflammatory atheroprotection in peripheral arterial disease by agents such as colchicine, methotrexate, anti-TNF-α agents and monoclonal antibodies against interleukin-signaling.
[Update on cholesterol crystal embolism].
Denis Le Seve J,Gourraud Vercel C,Connault J,Artifoni M
La Revue de medecine interne
Cholesterol crystal embolism is a systemic pathology associated with diffuse atherosclerosis. Pathophysiology corresponds to tissue necro-inflammation secondary to arteriolar occlusion associated with microembolism from atherosclerotic plaques of large diameter arteries. The clinical presentation is heterogeneous and polymorphic. Multiple organs may be the targets, but preferential damage is skin, kidneys and digestive system. It is a serious pathology, underdiagnosed, with a poor prognosis. The risk factors for developing the disease remain the same risk factors as atheroma. The factors favouring migration of microembolism remain mainly vascular interventional procedures; easy to diagnose, they oppose spontaneous embolic migrations or secondary to the introduction of antithrombotic treatment, whose diagnosis is more difficult and the prognosis more severe. The diagnosis of the disease remains mostly a diagnosis of elimination and often refers to a bundle of clinical, biological, morphological and histologic arguments. The treatment is poorly codified and the subject of few publications. It will favour both symptomatic treatment (and mainly that of pain) and complications (high blood pressure, renal insufficiency). The aetiological support remains less consensual. The treatment of atherosclerotic plaques consists, of course, in the correction of classical cardiovascular risk factors, the introduction of a statin. It will be discussed in the implementation of surgery or angioplasty to exclude potentially responsible atherosclerotic lesions. Eviction of antithrombotic therapy should be considered in terms of the benefit-risk balance, but often in favour of maintaining it. Finally, other treatments may be proposed in a case-by-case basis, such as oral or intravenous corticosteroid therapy, colchicine or LDL aphaeresis.
Targeting Inflammation to Reduce Residual Cardiovascular Risk.
Ajala Oluremi N,Everett Brendan M
Current atherosclerosis reports
PURPOSE OF REVIEW:Patients with established cardiovascular disease are at high risk for recurrent myocardial infarction, stroke, and cardiovascular death. The term residual risk refers to this risk that persists, even after optimal treatment. Considerable progress has been made to understand the biological basis of residual risk and to devise therapies that can safely and effectively reduce risk. The presence of ongoing subclinical vascular inflammation is known to be a marker of elevated residual risk, and reductions in measures of vascular inflammation predict improved outcome in these patients. RECENT FINDINGS:Recent trials of anti-inflammatory agents have specifically tested the hypothesis that inflammation reduction reduces residual cardiovascular risk. Most prominent among these are the CANTOS, COLCOT, and CIRT trials. CANTOS enrolled patients with prior myocardial infarction (MI) and a high-sensitivity C-reactive protein ≥ 2 mg/L and reported a 15% reduction in major adverse cardiovascular events (MACE; HR 0.85, 95% CI 0.74-0.98) with the interleukin-1β inhibitor canakinumab. In COLCOT, colchicine 0.5 mg daily led to a 23% relative risk reduction (HR 0.77, 95% CI 0.61-0.96) in major vascular events in patients with recent acute coronary syndrome. By contrast, CIRT was stopped early for lack of benefit of low-dose methotrexate in preventing MACE in patients with coronary artery disease and either type 2 diabetes or the metabolic syndrome. Ongoing subclinical inflammation is an important marker of risk in patients with established cardiovascular disease, and novel therapies targeted at specific inflammatory pathways now demonstrate efficacy for the prevention of major adverse cardiovascular events.
Inflammation and cardiovascular diseases: lessons from seminal clinical trials.
Liberale Luca,Montecucco Fabrizio,Schwarz Lena,Lüscher Thomas F,Camici Giovanni G
Inflammation has been long regarded as a key contributor to atherosclerosis. Inflammatory cells and soluble mediators play critical roles throughout arterial plaque development and accordingly, targeting inflammatory pathways effectively reduces atherosclerotic burden in animal models of cardiovascular (CV) diseases. Yet, clinical translation often led to inconclusive or even contradictory results. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) followed by the Colchicine Cardiovascular Outcomes Trial (COLCOT) were the first two randomized clinical trials (RCTs) to convincingly demonstrate the effectiveness of specific anti-inflammatory treatments in the field of CV prevention, while other phase III trials - including the Cardiovascular Inflammation Reduction Trial (CIRT) one using methotrexate - were futile. This manuscript reviews the main characteristics and findings of recent anti-inflammatory phase III trials in cardiology and discusses their similarities and differences in order to get further insights into the contribution of specific inflammatory pathways on CV outcomes. CANTOS and COLCOT demonstrated efficacy of two anti-inflammatory drugs (canakinumab and colchicine, respectively) in the secondary prevention of major adverse CV events (MACE) thus providing the first confirmation of the involvement of a specific inflammatory pathway in human atherosclerotic CV disease (ASCVD). Also, they highlighted the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-related pathway as an effective therapeutic target to blunt ASCVD. In contrast, other trials interfering with a number of inflammasome-independent pathways failed to provide benefit. Lastly, all anti-inflammatory trials underscored the importance of balancing the risk of impaired host defence with an increase in infections and the prevention of MACE in CV patients with residual inflammatory risk.
Effect of colchicine on atherosclerosis. III. Study of dermal elastic fibers by quantitative histochemistry, automated image analysis.
Godeau G,Gonnord G,Wegrowski J,Pompidou A,Schovaert D,Robert L,Lagrue G,Robert A M
Clinical physiology and biochemistry
Computerized automatic-image analytical procedure was applied on dermal biopsies stained for elastin by a new procedure giving a completely white background and staining only the elastic fiber system. In arteriosclerotic hypertensive patients, a 3-4 months' treatment with 1 mg colchicine per day resulted in a significant (60-80%, p less than 0.01) increase of the dermal elastic fiber density both in the superficial papillary dermis and in the deep dermis. This result shows that the age-dependent increase of elastic fibers can be influenced by pharmacological means. The inhibition by colchicine of the synthesis and secretion of the fibroblast-derived metalloelastase-type protease could be a plausible explanation of this finding.
Effect of colchicine on atherosclerosis. I. Clinical and biological studies.
Lagrue G,Wegrowski J,Rhabar K,Meyer-Heine A,Balanger S,Robert A M,Robert L
Clinical physiology and biochemistry
The effect of colchicine was studied in 51 hypertensive subjects with several other vascular risk factors. Colchicine was administered for 3-4 months in a daily dose of 1 mg per os. The treatment did not change the lipid content in the blood and in skin biopsies, and had no effect on systolic and diastolic blood pressure. On the contrary, colchicine treatment significantly improved the conjunctival biomicroscopy score, the duration of the dicrotic wave and the peripheral resistance index. The results show the improvement of the microcirculatory parameters (elasticity of arteries) without changes of serum and tissue lipid parameters in the patients treated with colchicine.
Mean platelet volume in children with familial Mediterranean fever.
Makay Balahan,Türkyilmaz Zeynep,Unsal Erbil
Familial Mediterranean fever (FMF) is the most common inherited periodic fever syndrome characterized by recurrent episodes of serositis. Recently, a few studies have suggested that FMF is related to increased risk of atherosclerosis. Mean platelet volume (MPV) is a marker of platelet activation. Larger platelets are associated with increased atherosclerosis risk. The aim of the study is to evaluate levels of MPV in pediatric FMF patients during and between attacks. The study consisted of 48 patients during an attack (group 1), 63 patients in attack-free period (at least 2 weeks after an attack, group 2), and 49 healthy controls (group 3). Erythrocyte sedimentation rate, C-reactive protein, white blood cell count, platelet count (PLT), and MPV levels were retrospectively recorded from the computerized patient database. Mean platelet volume was significantly lower in FMF patients during attack than in attack-free period (p = 0.00); however, there was no difference among attack-free patients and healthy controls (p = 0.38). The mean platelet counts of FMF patients during attack were higher than the healthy controls (p = 0.02). There was an inverse correlation between MPV and mean PLT in the attack-free period (r = -446, p = 0.01). This study suggests that an early atherosclerosis marker, MPV, is not elevated in pediatric FMF patients on colchicine treatment.
Assessment of epicardial adipose tissue thickness and the mean platelet volume in children with familial Mediterranean fever.
Uluca Ünal,Demir Fikri,Ece Aydın,Şen Velat,Güneş Ali,Aktar Fesih,Tan İlhan,Karabel Duran,Yazgan Ümitcan,Sabaz Muhammed Nurullah
Italian journal of pediatrics
BACKGROUND:Familial Mediterranean fever (FMF) is an inflammatory disease, which is suggested to be associated with increased risk of atherosclerosis. Epicardial adipose tissue (EAT) thickness and the mean platelet volume (MPV) are parameters used in prediction of atherosclerotic risk in various conditions. These parameters were evaluated in children with FMF and compared with healthy controls. METHODS:Forty-five patients with FMF and 54 age- and gender-matched healthy controls were assessed. Duration of symptoms, age at diagnosis, duration of delay in diagnosis, frequency and duration of FMF attacks, disease severity scores, response to colchicine therapy, MEditerraneanFeVer (MEFV) gene mutations, and MPV values were recorded. EAT thicknesses were measured by echocardiography. RESULTS:Epicardial adipose tissue thicknesses of the children with FMF were found to be significantly greater than that of controls (5.1 ± 1.4 vs. 4.5 ± 0.9 mm, p=0.036). FMF patients had significantly higher MPV values compared with the controls (7.8 ± 1.1 vs. 7.3 ± 1.4 fl, p=0.044). Age at diagnosis, duration of delay in diagnosis, and MPV values were found to be correlated with EAT thickness in the patient group (r=0.49, p=0.001 for the former parameters and r=0.32, p=0.04 for MPV). CONCLUSION:Epicardial adipose tissue thickness and MPV values seem to be increased in children with FMF. These findings may indicate an increased risk of atherosclerosis in FMF patients.
Effect of colchicine on atherosclerosis. II. Biochemical studies on skin biopsies from patients treated perorally with colchicine.
Wegrowski J,Moczar M,Lagrue G,Rhabar K,Robert A M,Robert L
Clinical physiology and biochemistry
The biosynthesis of proteins and glycosaminoglycans (GAGs) was determined in skin biopsies from atherosclerotic patients treated perorally for 3 months with 1 mg/day colchicine. The biopsies were incubated with 3H-glucosamine and 14C-proline for 5 h and subsequently digested with pronase. In an aliquot of the pronase digest, the specific radioactivity of 14C-proline and 14C-hydroxyproline were determined. The 3H-glucosamine-labeled GAGs were identified by specific enzymic assay and quantified after electrophoretic separation. 3 months treatment with colchicine did not modify the total amounts of proline and hydroxyproline in skin proteins, but diminished the amount of the GAGs as expressed by uronic acid content. Colchicine treatment decreased also the specific radioactivity of proline and hydroxyproline, which reflects a decrease of total protein and collagen synthesis. The incorporation of 3H-glucosamine in the 3H-GAGs was also decreased, mainly in hyaluronic acid. These results suggest that peroral administration of colchicine modifies the synthesis of extracellular matrix proteins and polysaccharides by skin fibroblasts.
Effects of methyl prednisolone and colchicine on the development of aortic atherosclerosis in swine.
Lee W M,Morrison E S,Scott R F,Lee K T,Kroms M
The effect of methyl prednisolone and colchicine on the development of both the early proliferative and advanced atherosclerotic lesion in swine aorta was studied. In order to accelerate the development of atherosclerosis, the abdominal aortic endothelium was partially denuded by a balloon before the animals were placed on either a moderate or severe hypercholesterolemic diet. Neither drug in either dietary group inhibited the development of atherosclerosis. Swine receiving methyl prednisolone and severe hypercholesterolemic diet actually had a significantly greater number of the advanced necrotic lesions and more arterial calcification than the group receiving the atherogenic diet alone. In addition, the thoracic aorta of swine receiving the moderate hypercholesterolemic diet and methyl prednisolone showed larger amounts of lipid than did the non-drug fed control group. In swine receiving the moderate hypercholesterolemic diet, methyl prednisolone significantly raised serum cholesterol levels. Colchicine only slightly worsened the atherosclerosis in swine aorta and had no effect on serum cholesterol levels.
From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection.
Ridker Paul M
Plasma levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or high-density lipoprotein cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of low-density lipoprotein cholesterol. Yet, although hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to interleukin (IL)-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1β-producing NOD-like receptor family pyrin domain containing 3 inflammasome. Cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia activate the NOD-like receptor family pyrin domain containing 3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker for upstream IL-1β activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute-phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with little change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10 065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials using alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis, including low-dose methotrexate and colchicine, are being explored. If successful, these trials will close the loop on the inflammatory hypothesis of atherosclerosis and serve as examples of how fundamental biologic principles can be translated into personalized medical practice.
A link between inflammation and thrombosis in atherosclerotic cardiovascular diseases: Clinical and therapeutic implications.
Oikonomou Evangelos,Leopoulou Marianna,Theofilis Panagiotis,Antonopoulos Alexios S,Siasos Gerasimos,Latsios George,Mystakidi Vasiliki Chara,Antoniades Charalambos,Tousoulis Dimitris
The association between thrombosis and acute coronary syndromes is well established. Inflammation and activation of innate and adaptive immunity are another important factor implicated in atherosclerosis. However, the exact interactions between thrombosis and inflammation in atherosclerosis are less well understood. Accumulating data suggest a firm interaction between these two key pathophysiologic processes. Pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin-6 and interleukin-1, have been implicated in the thrombotic cascade following plaque rupture and myocardial infarction. Furthermore, cell adhesion molecules accelerate not only atheromatosis but also thrombosis formation while activated platelets are able to trigger leukocyte adhesion and accumulation. Additionally, tissue factor, thrombin, and activated coagulation factors induce the release of pro-inflammatory cytokines such as prostaglandin and C reactive protein, which may further induce von Willebrand factor secretion. Treatments targeting immune activation (i.e. interleukin-1 inhibitors, colchicine, statins, etc.) may also beneficially modulate platelet activation while common anti-thrombotic therapies appear to attenuate the inflammatory process. Taken together in the context of cardiovascular diseases, thrombosis and inflammation should be studied and managed as a common entity under the concept of thrombo-inflammation.
Anti-inflammatory therapies for cardiovascular disease.
Ridker Paul M,Lüscher Thomas F
European heart journal
Atherothrombosis is no longer considered solely a disorder of lipoprotein accumulation in the arterial wall. Rather, the initiation and progression of atherosclerotic lesions is currently understood to have major inflammatory influences that encompass components of both the innate and acquired immune systems. Promising clinical data for 'upstream' biomarkers of inflammation such as interleukin-6 (IL-6) as well as 'downstream' biomarkers such as C-reactive protein, observations regarding cholesterol crystals as an activator of the IL-1β generating inflammasome, and recent Mendelian randomization data for the IL-6 receptor support the hypothesis that inflammatory mediators of atherosclerosis may converge on the central IL-1, tumour necrosis factor (TNF-α), IL-6 signalling pathway. On this basis, emerging anti-inflammatory approaches to vascular protection can be categorized into two broad groups, those that target the central IL-6 inflammatory signalling pathway and those that do not. Large-scale Phase III trials are now underway with agents that lead to marked reductions in IL-6 and C-reactive protein (such as canakinumab and methotrexate) as well as with agents that impact on diverse non-IL-6-dependent pathways (such as varespladib and darapladib). Both approaches have the potential to benefit patients and reduce vascular events. However, care should be taken when interpreting these trials as outcomes for agents that target IL-6 signalling are unlikely to be informative for therapies that target alternative pathways, and vice versa. As the inflammatory system is redundant, compensatory, and crucial for survival, evaluation of risks as well as benefits must drive the development of agents in this class.
Inflammatory cytokines in atherosclerosis: current therapeutic approaches.
Tousoulis Dimitris,Oikonomou Evangelos,Economou Evangelos K,Crea Filippo,Kaski Juan Carlos
European heart journal
The notion of atherosclerosis as a chronic inflammatory disease has intensified research on the role of cytokines and the way these molecules act and interact to initiate and sustain inflammation in the microenvironment of an atherosclerotic plaque. Cytokines are expressed by all types of cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects, and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leucocytes, and other vascular residing cells. It is now understood that widely used drugs such as statins, aspirin, methotrexate, and colchicine act in an immunomodulatory way that may beneficially affect atherogenesis and/or cardiovascular disease progression. Moreover, advancement in pharmaceutical design has enabled the production of highly specific antibodies against key molecules involved in the perpetuation of the inflammatory cascade, raising hope for advances in the treatment of atherosclerosis. This review describes the actions and effects of these agents, their potential clinical significance, and future prospects.
Colchicine therapy in patients with coronary artery disease: a systematic review and meta-analysis of randomized controlled trials.
Al-Abdouh Ahmad,Barbarawi Mahmoud,Khan Safi U,Osman Mohammed,Upadhrasta Sireesha,Solipuram Vinod,Abusnina Waiel,Radaideh Qais,Zhao Di,Michos Erin D
Coronary artery disease
INTRODUCTION:Inflammation is a substantial mediator of atherosclerosis. Colchicine has anti-inflammatory effects and has been investigated in many randomized controlled trials (RCTs) in patients with coronary artery disease (CAD). METHODS:We searched PubMed/MEDLINE, Cochrane library, and Embase databases (inception through 28 February 2020) for RCTs evaluating colchicine in CAD patients. The outcomes of interest were major adverse cardiovascular events (MACE), myocardial infarction (MI), all-cause mortality, cardiovascular mortality, and stroke. Estimates were pooled using inverse-variance random-effects model. We reported effect sizes as risk difference (RD) with 95% confidence interval (CI). RESULTS:A total of six RCTs with 6154 patients were included. The mean age ± SD for the patients in the colchicine group was 61.6 ± 10.8 and control group was 61.5 ± 10.7 years. At the median follow-up of 3.5 months, use of colchicine in patients with CAD was not associated with statistically significant reduction of MACE (RD -0.032; 95% CI -0.083 to 0.018; P = 0.15; I = 75%; low level of evidence), MI (RD -0.011; 95% CI -0.030 to 0.007; P = 0.16; I = 11.3%; low level of evidence), all-cause mortality (RD -0.001; 95% CI -0.009 to 0.006; P = 0.65; I = 0%; low level of evidence), cardiovascular mortality (RD -0.003; 95% CI -0.010 to 0.004; P = 0.34; I = 0%; low level of evidence), and stroke (RD -0.001, 95% CI -0.005 to 0.004; P = 0.69; I = 0%; very low level of evidence). CONCLUSION:This meta-analysis suggests that colchicine was not associated with a significant decrease in cardiovascular endpoints and mortality in patients with CAD.
Is There a Role for Colchicine in Acute Coronary Syndromes? A Literature Review.
Malik Jahanzeb,Javed Nismat,Ishaq Uzma,Khan Umar,Laique Talha
Inflammation is identified as a keystone of atherosclerosis. This review of the literature explores the unique anti-inflammatory effects of colchicine and summarizes the mechanisms of inflammation in acute coronary syndrome. It outlines other therapeutic strategies employed until now to target coronary inflammation and analyzes the role of colchicine in improving the outcomes of acute coronary syndrome. Despite the existence of guideline-directed medical therapy, there still remains a higher risk for recurrence due to continuous inflammation at remaining vascular sites. Several anti-inflammatory strategies have been employed, but they have not been shown to be beneficial. However, colchicine is becoming increasingly popular in tackling this problem. For this review, databases were searched for trials on the role of colchicine as an anti-inflammatory therapy in acute coronary syndrome.
Effect of colchicine compared with placebo on high sensitivity C-reactive protein in patients with acute coronary syndrome or acute stroke: a pilot randomized controlled trial.
Raju Nina C,Yi Qilong,Nidorf Mark,Fagel Nick D,Hiralal Rajesh,Eikelboom John W
Journal of thrombosis and thrombolysis
There is a need for more effective therapies to reduce morbidity and mortality from cardiovascular disease. Inflammation plays a central role in the pathogenesis of atherosclerosis but no randomized studies have evaluated anti-inflammatory therapy in patients with acute coronary or cerebrovascular disease. We performed a pilot randomized controlled trial comparing the effect of colchicine 1 mg per day with placebo on high sensitivity C-reactive protein (CRP) levels and platelet function in 80 patients with acute coronary syndrome or acute ischemic stroke who were followed for 30 days. Clinical status was ascertained for 74 (92.5%) patients and CRP levels were obtained in 68 (85%) of patients at follow up. Colchicine did not significantly reduce absolute hs-CRP at 30 days [median 1.0 mg/l (range 0.2, 162.0) versus 1.5 mg/l (0.2, 19.8), P = 0.22] or difference in CRP from baseline to 30 days [absolute difference 7.0 mg/l (-61.0, 87.8) vs. 7.1 mg/l (-1.0, 144), P = 0.64]. The proportion of patients with CRP <2 mg/l at follow up did not differ according to treatment allocation (77% vs. 62%, X (2) 1.84, P = 0.18). There was also no difference in platelet function assessed using platelet aggregation with ADP (5 μmol), arachidonic acid (0.5 mmol), collagen (1 μg/ml) and collagen (5 μg/ml) (P = 0.86, P = 0.64, P = 0.76, P = 0.20, respectively), and urine dehydrothromboxane B2 (P = 0.54). Colchicine was associated with an excess of diarrhoea (X(2) 4.14, P = 0.04). In conclusion, our pilot study provided no evidence that colchicine 1 mg daily for 30 days compared with placebo suppresses inflammation in patients with acute coronary syndrome or acute ischemic stroke.
The Utility of Anti-Inflammatory Agents in Cardiovascular Disease: A Novel Perspective on the Treatment of Atherosclerosis.
Kottoor Santhosh J,Arora Rohit R
Journal of cardiovascular pharmacology and therapeutics
Approximately 40% of heart attack survivors remain at increased risk of recurrent cardiovascular events, despite the current treatment options showing that atherothrombosis is not exclusively a disorder of lipoprotein aggregation in the arterial wall. Clinical and experimental data suggest that inflammation plays an important role in atherothrombosis independent of the cholesterol level. Acute-phase reactants, such as C-reactive protein, increase in patients with coronary artery disease and are known to predict adverse outcomes in such patients. The recent CANTOS trial published in The New England Journal of Medicine provides evidence that interleukin-1β along with other cytokines play central roles in the inflammatory reaction that drives the interleukin-6 signaling pathway and have profound effects on cardiovascular outcomes. Several other ongoing studies are focused on multiple immune mediators involved in this process to support the inflammatory hypothesis of cardiovascular diseases. These new classes of drugs could represent the biggest breakthrough in cardiovascular medicine, which could have the greatest impact on cardiovascular mortality since the advent of statins. The drug canakinumab has shown promise in lowering atherosclerosis, and other drugs, such as colchicine and methotrexate, are gaining interest and are being investigated in multiple ongoing trials. A major concern is the affordability of these drugs, as most cardiovascular diseases are noted among people of lower socioeconomic statuses. The LoDoCo trial showed some benefits of colchicine, and whether this old drug can be marketed with a new label for cardiovascular disease remains in question. Therefore, a clear understanding of the different inflammatory pathways involved in atherosclerosis is needed to help develop more effective treatment modalities that will benefit humankind.
Effects of Acute Colchicine Administration Prior to Percutaneous Coronary Intervention: COLCHICINE-PCI Randomized Trial.
Shah Binita,Pillinger Michael,Zhong Hua,Cronstein Bruce,Xia Yuhe,Lorin Jeffrey D,Smilowitz Nathaniel R,Feit Frederick,Ratnapala Nicole,Keller Norma M,Katz Stuart D
Circulation. Cardiovascular interventions
BACKGROUND:Vascular injury and inflammation during percutaneous coronary intervention (PCI) are associated with increased risk of post-PCI adverse outcomes. Colchicine decreases neutrophil recruitment to sites of vascular injury. The anti-inflammatory effects of acute colchicine administration before PCI on subsequent myocardial injury are unknown. METHODS:In a prospective, single-site trial, subjects referred for possible PCI (n=714) were randomized to acute preprocedural oral administration of colchicine 1.8 mg or placebo. RESULTS:Among the 400 subjects who underwent PCI, the primary outcome of PCI-related myocardial injury did not differ between colchicine (n=206) and placebo (n=194) groups (57.3% versus 64.2%, =0.19). The composite outcome of death, nonfatal myocardial infarction, and target vessel revascularization at 30 days (11.7% versus 12.9%, =0.82), and the outcome of PCI-related myocardial infarction defined by the Society for Cardiovascular Angiography and Interventions (2.9% versus 4.7%, =0.49) did not differ between colchicine and placebo groups. Among 280 PCI subjects in a nested inflammatory biomarker substudy, the primary biomarker end point, change in interleukin-6 concentrations did not differ between groups 1-hour post-PCI but increased less 24 hours post-PCI in the colchicine (n=141) versus placebo group (n=139; 76% [-6 to 898] versus 338% [27 to 1264], =0.02). High-sensitivity C-reactive protein concentration also increased less after 24 hours in the colchicine versus placebo groups (11% [-14 to 80] versus 66% [1 to 172], =0.001). CONCLUSIONS:Acute preprocedural administration of colchicine attenuated the increase in interleukin-6 and high-sensitivity C-reactive protein concentrations after PCI when compared with placebo but did not lower the risk of PCI-related myocardial injury. Registration: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT02594111, NCT01709981.
Colchicine--Update on mechanisms of action and therapeutic uses.
Leung Ying Ying,Yao Hui Laura Li,Kraus Virginia B
Seminars in arthritis and rheumatism
OBJECTIVES:To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. METHODS:We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed. RESULTS:The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis. CONCLUSION:Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions.
Colchicine: old and new.
Slobodnick Anastasia,Shah Binita,Pillinger Michael H,Krasnokutsky Svetlana
The American journal of medicine
Although colchicine has been a focus of research, debate, and controversy for thousands of years, the US Food and Drug Administration just approved it in 2009. Over the past decade, advances in the knowledge of colchicine pharmacology, drug safety, and mechanisms of action have led to changes in colchicine dosing and to potential new uses for this very old drug. In this review, we discuss the pharmacologic properties of colchicine and summarize what is currently known about its mechanisms of action. We then discuss and update the use of colchicine in a variety of illnesses, including rheumatic and, most recently, cardiovascular diseases.
Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction.
Tardif Jean-Claude,Kouz Simon,Waters David D,Bertrand Olivier F,Diaz Rafael,Maggioni Aldo P,Pinto Fausto J,Ibrahim Reda,Gamra Habib,Kiwan Ghassan S,Berry Colin,López-Sendón José,Ostadal Petr,Koenig Wolfgang,Angoulvant Denis,Grégoire Jean C,Lavoie Marc-André,Dubé Marie-Pierre,Rhainds David,Provencher Mylène,Blondeau Lucie,Orfanos Andreas,L'Allier Philippe L,Guertin Marie-Claude,Roubille François
The New England journal of medicine
BACKGROUND:Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis. METHODS:We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. RESULTS:A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03). CONCLUSIONS:Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.).
Colchicine and myocardial infarction: A review.
Akodad Mariama,Sicard Pierre,Fauconnier Jérémy,Roubille François
Archives of cardiovascular diseases
The inflammatory response is frequent after acute myocardial infarction, and may worsen ischaemia-reperfusion injuries, leading to increased infarct size and poor prognosis. Therefore, inflammation may be a promising therapeutic target, and anti-inflammatory drugs appear to be potential additional treatments in this context. Among these treatments, colchicine-a well-known drug that has been used for centuries in clinical practice for rheumatism-may represent the ideal candidate. Indeed, colchicine exerts direct anti-inflammatory and pleiotropic effects, with potential anti-arrhythmic, anti-fibrotic and anti-atherosclerotic effects, which are particularly interesting in this population of patients. The effects of colchicine in the context of acute myocardial infarction were first studied in preclinical models, with a decrease in inflammation demonstrated in several in vitro and in vivo models. Moreover, a decrease in infarct size and positive effects on haemodynamic variables were also recently demonstrated in a mouse model. Regarding clinical studies, the positive effect of colchicine in stable coronary disease and atherosclerosis was assessed initially. More recently, the value of colchicine in acute myocardial infarction has been studied, showing a positive effect on inflammation and infarct size reduction. Finally, a randomised trial (the COLCOT study) has shown a reduction in outcomes in patients with acute coronary syndrome treated with colchicine.
The Role of Colchicine in Acute Coronary Syndromes.
Vaidya Kaivan,Martínez Gonzalo,Patel Sanjay
PURPOSE:Because inflammation is a key process implicated in the pathogenesis of atherosclerosis at all stages, including plaque formation, progression, instability, and rupture, and because colchicine has unique anti-inflammatory properties, this review article summarizes the pathophysiologic mechanisms underpinning inflammation in atherosclerosis and acute coronary syndrome (ACS), outlines anti-inflammatory therapeutic approaches that have been tested thus far, and evaluates the evidence supporting the potential role of colchicine in improving outcomes and reducing cardiovascular morbidity and mortality in patients after ACS. METHODS:PubMed was searched for publications on colchicine and ACSs and atherosclerosis, and www.clinicaltrials.org was searched for completed and ongoing trials of colchicine use in ACSs. FINDINGS:Despite contemporary optimal medical therapy, patients remain at a high risk of future events after an ACS because of residual inflammation at culprit and nonculprit sites. Several attempts have been made to address this with targeted anti-inflammatory therapies, but until the recent promising results of canakinumab (an anti-interleukin-1β monoclonal antibody), most have failed to find any prognostic benefit in large clinical trials with hard end points. The pathogenic role of neutrophils and monocytes in atheroinflammation is well established, and a fundamental component in this process is the activation of the NOD-like receptor protein 3 inflammasome, a cytosolic multiprotein complex that, when activated by a stress signal such as cholesterol crystals, drives caspase-1-dependent release of 2 key proinflammatory cytokines, which are predictive of future adverse cardiovascular events: interleukin-1β and interleukin-18. Colchicine is a widely available, inexpensive, and well-tolerated medication that, among several anti-inflammatory mechanisms of action, inhibits activation of the NOD-like receptor protein 3 inflammasome complex. A seminal trial has found the beneficial properties of colchicine in reducing adverse cardiovascular events in the stable coronary artery disease population. IMPLICATIONS:Despite promising results in small prospective observational and randomized trials, there is a need for more evidence evaluating the role of colchicine as a secondary preventive agent after ACSs.
The Beneficial Therapy with Colchicine for Atherosclerosis via Anti-inflammation and Decrease in Hypertriglyceridemia.
Spartalis Michael,Spartalis Eleftherios,Tzatzaki Eleni,Tsilimigras Diamantis I,Moris Demetrios,Kontogiannis Christos,Kaminiotis Vaios Vasileios,Paschou Stavroula A,Chatzidou Sofia,Siasos Gerasimos,Voudris Vassilis,Iliopoulos Dimitrios C
Cardiovascular & hematological agents in medicinal chemistry
BACKGROUND:Lipid-lowering therapy and control of cardiovascular risk factors are the current recommendations of atherosclerotic disease management. Despite optimal treatment the rate of acute coronary syndrome events remains high. Inflammation plays an essential role in the pathophysiology of atherosclerotic plaque formation, progression and rupture, which conclusively causes acute clinical episodes. OBJECTIVE:This review aims to give a conceptual description of the potential therapeutic benefits and effects of colchicine in inflammation-mediated atherosclerotic disease and hypertriglyceridemia. METHOD:A complete literature survey was performed using the PubMed database search to collect available information regarding colchicine, atherosclerosis, and hypertriglyceridemia. RESULTS:A total of 42 studies met the selection criteria for inclusion in the review. Inflammation is a well-known key mediator of atherogenesis in coronary artery disease. Colchicine has direct antiinflammatory effects by inhibiting critical inflammatory signaling networks as the inflammasome, pro-inflammatory cytokines, and expression of adhesion molecules, preventing both local chemoattraction of inflammatory cells such as neutrophils and systemic inflammation including the decrease of the release of IL-1β by the neutrophils. CONCLUSION:Colchicine reduces the levels of inflammatory markers, stabilizes the coronary plaque, leads to more favorable cardiac healing after damage, and reduces the acute coronary syndromes event recurrence. Colchicine reduces the myocardial infarct size, myocardial fibrosis, and improves the hemodynamic parameters. Several studies report the potential attenuating role of colchicine on triglyceride levels. Current evidence though regarding the pathophysiological mechanism of colchicine's triglyceride-lowering effect remains scarce.
The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation.
Martínez Gonzalo J,Celermajer David S,Patel Sanjay
Atherosclerosis is considered a chronic inflammatory disease of the arterial wall. Recently, compelling evidence has arisen for the role of monocytes and neutrophils and a particular protein complex that resides within these cells - the NLRP3 inflammasome - in atherosclerosis-associated inflammation. It is now also known that cholesterol crystals are present through all stages of atherosclerosis and can activate the NLRP3 inflammasome within these inflammatory cells to produce interleukin 1β and interleukin 18 - key mediators in the inflammatory cascade that drive plaque progression and instability. In this review, we describe the role of monocytes/macrophages and neutrophils in atherosclerosis, outline mechanisms of activation of the NLRP3 inflammasome in the setting of atherosclerosis-associated inflammation and discuss potential therapies that specifically target the NLRP3 inflammasome and/or its downstream mediators in atherosclerosis, with a particular focus on the emerging role of colchicine.
Colchicine: an affordable anti-inflammatory agent for atherosclerosis.
Thompson Peter L,Nidorf S Mark
Current opinion in lipidology
PURPOSE OF REVIEW:Inflammation has been shown to be central to the development and progression of atherosclerosis. Despite detailed understanding of its central role and the cellular dynamics, which contribute to atherosclerotic inflammation, there has been slow progress in finding suitable agents to treat it. The recent CANTOS trial showed that the interleukin-1β inhibitor canakinumab can improve outcomes after acute coronary syndromes. Being a monoclonal antibody, it is expensive and inconvenient to administer for long-term treatment. This review summarizes recent work in finding effective, affordable alternatives to canakinumab. RECENT FINDINGS:Statin drugs have anti-inflammatory properties but separating their LDL lowering effect from their anti-inflammatory effect has been difficult. Drugs acting on targets outside of the interleukin-1β (IL-1β) pathway have been tested without finding a suitable candidate. Following the proof of principle provided by the success of canakinumab, other candidates targeting the IL-1β pathway are undergoing detailed evaluation. The most likely candidates are low-dose methotrexate and low-dose colchicine. The potential mechanisms and ongoing clinical trials are described. SUMMARY:Targeting the IL-1β pathway has already been successful with canakinumab but its expense and inconvenience of administration may limit its widespread uptake for controlling inflammation in atherosclerosis. Low-dose methotrexate and low-dose colchicine are affordable and more accessible alternatives, currently undergoing detailed evaluation for safety and efficacy in large randomized controlled trials.
Why Colchicine Should Be Considered for Secondary Prevention of Atherosclerosis: An Overview.
Nidorf Stefan Mark,Thompson Peter Lindsay
PURPOSE:Colchicine is a widely available, inexpensive drug with a range of antiinflammatory properties that may make it suitable for the secondary prevention of atherosclerosis. This review examines how past and contemporary approaches to antiinflammatory therapy for atherosclerosis have led to a better understanding of the nature of the disease and sets out the reasons why colchicine has the potential to become a cornerstone therapy in its management. METHODS:We performed a literature search using PubMed, the Cochrane library, and clinical trial registries to identify completed and ongoing clinical studies on colchicine in coronary artery disease, and a PubMed search to identify publications on the mechanism of action of colchicine relevant to atherosclerosis. FINDINGS:A large body of data confirms that inflammation plays a pivotal role in atherosclerosis. The translation of this extensive knowledge into improved clinical outcomes has until recently been elusive. Findings from statin trials support the possibility that targeting inflammation may be beneficial, but this evidence has been inconclusive. Direct inhibition of atherosclerotic inflammation is being explored in current clinical trials. Targeted inhibition of interleukin 1β with canakinumab provided the proof of principle that limiting inflammation can improve outcomes in atherosclerotic vascular disease, but long-term treatment with a monoclonal antibody is unlikely to have widespread uptake. Other approaches using agents with a wider set of targets are being explored. Findings from observational studies suggest that methotrexate may reduce cardiovascular risk in patients with rheumatoid arthritis, but CIRT (Cardiovascular Inflammation Reduction Trial) demonstrated that methotrexate provided no cardiovascular benefit in patients with atherosclerotic vascular disease. Recent demonstration that cholesterol crystals trigger the NLRP3 (nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3) inflammasome and the release of inflammatory cytokines that also drive uric acid crystal-induced inflammation indicates that the multiple actions of colchicine that make it effective in gout may be relevant to preventing inflammation and limiting inflammatory injury in atherosclerosis. The ongoing LoDoCo2 (Low Dose Colchicine2) and COLCOT (Colchicine Cardiovascular Outcomes Trial) trials and several other planned large-scale rigorous trials will determine the long-term tolerability and efficacy of low-dose colchicine for secondary prevention in patients with coronary disease. IMPLICATION:Colchicine holds promise as an important, accessible drug that could be successfully repurposed for the secondary prevention of atherosclerotic cardiovascular disease should its tolerability and cardiovascular benefits be confirmed in ongoing clinical trials.
Colchicine for secondary prevention of cardiovascular disease.
Nidorf Stefan M,Eikelboom John W,Thompson Peter L
Current atherosclerosis reports
Preliminary evidence demonstrating that adding 0.5 mg of colchicine per day to statin and antiplatelet therapy reduced the risk of acute coronary events in patients with stable coronary artery disease has raised the hope that it may prove effective for the long-term secondary prevention of cardiovascular disease. The ability of colchicine to suppress blood levels of inflammatory mediators and prevent cholesterol-crystal-induced neutrophil-mediated inflammation implicated in the progression and instability of atherosclerosis adds plausibility to this clinical observation. Early intestinal intolerance in some patients is well recognized, but clinical experience gained over more than half a century with the continuous use of colchicine for the prevention of neutrophil-mediated inflammation in patients with familial Mediterranean fever and gout indicates that low-dose long-term therapy is safe. Nonetheless, before colchicine can be recommended for the secondary prevention of cardiovascular disease, further studies are required to confirm its safety and efficacy in a broad range of patients with coronary disease, and to determine whether doses of colchicine less than 0.5 mg/day might be effective and even better tolerated. Trials exploring the role of colchicine in the treatment of patients with acute coronary syndromes would also be of special interest but may require the use of doses higher than those used for long-term secondary prevention.
Novel anti-inflammatory therapies for the treatment of atherosclerosis.
Khan Razi,Spagnoli Vincent,Tardif Jean-Claude,L'Allier Philippe L
The underlying role of inflammation in atherosclerosis has been characterized. However, current treatment of coronary artery disease (CAD) predominantly consists of targeted reductions in serum lipoprotein levels rather than combating the deleterious effects of acute and chronic inflammation. Vascular inflammation acts by a number of different molecular and cellular pathways to contribute to atherogenesis. Over the last decades, both basic studies and clinical trials have provided evidence for the potential benefits of treatment of inflammation in CAD. During this period, development of pharmacotherapies directed towards inflammation in atherosclerosis has accelerated quickly. This review will highlight specific therapies targeting interleukin-1β (IL-1β), P-selectin and 5-lipoxygenase (5-LO). It will also aim to examine the anti-inflammatory effects of serpin administration, colchicine and intravenous HDL-directed treatment of CAD. We summarize the mechanistic rationale and evidence for these novel anti-inflammatory treatments at both the experimental and clinical levels.
Synergistic effects of colchicine combined with atorvastatin in rats with hyperlipidemia.
Huang Congwu,Cen Chuan,Wang ChengXu,Zhan Haiyong,Ding Xin
Lipids in health and disease
BACKGROUND:Inflammation and endothelial dysfunction is implicated in the atherosclerosis initiation and progression in the setting of hyperlipidemia. Colchicine is a potent anti-inflammatory agent and whether colchicine combined with atorvastatin has synergistic effects on inflammation amelioration and endothelial function improvement is unknown. METHODS:Hyperlipidemic rat model was produced by high-fat and high-cholesterol diet for 6 weeks. Rats with normal diet were served as shame group. In hyperlipidemic group, normal saline, atorvastatin (10 mg/kg body weight/day), colchicines (0.5 mg/kg body weight/day), or atorvastatin combined with colchicines (same dosages) were prescribed for 2 weeks. Serum levels of lipid profile, C-reactive protein (CRP), liver enzyme, lipoprotein associated phospholipase A2 (Lp-PLA2) and nitric oxide (NO) production were serially assessed. RESULTS:Before the beginning of the study, all laboratory variables were comparable among each group. After 6 weeks of hyperlipidemic model production, serum levels of cholesterols, CRP and Lp-PLA2 were significantly increased when compared to sham group, whereas NO production was reduced. With 2 weeks of colchicine therapy, serum levels of CRP and Lp-PLA2 were decreased and NO production was enhanced in the colchicine group in a lipid-lowering independent manner. Added colchicine into atorvastatin therapy further improved NO production and decreased CRP and Lp-PLA2 levels, indicating a potential synergism of colchicine and atorvastatin. CONCLUSION:Colchicine combined with atorvastatin may have stronger protective effects on improving endothelial function and ameliorating inflammation in rats with hyperlipidemia.
Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome.
Martínez Gonzalo J,Robertson Stacy,Barraclough Jennifer,Xia Qiong,Mallat Ziad,Bursill Christina,Celermajer David S,Patel Sanjay
Journal of the American Heart Association
BACKGROUND:Interleukin (IL)-1β, IL-18, and downstream IL-6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP3 inflammasome, a cytosolic complex responsible for the production of IL-1β and IL-18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes (ACS), stable coronary artery disease and in controls; and (2) determine whether acute administration of colchicine inhibits their production. METHODS AND RESULTS:Forty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood samples from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL-1β, IL-18, and IL-6 using ELISA. In ACS patients, coronary sinus levels of IL-1β, IL-18, and IL-6 were significantly higher than arterial and venous levels (P=0.017, <0.001 and <0.001, respectively). Transcoronary (coronary sinus-arterial) gradients for IL-1β, IL-18, and IL-6 were highest in ACS patients and lowest in controls (P=0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (P=0.028, 0.032, and 0.032, for IL-1β, IL-18, and IL-6, respectively). CONCLUSIONS:ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short-term colchicine administration rapidly and significantly reduces levels of these cytokines.
Targeting cholesterol crystal-induced inflammation for the secondary prevention of cardiovascular disease.
Nidorf Stefan M,Eikelboom John W,Thompson Peter L
Journal of cardiovascular pharmacology and therapeutics
Cholesterol crystals are present in nascent and advanced atherosclerotic plaque. Under some conditions, they may enlarge and cause direct plaque trauma or trigger an inflammatory cascade that promotes the growth and instability of atherosclerotic plaque. Therapies that reduce the risk of cholesterol crystal formation or prevent the associated inflammatory response have the potential to improve the clinical outcome of patients with cardiovascular disease. Statins have pleiotropic effects that can reduce the size of the free cholesterol pool contained within atherosclerotic plaques and prevent the formation of cholesterol crystals. Colchicine prevents crystal-induced inflammation by virtue of its ability to inhibit macrophage and neutrophil function. Both statins and colchicine have been demonstrated to reduce the risk of cardiovascular events in patients with stable coronary disease. The efficacy of statins and colchicine for cardiovascular prevention supports the hypothesis that crystal-induced inflammation plays an integral role in the progression and instability of coronary disease. Inhibition of cholesterol crystal-induced inflammation offers a promising new target for the secondary prevention of cardiovascular disease.
Cardiac disease in familial Mediterranean fever.
Erken Eren,Erken Ertugrul
Familial Mediterranean fever (FMF) is an autoinflammatory disease manifested by inflammatory attacks of peritonitis, pleuritis, pericarditis accompanied by fever and arthritis. Mutations of MEFV gene results in pyrin dysfunction, which causes uncontrolled interleukin-1 beta production and triggers the inflammatory attacks. Inflammation persists even during attack-free periods in one-third of the FMF patients. Findings of elevated proinflammatory cytokine patterns during remission as well as inflammatory attacks indicate the continuous subclinical disease activity and inflammation. Chronic inflammation was thought to be related to the cardiovascular risk in FMF patients. Main cardiac manifestations reported in FMF are pericarditis, idiopathic recurrent pericarditis, pericardiac tamponade, coronary heart disease and abnormal cardiovascular reactivity. Cardiac involvement in FMF may often be related to secondary AA amyloidosis. Deposition of amyloid may lead to cardiovascular morbidity and mortality in FMF patients. Associations of several vasculitic disorders such as Immunoglobulin A-associated vasculitis, polyarteritis nodosa and Behcet's disease are common in FMF. Appropriate prophylactic treatment with colchicine is recommended to prevent from cardiovascular risks. For those resistant to colchicine, IL-1 inhibitor agents can be used. Associated vasculitis should be treated with immunosuppressive agents. This review article aims to compile information about cardiac disease in FMF and refer to recent studies on the topic.
Novel Antiatherosclerotic Therapies.
Libby Peter,Everett Brendan M
Arteriosclerosis, thrombosis, and vascular biology
Many measures can control lipid risk factors for atherosclerosis. Yet, even with excellent control of dyslipidemia, other sources of risk remain. Hence, we must look beyond lipids to address residual risk. Lifestyle measures should form the foundation of cardiovascular risk control. Many pharmacological interventions targeting oxidation have proven disappointing. A large program tested inhibition of a LpPLA (lipoprotein-associated phospholipase A), culminating in 2 large-scale clinical trials that did not meet their primary end points. A variety of antioxidants have not shown benefit in clinical trials. Numerous laboratory and clinical studies have inculpated inflammatory pathways in the pathogenesis of atherosclerotic events. The p38 MAPK (mitogen-activated protein kinase) inhibitor losmapimod and an inhibitor of a leukocyte adhesion molecule, P-selectin, did not alter adverse events in trials. Low-dose methotrexate, despite the promising observational studies, did not lower biomarkers of inflammation or alter cardiovascular outcomes in the CIRT (cardiovascular inflammation reduction trial). Four large-scale investigations underway will determine colchicine's ability to reduce recurrent events in secondary prevention. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showed that an antibody that neutralizes IL (interleukin)-1β can reduce recurrent cardiovascular events in secondary prevention. The success of CANTOS points to the pathway that leads from the NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammasome through IL-1β to IL-6 as an attractive target for further study and clinical development beyond lipid therapies to address the unacceptable burden of risk that remains despite our best current care in secondary prevention.
Old Drugs for New Indications in Cardiovascular Medicine.
Arbel Yaron,Abuzeid Wael,Rosenson Robert S,Weisman Alanna,Farkouh Michael E
Cardiovascular drugs and therapy
Inflammation participates in the initiation and progression of atherosclerotic cardiovascular disease, and it is a critical inciting factor leading to acute ischemic events. Evidence has shown that certain anti-inflammatory medications used to treat non-atherosclerotic inflammatory diseases reduce cardiovascular events. This article reviews evidence that commonly used anti-inflammatory therapies (colchicine, allopurinol, methotrexate), reduce cardiovascular events. We discuss potential mechanisms of action, efficacy, and safety of these therapies and propose a clinical trials design to investigate their efficacy.
Atherogenic index as a predictor of atherosclerosis in subjects with familial Mediterranean fever.
Acay Akif,Ulu Memnune Sena,Ahsen Ahmet,Ozkececi Gulay,Demir Kasim,Ozuguz Ufuk,Yuksel Seref,Acarturk Gursel
Medicina (Kaunas, Lithuania)
BACKGROUND AND OBJECTIVE:Numerous inflammatory and innate immune pathways are involved in atherogenesis. We aimed to investigate the atherogenic index and other lipid parameters in individuals with familial Mediterranean fever (FMF), as a predictor of atherosclerosis. MATERIALS AND METHODS:A total of 60 patients with FMF and 60 healthy age- and sex-matched controls were included in this study. The patients with acute infection, chronic metabolic and rheumatic diseases, use of drugs other than colchicine and smoking history were excluded. CRP, ESR, total cholesterol, triglycerides, LDL-C, and HDL-C levels of patients and the control group were measured. Atherogenic index (TG/HDL-C) was calculated. RESULTS:We found that the atherogenic index values of the patients were significantly higher than those of the control group. HDL-C levels were lower and ESR and TG levels were higher in patients. Total cholesterol, LDL-C and CRP levels did not differ significantly between the two groups. There was no significant difference in the values of total cholesterol, LDL-C, triglycerides (TG), HDL-C, and atherogenic indexes between the groups of patients with and without M694V mutation. CONCLUSIONS:Elaboration of clinical models of inflammation-induced atherogenesis may further advance our knowledge of multiple inflammatory pathways implicated in atherogenesis and provide a useful tool for cardiovascular prevention. We believe that the atherogenic index also be used as a preliminary indication of accelerated atherosclerosis in FMF. However, large-scale prospective studies on this issue are needed.
What's Old is New Again - A Review of the Current Evidence of Colchicine in Cardiovascular Medicine.
Yan Bryan P,Tan Guang-Ming
Current cardiology reviews
Colchicine is a well-established drug approved by the Food and Drug Administration (FDA) for the prevention and treatment of gout. It possesses unique anti-inflammatory properties. Interests in the usage of colchicine in cardiovascular medicine have been rekindled recently with several large trials been carried out to investigate its efficacy in treatment of various cardiac conditions including pericarditis, postpericardiotomy syndrome, atrial fibrillation and coronary artery disease. In this review, the basic pharmacological properties of colchicine will be discussed, and the evidences of its benefits for different applications in cardiovascular medicine will be reviewed.
Early ultrasonographic markers of atherosclerosis in patients with familial Mediterranean fever.
Sari Ismail,Karaoglu Oguzhan,Can Gercek,Akar Servet,Gulcu Aytac,Birlik Merih,Akkoc Nurullah,Tunca Mehmet,Goktay Yigit,Onen Fatos
Systemic inflammation plays an important role in the development of atherosclerosis (AS). The aim of this study was to evaluate the presence of early AS in patients with familial Mediterranean fever (FMF) that is characterized by recurrent inflammatory attacks of serositis. Sixty-one FMF patients (30 Male/31 Female; 31.5 [18-54] years) and 31 healthy controls (16 Male/15 Female; 31 [22-58] years) were studied. All FMF patients were on regular daily colchicine treatment and during attack-free periods. Both the FMF patients and controls with a history of diabetes mellitus (DM), hypertension, and hyperlipidemia were excluded. Body mass index (BMI) was calculated. Serum lipids, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were assessed. Two-hour oral glucose tolerance test was performed to rule out DM and glucose intolerance. To investigate early AS "endothelium-dependent flow-mediated dilatation (FMD%)," "nitroglycerin-induced endothelium-independent peripheral vasodilatation (NTG%)," and intima-media thickness (IMT) of common carotid arteries (CCA) were measured by ultrasonograpy. The median disease duration for FMF patients was 16 (1-45) years. Age, sex, BMI, smoking status, and serum lipids were comparable in patients and controls (p > 0.05). However, ESR and standard CRP were significantly higher in the patients group (p < 0.05). There were no differences in the measurements of right, left, and averaged IMT of CCA between patients and controls ([0.49 vs 0.5], [0.51 vs 0.52] and [0.5 vs 0.51]; p > 0.05, respectively). None of the subjects had carotid artery plaques. FMD% and NTG% were also similar in patients and controls group ([18.2 vs 20.6] and [24.2 vs 22.5]; p > 0.05, respectively). This study suggests that the markers of early AS are not impaired in FMF patients on regular daily colchicine treatment.
Colchicine Therapy and Plaque Stabilization in Patients With Acute Coronary Syndrome: A CT Coronary Angiography Study.
Vaidya Kaivan,Arnott Clare,Martínez Gonzalo J,Ng Bernard,McCormack Samuel,Sullivan David R,Celermajer David S,Patel Sanjay
JACC. Cardiovascular imaging
OBJECTIVES:The authors sought to evaluate the plaque-modifying effects of low-dose colchicine therapy plus optimal medical therapy (OMT) in patients post-acute coronary syndrome (ACS), as assessed by coronary computed tomography angiography (coronary CTA). BACKGROUND:Colchicine therapy has been postulated to have beneficial anti-inflammatory effects in patients with ACS, translating into reduction in future adverse cardiovascular events. However, whether favorable plaque modification underpins this is yet unproven. METHODS:In this prospective nonrandomized observational study of 80 patients with recent ACS (<1 month), patients received either 0.5 mg/day colchicine plus OMT or OMT alone and were followed for 1 year. Our primary outcome was change in low attenuation plaque volume (LAPV), a marker of plaque instability on coronary CTA and robust predictor of adverse cardiovascular events. Secondary outcomes were changes in other coronary CTA measures and in high-sensitivity C-reactive protein (hsCRP). RESULTS:Mean duration of follow-up was 12.6 months; mean age was 57.4 years. Colchicine therapy significantly reduced LAPV (mean 15.9 mm [-40.9%] vs. 6.6 mm [-17.0%]; p = 0.008) and hsCRP (mean 1.10 mg/l [-37.3%] vs. 0.38 mg/l [-14.6%]; p < 0.001) versus controls. Reductions in total atheroma volume (mean 42.3 mm vs. 26.4 mm; p = 0.28) and low-density lipoprotein levels (mean 0.44 mmol/l vs. 0.49 mmol/l; p = 0.21) were comparable in both groups. With multivariate linear regression, colchicine therapy remained significantly associated with greater reduction in LAPV (p = 0.039) and hsCRP (p = 0.004). There was also a significant linear association (p < 0.001) and strong positive correlation (r = 0.578) between change in LAPV and hsCRP. CONCLUSIONS:Our findings suggest, for the first time, that low-dose colchicine therapy favorably modifies coronary plaque, independent of high-dose statin intensification therapy and substantial low-density lipoprotein reduction. The improvements in plaque morphology are likely driven by the anti-inflammatory properties of colchicine, as demonstrated by reductions in hsCRP, rather than changes in lipoproteins. Colchicine may be beneficial as an additional secondary prevention agent in patients post-ACS if validated in future studies.
The effect of low-dose colchicine in patients with stable coronary artery disease: The LoDoCo2 trial rationale, design, and baseline characteristics.
Nidorf Stefan M,Fiolet Aernoud T L,Eikelboom John W,Schut Astrid,Opstal Tjerk S J,Bax Willem A,Budgeon Charley A,Tijssen Jan G P,Mosterd Arend,Cornel Jan H,Thompson Peter L,
American heart journal
Because patients with stable coronary artery disease are at continued risk of major atherosclerotic events despite effective secondary prevention strategies, there is a need to continue to develop additional safe, effective and well-tolerated therapies for secondary prevention of cardiovascular disease. RATIONALE AND DESIGN: The LoDoCo (Low Dose Colchicine) pilot trial showed that the anti-inflammatory drug colchicine 0.5 mg once daily appears safe and effective for secondary prevention of cardiovascular disease. Colchicine's low cost and long-term safety suggest that if its efficacy can be confirmed in a rigorous trial, repurposing it for secondary prevention of cardiovascular disease would have the potential to impact the global burden of cardiovascular disease. LoDoCo2 is an investigator-initiated, international, multicentre, double-blind, event driven trial in which 5522 patients with stable coronary artery disease tolerant to colchicine during a 30-day run-in phase have been randomized to colchicine 0.5 mg daily or matching placebo on a background of optimal medical therapy. The study will have 90% power to detect a 30% reduction in the composite primary endpoint: cardiovascular death, myocardial infarction, ischemic stroke and ischemia-driven coronary revascularization. Adverse events potentially related to the use of colchicine will also be collected, including late gastrointestinal intolerance, neuropathy, myopathy, myositis, and neutropenia. CONCLUSION: The LoDoCo2 Trial will provide information on the efficacy and safety of low-dose colchicine for secondary prevention in patients with stable coronary artery disease.