The Role of Colchicine in Atherosclerotic Cardiovascular Disease.

Colchicine, an inexpensive immunomodulatory drug used traditionally to treat gout and familial Mediterranean fever, is rapidly accumulating basic and clinical evidence for a therapeutic role in atherosclerotic cardiovascular disease. Its athero-protective properties are thought to be mainly related to its effect on tubulin polymerisation, enabling a broad range of effect on multiple atherosclerotic plaque cell types and cellular processes, including cell division, cell migration as well as pro-inflammatory cytokine and chemokine secretion. These properties indicate the potential to favourably affect all stages of atherosclerotic plaque development including formation, progression, destabilisation, and plaque rupture. This review focusses on the pharmacology of colchicine, the mechanisms by which it modulates atherosclerosis pathobiology, and summarises the current clinical evidence for its use along with the upcoming clinical trial landscape. Given the current lack of primary immunomodulatory drugs in the treatment of atherosclerosis, colchicine is a promising candidate to fill this therapeutic gap.

The Low Dose Colchicine after Myocardial Infarction (LoDoCo-MI) study: A pilot randomized placebo controlled trial of colchicine following acute myocardial infarction.

Following an acute myocardial infarction (MI), patients with persistently elevated biomarkers of inflammation, in particular C-reactive protein (CRP), are at significantly increased risk of further cardiovascular events. Colchicine is a unique anti-inflammatory medication that has shown promise in reducing such events in patients with stable coronary heart disease. The current study tested the ability of low dose colchicine to reduce CRP levels at 30 days after an acute MI, a key marker of future outcome, and its safety and tolerability in this setting. METHODS: We conducted a randomized, double-blind, trial of low-dose colchicine (0.5 mg daily) or matching placebo in 237 patients admitted with an acute MI. The primary end-point was the proportion of patients with a residual high sensitivity CRP level ≥2 mg/L after 30 days of treatment, a threshold associated with a worse prognosis. RESULTS: At 30-day follow-up, 44% of patients treated with colchicine had a CRP level ≥2 mg/L compared to 50% of those randomized to placebo (P = .35) and the median CRP in patients randomized to colchicine was 1.6 mg/L (interquartile range [IQR] 0.7-3.5) compared to 2.0 mg/L (IQR 0.9-4.0) in patients randomized to placebo (P = .11). The median absolute reduction in CRP levels was -4.3 mg/L (IQR -1.1 to -14.1) among colchicine treated patients and -3.3 mg/L (IQR -0.9 to -14.4, P = .44) in placebo treated patients. The relative reduction was a fall of 78% compared to a fall of 64% (P = .09). Low dose colchicine was well tolerated and did not reduce compliance with other secondary preventative medications at 30-days. CONCLUSION: Treatment with low dose colchicine was safe and well tolerated, but was not associated with a significantly increased likelihood of achieving a CRP level <2 mg/L or lower absolute levels of CRP 30 days after an acute MI.

Complete Versus Incomplete Percutaneous Coronary Intervention-Mediated Revascularization in Patients With Chronic Coronary Syndromes.

Multivessel coronary artery disease (CAD) is associated with worse outcomes across the spectrum of clinical presentations. The prognostic implications of completeness of revascularization in CAD patients, especially those with chronic coronary syndromes (CCS), remain highly debated. This is largely due to the use of non-standardized definitions for complete revascularization (CR) and incomplete revascularization (ICR) within previously published studies, lack of randomized clinical data, varying revascularization methods and heterogenous study populations. In particular, the utility and effectiveness of PCI-mediated CR for CCS remains unknown. In this review, we discuss the various definitions used for CR vs. ICR, highlight the rationale for pursuing CR and summarise the current literature regarding the effects of PCI-mediated CR on clinical outcomes in patients with CCS.

Angiographically Patent Saphenous Vein Graft to Left Anterior Descending Artery at 51 Years Post-Coronary Artery Bypass Grafting.

We describe an unusual case of an angiographically patent saphenous vein graft to the left anterior descending artery at 51 years post coronary artery bypass grafting surgery in a patient who presents with exertional dyspnea and only relatively recent tobacco-smoking cessation. Factors associated with improved saphenous vein graft patency include the target vessel used for grafting, good distal run-off, and the use of optimal medical therapy alongside aggressive cardiovascular risk-factor modification.

Nous rapportons le cas inhabituel d'un greffon de veine saphène perméable à l'angiographie, greffé à l'artère interventriculaire antérieure 51 ans auparavant après un pontage aorto-coronarien, chez une patiente présentant une dyspnée à l'effort et ayant arrêté de fumer assez récemment. Parmi les facteurs associés à une meilleure perméabilité du greffon de veine saphène, citons le vaisseau cible utilisé pour la greffe, la bonne qualité du lit d'aval et l'utilisation d'un traitement médical optimal associé à une prise en charge énergique des facteurs de risque cardiovasculaire.

Erythrocyte interaction with neutrophil extracellular traps in coronary artery thrombosis following myocardial infarction.

Cardiovascular disease, including myocardial infarction (MI), is the leading cause of death globally. Current antithrombotic medications used during MI treatment are predominantly directed towards platelet inhibition and, to a lesser extent, anticoagulation. Bleeding is a major risk of such treatment and could be circumvented by targeting other causative factors essential for arterial thrombus formation. We sought to re-evaluate the cellular composition of arterial thrombus in order to better understand mechanisms that lead to coronary artery thrombosis in acute MI. We performed detailed histological and immunohistochemical analysis of coronary artery thrombi aspirated from 26 patients undergoing emergency percutaneous coronary intervention for acute ST elevated myocardial infarction (STEMI). Coronary arterial thrombi had an unanticipated cellular heterogeneity. Neutrophil extracellular traps (NETs) were observed in thrombi as identified by anti-citrullinated histone 3 and anti-myeloperoxidase staining. Increased abundance of NETs was seen directly surrounding erythrocytes. Extracellular iron and erythrocyte fragments were also associated with areas of NETs suggesting a possible link. Our results shed light on potential involvement of erythrocytes in coronary arterial thrombosis through activation of platelets and induction of NETs. If supported by further in vitro and in vivo studies, novel therapies to inhibit NET formation or coagulation activation by erythrocyte release products, could bolster current myocardial infarction treatment.

Colchicine Inhibits Neutrophil Extracellular Trap Formation in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention.

Background Release of neutrophil extracellular traps (NETs) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) is associated with periprocedural myocardial infarction, as a result of microvascular obstruction via pro-inflammatory and prothrombotic pathways. Colchicine is a well-established anti-inflammatory agent with growing evidence to support use in patients with coronary disease. However, its effects on post-PCI NET formation in ACS have not been explored. Methods and Results Sixty patients (40 ACS; 20 stable angina pectoris) were prospectively recruited and allocated to colchicine or no treatment. Within 24 hours of treatment, serial coronary sinus blood samples were collected during PCI. Isolated neutrophils from 10 patients with ACS post-PCI and 4 healthy controls were treated in vitro with colchicine (25 nmol/L) and stimulated with either ionomycin (5 µmol/L) or phorbol 12-myristate 13-acetate (50 nmol/L). Extracellular DNA was quantified using Sytox Green and fixed cells were stained with Hoechst 3342 and anti-alpha tubulin. Baseline characteristics were similar across both treatment and control arms. Patients with ACS had higher NET release versus patients with stable angina pectoris (P<0.001), which was reduced with colchicine treatment (area under the curve: 0.58 versus 4.29; P<0.001). In vitro, colchicine suppressed unstimulated (P<0.001), phorbol 12-myristate 13-acetate-induced (P=0.009) and ionomycin-induced (P=0.002) NET formation in neutrophils isolated from patients with ACS post-PCI, but not healthy controls. Tubulin organization was impaired in neutrophils from patients with ACS but was restored by colchicine treatment. Conclusions Colchicine suppresses NET formation in patients with ACS post-PCI by restoring cytoskeletal dynamics. These findings warrant further investigation in randomized trials powered for clinical end points. Registration URL: https://anzctr.org.au; Unique identifier: ACTRN12619001231134.

Colchicine as a Novel Therapy for Suppressing Chemokine Production in Patients With an Acute Coronary Syndrome: A Pilot Study.

PURPOSE: Existing literature reports that colchicine inhibits inflammasome activation and downstream inflammatory cytokine production and stabilizes coronary plaque. However, colchicine's effect on chemokines, which orchestrate multiple atheroinflammatory pathways, is unknown. METHODS: Patients with acute coronary syndrome (ACS) were randomly assigned to colchicine (1.5 mg PO) (n = 12; mean age, 65.2 years) or no treatment (n = 13; mean age, 62.2 years). Blood samples were collected during cardiac catheterization within 24 hours of colchicine administration from the coronary sinus, aortic root, and right atrium. Patients with colchicine-naive stable angina (SAP) (n = 13; mean age, 66.8 years) were additionally sampled. Serum chemokine levels were analyzed with ELISA. In parallel, monocytes from healthy donors were isolated and subjected to colchicine treatment. FINDINGS: Transcoronary (TC) levels of chemokine ligand 2 (CCL2) and C-X3-C motif chemokine ligand 1 (CX3CL1) were significantly elevated in patients with ACS versus patients with SAP (P < 0.01). TC chemokine ligand 5 (CCL5) levels were not significantly (P = 0.084) elevated in patients with ACS versus patients with SAP. Colchicine treatment markedly reduced TC levels of CCL2, CCL5, and CX3CL1 in patients with ACS (P < 0.05). In vitro colchicine suppressed CCL2 gene expression in stimulated monocytes (P < 0.05). Colchicine treatment reduced the intracellular concentration of all 3 chemokines (P < 0.01) and impaired monocyte chemotaxis (P < 0.05). IMPLICATIONS: Here, we report for the first time that short-term colchicine therapy significantly reduces the local production of coronary chemokines, in part by attenuating production of these mediators by monocytes. These data provide further evidence of colchicine's beneficial role in patients with ACS.

Transcatheter non-contact microwave ablation may enable circumferential renal artery denervation while sparing the vessel intima and media.

AIMS: Trials of transcatheter renal artery denervation (RDN) have failed to show consistent antihypertensive efficacy. Procedural factors and limitations of radiofrequency ablation can lead to incomplete denervation. The aim of the study was to show that non-contact microwave catheter ablation could produce deep circumferential perivascular heating while avoiding injury to the renal artery intima and media. METHODS AND RESULTS: A novel microwave catheter was designed and tested in a renal artery model consisting of layers of phantom materials embedded with a thermochromic liquid crystal sheet, colour range 50-78°C. Ablations were performed at 140 W for 180 sec and 120 W for 210 sec, delivering 25,200 J with renal arterial flow at 0.5 L/min and 0.1 L/min. Transcatheter microwave ablations 100-160 W for 180 sec were then performed in the renal arteries of five sheep. In vitro, ablations at 140 W and 0.5 L/min flow produced circumferential lesions 5.9±0.2 mm deep and 19.2±1.5 mm long with subendothelial sparing depth of 1.0±0.1 mm. In vivo, transcatheter microwave ablation was feasible with no collateral visceral thermal injury. There was histological evidence of preferential outer media and adventitial ablation. CONCLUSIONS: Transcatheter microwave ablation for RDN appears feasible and provides a heating pattern that may enable more complete denervation while sparing the renal arterial intima and media.

Mobile Telephone Text Messaging for Medication Adherence in Chronic Disease: A Meta-analysis.

IMPORTANCE: Adherence to long-term therapies in chronic disease is poor. Traditional interventions to improve adherence are complex and not widely effective. Mobile telephone text messaging may be a scalable means to support medication adherence. OBJECTIVES: To conduct a meta-analysis of randomized clinical trials to assess the effect of mobile telephone text messaging on medication adherence in chronic disease. DATA SOURCES: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, and CINAHL (from database inception to January 15, 2015), as well as reference lists of the articles identified. The data were analyzed in March 2015. STUDY SELECTION: Randomized clinical trials evaluating a mobile telephone text message intervention to promote medication adherence in adults with chronic disease. DATA EXTRACTION: Two authors independently extracted information on study characteristics, text message characteristics, and outcome measures as per the predefined protocol. MAIN OUTCOMES AND MEASURES: Odds ratios and pooled data were calculated using random-effects models. Risk of bias and study quality were assessed as per Cochrane guidelines. Disagreement was resolved by consensus. RESULTS: Sixteen randomized clinical trials were included, with 5 of 16 using personalization, 8 of 16 using 2-way communication, and 8 of 16 using a daily text message frequency. The median intervention duration was 12 weeks, and self-report was the most commonly used method to assess medication adherence. In the pooled analysis of 2742 patients (median age, 39 years and 50.3% [1380 of 2742] female), text messaging significantly improved medication adherence (odds ratio, 2.11; 95% CI, 1.52-2.93; P < .001). The effect was not sensitive to study characteristics (intervention duration or type of disease) or text message characteristics (personalization, 2-way communication, or daily text message frequency). In a sensitivity analysis, our findings remained robust to change in inclusion criteria based on study quality (odds ratio, 1.67; 95% CI, 1.21-2.29; P = .002). There was moderate heterogeneity (I2 = 62%) across clinical trials. After adjustment for publication bias, the point estimate was reduced but remained positive for an intervention effect (odds ratio, 1.68; 95% CI, 1.18-2.39). CONCLUSIONS AND RELEVANCE: Mobile phone text messaging approximately doubles the odds of medication adherence. This increase translates into adherence rates improving from 50% (assuming this baseline rate in patients with chronic disease) to 67.8%, or an absolute increase of 17.8%. While promising, these results should be interpreted with caution given the short duration of trials and reliance on self-reported medication adherence measures. Future studies need to determine the features of text message interventions that improve success, as well as appropriate patient populations, sustained effects, and influences on clinical outcomes.