Colchicine in Cardiovascular Disease: In-Depth Review.

Inflammation plays a prominent role in the development of atherosclerosis and other cardiovascular diseases, and anti-inflammatory agents may improve cardiovascular outcomes. For years, colchicine has been used as a safe and well-tolerated agent in diseases such as gout and familial Mediterranean fever. The widely available therapeutic has several anti-inflammatory effects, however, that have proven effective in a broad spectrum of cardiovascular diseases as well. It is considered standard-of-care therapy for pericarditis, and several clinical trials have evaluated its role in postoperative and postablation atrial fibrillation, postpericardiotomy syndrome, coronary artery disease, percutaneous coronary interventions, and cerebrovascular disease. We aim to summarize colchicine's pharmacodynamics and the mechanism behind its anti-inflammatory effect, outline thus far accumulated evidence on treatment with colchicine in cardiovascular disease, and present ongoing randomized clinical trials. We also emphasize real-world clinical implications that should be considered on the basis of the merits and limitations of completed trials. Altogether, colchicine's simplicity, low cost, and effectiveness may provide an important addition to other standard cardiovascular therapies. Ongoing studies will address complementary questions pertaining to the use of low-dose colchicine for the treatment of cardiovascular disease.

Left Distal Radial Artery Access for Coronary Angiography and Interventions: A 12-Month All-Comers Study.

BACKGROUND: Interventional cardiologists prefer the right radial artery (RA) approach for coronary angiography and interventions, mainly for ergonomic reasons. However, the use of the left RA presents certain advantages, and the snuffbox approach has further potential advantages, including lower probability for RA occlusion, avoidance of direct puncture of the RA (thus maintaining its suitability for use as a graft), as well as easier and faster hemostasis. METHODS: Consecutive patients scheduled for coronary catheterization were included, using the left distal RA (ldRA) in the anatomical snuffbox as the default vascular access site. RESULTS: Out of 2034 consecutive cases, the ldRA was used as initial vascular access in 1977 patients (97.2%). The procedural failure rate was 9.9% (21.9% inability to puncture the artery, 75.0% inability to advance the wire, 3.1% other reasons). There was a sharp decrease in failure rate after about the first 200 cases (20.8% in the first decile vs 8.7% throughout the rest of the caseload; P<.001). No or very weak palpable pulse was the most important predictor of failure (odds ratio, 16.0; 95% confidence interval, 11.2-23.1; P<.001), in addition to older age, small stature, and female gender (although, after adjustment for height, the latter was no longer significant). CONCLUSION: In a large series of consecutive patients scheduled for left heart catheterization, through a period of 12 months, with virtually no exclusions except those few imposed by anatomy or compelling clinical needs, the ldRA arterial access approach was shown to be highly effective, feasible, and safe.

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review.

The prevalence of atrial fibrillation (AF) is bound to increase globally in the following years, affecting the quality of life of millions of people, increasing mortality and morbidity, and beleaguering health care systems. Increasingly effective therapeutic options against AF are the constantly evolving electroanatomic substrate mapping systems of the left atrium (LA) and ablation catheter technologies. Yet, a prerequisite for better long-term success rates is the understanding of AF pathogenesis and maintenance. LA electrical and anatomical remodeling remains in the epicenter of current research for novel diagnostic and treatment modalities. On a molecular level, electrical remodeling lies on impaired calcium handling, enhanced inwardly rectifying potassium currents, and gap junction perturbations. In addition, a wide array of profibrotic stimuli activates fibroblast to an increased extracellular matrix turnover via various intermediaries. Concomitant dysregulation of the autonomic nervous system and the humoral function of increased epicardial adipose tissue (EAT) are established mediators in the pathophysiology of AF. Local atrial lymphomononuclear cells infiltrate and increased inflammasome activity accelerate and perpetuate arrhythmia substrate. Finally, impaired intracellular protein metabolism, excessive oxidative stress, and mitochondrial dysfunction deplete atrial cardiomyocyte ATP and promote arrhythmogenesis. These overlapping cellular and molecular alterations hinder us from distinguishing the cause from the effect in AF pathogenesis. Yet, a plethora of therapeutic modalities target these molecular perturbations and hold promise in combating the AF burden. Namely, atrial selective ion channel inhibitors, AF gene therapy, anti-fibrotic agents, AF drug repurposing, immunomodulators, and indirect cardiac neuromodulation are discussed here.

Repurposing colchicine's journey in view of drug-to-drug interactions. A review.

Colchicine's medical evolution is historically bound to the Mediterranean basin, since remarkable researchers from this region underscored its valuable properties. With the passing of years colchicine became an essential pharmaceutical substance for the treatment of rheumatologic and cardiovascular diseases. In light of recent findings, the therapeutic value of colchicine has grown. In clinical practice, colchicine remains underutilized in view of its proven efficacy and safety. Its complex pharmacokinetics and multifaceted anti-inflammatory role remain under investigation. The current review addresses the safe administration of colchicine in view of key drug to drug interactions. Finally, we are briefly presenting colchicine's future potential applications.

Atrial fibrillation risk in patients suffering from type I diabetes mellitus. A review of clinical and experimental evidence.

Atrial fibrillation (AF) and diabetes mellitus (DM) are commonly encountered in clinical practice. Although, the long term macrovascular and microvascular sequela of DM are well validated, the association between the less prevalent type 1 DM (T1DM) and atrial arrhythmogenesis is poorly understood. In the present review we highlight the current experimental and clinical data addressing this complex interaction. Animal studies support that T1DM, characterized by insulin deficiency and glycemic variability, impairs phosphatidylinositol 3­kinase (PI3K)/protein kinase B signaling pathway. This pathway holds a central role in atrial electrical and structural remodeling responsible for arrhythmia initiation and maintenance. The molecular ''footprint'' of T1DM in atrial myocytes seems to involve a state of increased oxidative stress, impaired glucose transportation, ionic channel dysregulation and eventually fibrosis. On the contrary only a few clinical studies have examined the role of T1DM as an independent risk factor for AF development, and are discussed here. Further research is needed to solidify the real magnitude of this association and to investigate the clinical implications of PI3K molecular signaling pathway in atrial fibrillation management.

Could Sodium/Glucose Co-Transporter-2 Inhibitors Have Antiarrhythmic Potential in Atrial Fibrillation? Literature Review and Future Considerations.

The global burden of atrial fibrillation (AF) is constantly increasing, necessitating novel and effective therapeutic options. Sodium glucose co-transporter 2 (SGLT2) inhibitors have been introduced in clinical practice as glucose-lowering medications. However, they have recently gained prominence for their potential to exert substantial cardiorenal protection and are being evaluated in large clinical trials including patients with type 2 diabetes and normoglycemic adults. In this review we present up-to-date available evidence in a pathophysiology-directed manner from cell to bedside. Preclinical and clinical data regarding a conceivable antiarrhythmic effect of SGLT2 inhibitors are beginning to accumulate. Herein we comprehensively present data that explore the potential pathophysiological link between SGLT2 inhibitors and AF. With regard to clinical data, no randomized controlled trials evaluating SGLT2 inhibitors effects on AF as a pre-specified endpoint are available. However, data from randomized controlled trial post-hoc analysis as well as observational studies point to a possible beneficial effect of SGLT2 inhibitors on AF. Meta-analyses addressing this question report inconsistent results and the real magnitude of AF prevention by SGLT2 inhibition remains unclear. Still, while (i) pathophysiologic mechanisms involved in AF might be favorably affected by SGLT2 inhibitors and (ii) emerging, yet inconsistent, clinical data imply that SGLT2 inhibitor-mediated cardiorenal protection could also exert antiarrhythmic effects, the argument of whether these novel drugs will reduce AF burden is unsettled and mandates appropriately designed and adequately sized randomized controlled studies.

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.

BACKGROUND: Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission. METHODS: The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants. FINDINGS: Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001). INTERPRETATION: In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended. FUNDING: The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.

The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): Rationale and study design.

OBJECTIVE: Colchicine has been utilized safely in a variety of cardiovascular clinical conditions. Among its potential mechanisms of action is the non-selective inhibition of NLRP3 inflammasome which is thought to be a major pathophysiologic component in the clinical course of patients with COVID-19. GRECCO-19 will be a prospective, randomized, open-labeled, controlled study to assess the effects of colchicine in COVID-19 complications prevention. METHODS: Patients with laboratory confirmed SARS-CoV-2 infection (under RT PCR) and clinical picture that involves temperature >37.5 oC and at least two out of the: i. sustained coughing, ii. sustained throat pain, iii. Anosmia and/or ageusia, iv. fatigue/tiredness, v. PaO2<95 mmHg will be included. Patients will be randomised (1:1) in colchicine or control group. RESULTS: Trial results will be disseminated through peer-reviewed publications and conference presentations. CONCLUSION: GRECCO-19 trial aims to identify whether colchicine may positively intervene in the clinical course of COVID-19. (ClinicalTrials.gov Identifier: NCT04326790).

Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.

Importance: Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile. Objective: To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19). Design, Setting, and Participants: In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece. Intervention: Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks. Main Outcomes and Measures: Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis. Results: A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003). Conclusions and Relevance: In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution. Trial Registration: ClinicalTrials.gov Identifier: NCT04326790.

The Role of Colchicine in Treating Postoperative and Post-catheter Ablation Atrial Fibrillation.

PURPOSE: The goal of this review was to summarize, analyze, and compare trials studying the efficacy of colchicine in the prevention of atrial fibrillation (AF) post-operatively (POAF) and post-catheter ablation. Ongoing studies and current guidelines are also presented and reviewed. METHODS: Published studies on the field were identified through a literature search of the PubMed and clinicaltrials.gov databases. FINDINGS: Four original studies regarding POAF, two original studies regarding post-catheter ablation AF, and six meta-analyses were identified. In addition, the 3 most recent guidelines/expert consensus documents were scrutinized. IMPLICATIONS: AF occurs frequently after cardiac surgery (POAF) and catheter pulmonary vein isolation (postablation AF) and is associated with increased cardiovascular morbidity. A number of trials over the last few years have investigated the role of colchicine in the prevention of POAF and postablation AF targeting the local and systemic inflammatory process that leads to initiation and maintenance of AF. Available data imply that colchicine may have a preventive role in POAF and/or postablation AF. However, certain limitations of these studies underline the need for further investigation.

Invasive treatment in peripheral artery disease.

Invasive treatment in peripheral artery disease (PAD) has evolved as a viable alternative to surgical treatment. However, beyond the common pathophysiological substrate, as far as treatment is concerned, each site of atherosclerotic disease (subclavian and vertebral arteries; carotid arteries; intracranial arterial tree; renal arteries; lower extremity arteries) features unique characteristics. Treatment options include medical treatment, endovascular management and/or surgery. Sound clinical evaluation is required as individual patient assessment often limits intervention options, while available data regarding benefits of invasive and surgical management are questioned by advances in medical treatment. In the present article, we aim to summarize existing evidence and guidance on the role of invasive procedures in PAD.

Sphenopalatine ganglion block: an external gate to modulate cardiac autonomic tone and suppress premature ventricular beats?

BACKGROUND: Autonomic modulation is used for treating various cardiovascular diseases, such as cardiac arrhythmias. Sphenopalatine ganglion (SPG) block is an easy, non-invasive therapy for migraine with a potential cardiovascular impact that remains unclear. In this study, we sought to assess the effect of SPG block on cardiac autonomic tone, as expressed by heart rate variability (HRV), and on ventricular arrhythmogenesis. METHODS: Forty patients (14 male and 26 female) suffering from migraine were randomized by 1:1 to SPG block or placebo (controls) and HRV parameters were evaluated 1 hour before and hourly after the intervention. Twenty-four additional patients (11 men and 13 women) with premature ventricular contractions (PVCs) from the right ventricular outflow tract underwent the same randomization and the number of PVCs was assessed during 1 hour before and every hour after treatment. Values were summarized as median (1st-3rd quartile). RESULTS: During the first four hours after SPG block, an increase in mean RR [883 (IQR, 869-948) vs. 839 (IQR, 806-887) ms at baseline, P<0.01], SDNN [64 (IQR, 59-69) vs. 51 (IQR, 47-55) ms, P<0.01], SDANN [39 (IQR, 36-43) vs. 27 (IQR, 22-29) ms, P<0.01], ASDNN [51 (IQR, 47-53) vs. 40 (IQR, 37-44) ms, P<0.01], rMSSD [30 (IQR, 27-32) vs. 25 (IQR, 23-27) ms, P<0.01], VLF [26 (IQR, 24-29) vs. 23 (IQR, 22-25) ms2, P<0.01] and HF [14 (IQR, 11-16) vs. 11 (IQR, 9-12) ms2, P<0.01], along with a decrease in LF/HF ratio [1.7 (IQR, 1.4-1.9) vs. 2.0 (IQR, 1.7-2.5), P<0.01] was observed in patients with migraine. In patients with PVCs, the number of ectopic ventricular beats per hour was decreased for the first five hours following SPG block [360 (IQR, 264-850) from 956 (IQR, 545-1,412), P<0.001]. No such differences were observed in controls. CONCLUSIONS: SPG block is associated with a transient increase in those HRV parameters that mainly express parasympathetic activity. It is also followed by a significant decrease in ventricular arrhythmic burden. These findings imply an effect on cardiac autonomic tone with a potential favorable clinical impact on arrhythmogenesis.

Colchicine in Post-operative Atrial Fibrillation: A Review.

Post-operative atrial fibrillation (POAF) is a frequent entity increasing hospitalization duration, stroke and mortality. In the recent years, a few studies have sought to investigate the potential effect of colchicine in POAF prevention after cardiac surgery or catheter pulmonary vein isolation for AF. In the present review article, we intend to provide a synopsis of clinical practice guidelines, summarize and critically approach current evidence for or against colchicine as a means of POAF prevention.

Peri-procedural Anticoagulation in Catheter Ablation for Atrial Fibrillation: A Review.

Catheter ablation for rhythm control in atrial fibrillation has been recognized as an established treatment. Patients with atrial fibrillation suffer from an increased risk of thromboembolic events. Long-term stroke risk and mortality have been shown to be reduced after catheter ablation, still the procedure per se is associated with an additive peri-procedural thromboembolic risk. Maintenance of the thrombotic - bleeding equilibrium in such patients during interventional procedures is compelling. Lack of data from randomized studies along with the recent introduction of novel oral anticoagulants in clinical practice has resulted in a wide variance of antithrombotic treatment approaches. Procedural interruption of anticoagulants, switching of anticoagulation scheme (i.e. from novel oral anticoagulants to vitamin K antagonists), bridging with heparin, timing of re-initiation of therapy and/or utilization of novel oral anticoagulants have all been points of dispute. In the present review we present the available data regarding optimal peri-procedural anticoagulation strategies in patients undergoing catheter ablation for atrial fibrillation.