Colchicine and diabetes in patients with chronic coronary artery disease: insights from the LoDoCo2 randomized controlled trial

IntroductionDespite optimal treatment, patients with chronic coronary artery disease (CAD) and diabetes mellitus (DM) are at high risk of cardiovascular events, emphasizing the need for new treatment options. The Low-Dose Colchicine 2 (LoDoCo2) trial demonstrated that colchicine reduces cardiovascular risk in patients with chronic CAD. This analysis determines the efficacy of colchicine in patients with chronic CAD and DM as well as the effect of colchicine on the development of new-onset type 2 diabetes mellitus (T2DM).MethodsThe LoDoCo2 trial randomized 5,522 patients to placebo or colchicine 0.5 mg once daily, with a median follow-up of 28.6 months. The primary composite endpoint was cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven revascularization. The effect of its treatment in patients with and without DM was evaluated by including an interaction term in the model.ResultsA total of 1,007 participants (18.2%) had T2DM at baseline. The adjusted hazard ratio (HR) [(95% confidence interval (CI)] for the primary endpoint in the T2DM group was 1.52 (1.15–2.01, p < 0.01) compared with the group without T2DM. The HR for the treatment effect on the primary endpoint was 0.87 (0.61–1.25) in participants with T2DM and 0.64 (0.51–0.80) in participants without diabetes (pinteraction = 0.14). The incidence of new-onset T2DM was 1.5% (34 out of 2,270) in the colchicine group and 2.2% (49 out of 2,245) in the placebo group (p = 0.10).DiscussionIn conclusion, based on the current evidence, the beneficial effects of colchicine on cardiovascular endpoints are consistent regardless of DM status. The potential benefits of colchicine in preventing new-onset DM need further investigation. These findings are only hypothesis-generating and require larger prospective trials to confirm the results

A systematic review and meta-analysis of the protective effects of metformin in experimental myocardial infarction

Contains fulltext : 177026.pdf (publisher's version ) (Open Access)Metformin improves cardiovascular prognosis in patients with diabetes mellitus, compared to alternative glucose-lowering drugs, despite similar glycemic control. Direct cardiovascular protective properties have therefore been proposed, and studied in preclinical models of myocardial infarction. We now aim to critically assess the quality and outcome of these studies. We present a systematic review, quality assessment and meta-analysis of the effect of metformin in animal studies of experimental myocardial infarction. Through a comprehensive search in Pubmed and EMBASE, we identified 27 studies, 11 reporting on ex vivo experiments and 18 reporting on in vivo experiments. The primary endpoint infarct size as percentage of area at risk was significantly reduced by metformin in vivo (MD -18.11[-24.09,-12.14]) and ex vivo (MD -18.70[-25.39, -12.02]). Metformin improved the secondary endpoints left ventricular ejection fraction (LVEF) and left ventricular end systolic diameter. A borderline significant effect on mortality was observed, and there was no overall effect on cardiac hypertrophy. Subgroup analyses could be performed for comorbidity and timing of treatment (infarct size and mortality) and species and duration of ischemia (LVEF), but none of these variables accounted for significant amounts of heterogeneity. Reporting of possible sources of bias was extremely poor, including randomization (reported in 63%), blinding (33%), and sample size calculation (0%). As a result, risk of bias (assessed using SYRCLE's risk of bias tool) was unclear in the vast majority of studies. We conclude that metformin limits infarct-size and improves cardiac function in animal models of myocardial infarction, but our confidence in the evidence is lowered by the unclear risk of bias and residual unexplained heterogeneity. We recommend an adequately powered, high quality confirmatory animal study to precede a randomized controlled trial of acute administration of metformin in patients undergoing reperfusion for acute myocardial infarction

Innate immune cells in the pathophysiology of calcific aortic valve disease: lessons to be learned from atherosclerotic cardiovascular disease?

Calcific aortic valve disease (CAVD) is the most common valvular disease in the developed world with currently no effective pharmacological treatment available. CAVD results from a complex, multifactorial process, in which valvular inflammation and fibro-calcific remodelling lead to valve thickening and cardiac outflow obstruction. The exact underlying pathophysiology of CAVD is still not fully understood, yet the development of CAVD shows many similarities with the pathophysiology of atherosclerotic cardiovascular disease (ASCVD), such as coronary artery disease. Innate immune cells play a crucial role in ASCVD and might also play a pivotal role in the development of CAVD. This review summarizes the current knowledge on the role of innate immune cells, both in the circulation and in the aortic valve, in the development of CAVD and the similarities and differences with ASCVD. Trained immunity and clonal haematopoiesis of indeterminate potential are proposed as novel immunological mechanisms that possibly contribute to the pathophysiology of CAVD and new possible treatment targets are discussed

Psychological distress is independently related to new coronary events at 8 years? follow-up in elderly primary care patients with hypertension

Objective:  Occurrence of psychological distress in hypertensive patients could have a negative synergistic effect on future cardiovascular events (CVEs). The aim of this study was to determine the association between anxiety or depressive symptoms in elderly hypertensive primary care patients and the development of new CVEs and allcause mortality.  Methods:  A prospective cohort study was conducted in five Dutch general practices between June 2010 and January 2012. Patients with primary care managed hypertension, aged 60-85 years, were included and completed the GAD-7 and PHQ-9, measuring anxiety and depressive symptoms respectively. The incidence of new CVEs (coronary event, cerebrovascular disease, atrial fibrillation and heart failure) and all-cause mortality at 8 years' follow-up was recorded by data extraction of the digital information systems.  Results:  Among the 555 included participants (mean age 70 +/- 6.6 years; 56% female), 29 (5.2%) had a new coronary event, 42 (7.6%) a cerebrovascular disease, 57 (10.3%) atrial fibrillation, 22 (4%) heart failure and 68 (12.3%) died. Elevated anxiety and depression scores increased the risk of a coronary event independently and significantly by 12% (HR 1.12; 95% CI [1.04-1.22], p = 0.005) and 18% (HR 1.18; 95% CI [1.08-1.28], p < 0.0001), respectively, adjusted for relevant (Framingham) baseline covariates. No associations were found with regard to other CVEs and all-cause mortality.  Conclusion:  In a random sample of elderly primary care hypertension patients there was a significant association between psychological distress and the occurrence of new coronary events after 8 years' follow-up but not with other CVEs and all-cause mortality

Dual-Pathway Inhibition with Rivaroxaban and Low-Dose Aspirin Does Not Alter Immune Cell Responsiveness and Distribution in Patients with Coronary Artery Disease

Abstract Introduction Cardiovascular diseases (CVD) are the leading cause of death globally. Inflammation is an important driver of CVD where tissue damage may lead to the formation of deadly thrombi. Therefore, antithrombotic drugs, such as platelet inhibitors, are crucial for secondary risk prevention in coronary artery disease (CAD) and peripheral artery disease (PAD). For severe forms of the disease, dual-pathway inhibition (DPI) where low-dose aspirin is combined with rivaroxaban has shown improved efficacy in reducing cardiovascular mortality. Methods Given this greater improvement in mortality, and the importance of inflammation in driving atherosclerosis, the potential for off-target inflammation-lowering effects of these drugs was evaluated by looking at the change in immune cell distribution and responsiveness to ex vivo lipopolysaccharide (LPS) stimulation after 3 months of DPI in patients with CAD. Results We observed no changes in whole blood or peripheral blood mononuclear cell (PBMC) immune cell responsiveness to LPS after 3 months of DPI. Additionally, we did not observe any changes in the distribution of total white blood cells, monocytes, neutrophils, lymphocytes, or platelets during the study course. Signs of systemic inflammation were studied using Olink proteomics in 33 patients with PAD after 3 months of DPI. No changes were observed in any of the inflammatory proteins measured after the treatment period, suggesting that the state of chronic inflammation was not altered in these subjects. Conclusion Three months of DPI does not result in any meaningful change in immune cell responsiveness and distribution in patients with CAD or PAD. Trial Registration ClinicalTrials.gov ID: NCT0521072

Correction: A systematic review and meta-analysis of the protective effects of metformin in experimental myocardial infarction.

[This corrects the article DOI: 10.1371/journal.pone.0183664.]

Forest plot of the effect of metformin on cardiac hypertrophy after myocardial infarction <i>in vivo</i>.

<p>Outcome data from metformin-treated groups and control groups were extracted from primary studies and expressed as standardized mean differences (green squares). The pooled effect estimate (diamond) indicates no difference in cardiac hypertrophy between metformin-treated animals and controls. SD = standard deviation, Total = sample size, CI = confidence interval, IV = inverse variance, 60I = 60 minutes of ischemia, 1xM = single dose of metformin, 28xM = 28 doses of metformin in total, LV/BW = left ventricle/body weight, DMHFD = diabetes mellitus and high-fat diet.</p

Forest plot of the effect of metformin on mortality after myocardial infarction <i>in vivo</i>.

<p>Outcome data from metformin-treated groups and control groups were extracted from primary studies and expressed as odds ratios (blue squares). The pooled effect estimate (diamond) indicates a borderline significant difference in mortality between metformin-treated animals and controls. SD = standard deviation, Total = sample size, CI = confidence interval, IV = inverse variance.</p