Low bone mineral density and coronary artery disease: A systematic review and meta-analysis.

Coronary artery disease (CAD) and osteoporosis both cause significant morbidity and mortality. Recent interest in inflammation and the bone-vascular axis suggests a mechanistic link between the two conditions. This review and meta-analysis was conducted to examine the potential association between low bone mineral density (BMD) and CAD in adults. Two authors searched for studies that examined the association between low BMD and CAD. Risk of bias assessment was conducted using the modified Newcastle Ottawa score. Ten studies were selected from the 2258 unique records identified. Pooled analysis showed a significant association between low BMD and CAD (OR 1.65, 95%CI 1.37-2.39, p < 0.01). Subgroup analysis investigating males and females separately was not significant. The subgroup analyses looking for any differences across geographic locations and differences between coronary imaging modalities were also negative. Studies with adjusted ORs (n = 4) were also pooled (OR 3.01, 95%CI 0.91-9.99, p = 0.07). Low BMD is associated with CAD; however, it is unclear whether this result is confounded by common risk factors given the heterogeneity between study populations and methodologies. Further large-scale epidemiological studies are required.

Acute Coronary Syndromes (ACS)-Unravelling Biology to Identify New Therapies-The Microcirculation as a Frontier for New Therapies in ACS.

In acute coronary syndrome (ACS) patients, restoring epicardial culprit vessel patency and flow with percutaneous coronary intervention or coronary artery bypass grafting has been the mainstay of treatment for decades. However, there is an emerging understanding of the crucial role of coronary microcirculation in predicting infarct burden and subsequent left ventricular remodelling, and the prognostic significance of coronary microvascular obstruction (MVO) in mortality and morbidity. This review will elucidate the multifaceted and interconnected pathophysiological processes which underpin MVO in ACS, and the various diagnostic modalities as well as challenges, with a particular focus on the invasive but specific and reproducible index of microcirculatory resistance (IMR). Unfortunately, a multitude of purported therapeutic strategies to address this unmet need in cardiovascular care, outlined in this review, have so far been disappointing with conflicting results and a lack of hard clinical end-point benefit. There are however a number of exciting and novel future prospects in this field that will be evaluated over the coming years in large adequately powered clinical trials, and this review will briefly appraise these.

Inflammation during Percutaneous Coronary Intervention-Prognostic Value, Mechanisms and Therapeutic Targets.

Periprocedural myocardial injury and myocardial infarction (MI) are not infrequent complications of percutaneous coronary intervention (PCI) and are associated with greater short- and long-term mortality. There is an abundance of preclinical and observational data demonstrating that high levels of pre-, intra- and post-procedural inflammation are associated with a higher incidence of periprocedural myonecrosis as well as future ischaemic events, heart failure hospitalisations and cardiac-related mortality. Beyond inflammation associated with the underlying coronary pathology, PCI itself elicits an acute inflammatory response. PCI-induced inflammation is driven by a combination of direct endothelial damage, liberation of intra-plaque proinflammatory debris and reperfusion injury. Therefore, anti-inflammatory medications, such as colchicine, may provide a novel means of improving PCI outcomes in both the short- and long-term. This review summarises periprocedural MI epidemiology and pathophysiology, evaluates the prognostic value of pre-, intra- and post-procedural inflammation, dissects the mechanisms involved in the acute inflammatory response to PCI and discusses the potential for periprocedural anti-inflammatory 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 for Stroke Prevention: A Systematic Review and Meta-analysis.

PURPOSE: There has been recent interest in the role of colchicine in cardiovascular diseases, given the implication of inflammation in the pathogenesis of atherothrombosis. This systematic review assessed the role of colchicine in preventing primary or secondary stroke/transient ischemic attack (TIA) in an adult population. METHODS: Four databases were electronically searched: MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), and OpenGrey. Studies were eligible if they reported stroke or TIA incidence as a primary/secondary end point, or as an adverse event. Only case-control studies, cohort studies, and randomized controlled trials (RCTs) were eligible. The primary end point was a pooled estimate using relative risk ratios (RRs) with 95% CIs. Two-sided P values were considered significant if P < 0.05. Statistical heterogeneity was assessed by using the Cochrane Q statistic and the Higgin's I2 statistic. An a priori decision was made to conduct a subgroup analysis based on study type. FINDINGS: A total of 5 studies were eligible for inclusion: 4 RCTs and 1 cohort study. There were 77 reported stroke/TIA events of a combined 2170 patients. Pooling all studies, stroke incidence was lower in the colchicine versus non-colchicine users (RR, 0.37; 95% CI, 0.22-0.62; P = 0.0002). There was no statistical heterogeneity (χ2 = 2.72; df = 4; P = 0.61; I2 = 0%). Pooling 4 RCTs as determined a priori, there was no significant effect of colchicine on stroke incidence (RR, 0.61; 95% CI, 0.17-2.17; P = 0.57). Results of the single cohort study suggested that colchicine reduced stroke incidence (RR, 0.33; 95% CI, 0.19-0.59; P = 0.0002). IMPLICATIONS: Colchicine has a potential protective benefit in both primary and secondary stroke/TIA incidence. Current data are inconclusive, likely due to the small sample sizes of available RCTs. Large-scale pragmatic RCTs are required to provide robust evidence in this domain.

The Role of Colchicine in Acute Coronary Syndromes.

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-1ß 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-1ß 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.

Colchicine Therapy and Plaque Stabilization in Patients With Acute Coronary Syndrome: A CT Coronary Angiography Study.

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 mm3 [-40.9%] vs. 6.6 mm3 [-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 mm3 vs. 26.4 mm3; 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.

Current management aspects in adult congenital heart disease: non-surgical closure of patent foramen ovale.

A patent foramen ovale (PFO) is a remnant interatrial communication, best diagnosed with transoesophageal echocardiography (TOE) and bubble study. Although quite common and often asymptomatic, PFO is associated with cryptogenic stroke and migraine. Approximately one-half of patients with a cryptogenic stroke have a PFO, and the dilemma regarding whether or not to proceed with percutaneous device closure, to reduce the risk of future recurrent events due to paradoxical embolism, has been subject to debate for nearly two decades. Despite promising observational data, initial randomised clinical trials failed to demonstrate superiority of closure over medical therapy. However, long-term follow-up data from one of these early trials, combined with two new randomised trials, have provided more evidence for the benefits of closure in selected patients. This new evidence suggests that younger patients with high-risk features such as an atrial septal aneurysm (ASA) or large interatrial shunt are more likely to benefit from PFO closure, after fastidious exclusion of an alternative cause for the index stroke. However, issues which require further clarification include whether anticoagulant therapy is preferable to antiplatelet therapy for medical management, and which particular type of closure device is optimal. Finally, despite promising retrospective observational data suggesting improvement in migraine attacks after PFO closure, high quality evidence is lacking in this regard.

Atrial Fibrillation in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder with a spectrum of clinical manifestations. Patients with HCM are predisposed to developing atrial fibrillation (AF) due primarily to advanced diastolic dysfunction and left atrial (LA) dilatation and remodelling. Atrial fibrillation causes a progressive symptomatic and functional decline, as well as increased thromboembolic risk and mortality, particularly in the setting of rapid ventricular rates and left ventricular outflow tract (LVOT) obstruction. The mainstay of management of AF in HCM is a combination of non-pharmacological lifestyle and risk factor modification, long-term anticoagulation, and rhythm control with antiarrhythmic medications. There is a growing body of evidence indicating that an early and aggressive rhythm control strategy may result in more favourable outcomes.

Pulmonary Vein Isolation Compared to Rate Control in Patients with Atrial Fibrillation: A Systematic Review and Meta-analysis.

BACKGROUND: Atrial fibrillation (AF) often coexists with congestive cardiac failure (CCF), with multiple treatment options available. METHODS: Systematic review and meta-analysis of randomised control trials (RCT) comparing pulmonary vein isolation (PVI), pharmacological rate control, and atrioventricular junction ablation with pacemaker insertion (AVJAP) for AF, with a subgroup analysis in patients with CCF. We analysed changes in left ventricular ejection fraction (LVEF), Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, six-minute walk distance (6MWD), treadmill exercise time, and treatment complications. Results were expressed as weighted mean differences (WMD) with 95% Confidence-Intervals (95%CI). RESULTS: We included seven RCT (425 participants). PVI was associated with a greater increase in LVEF (WMD+6.5%, 95%CI:+0.6to+12.5) and decrease in MLHFQ score (WMD-11.0, 95%CI:-2.6to-19.4) than pharmacological rate control in patients with CCF. PVI was also associated with a greater increase in LVEF (WMD+9.0%, 95%CI:+6.3to+11.7) and 6MWD (WMD+55.0metres, 95%CI:+34.9to+75.1), and decrease in MLHFQ score (WMD-22.0, 95%CI:-17.0to-27.0), compared to AVJAP in patients with CCF. Irrespective of cardiac function, pharmacological rate control had similar effects to AVJAP on LVEF (WMD+0.6%, 95%CI:-8.3to+9.4) and treadmill exercise time (WMD+0.5minutes, 95%CI:-0.4to+1.3). CONCLUSIONS: Our results support the clinical implementation of PVI over AVJAP or pharmacological rate control in AF patients with CCF, who may or may not have already trialled pharmacological rhythm control.