From angiotensin-converting enzyme 2 disruption to thromboinflammatory microvascular disease: A paradigm drawn from COVID-19.

We concisely review clinical, autopsy, experimental and molecular data of 2019 coronavirus disease (COVID-19). Angiotensin-converting enzyme 2 disruption and thromboinflammatory microangiopathy emerge as distinctive features. Briefly, entry of the virus into microvessels can profoundly disrupt the local renin-angiotensin system, cause endothelial injury, activate the complement cascade and induce powerful thromboinflammatory reactions, involving, in particular, von Willebrand factor, that, if widespread, may lead to microvascular plugging, ischemia and, ultimately, organ failure. We believe the current COVID-19 data consolidate a widely unrecognised paradigm of potentially fatal thromboinflammatory microvascular disease.

Female sex as an independent risk factor for stroke in atrial fibrillation: possible mechanisms.

Atrial fibrillation (AF) is an independent risk factor for thromboembolism and stroke. Women with AF are at a higher overall risk for thromboembolic stroke when compared to men with AF. Recent evidence suggests that female sex, after adjusting for stroke risk profile and sex differences in utilisation of anticoagulation, is an independent stroke risk factor in AF. The inclusion of female sex has improved the accuracy of the CHADS2 stroke risk stratification schema (Congestive heart failure, Hypertension, Age 75 years or greater, Diabetes mellitus, and prior Stroke or TIA). The newly revised and validated schema, CHA2DS2-VASc, dichotomises age and incorporates female sex and vascular disease history. The pathophysiological mechanisms to explain this increased risk in women are not well understood. According to Virchow's triad, thrombosis that leads to stroke in AF should arise from three co-existing phenomena: structural abnormalities, blood stasis, and a hypercoagulable state. Herein, we explore the sex differences in the biological processes that lead to thrombus formation as applied to Virchow's Triad. The objective of this review is to describe the potential mechanisms behind the increased risk of stroke in AF associated with female sex.

Parenteral anticoagulants in heart disease: current status and perspectives (Section II). Position paper of the ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease.

Anticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases.

Effect of pravastatin on endothelial function and endothelial progenitor cells in healthy postmenopausal women.

PURPOSE: Coronary heart disease is the leading cause of morbidity and mortality in postmenopausal women. Among statins, pravastatin has been shown to significantly reduce fatal and non-fatal cardiovascular events in primary and secondary prevention trials. The aim of the present research was to investigate whether treatment with pravastatin can modify some indices of cardiovascular risk in healthy postmenopausal women such as significant reductions in total and LDL cholesterol and triglyceride levels. METHODS: 20 patients were randomized in double-blind fashion to treatment for eight weeks with either pravastatin 40 mg/day or placebo, and subsequently, after one-week wash-out, crossed-over to the alternative treatment (placebo or pravastatin) for the following eight weeks. We performed clinical and laboratory investigations, before and at the end of each treatment period, to evaluate patient response to the treatment with pravastatin. RESULTS: After eight weeks pravastatin therapy reduced the median low density lipoprotein (LDL) and total cholesterol (p < 0.01 in both cases). In contrast, insulin level and insulin sensitivity did not show any difference with regard to values observed after placebo treatment. The absolute number of endothelial progenitor cells-colony forming unit (EPC-CFU) was significantly increased by pravastatin treatment (30.6% increase, p < 0.05) and the number of senescent cells was significantly decreased. However pravastatin did not increase tube-like formation by EPC and did not improve endothelial function. CONCLUSIONS: Despite beneficial effect on lipids and EPC, short term pravastatin does not seem to improve other cardiovascular risk factors, at least in healthy postmenopausal women.

Low-molecular-weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis.

BACKGROUND: The aim of the current study was to perform two separate meta-analyses of available studies comparing low-molecular-weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST-elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. METHODS: All-cause mortality was the pre-specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. RESULTS: Ten studies comprising 16,286 patients were included. The median follow-up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41-0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49-0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta-regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). CONCLUSIONS: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta-analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.

Early vs. delayed invasive strategy in patients with acute coronary syndromes without ST-segment elevation: a meta-analysis of randomized studies.

Although early percutaneous coronary intervention has been demonstrated to reduce the risk of mortality in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), there are emerging conflicting data as to whether the catheterization needs to be done very early or whether it could be delayed while the patient receives medical therapy. The aim of the current study was to perform a meta-analysis of randomized controlled trials (RCTs) comparing early vs. delayed invasive strategies for NSTE-ACS patients. Medline/CENTRAL and the Web were searched for RCTs comparing early vs. delayed invasive strategies for NSTE-ACS patients. The primary endpoint was all cause mortality, whereas myocardial infarction (MI), coronary revascularizations and 30-day major bleeding complications were secondary end points. Fixed or random effects models were used based on statistical heterogeneity. As a sensitivity analysis, Bayesian random effects meta-analysis was performed in addition to the classical random effects meta-analysis. A total of 5 RCTs were finally included, enrolling 4155 patients. As compared with a delayed strategy, an early invasive approach did not significantly reduce the rates of death [odds ratio (OR) 95% confidence interval (95% CI) = 0.81 (95% CI 0.60-1.09), P = 0.17], MI [OR = 1.18 (95% CI 0.68-2.05), P = 0.55] or revascularizations [OR = 0.97 (0.77-1.24), P = 0.82]. There was a not significant trend toward fewer major bleeding complications for the early invasive approach [OR (95% CI) = 0.76 (0.55-1.04), P = 0.08]. The present meta-analysis shows that for NSTE-ACS patients a routine early invasive strategy does not significantly improve survival nor reduce MI and revascularization rates as compared with a delayed approach.

Pexelizumab in ischemic heart disease: a systematic review and meta-analysis on 15,196 patients.

OBJECT: Pexelizumab is a humanized monoclonal antibody inhibiting C5 complement. It has been postulated to improve outcomes in patients undergoing coronary artery bypass surgery and urgent reperfusion therapy for ST elevation myocardial infarction. We aimed at evaluating the risk/benefit profile of pexelizumab (bolus + infusion) versus placebo on top of current approaches in the management of patients with ST elevation myocardial infarction or undergoing coronary artery bypass. METHODS: We conducted a search of BioMedCentral, CENTRAL, mRCT, and PubMed without language restrictions (updated October 2007) for randomized controlled trials. Outcomes of interest were the risk of major adverse events (the composite of all-cause death, myocardial infarction, and thromboembolic stroke), the risk of single end points, and heart failure. RESULTS: Seven trials were included (15,196 patients: 7019 patients with ST elevation myocardial infarction and 8177 undergoing coronary bypass surgery). No benefit of adding pexelizumab was found in the overall analysis for major adverse events (OR 0.91 [0.76-1.09]; P = .29], death (OR 0.79 [0.61-1.03], P = .11], myocardial infarction (OR 1.04 [0.89-1.22]; P = .14), stroke (OR 0.95 [0.66-1.38]; P = .8), heart failure (OR1.0 [0.82-1.22]; P = .99), nor in the settings of patients with ST elevation myocardial infarction treated with mechanical or pharmacologic reperfusion therapy. Pexelizumab was associated with a 26% reduction of the risk of death in the setting of coronary artery bypass (OR 0.74 [0.58-0.94]; P = .01). The number needed to treat was 100. CONCLUSION: Our data ruled out the hypothesis of any benefit of adding pexelizumab on top of currently available therapies for ST elevation myocardial infarction. However, pexelizumab reduces the risk of death in patients undergoing coronary artery bypass grafting.

Ximelagatran/melagatran against conventional anticoagulation: a meta-analysis based on 22,639 patients.

BACKGROUND: The oral direct thrombin inhibitor ximelagatran, and its active form, melagatran, have been tested in various clinical conditions as a promising alternative to conventional anticoagulant therapy (CAT), despite some concerns over potentially serious liver injury. OBJECTIVES: To assess its risk/benefit profile, a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing xi-/melagatran to CAT was performed. METHODS: Leading medical databases were searched. The rates of major adverse events (MAE: all cause death, nonfatal myocardial infarction, nonfatal thromboembolic stroke, nonfatal pulmonary embolism), major bleeds (MB), and hepatotoxicity were compared. Out of 140 potentially relevant citations, 13 RCTs enrolling 22,639 patients were included. Indications for treatment were: 1) perioperative prophylaxis of deep vein thrombosis (DVT); 2) management of DVT; and 3) stroke prevention in atrial fibrillation. RESULTS: Overall, the risk of MAE (OR 0.98 [0.83-1.17]) and MB (OR 1.01 [0.69-1.47]) did not differ significantly between xi-/melagatran and CAT. There was a clear trend towards an increased risk of hepatotoxicity (OR 1.74 [0.50-6.01]), with an incidence of 5.8% with xi-/melagatran versus 2.3% with CAT (p<0.001); more specifically, the rate of hepatotoxicity was markedly augmented in the management of DVT (OR 5.16 [3.38-7.89]), for treatment durations > or = 3 months (OR 6.73 [5.01-9.05]), and in the prevention of atrial fibrillation-related stroke (OR 8.31 [5.65-12.23]). Two fatal cases of liver injury occurred with xi-/melagatran. CONCLUSIONS: Although comparable to CAT in terms of MAE and MB, xi-/melagatran carries a prohibitive risk of hepatotoxicity that cannot be ignored. Newer long-term alternatives are urgently needed.

Aspirin reduces anticardiolipin antibodies in patients with coronary artery disease.

BACKGROUND: Anticardiolipin antibodies (aCL) have been found to be elevated in patients with coronary artery disease (CAD) and have been associated with an adverse outcome owing to their prothrombotic activity. The aim of this study was to investigate the effect of aspirin treatment on aCL levels in patients with chronic CAD. MATERIALS AND METHODS: Forty patients with chronic CAD scheduled for elective coronary artery bypass graft surgery (CABG) and 40 healthy controls participated in the study. Patients were treated with 300 mg of aspirin once daily (o.d.) for the first 12 days and placebo for the following 12 days before CABG in a double-blind, cross-over trial. Immunoglobulin (Ig) G-, IgM-, IgA-aCL and C-reactive protein (CRP) levels were measured in the controls and at the end of each treatment period in the patients with CAD. RESULTS: The IgA- and IgG-aCL levels were greater in patients with CAD than in the controls. Compared with the placebo, IgA, IgG subtypes and CRP levels were reduced after aspirin treatment (P = 0.001, P = 0.02, P = 0.04, respectively). The percentage reduction of IgA- and IgG-aCL was related to the percentage reduction of CRP after aspirin (P < 0.05). CONCLUSION: Aspirin treatment with 300 mg o.d. reduced the serum levels of IgA and IgG subtypes in patients with chronic CAD in parallel to a reduction in CRP. These findings offer an additional pathophysiological mechanism of the beneficial effects of aspirin in patients with chronic CAD.

Women in cardiology: a European perspective.

Women may be under-represented in cardiology in the UK, but what about the rest of Europe?

Rate-control or rhythm-control: where do we stand?

Atrial fibrillation is the most common sustained rhythm disturbance and its prevalence is increasing worldwide due to the progressive aging of the population. Current guidelines clearly depict the gold standard management of acute symptomatic atrial fibrillation but the best-long term approach for first or recurrent atrial fibrillation is still debated with regard to quality of life, risk of new hospitalizations, and possible disabling complications, such as thromboembolic stroke, major bleeds and death. Some authors propose that regaining sinus rhythm in all cases, thus re-establishing a physiologic cardiac function not requiring a prolonged antithrombotic therapy, avoids the threat of intracranial or extracranial haemorrhages due to Vitamin K antagonists or aspirin. On the contrary, advocates of a rate control approach with an accurate antithrombotic prophylaxis propose that such a strategy may avoid the risk of cardiovascular and non cardiovascular side effects related to antiarrhythmic drugs. This review aims to explore the state of our knowledge in order to summarize evidences and issues that need to be furthermore clarified.

Reduction of daily life ischaemia by aspirin in patients with angina: underlying link between thromboxane A2 and macrophage colony stimulating factor.

OBJECTIVES: To evaluate whether aspirin reduces the incidence and frequency of daily life myocardial ischaemia in a cohort of patients with chronic stable coronary artery disease. SETTING: Tertiary referral centre. METHODS: 60 patients with chronic stable coronary artery disease underwent 48 hour Holter monitoring to assess the incidence and frequency of daily life myocardial ischaemia. Those with myocardial ischaemia (40/60) entered a double blind, crossover trial of aspirin (300 mg/day for three weeks) versus placebo. After each treatment arm, 48 hour Holter monitoring was repeated and urinary thromboxane (Tx) B2, 11-dehydro-TxB2, plasma prothrombin fragment F1+2, macrophage colony stimulating factor (MCSF), and interleukin (IL)-6 were measured. RESULTS: Aspirin reduced the total number and duration of ischaemic episodes from 339 to 251 and from 1765 to 1365 minutes, respectively (p < 0.01 for both). TxB2 was also reduced from 0.2 to 0.1 ng/mg creatinine, 11-dehydro-TxB2 from 3.3 to 1.3 ng/mg creatinine, F1+2 from 1.5 to 1.2 nmol/l, MCSF from 991 to 843 pg/ml, and IL-6 from 3.5 to 2.9 pg/ml (p < 0.05 for all). 11-dehydro-TxB2 excretion with and without aspirin was related to MCSF concentrations (p < 0.01), and the percentage reduction of MCSF by aspirin was related to the reduction of 11-dehydro-TxB2 (p < 0.05) and the reduction of the ischaemic burden compared with placebo (p < 0.05). CONCLUSIONS: In patients with daily life ischaemia, aspirin reduces the incidence and frequency of ischaemic episodes as well as the systemic concentrations of haemostatic/inflammatory markers. Aspirin may prevent transient coronary flow reductions through platelet, thrombin, and cytokine inhibition.

G20210A prothrombin gene polymorphism and coronary ischaemic syndromes: a phenotype-specific meta-analysis of 12 034 subjects.

OBJECTIVE: To investigate the possible link between the G20210A prothrombin gene variant and different forms of ischaemic heart disease. DESIGN: Phenotype-specific meta-analysis of 19 studies published within March 2002, globally including 4944 patients and 7090 controls. Sample size, inclusion criteria, geographical location, clinical presentation, age, cardiovascular risk factors, and angiographic extent of disease were extracted from each study. Analyses were done according to Mantel-Haenszel. RESULTS: Overall, the odds ratio (OR) for unspecified ischaemic heart disease associated with the 20210A allele was 1.21 (95% confidence interval (CI) 0.99 to 1.59, n = 12 034). Similar findings were seen for acute coronary syndromes (unstable angina and myocardial infarction) and for myocardial infarction without age limits (OR 1.24, 95% CI 0.98 to 1.63, n = 10 240; and OR 1.19, 95% CI 0.93 to 1.58, n = 9765). The effects were similar in male and female subjects. In the 1931 subjects < 55 years of age, the OR for myocardial infarction increased to 1.77 (95% CI 1.16 to 3.42) and in the 1359 subjects < 45 years to 2.30 (95% CI 1.27 to 4.59). No significant association was found between the 20210A allele and the presence of angiographically documented coronary disease (OR 1.08, 95% CI 0.70 to 1.64, n = 3444). However, patients with 0/1 vessel disease at angiography showed a greater prevalence of the A allele than those with multivessel disease (relative risk 2.0, 95% CI 1.2 to 3.1, n = 2376). CONCLUSIONS: G20210A prothrombin gene polymorphism may represent a modest but significant risk factor for myocardial infarction at young ages and favour the expression of ischaemic heart disease among individuals who have a limited extent of coronary atherosclerosis at angiography.

Inflammatory gene polymorphisms and ischaemic heart disease: review of population association studies.

Inflammation and genetics are both prominent mechanisms in the pathogenesis of atherosclerosis and arterial thrombosis. Accordingly, a number of population studies have explored the association of ischaemic heart disease with gene polymorphisms of the inflammatory molecules tumour necrosis factors (TNF) alpha and beta, transforming growth factors (TGF) beta1 and 2, interleukin (IL) 1 and its receptor antagonist (IL 1ra), CD14 (the receptor for lipopolysaccharide), P and E selectins, and platelet endothelial cell adhesion molecule (PECAM) 1. Although they are very preliminary and partly conflicting, the data provide some evidence that alterations in the genetics of the inflammatory system may modify the risk of ischaemic heart disease.

Increased prevalence of the G20210A prothrombin gene variant in acute coronary syndromes without metabolic or acquired risk factors or with limited extent of disease.

AIMS: To investigate the prevalence of the G20210A prothrombin and G1691A factor V gene variants in patients with acute coronary syndrome stratified according to risk factor profile and to extent of coronary disease, in comparison with matched healthy controls. METHODS AND RESULTS: The 20210 prothrombin and the 1691 factor V loci were genotyped in 247 patients < or =65 years of age (190 myocardial infarction and 57 unstable angina as first presentation of disease) and in 247 healthy age- and sex-matched controls. The prevalence of the 1691A factor V allele was similar in cases and controls. The frequency of heterozygotes for the 20210A prothrombin allele was 6.5% among patients and 2.8% among controls (OR 2.4, 95% CI 1.0-5.9), increasing to 8.7% in patients with a family history of myocardial infarction (OR 3.3, 95% CI 1.2-9.1), to 9.9% in patients (n=81) with < or =1 vessel disease (OR 3.8, 95% CI 1.3-10.8), and to 13.0% in patients who were normocholesterolaemic, non-diabetic, normotensive and non-smokers (OR 5.1, 95% CI 1.2-21.4). CONCLUSIONS: These findings suggest that the 20210A prothrombin allele represents an inherited risk factor for acute coronary syndrome among patients who have limited extent of coronary disease at angiography or who lack major metabolic and acquired risk factors.

Relation of the -174 G/C polymorphism of interleukin-6 to interleukin-6 plasma levels and to length of hospitalization after surgical coronary revascularization.

Interleukin (IL)-6 plasma levels are predictive of major cardiovascular events. The -174 G/C promoter polymorphism of the IL-6 gene affects basal levels in vivo and transcription rates in vitro, but its association with IL-6 acute phase levels among patients with coronary artery disease has not been investigated. In 111 patients with multivessel coronary artery disease undergoing elective coronary artery bypass graft surgery, we prospectively assessed genotype at position -174 and serial blood levels of IL-6 and other inflammatory indexes. Clinical and surgical characteristics did not differ among genotypic groups. IL-6 levels--measured daily up to 72 hours before surgery, after surgery, and at discharge--showed a mean 17-fold increase, peaking at 24 hours (p <0.0001). IL-6 levels (but not fibrinogen, white-blood cell count, and C-reactive protein values) differed significantly according to the -174 genotype (p = 0.042 for difference between areas under the curve), the 62 GG homozygotes exhibiting higher concentrations than the 49 carriers of the C allele (widest difference at 48 hours, p = 0.015 in multivariate analysis). GG homozygosity was associated with longer stays in the intensive care unit (2.5 +/- 3.4 vs 1.4 +/- 0.9 days, p = 0.02) and in the hospital (6.7 +/- 4.0 vs 5.3 +/- 1.4 days, p = 0.02) than C carriership. Rates of postoperative death, myocardial infarction, and stroke were 8% in GG homozygotes and 2% in C-carriers (p = 0.16). The IL-6-174 GG genotype is associated with higher acute phase levels of IL-6 and with longer stays in the hospital and in the intensive care unit than C allele carriership after surgical coronary revascularization.

Platelet aggregability in cardiac syndrome X.

AIMS: To assess platelet aggregability at rest and in response to exercise in patients with cardiac syndrome X (anginal chest pain, ST-segment depression on exercise, angiographically normal coronary arteries). METHODS AND RESULTS: We performed a symptom/sign-limited exercise test in 31 patients with syndrome X, 25 patients with coronary artery disease and 29 healthy subjects. Platelet aggregability was measured in flowing whole blood at baseline, at peak exercise, and after 30 and 120 min, as the time to occlude a collagen/adenosine diphosphate coated ring (aggregation time). Resting aggregation time was shorter in syndrome X patients (83.2+/-12 s), compared to patients with coronary disease (94.0+/-18 s, P<0.01) and to healthy subjects (96.4+/-21 s, P<0.01). With exercise, aggregation time did not change in healthy controls, decreased in patients with coronary disease (-13.8 s at peak; 95% CI, -10.2, -17.3 s;P<0.001), but increased in syndrome X (+17.4 s 30 min after exercise; 95% CI, +10.4, +24.4 s;P<0.0001). The intravenous administration of an adenosine antagonist (theophylline) prevented the exercise-induced prolongation of aggregation time in syndrome X patients (n=11), but had no effect in healthy controls (n=11). CONCLUSION: Platelet aggregability at rest was increased in syndrome X patients, compared to patients with coronary artery disease and healthy subjects. In contrast to patients with coronary disease, however, platelet aggregability was reduced by exercise. This response was prevented by theophylline, strongly suggesting the involvement of adenosine.