Monocyte responses to pro-atherogenic microenvironmental stimuli

Atherosclerosis is a disease process that reduces arterial blood vessel calibre, and is a major cause of morbidity and mortality in the industrialised world. Decreased vascular flow reduces tissue viability, resulting in cardiac, cerebrovascular, renovascular and peripheral arterial diseases. Inflammatory leukocyte responses underlie atherosclerosis. Clinical epidemiological data show that pro-atherogenic factors, including hyperlipidaemia, uncontrolled hypertension and cigarette smoking increase vascular inflammation, elevating an individual's risk of developing atherosclerosis. Local inflammation may alter leukocyte phenotype, function and survival, activating resident atherosclerotic plaque macrophages, and exacerbating vascular injury.This thesis aimed to assess whether monocyte survival, phenotype and gene transcription alters in response to pro-atherogenic and pro-inflammatory micro-environmental stimuli including oxidised low-density lipoprotein and cyclopentenone prostaglandins, metabolites of arachidonic acid.Oxidised low-density lipoproteins and cyclopentenone prostaglandins accelerated monocyte apoptosis, in serum-free conditions, in a concentration dependent manner. Cyclopentenone prostaglandin-induced monocyte apoptosis was caspase dependent, but oxidised low-density lipoprotein-induced monocyte apoptosis only partially caspase-dependent. Monocyte apoptosis appeared to be independent of the nuclear receptor and transcriptional controller peroxisome proliferator receptor gamma PPARy. Arachidonate-induced monocyte apoptosis appeared to be caused by a disruption of NF-kB mediated signalling. Monocyte apoptosis appeared inversely related to maturation, with nai've undifferentiated monocytes being more susceptible to programmed cell death than committed macrophages.Monocyte transcriptional responses to oxidised LDL were assessed using gene mini-arrays. Genes for CD47 and CD1 la showed significant levels of variation on the array, with CD1 la changes being confirmed by polymerase chain reaction assessment.Monocyte surface molecular changes induced by low-density lipoprotein were directly assessed by indirect immuno-labelling and flow cytometric analysis. Oxidised low-density lipoprotein elevated monocyte surface CD54 in early suspension culture, but then caused a down-regulation of CD54 in prolonged adherent culture. Oxidised low-density lipoprotein diminished monocyte surface expression of CD1 lb and CD1 lc in a manner dependent upon adhesion and maturation. CD49d expression appeared to be reduced by oxidised low-density lipoprotein in mature adherent monocytes. Early marginal reductions in CDlla expression were not seen in more mature monocytes.Pro-atherogenic and pro-inflammatory micro-environmental influences thus appeared to regulate monocyte viability and gene transcription, although this is not necessarily reflected at a protein level. Monocyte surface phenotype appeared to alter following exposure to modified lipoproteins, in a manner that may cause changes in monocyte mobility. These findings may contribute to our understanding of cell death in atherosclerotic lesions, and potential limitations on cell mobility out of atherosclerotic plaque

Effect of ω-3 fatty acid supplementation on endothelial function, endogenous fibrinolysis and platelet activation in patients with a previous myocardial infarction:a randomised controlled trial

OBJECTIVE: The mechanisms through which ω-3 fatty acids reduce adverse cardiac events remain uncertain. We aimed to investigate the effect of ω-3 fatty acid supplementation on endothelial vasomotor function, endogenous fibrinolysis, and platelet and monocyte activation in patients with coronary heart disease. DESIGN: Randomised, double-blind, placebo-controlled, cross-over trial. SETTING: Academic cardiac centre. PARTICIPANTS: 20 male patients with a previous myocardial infarction. INTERVENTION: ω-3 Fatty acid supplementation (2 g/day for 6 weeks) versus olive oil placebo. OUTCOME MEASURES: Peripheral blood was taken for analysis of platelet and monocyte activation, and forearm blood flow (FBF) was assessed in a subset of 12 patients during intrabrachial infusions of acetylcholine, substance P and sodium nitroprusside. Stimulated plasma tissue plasminogen activator (t-PA) concentrations were measured during substance P infusion. RESULTS: All vasodilators caused dose-dependent increases in FBF (p<0.0001). ω-3 Fatty acid supplementation did not affect endothelium-dependent vasodilation with acetylcholine and substance P compared with placebo (p=0.5 and 0.9). Substance P caused a dose-dependent increase in plasma t-PA concentrations (p<0.0001), which was not affected by ω-3 fatty acid supplementation (p=0.9). ω-3 Fatty acids did not affect platelet–monocyte aggregation, platelet P-selectin or CD40L, or monocyte CD40. CONCLUSIONS: We have demonstrated that dietary supplementation with ω-3 fatty acids does not affect endothelial vasomotor function, endothelial t-PA release, or platelet and monocyte activation in patients with coronary heart disease. Cardiac benefits conferred by ω-3 fatty acids in coronary heart disease are unlikely to be mediated through effects on these systems

Percutaneous revascularization for ischemic left ventricular dysfunction: Cost-effectiveness analysis of the REVIVED-BCIS2 trial

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. METHODS: REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. RESULTS: Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: −0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. CONCLUSIONS: A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom

Arrhythmia and death following percutaneous revascularization in ischemic left ventricular dysfunction: Prespecified analyses from the REVIVED-BCIS2 trial

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82–1.30]; P =0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920048

The effect of intensive lipid lowering on coronary atheroma and clinical outcome

The association between raised plasma cholesterol and cardiovascular risk is well established, with consistent evidence associating LDL‐cholesterol reduction with a reduction in primary and secondary cardiovascular events. It is believed that intensive lipid lowering may improve clinical outcomes further by acting to stabilise plaque and preventing plaque progression, ultimately reducing plaque vulnerability. However, it remains uncertain whether a continued clinical benefit occurs with intensive lipid lowering or if there is a threshold level below which no further benefit occurs

Impact of CV Risk Factors/Disease on Length of Stay and Mortality in Patients Presenting with MI

Background: Classical risk factors for cardiovascular disease such as hypertension and diabetes, and their association with myocardial infarction (MI), have been thoroughly investigated. However, more research is needed to investigate the correlation between these risk factors and the impact on length of stay (LOS) and mortality in patients presenting with MI, which was the aim of this study. Methods: We reviewed anonymous patient data including demographics, LOS, prevalence of cardiovascular comorbidities, and mortality during 25,287 consecutive admissions for MI from seven hospitals in the North West of England between 1 January 2000 and 31 March 2013. The ACALM (Algorithm for Comorbidities, Associations, Length of stay and Mortality) protocol, using ICD-10 and OPCS-4 coding systems, was used to track patient data. LOS and mortality of MI patients with and without cardiovascular comorbidities was compared by multinomial logistic regression. P values <0.05 were taken as statistically significant. Results: Of 25,287 patients admitted with MI over the study period, mean (± SD) age was 66.6 ± 14.3 and 64.2% were male. The mean (± SD) LOS was 7.0 ± 16.2 days and there were a total of 9,653 (38.2%) deaths. The classical cardiovascular risk factors hypertension and hyperlipidaemia were associated with a decreased LOS and mortality (7.0 and 4.8 days respectively, P < 0.001; 36.8% OR 0.72 [95% CI 0.67–0.77] and 19.4% OR 0.42 [95% CI 0.39–0.46] respectively, P < 0.001), whereas diabetes was associated with a longer LOS and higher mortality (7.8 days, P < 0.05; 44.4% OR 1.3 [95% CI 1.20–1.41], P < 0.001). Angina pectoris was associated with shorter LOS and reduced mortality (5.4 days; 33.5% OR 0.75 [95% CI 0.68–0.82], P < 0.001). Other concomitant cardiovascular diseases were associated with an increased LOS and mortality: PVD (8.6 days, P < 0.05; 53% OR 1.93 [95% CI 1.68–2.21], P < 0.001), AF (10.9 days; 63.5% OR 1.51 [95% CI 1.38–1.66], P < 0.001), Cerebrovascular disease (15.9 days; 76% OR 2.29 [95% CI 1.67–3.15], P < 0.001), HF (11 days; 69.9% OR 3.28 [95% CI 3.03–3.56], P < 0.001), and IHD (6.7 days, P < 0.001; 38.7% OR 1.16 [95% CI 1.06–1.26], P < 0.05). Conclusion: Cardiovascular risk factors and concomitant disease have a significant impact on LOS and mortality in patients presenting with MI. The presence of these diseases should be used to identify patients at an increased risk of prolonged admissions and death post MI, and services should be directed accordingly