Jehangir N. Din

Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment

Omega 3 fatty acids from fish and fish oils can protect against coronary heart disease. Both health professionals and the public are increasingly interested in their role in the prevention and management of coronary heart disease. In this era of multiple pharmacological treatments for cardiovascular disease many believe that simple dietary interventions or nutritional supplements may be a more natural and acceptable method of providing benefits. Several areas of uncertainty remain. The optimal intake of omega 3 fatty acids is not firmly established, nor is their mechanism of action fully understood. Some studies have produced conflicting results, and concerns have been increasing about environmental contamination of certain fish. This article reviews the current evidence regarding fish oils and cardiovascular disease, their possible mechanism of action, and potential future developments and research strategies.

Influence of the Menstrual Cycle, Pregnancy, and Preeclampsia on Arterial Stiffness

Arterial stiffness and compliance are major predictors of adverse cardiovascular events and are influenced by female sex hormones, including estrogen and progesterone. The aim of this longitudinal study was to evaluate the effect of the menstrual cycle, normal pregnancy, and preeclampsia on central and systemic arterial stiffness. Ten healthy nulliparous women with regular menses were studied in the early and midfollicular, periovulatory, and luteal phases of a single menstrual cycle. Twenty-two primigravida pregnant women were studied throughout pregnancy at 16, 24, 32, and 37 weeks gestation and at 7 weeks postpartum. Fifteen primigravida women with preeclampsia were studied at diagnosis and 7 weeks postpartum. Augmentation index and carotid-radial and carotid-femoral pulse wave velocities were measured using applanation tonometry. Augmentation index fell during the luteal phase of the menstrual cycle (luteal phase versus periovulatory phase; P<0.05). In normal pregnancy, pulse wave velocity and augmentation index increased from 24 weeks over the third trimester (P≤0.01 for both). All of the measures were increased in women with preeclampsia (P≤0.01), with augmentation index and carotid-femoral pulse wave velocity remaining elevated 7 weeks postpartum (P≤0.02). We conclude that systemic arterial stiffness undergoes major changes during the menstrual cycle and pregnancy and that preeclampsia is associated with greater and more prolonged increases in arterial stiffness. These effects may contribute to adverse cardiovascular outcomes of pregnancy and preeclampsia.

Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers.

Background—Smoking is a potent cardiovascular risk factor and is associated with proinflammatory and prothrombotic responses. The CD40/CD40 ligand (CD40L) dyad and platelet-monocyte aggregation mediate a range of proinflammatory and prothrombotic processes thought to be important in atherothrombosis. We investigated whether expression of the CD40/CD40L dyad and platelet-monocyte aggregation are altered in cigarette smokers. Methods and Results—C-reactive protein (CRP), soluble (s) CD40L, and surface expression of CD40L on platelets and T cells and of CD40 on monocytes and platelet-monocyte aggregates were compared in 25 cigarette smokers and 25 age-and gender-matched nonsmokers. Cigarette smokers had increased serum CRP (2.47±2.60 versus 0.94±0.96 mg/L, P =0.008) and appeared to have elevated plasma sCD40L (0.8±1.09 versus 0.37±0.21 ng/mL, P =0.07) concentrations. Smokers also had increased surface expression of CD40 on monocytes (45.9±7.7% versus 39.9±6.5%, P =0.006), of CD40L on platelets (2.9±1.0% versus 2.3±0.6%, P =0.03), and of platelet-monocyte aggregates (26.6±10.9% versus 19.7±8.6%, P =0.02). Plasma cotinine concentrations correlated with monocyte CD40 expression, platelet CD40L expression, and platelet-monocyte aggregates. Conclusions—Cigarette smokers have upregulation of the CD40/CD40L dyad and platelet-monocyte aggregation that may account for the atherothrombotic consequences of this major cardiovascular risk factor.

Flow cytometric analysis of circulating platelet-monocyte aggregates in whole blood: Methodological considerations

Platelet-monocyte aggregates are increasingly being used to quantify platelet activation. The variables that influence platelet-monocyte aggregates have not been well defined. We sought to determine the effect of blood collection, handling and processing techniques on detected levels of platelet-monocyte aggregates using a flow cytometric assay. Whole blood was labelled with anti-CD14-PE and anti-CD42a-FITC. Thereafter, samples were fixed and red cells lysed. Analysis was performed with the flow cytometer initially triggering on light scatter and then on FL-2 to identify CD14-PE positive monocytes. Platelet-monocyte aggregates were defined as monocytes positive for CD42a. The effect of collection, handling and processing techniques on this assay were assessed. Anticoagulation with heparin (20.1 +/- 2.0%), PPACK (16.8 +/- 1.9%), sodium citrate (12.3 +/- 1.6%) and EDTA (9.5 +/- 1.0%) resulted in markedly different levels of platelet-monocyte aggregation (P < 0.0001). Platelet-monocyte aggregation was higher in samples obtained from intravenous cannulae compared to those obtained by venepuncture (20.9 +/- 3.9% vs.13.8 +/- 2.4%, P = 0.03). For every 10 minutes of delay prior to processing platelet-monocyte aggregates increased by 2.8% (P = 0.0001) in PPACK anticoagulated blood and 1.7% (P = 0.01) in citrate anticoagulated blood. Erythrocyte lysis together with fixation does not affect platelet-monocyte aggregation. Platelet-monocyte aggregates remained stable over 24 hours when fixed and stored at 4 degrees C. Multiple handling and processing factors may affect platelet-monocyte aggregation. We recommend the measurement of platelet-monocyte aggregates on samples collected by direct venepuncture, using a direct thrombin inhibitor as the anticoagulant and minimising the time delay before sample fixation.

Cardiovascular effects of tumour necrosis factor α antagonism in patients with acute myocardial infarction: a first in human study

Objective The inflammatory cytokine, tumour necrosis factor α (TNF-α), exerts deleterious cardiovascular effects. We wished to determine the effects of TNF-α antagonism on endothelial function and platelet activation in patients with acute myocardial infarction. Design and setting and patients A double-blind, parallel group, randomised controlled trial performed in a tertiary referral cardiac centre. 26 patients presenting with acute myocardial infarction randomised to receive an intravenous infusion of etanercept (10 mg) or saline placebo. Main outcome measures Leucocyte count, plasma cytokine concentrations, flow cytometric measures of platelet activation and peripheral vasomotor and fibrinolytic function were determined before and 24 h after study intervention. Results Consistent with effective conjugation of circulating TNF-α, plasma TNF-α concentrations increased in all patients following etanercept (254±15 vs 0.12±0.02 pg/ml; p<0.0001), but not saline infusion. Etanercept treatment reduced neutrophil (7.4±0.6 vs 8.8±0.6×109 cells/l; p=0.03) and plasma interleukin-6 concentrations (5.8±2.0 vs 10.6±4.0 pg/ml; p=0.012) at 24 h but increased platelet–monocyte aggregation (30±5 vs 20±3%; p=0.02). Vasodilatation in response to substance P, acetylcholine and sodium nitroprusside, and acute tissue plasminogen activator release were unaffected by either treatment (p>0.1 for all). Conclusions Following acute myocardial infarction, etanercept reduces systemic inflammation but increases platelet activation without affecting peripheral vasomotor or fibrinolytic function. We conclude that TNF-α antagonism is unlikely to be a beneficial therapeutic strategy in patients with acute myocardial infarction.

Cardiovascular effects of tumour necrosis factor α antagonism in patients with acute myocardial infarction

Objective The inflammatory cytokine, tumour necrosis factor α (TNF-α), exerts deleterious cardiovascular effects. We wished to determine the effects of TNF-α antagonism on endothelial function and platelet activation in patients with acute myocardial infarction. Design and setting and patients A double-blind, parallel group, randomised controlled trial performed in a tertiary referral cardiac centre. 26 patients presenting with acute myocardial infarction randomised to receive an intravenous infusion of etanercept (10 mg) or saline placebo. Main outcome measures Leucocyte count, plasma cytokine concentrations, flow cytometric measures of platelet activation and peripheral vasomotor and fibrinolytic function were determined before and 24 h after study intervention. Results Consistent with effective conjugation of circulating TNF-α, plasma TNF-α concentrations increased in all patients following etanercept (254±15 vs 0.12±0.02 pg/ml; p<0.0001), but not saline infusion. Etanercept treatment reduced neutrophil (7.4±0.6 vs 8.8±0.6×109 cells/l; p=0.03) and plasma interleukin-6 concentrations (5.8±2.0 vs 10.6±4.0 pg/ml; p=0.012) at 24 h but increased platelet–monocyte aggregation (30±5 vs 20±3%; p=0.02). Vasodilatation in response to substance P, acetylcholine and sodium nitroprusside, and acute tissue plasminogen activator release were unaffected by either treatment (p>0.1 for all). Conclusions Following acute myocardial infarction, etanercept reduces systemic inflammation but increases platelet activation without affecting peripheral vasomotor or fibrinolytic function. We conclude that TNF-α antagonism is unlikely to be a beneficial therapeutic strategy in patients with acute myocardial infarction.

Effect of moderate walnut consumption on lipid profile, arterial stiffness, and platelet activation in humans

Background/Objectives:A large intake of walnuts may improve lipid profile and endothelial function. The effect of moderate walnut consumption is not known. We investigated whether a moderate intake of walnuts would affect lipid profile, arterial stiffness and platelet activation in healthy volunteers.Subjects/Methods:A total of 30 healthy males were recruited into a single-blind randomized controlled crossover trial of 4 weeks of dietary walnut supplementation (15 g/day) and 4 weeks of control (no walnuts). Arterial stiffness was assessed using pulse waveform analysis to determine the augmentation index and augmented pressure. Platelet activation was determined using flow cytometry to measure circulating platelet–monocyte aggregates.Results:There were no differences in lipid profile after 4 weeks of walnut supplementation compared with control. Dietary intake of α-linolenic acid was increased during the walnut diet (2.1±0.4 g/day versus 0.7±0.4 g/day, P<0.0001). There were no differences in augmentation index or augmented pressure during walnut supplementation. Walnut supplementation did not affect platelet–monocyte aggregation.Conclusions:Dietary intervention with a moderate intake of walnuts does not affect lipid profile, arterial stiffness or platelet activation in man. Our results suggest that the potentially beneficial cardiac effects of walnuts may not be apparent at lower and more practical levels of consumption.

The influence of the menstrual cycle, normal pregnancy and pre-eclampsia on platelet activation

Platelet activation has a key role in mediating thrombotic and inflammatory events. This study aimed to determine the influence of the menstrual cycle, pregnancy and pre-eclampsia on in vivo platelet activation. Twelve healthy nulliparous, non-smoking women with regular menses were studied over a single menstrual cycle. Twenty-one healthy primigravida pregnant women were studied longitudinally at 16, 24, 32 and 37 weeks gestation and seven weeks post-partum. Sixteen primigravida women with pre-eclampsia were studied at time of diagnosis and at seven weeks post-partum. Platelet-monocyte aggregates and platelet-surface P-selectin expression were assessed by flow-cytometry. Soluble P-selectin and CD40 ligand (CD40L) were measured by ELISA. Markers of platelet activation did not vary over the menstrual cycle. Platelet-monocyte aggregates were greater in the third trimester of pregnancy compared to non-pregnant women (p=0.003). Platelet surface and plasma soluble P-selectin concentrations increased with gestation (p<0.0001) and were raised by 24 weeks of pregnancy compared to non-pregnant women (p< or =0.02 for both) and together with platelet monocyte aggregates, decreased post-partum (p< or =0.02). Soluble CD40L concentrations fell in pregnancy, reaching a nadir at mid-gestation (p=0.002). There were no differences in markers of platelet activation between normal and pre-eclamptic pregnancies. In conclusion, platelet activation is increased in pregnancy and increases with gestation but is unaffected by pre-eclampsia. This suggests that systemic platelet activation is a feature of pregnancy but this is not affected by established pre-eclampsia.

Promotion of proinflammatory interactions between platelets and monocytes by unfractionated heparin

Objectives: To determine the in vitro effects of unfractionated heparin, fractionated heparin and direct thrombin inhibition on platelet–monocyte aggregation, and to establish the in vivo effects of unfractionated heparin and direct thrombin inhibition on platelet–monocyte aggregates in patients scheduled for percutaneous coronary intervention (PCI). Design: Platelet–monocyte aggregates were assessed in whole blood from 18 healthy volunteers after the addition of unfractionated heparin (1 U/ml), enoxaparin (0.8 U/ml) or lepirudin (5.6 µg/ml), and in 28 patients scheduled for elective PCI before and after administration of 100 U/kg of unfractionated heparin or 0.75 mg/kg bivalirudin. The influence of P-selectin-mediated platelet–monocyte aggregation was assessed with specific blocking antibodies. Results: Addition of unfractionated heparin in vitro was associated with a higher level of platelet–monocyte aggregates than in controls (20.1 (1.9)% v 16.2 (1.6)%, respectively, p < 0.001). However, platelet–monocyte aggregation was not affected by enoxaparin or lepirudin (16.9 (2.0)% and 17.0 (2.2)%, respectively, NS). Intravenous unfractionated heparin in vivo also resulted in an increase in platelet–monocyte aggregates (absolute Δ 7.1 (2.7)%, p < 0.01), whereas intravenous bivalirudin had no effect (absolute Δ −1.5 (2.4)%, NS). The addition of P-selectin blockade abolished any increase in platelet–monocyte aggregates associated with heparin. Conclusions: In vitro and in vivo unfractionated heparin is associated with increased platelet–monocyte aggregation through a P-selectin-dependent mechanism. These findings provide a potential explanation for the superior cardiovascular outcomes associated with fractionated heparins and direct thrombin inhibitors.

Coronary Angiitis and Cardiac Arrest in Antineutrophil Cytoplasmic-Antibody Associated Systemic Vasculitis

A 58-year-old man was admitted with a 6-week history of fever, lethargy, arthralgia, and dyspnea on exertion. He had no prior illness or cardiovascular risk factors, and with the exception of a pyrexia, his physical examination was unremarkable. Investigations were performed, including blood and urine cultures and a connective tissue screen. He was subsequently discharged with a view to an early outpatient review when he collapsed at home with cardiac arrest. The initial rhythm was ventricular fibrillation, which was successfully cardioverted. His postarrest electrocardiogram revealed transient right bundle-branch block and his plasma troponin I concentration was raised at 8.5 μg/L. His renal function was normal, but markers of …