Novel therapies for the prevention of stroke

The health and economic burden of stroke to society is enormous. Pharmacological therapies remain the primary stroke prevention strategy for the vast majority. Several existing and newer pharmacological agents aimed at the treatment of hypertension and lowering cholesterol are proving to be effective. For example, the antiplatelet agent clopidogrel has reduced end points in the secondary prevention of stroke, as have combinations of aspirin with traditional therapies, including dipyramidole. The direct oral thrombin inhibitor ximelagatran is a novel oral anticoagulant that has shown significant potential as a possible replacement to warfarin therapy, for the prevention of stroke for patients with non-valvular atrial fibrillation. Additional novel agents with hypothetical, although not yet proven, benefits in stroke prevention include fish oils, homocysteine-lowering therapy and anti-inflammatory agents. Finally, a controversial novel polypill, which would include fixed combinations of several pharmacological agents, may yet become a realistic and promising stroke prevention option.     

Diastolic heart failure: recognition, diagnosis and management

A variety of community-based epidemiological studies have suggested that 30-50% of patients with heart failure symptoms appear to have preserved left ventricular (LV) systolic function when assessed by echocardiography or similar techniques suggesting 'diastolic heart failure' (DHF) as its cause. The prognosis of these patients is characterised by morbidity and mortality similar to, but less overt than, patients with systolic dysfunction. However, rates of readmission for symptom control are broadly similar in patients with DHF or in those with systolic impairment. Thus, there are many similarities in the portrayal of both systolic and DHF but equally; there are also many key differences. Certainly, while there are several successful therapies for patients with systolic heart failure, the management of patients with DHF is poorly defined. In this review, the gaps in current knowledge and practice, which is creating this therapeutic void will be addressed.     

Predictive value of indexes of inflammation and hypercoagulability on success of cardioversion of persistent atrial fibrillation

The aim of the present study was to investigate whether success or failure of direct-current cardioversion in patients with persistent atrial fibrillation may be related to indexes of inflammation (as indicated by C-reactive protein and interleukin-6, platelet activation [soluble P-selectin levels], endothelial damage/dysfunction [von Willebrand factor], coagulation cascade [tissue factor and fibrinogen], and rheology [plasma viscosity and hematocrit]). We found that C-reactive protein levels are a predictor of initial cardioversion success, although they failed to predict long-term outcome. Although inflammation may be associated with "permanence" of atrial fibrillation, indexes of platelet activation, endothelial damage/dysfunction, or coagulation showed no relation to the immediate and long-term (2-month) cardioversion outcome.     

Platelet morphology, soluble P selectin and platelet P-selectin in acute ischaemic stroke. The West Birmingham Stroke Project

The pathophysiology of ischaemic stroke involves the platelet. In this study, we hypothesised that abnormalities in platelet morphology, as well as soluble (sPsel) and total platelet P-selectin (pPsel) levels would be present in patients presenting with an acute ischaemic stroke, and that these changes would improve at > or = 3 months' follow-up.We studied 59 hypertensive patients (34 male; mean age 68 +/- 12 years) who presented with an acute ischaemic stroke (ictus < 24 hours), and compared them with 2 groups: (i) age-, sex- and ethnic- origin matched normotensive healthy controls; and (ii) uncomplicated 'high risk' hypertensive patients as 'risk factor control' subjects. Platelet morphology (volume and mass) was quantified, and sPsel (plasma marker of platelet activation) was measured (ELISA) in citrated plasma. The mass of P-selectin in each platelet (pPsel) was determined by lysing a fixed number of platelets and then determining the levels of P-selectin in the lysate. Results show that patients who presented with a stroke had significantly higher levels of sPsel and pPsel (both p < 0.001), compared to the normal controls and the hypertensive patients. Patients with an acute stroke had lower mean platelet mass (MPM) and mean platelet volume (MPV) as compared to the uncomplicated hypertensive patients, who had significantly higher mean MPM and MPV values, as compared to normal controls. On follow-up, the levels of both sPsel (p = 0.011), pPsel (< 0.001) and MPV (p = 0.03) were significantly lower. Mean MPM levels remained unchanged. We conclude that patients presenting with an acute ischaemic stroke have activated platelets, as evident by the increased levels of soluble and platelet P-selectin. Further study of platelet activation and the role of P-selectin is warranted.     

Alterations of thrombogenesis,endothelial damage and oxidative stress with reperfusion during femoral artery bypass surgery for peripheral vascular disease

Peripheral vascular disease (PVD) is a significant cause of cardiovascular morbidity. We hypothesised that there would be significant alterations of thrombogenesis, platelet activation and endothelial damage, which could be associated with abnormal oxidative stress during femoral artery bypass surgery for PVD, where the femoral artery is cross-clamped (causing acute ischaemia) and reperfused (following revascularisation). To test this hypothesis, we measured sequential changes in von Willebrand factor (vWF, and index of endothelial damage/dysfunction), tissue factor (TF, an index of thrombogenesis) and soluble P-selectin (sP-sel, an index of platelet activation) as well as lipid hydroperoxides (LPO, an index of oxidative stress) in 28 consecutive patients undergoing elective peripheral artery bypass surgery. Mean baseline vWF and sP-sel levels in PVD patients (before clamping) were significantly higher compared with age- and sex-matched controls (unpaired t test, both p < 0.05), but there were no significant differences in TF and LPO levels. There was a correlation between TF and vWF (Spearman's, r = 0.374, p = 0.05), as well as between sP-sel and vWF at the start of surgery (r = 0.467, p = 0.012). The patients undergoing peripheral artery bypass surgery had a mean femoral artery clamp time of 28 min (standard deviation 14 min; range 11-65 min). There were no significant overall changes in sP-sel, vWF, TF and LPO with femoral artery cross-clamping and reperfusion (repeated measures ANOVA, p = NS). In conclusion, we found that during ischaemia-reperfusion during peripheral arterial bypass surgery, thrombogenesis (as measured by plasma TF) and oxidative damage (as measured by LPO) within the affected leg does not increase in the immediate perioperative period. Further studies are required to assess the mechanism(s) of ischaemia-reperfusion injury in PVD, and the contributory role(s) of the endothelium and platelets.