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Original Article
| doi: 10.1111/j.1365-2796.2006.01735.x
Haemorheological, platelet and endothelial indices in relation to global measures of cardiovascular risk in hypertensive patients: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial C. G. C. Spencer, D. C. Felmeden, A. D. Blann & G. Y. H. Lip From the Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
Abstract. Spencer CGC, Felmeden DC, Blann AD, Lip GY (City Hospital, Birmingham, UK). Haemorheological, platelet and endothelial indices in relation to global measures of cardiovascular risk in hypertensive patients. J Intern Med 2007; 261: 82–90. Introduction and Methods. We tested the hypothesis that there was a significant relationship between haemorheological markers [white blood cell count (WCC), plasma viscosity (PV), haematocrit (HCT) and fibrinogen], as well as plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and soluble P-selectin (sP-sel, an index of platelet activation), to five global measures of cardiovascular risk [i.e. Framingham coronary heart disease (CHD), stroke and cardiovascular death score, the Pocock cardiovascular risk score and the sum of individual risk factors]. Results. Men with a high (‡median, n ¼ 156) Framingham 10-year CHD risk score had higher levels of WBC (P ¼ 0.027), fibrinogen (P ¼ 0.012) and vWF (P ¼ 0.002) than 153 men with results < median.
Introduction Increasing emphasis is being placed on the assessment and quantification of overall cardiovascular risk in making decisions about the treatment of patients with hypertension and other single cardiovascular risk factors. In 2002, we reported a substudy of 382 consecutive patients participating in the Anglo-Scandinavian
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Men with a high 10-year stroke risk score had significantly higher levels of fibrinogen (P ¼ 0.01) and vWF (P < 0.0001). In stepwise linear regression analysis in men, vWF and fibrinogen were independent predictors of the number of risk factors (P < 0.0001), whilst WCC, vWF and fibrinogen emerged as independent predictors of Framingham CHD risk (P < 0.0001), and fibrinogen and vWF predicted Framingham stroke risk (R2 ¼ 0.089, P < 0.0001). vWF, PV and fibrinogen were predictors of Pocock cardiovascular death risk (P < 0.0001) but vWF was the only independent predictor of Framingham cardiovascular death risk (P ¼ 0.001). Conclusions. Abnormal haemorheological factors (particularly high plasma fibrinogen levels) and endothelial damage/dysfunction (high vWF), but not platelet activation (sP-sel), are related to established cardiovascular and death risk scores. This relationship was most evident amongst male ‘high-risk’ hypertensive subjects. Keywords: hypertension, soluble P-selectin, von Willebrand factor.
Cardiac Outcomes Trial (ASCOT) trial at our centre, and found that patients with hypertensive target organ damage (TOD) had significantly higher plasma von Willebrand factor (vWF, an index of endothelial damage/dysfunction), but there were no statistically significant differences in plasma viscosity (PV), fibrinogen, haematocrit (HCT), white blood cell count (WBC), platelet count or soluble P-selectin (sP-sel, an index of platelet activation) compared with controls [1]. In
C. G. C. Spencer et al.
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Haemorheological factors and cardiovascular risk
multivariate analysis, vWF was a significant independent predictor for TOD. In a subset of 76 patients, we also reported a significant relationship of tissue factor (an index of coagulation), vWF and vascular endothelial growth factor (an index of angiogenesis) to the patient’s 10-year cardiovascular and cerebrovascular risk score using the Framingham equation [2]. The present study extends our previous work by comparing levels of haemorheological markers with estimates of cardiovascular risk based on data derived from two different prospective cohort databases, the Framingham [3] and Pocock [4] scores, as well as the crude number of risk factors. The risk factor equations [3, 4] used may provide a more accurate estimation of cardiovascular risk than simply counting individual risk factors as they treat variables such as cholesterol as continuous rather than as dichotomous variables. Furthermore, they take into account the fact that risk factors are not simply additive but those with several risk factors are at very high risk [5]. By comparing global measures of cardiovascular risk based on conventional risk factors with haemorheological variables it may be possible to detect the results of multiple small increases in heaemorheological variables from many risk factors. Furthermore, it may help establish how much of the increased risk conveyed by haemorheological variables may be accounted for by conventional risk factors. We hypothesized that there was a significant relationship between the haemorheological factors [WBC, HCT, PV and fibrinogen] as well as vWF, sP-sel and platelet count, to five global measures of cardiovascular risk. We tested this hypothesis in the study cohort of 383 ‘high-risk’ hypertensives screened for the ASCOT trial in our study centre in Birmingham.
Methods The methods and results of the ASCOT trial have previously been published [6, 7]. The hypertensive patients entered into ASCOT required three or more risk factors to be included, as follows: (i) left ventricular hypertrophy (LVH) according to Cornell voltage
duration product (0.2440) or Sokolow Lyon criteria (0.38 mV), (ii) other ECG abnormalities (left ventricle strain pattern, abnormal Q waves, left bundle branch block, ST-T changes compatible with ischaemic heart disease), (iii) history of diabetes mellitus according to World Health Organization criteria, (iv) past medical history of cerebrovascular event, including transient ischaemic attack, (v) male sex, (vi) age >55 years, (vii) microalbuminuria/proteinuria, (viii) smoking, (ix) adverse plasma total cholesterol/HDL cholesterol ratio ‡6, (x) family history of premature coronary heart disease first-degree relative before the age of 55 (men) or 60 (women), and (xi) peripheral vascular disease according to Edinburgh claudication questionnaire. The measures chosen for cardiovascular risk assessments/scoring in our patients, as part of this substudy were the following: (i) the crude number of risk factors using the ASCOT trial definitions of risk factors [LVH, ST/T wave changes on ECG, type 2 diabetes, peripheral vascular disease, a past history of cerebrovascular event, male gender, age ‡55 years, microalbuminuria/proteinuria, smoking, plasma total/HDL cholesterol ratio ‡6 and a family history of premature coronary heart disease (CHD)]. Full definitions of the risk factors have been reported previously [6]; (ii) the 10-year CHD risk score using the Framingham equation [3]; (iii) the 10-year stroke risk score using the Framingham equation [3]; (iv) the 5-year cardiovascular death risk using the new Pocock risk score [4]; and (v) the 5-year cardiovascular death risk using the Framingham equation [3]. The Pocock risk score was used as it was directly applicable to the study patients, and is unlike the Framingham equation which is not designed for patients who have already had a cardiovascular event and does not take into account BP treatment. The 5-year Framingham cardiovascular death score is included as a comparator to the Pocock score. The risk scores were calculated using the risk calculator supplied with the Joint British Recommendations on the Prevention of Coronary Heart Disease in Clinical Practice which uses the Framingham equation, and the Pocock score calculator which was downloaded from http://www. riskscore.org.uk.
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Laboratory von Willebrand factor was measured by an established enzyme-linked immunosorbent assay using commercial antisera from Dako (Ely, Cambs, UK) and reference vWF from the National Institute for Biological Standards and Control (Potters Bar). Soluble P-selectin (sP-sel) was measured in citrated plasma by enzyme-linked immunosorbent assay using commercial reagents (R&D Systems, Abingdon, UK). The intraassay coefficient of both assays was
