Kaeng W. Lee

Plasma Angiopoietin-1, Angiopoietin-2, Angiopoietin Receptor Tie-2, and Vascular Endothelial Growth Factor Levels in Acute Coronary Syndromes

Background—Angiopoietin (Ang) -1 and -2, their receptor Tie-2, and vascular endothelial growth factor (VEGF) regulate angiogenesis and may be important in myocardial collateral development. Elevated levels of growth factors and their receptors are reported in myocardial infarction (MI), but changes after an acute coronary event are unknown. Methods and Results—Plasma Ang-1, Ang-2, Tie-2, and VEGF levels were measured on admission (baseline) and at 48 hours (acute stage) in 126 patients with acute coronary syndrome (82 MI, 44 unstable angina pectoris). Baseline levels were compared with those of 40 patients with stable angina and 40 healthy controls. Measurements were repeated in 38 MI patients at 6 and 18 weeks (chronic stage). Baseline Ang-2 and Tie-2 levels were highest in MI patients (P<0.001). Patients with MI and unstable angina pectoris had higher VEGF levels compared with stable angina patients and healthy control subjects (P<0.001). In patients with acute MI, serial changes in all indexes from baseline to 18 weeks were observed (all P<0.001). Ang-1 levels were unchanged from baseline to 6 weeks but were elevated at 18 weeks. Ang-2 changes followed a biphasic pattern, being higher at baseline and 6 weeks but lower at 48 hours and 18 weeks. Tie-2 levels increased from baseline and remained elevated in the chronic phase. VEGF peaked at 6 weeks and then decreased toward baseline at 18 weeks. Conclusions—Plasma Ang-2, Tie-2, and VEGF levels but not Ang-1 levels were increased in patients with acute coronary syndrome. Serial changes in the plasma levels and interrelationships among Ang-1, Ang-2, Tie-2, and VEGF levels from the acute to the chronic stages in MI may reflect the progressive stages of angiogenesis activity in the ischemic-necrotic myocardium in vivo.

Circulating endothelial cells in acute ischaemic stroke.

Increased numbers of CD146-bearing circulating endothelial cells (CECs) in the peripheral blood probably represent the most direct evidence of endothelial cell damage. As acute ischaemic strokes are associated with endothelial abnormalities, we hypothesised that these CECs are raised in acute stroke, and that they would correlate with the other indices of endothelial perturbation, i.e. plasma von Willebrand factor (vWf) and soluble E-selectin. We studied 29 hypertensive patients (19 male; mean age 63 years) who presented with an acute stroke and compared them with 30 high risk hypertensive patients (21 male; mean age 62 years) and 30 normotensive controls (16 male; mean age 58 years). CECs were estimated by CD146 immunobead capture, vWf and soluble E-selectin by ELISA. Patients with an acute ischaemic stroke had significantly higher numbers of CECs/ml of blood (p<0.001) plasma vWf (p=0.008) soluble E-selectin (p=0.002) and higher systolic blood pressure (SBP) as compared to the other groups. The number of CECs significantly correlated with soluble E-selectin (r=0.432, p<0.001) and vWf (r=0.349, p=0.001) but not with SBP (r=0.198, p=0.069). However, in multivariate analysis, only disease group (i.e. health, hypertension or stroke) was associated with increased CECs. Acute ischaemic stroke is associated with increased numbers of CECs. The latter correlate well with established plasma markers of endothelial dysfunction or damage, thus unequivocally confirming severe vasculopathy in this condition. However, the greatest influence on CECs numbers was clinical group.

Home-based versus hospital-based cardiac rehabilitation after myocardial infarction or revascularisation: design and rationale of the Birmingham Rehabilitation Uptake Maximisation Study (BRUM): a randomised controlled trial [ISRCTN72884263]

BackgroundCardiac rehabilitation following myocardial infarction reduces subsequent mortality, but uptake and adherence to rehabilitation programmes remains poor, particularly among women, the elderly and ethnic minority groups. Evidence of the effectiveness of home-based cardiac rehabilitation remains limited. This trial evaluates the effectiveness and cost-effectiveness of home-based compared to hospital-based cardiac rehabilitation.Methods/designA pragmatic randomised controlled trial of home-based compared with hospital-based cardiac rehabilitation in four hospitals serving a multi-ethnic inner city population in the United Kingdom was designed. The home programme is nurse-facilitated, manual-based using the Heart Manual. The hospital programmes offer comprehensive cardiac rehabilitation in an out-patient setting.PatientsWe will randomise 650 adult, English or Punjabi-speaking patients of low-medium risk following myocardial infarction, coronary angioplasty or coronary artery bypass graft who have been referred for cardiac rehabilitation.Main outcome measuresSerum cholesterol, smoking cessation, blood pressure, Hospital Anxiety and Depression Score, distance walked on Shuttle walk-test measured at 6, 12 and 24 months. Adherence to the programmes will be estimated using patient self-reports of activity.In-depth interviews with non-attendees and non-adherers will ascertain patient views and the acceptability of the programmes and provide insights about non-attendance and aims to generate a theory of attendance at cardiac rehabilitation. The economic analysis will measure National Health Service costs using resource inputs. Patient costs will be established from the qualitative research, in particular how they affect adherence.DiscussionMore data are needed on the role of home-based versus hospital-based cardiac rehabilitation for patients following myocardial infarction and revascularisation, which would be provided by the Birmingham Rehabilitation Uptake Maximisation Study (BRUM) study and has implications for the clinical management of these patients. A novel feature of this study is the inclusion of non-English Punjabi speakers.

Incremental shuttle walking is associated with activation of haemostatic and haemorheological markers in patients with coronary artery disease: the Birmingham rehabilitation uptake maximisation study (BRUM)

Objective: To test the hypothesis that an incremental shuttle walk test (ISWT) affects plasma indices of endothelial damage and dysfunction (von Willebrand factor (vWf)), platelet activation (soluble P-selectin), thrombogenesis (D-dimer), fibrinogen, and plasma viscosity more adversely in coronary artery disease (CAD) than in health. ISWT is a standardised walking test that provokes maximal performance and correlates strongly with maximum oxygen uptake. Methods: Research indices were measured before a practice ISWT and immediately after the second ISWT in 53 patients with CAD (48 men, mean (SD) age 59 (10) years) and in 19 matched healthy controls (16 men, 61 (10) years). Data were analysed before and after ISWT. Results: Despite no significant difference in total distance walked between patients and controls, vWf (162 (45) before v 170 (48) UI/dl after) and fibrinogen (2.9 (0.7) v 3.1 (0.7) g/l) concentrations, plasma viscosity (1.63 (0.12) v 1.71 (0.14) mPa·s), and D-dimer (0.20 (interquartile range 0.10–0.30) v 0.21 (0.12–0.31 mg/l; all p < 0.05), but not soluble P-selectin, were significantly increased after ISWT in patients with CAD, even after correction for plasma volume change. Only fibrinogen (2.5 (0.7) v 2.7 (0.7 g/l) and plasma viscosity (1.60 (0.08) v 1.64 (0.08) mPa·s; both p < 0.01) increased among controls. The increment of fibrinogen was significantly higher in patients than in controls (p  =  0.035) and correlated with total walking distance (r  =  0.46, p < 0.001) and peak heart rate (r  =  0.28, p  =  0.02). The increment of plasma viscosity rise also significantly correlated with total distance walked (r  =  0.66, p < 0.001). Conclusions: ISWT in patients with CAD appears to increase fibrinogen, vWf, and D-dimer compared with healthy controls.

Plasma haemostatic markers, endothelial function and ambulatory blood pressure changes with home versus hospital cardiac rehabilitation: the Birmingham Rehabilitation Uptake Maximisation Study

Background: Cardiac rehabilitation is an accepted therapeutic intervention in patients after myocardial infarction or coronary revascularisation. The effects of cardiac rehabilitation programmes, whether home based or hospital based, on haemostatic indices (as reflected by fibrinogen, plasma viscosity, fibrin D-dimer (an index of thrombogenesis), von Willebrand factor (vWf, an index of endothelial damage/dysfunction), soluble P-selectin (an index of platelet activation)), vasomotor function (using flow-mediated dilatation (FMD)) and ambulatory blood pressure (ABP) in patients with coronary heart disease are unknown. Methods: 81 patients (66 men, mean (SD) 59 (11) years) after myocardial infarction or coronary revascularisation were randomised to comprehensive hospital-based (n = 40) or home-based (n = 41) cardiac rehabilitation. Plasma levels of vWf, D-dimer, fibrinogen, soluble P-selectin and plasma viscosity, as well as FMD and 24-h ABP, were measured at baseline and after 3 months of cardiac rehabilitation. Results: In patients who completed cardiac rehabilitation, levels of vWf, fibrinogen and D-dimer were significantly lower and FMD improved (all p⩽0.001), whereas levels were unchanged in controls. Significant reductions were also observed in 24-h mean systolic blood pressure, diastolic blood pressure and mean aortic pressure after completion of cardiac rehabilitation (all p<0.05). No significant differences were observed between the hospital-based and home-based cardiac rehabilitation programmes on these indices. Conclusions: Cardiac rehabilitation improves haemostasis, endothelial function and ABP in patients with coronary heart disease, with no significant differences between home-based and hospital-based cardiac rehabilitation programmes. These effects may contribute to the beneficial effects of cardiac rehabilitation programmes on CV outcomes.

Synergism between factor XII –4C>T and factor XIII Val34Leu polymorphisms in fibrinolytic therapy in acute myocardial infarction

Synergism between factor XII –4C>T and factor XIII Val34Leu polymorphisms in fibrinolytic therapy in acute myocardial infarction -

Statins and the assessment of endothelial function.

DEAR SIR We read with great interest the paper by Šebeštjen et al. [1], which showed that lipid-lowering with both cerivastatin and fenofibrate improved arterial vasoreactivity in patients with combined hyperlipidaemia, although the effects were greater in the patients receiving the statin. This small but welldesigned study adds to the existing literature [2] that the statins have beneficial effects beyond lipidlowering, such as improvement in peripheral endothelial function [as measured by flow-mediated dilation (FMD) of the brachial artery], antithrombotic or antiinflammatory effects and plaque stabilization, which may contribute to the beneficial effects in reducing cardiovascular events. Endothelial dysfunction has been regarded as an early event in atherosclerosis, preceding the formation of atherosclerotic plaques and evidence of endothelial damage/dysfunction has been clearly demonstrated in patients with vascular diseases, as well as in risk factors for coronary disease, such as hypertension, diabetes mellitus, hypercholesterolaemia and smoking [3]. However, the best way of assessing endothelial damage/dysfunction is still uncertain, and it is likely that a continuum exists between endothelial activation (likely to be related to early exposure to risk factors, such as smoking), endothelial dysfunction (leading to thrombogenesis and atherogenesis) and, finally, endothelial damage (leading to overt vascular damage and atherosclerosis) [4]. Noninvasive assessment of endothelial function usually relies on postischaemic dilation of forearm vessels, using plethysmography or by FMD of the brachial artery. However, these techniques have several disadvantages, as they are observer-dependent, require expensive specialized equipment, which require trained observer(s), and the possibility of interand intraobserver variability. Such techniques are also not practically possible to be used in large population-based epidemiological studies. Nevertheless, it is of note that almost all previous studies on the effect of statins on endothelial function have employed FMD of the brachial artery. An alternative assessment of endothelial damage/ dysfunction is by measurement or plasma markers that are related to the endothelium, such as von Willebrand factor (vWf), soluble thrombomodulin or E-selectin [3]. For example, vWf has been widely accepted and well-established as a marker of endothelial damage. Raised levels of vWf been found in patients with all the major risk factors for atherosclerotic vascular disease and that treatment of these risk factors lowers vWf levels [3]. Goldsmith et al. [5] also reported a scanning electron microscopy study, which related the severity of atrial endothelial/endocardial damage to increasing plasma levels of vWf. Furthermore, we have pilot data in 89 hypertensive patients (78 men; mean age 64 years, SD 8.4; mean BP 167/91 mmHg) where plasma vWf levels significantly correlated with FMD (Spearman, r 1⁄4 )0.517, P < 0.001). Plasma markers such as vWf also have prognostic value in cardiovascular disease [3]. Indeed, prospective epidemiological studies have repeatedly shown vWf as an independent predictor of subsequent myocardial infarction or sudden death from coronary artery disease in patients with or without established coronary artery disease. Assessment of plasma markers is also relatively cheaper, more easily measured and readily available, with good reproducibility and low interand intraobserver variability, when compared with observer-dependent techniques such as FMD measurements. Plasma markers of endothelial damage/ dysfunction can even be measured in thousands of patients – an essential feature for a potential screening tool in large population-based epidemiological studies. Journal of Internal Medicine 2002; 251: 452–454

The effect of home-based versus hospital-based cardiac rehabilitation on 24-hour ambulatory blood pressure and lipid profile in patients with coronary heart disease: the birmingham rehabilitation uptake maximisation study (BRUM)

Although cardiac rehabilitation (CR) is now an accepted therapeutic intervention in patients following myocardial infarction (MI) or coronary revascularisation, the differential effects of home-based (nurse facilitated, based on the UK Heart Manual) versus hospital-based CR programmes on 24-hr ambulatory blood pressure (ABP) and lipid profile in these patients are unknown. 72 patients (58 male, 59 11 yrs) with coronary heart disease (CHD) (following MI or coronary revascularisation) were randomised to either a comprehensive hospital (n 35) or home-based (n 37) CR programme. Fasting lipid profile and average 24-hr ABP variables were measured at baseline and after 3 months of CR. There were no significant alterations in antihypertensive treatments for the period of the study. In the overall group, there were significant reductions in 24-hr systolic blood pressure (BP) (124 15 vs 120 13 mmHg, p 0.001), diastolic BP (73 10 vs 71 8 mmHg, p 0.01), mean arterial BP (91 11 vs 87 9 mmHg, p 0.001) and the 24-hr pulse pressure (51 11 vs 48 9 mmHg, p 0.04) after 3 months of CR. The 24-hr mean heart rate was not significantly changed. Plasma total cholesterol (4.0 0.9 vs 3.7 0.7 mmol/l, p 0.006) was significantly reduced whilst high-density lipoprotein cholesterol was significantly raised (1.1 0.3 vs 1.3 0.3 mmol/l, p 0.012). There were no significant differences between the hospital-based and home-based CR programmes on BP variables and lipid profile. These data suggest that 3 months of CR can result in successful reduction of BPs and favourable changes in lipid profile that would be beneficial to patients with CHD. Furthermore, hospital-based and homebased CR programmes were equally effective in achieving these improvements.

P-579: Nondipping status and high pulse pressure: relationship to endothelial damage/dysfunction

Abstract P-579 (mean ± sd) or median (IQR). Patients with CAD had significantly abnormal vWf levels and FMD but not NMD compared to controls (p Patients with CAD who were nondippers and with higher ambulatory PP had the highest vWf levels, whereas dippers with lower ambulatory PP had the lowest levels. vWf levels were closely associated with FMD, whilst ambulatory PP and circadian BP patterns had no relationship with FMD. Key Words: Endothelial Damage/Dysfunction, Pulse Pressure, Nondipping

Airborne occupational exposure and ABO phenotype: an example of gene-environment interaction in ischaemic heart disease?

Correspondence and requests for reprints to Professor G.Y.H. Lip, Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK. Tel: þ44 121 507 5080; fax: þ44 121 554 4083; e-mail: g.y.h.lip@bham.ac.uk Association studies between gene variants (polymorphisms) and measured intermediate phenotypes (such as lipid/lipoprotein levels), or disease phenotypes (such as ischaemic heart disease (IHD)) are increasingly common in the literature. Indeed, there is mounting evidence that classical risk factors for IHD, such as hypertension, diabetes mellitus and hyperlipidaemia, are polygenic traits, and their interaction with environment factors (such as diet, lifestyle, occupational, socioeconomic factors, etc.) are important in determining their phenotypic expression.