Natali A.Y. Chung

Vascular endothelial growth factor and soluble P-selectin in acute and chronic congestive heart failure

Because congestive heart failure (CHF) is characterized clinically by tissue hypoxia, we hypothesized that there would be evidence of neovascularization, possibly resulting from this process. To test this, we measured levels of vascular endothelial growth factor (VEGF), associated with angiogenesis, in the plasma of patients with varying degrees of CHF (presenting acutely and in the chronic phase) and compared levels with those in healthy controls. To test the hypothesis of a link between VEGF and platelet activation and a tendency to hypercoagulability in CHF, 1,2 we also measured plasma levels of fibrinogen and soluble P-selectin, because these markers of coagulation and platelet activation have previously been shown to increase in patients with chronic CHF. 2 Our methods to testing these hypotheses were cross sectional (comparing patients with acute and chronic CHF with healthy controls), interventional (examining markers before and after successful treatment of acute CHF), and using a follow-up approach (at which time we questioned whether or not plasma markers could predict those at risk of mortality). ••• We recruited consecutive patients admitted with acute CHF secondary to impaired left ventricular systolic function, which was documented as an ejection fraction 40%, either by echocardiography, radionuclide imaging, or left ventriculography on admission, or within the previous 6 months. Patients were excluded from the study for the following criteria: concomitant acute coronary syndromes; infection or pyrexial illness; recent (3 months) myocardial infarction or stroke; unstable angina or ventricular arrhythmias; chronic and systemic illnesses including renal failure, hepatic impairment, cancer, and inflammatory connective tissue disease; and use of oral steroids or hormone replacement therapy. Baseline results from patients with acute CHF (i.e., subjects presenting acutely with severe symptomatic disease) were compared with 2 age- and gender-matched control groups; these were outpatients with chronic stable CHF in sinus rhythm (chronic CHF) and healthy control subjects recruited from among healthy hospital staff and from subjects attending the hospital for hernia repairs, varicose vein procedures, or other relatively minor operations. Subjects with CHF were classified according to the New York Heart Association (NYHA) criteria, with class I to II being no or mild symptoms and class III to IV being moderate to severe symptoms. Left ventricular ejection fraction was estimated using transthoracic M-mode echocardiography. All healthy controls had no clinical evidence of vascular, metabolic, neoplastic, diabetic, or in flammatory disease on careful history, examination, and routine laboratory tests. Blood tests were performed in patients with acute decompensated CHF between days 1 and 7 after hospital admission, and again at 3 months after standard treatment for heart failure according to local guidelines. 3 Patients were followed up for clinical end points that consisted of all-cause mortality and hospitalizations for stroke, myocardial infarction, thromboembolism, unstable angina, and revascularization for up to 6 months. Citrated plasma and serum were obtained from

Is the Hypercoagulable State in Atrial Fibrillation Mediated by Vascular Endothelial Growth Factor

Background and Purpose— Tissue factor (TF; an initiator of coagulation) and vascular endothelial growth factor (VEGF; a marker of angiogenesis) are involved in the hypercoagulable state associated with malignancy. We investigated their roles in chronic atrial fibrillation (AF), a condition also associated with increased risk of stroke and thromboembolism, as well as a prothrombotic or hypercoagulable state. Methods— We studied 25 patients with AF (20 men; mean±SD age, 62±13 years) who were compared with 2 control groups in sinus rhythm: 30 healthy control subjects (17 men; mean age, 60±9 years) and 35 patient control subjects with coronary artery disease (CAD; 27 men; mean age, 60±12 years). Plasma levels of TF, VEGF, and the VEGF receptor sFlt-1 were measured by enzyme-linked immunosorbent assay. Results— VEGF, sFlt-1, and TF were significantly different between the 3 groups, with abnormal levels in AF and CAD patients compared with control subjects (P <0.001, P =0.022, and P =0.008, respectively). Among the AF patients, TF levels were significantly correlated with VEGF (Spearman’s r =0.65, P <0.001) and sFlt (r =0.54, P =0.006) levels. Only TF and VEGF levels were significantly correlated in CAD patients (r =0.39, P =0.02). There were no significant correlations among the healthy control subjects. Conclusions— Patients with chronic AF have high TF levels, in keeping with the prothrombotic state associated with this arrhythmia. The relationships between TF and VEGF and its receptor sFlt-1 in AF suggest a possible role for VEGF in the hypercoagulable state found in AF, as seen in malignancy and atherosclerosis.

Management of Hypertension in Pregnancy

Hypertension is an important cause of both maternal and fetal morbidity and mortality in pregnant women. There are still no definitive guidelines as to when and how patients should be treated, but it is important that appropriate treatment is initiated early in patients at highest risk and they are closely monitored. Hypertension in pregnancy can be a difficult condition to diagnose and treat because of the numerous and differing classification systems that have been used in the past. One classification system, which accounts for the multisystem involvement which can occur in pre-eclampsia and eclampsia, divides hypertension in pregnancy into 3 main groups: pre-eclampsia, gestational hypertension and chronic hypertension.Little benefit to the fetus has been shown from treating gestational and chronic hypertension, but studies in this area have been small and would not have had the power to show a difference in outcome between treated and untreated groups. However, the reduction in morbidity and mortality in the treatment of preeclampsia is significant. Therefore, all pregnancies complicated by hypertension require monitoring to detect the possible onset of superimposed pre-eclampsia/eclampsia. Institutions should have a management strategy for those mothers with severe hypertension including a multidisciplinary approach, where the patient is to be monitored and which antihypertensive agents are to be used. It should not be forgotten that the definitive treatment for severe hypertension is delivery of the fetus despite risks to fetal morbidity and mortality. This will reduce blood pressure, but hypertension per se may still persist post partum requiring short term therapy.

Indices of Thrombogenesis, Endothelial Damage and Platelet Function following Percutaneous Peripheral Artery Angiography and Angioplasty for Peripheral Vascular Disease

We hypothesised that there would be alterations in markers of endothelial damage/dysfunction, platelet activation and thrombogenesis in patients with peripheral vascular disease (PVD) as a result of undergoing diagnostic angiography and therapeutic angioplasty. To test this hypothesis, we measured sequential changes in von Willebrand factor (vWf, an index of endothelial damage/dysfunction), tissue factor (TF, an index of thrombogenesis) and soluble P-selectin (sP-sel, an index of platelet activation) in 52 consecutive patients (32 male; mean age 69 years, SD 10) who were undergoing elective angiography and angioplasty for PVD. Patients with PVD had significantly higher vWf and sP-sel levels compared to healthy controls (both p < 0.001), but median TF levels were not significantly different (p = 0.344). In the whole group, there was a significant reduction in sP-sel levels (p < 0.001, paired t test) post-angiography/angioplasty, but no significant change in vWf and TF levels. In patients undergoing angiography only, there was a significant drop in mean sP-sel (p < 0.001, paired t test) and vWf (p = 0.044) values after the procedure, whilst TF levels were not significantly changed (p = 0.370, Mann-Whitney U test). In patients undergoing angioplasty and stent, mean sP-sel levels fell immediately after the procedure (p = 0.001, paired t test), but there were no statistically significant changes in vWf and TF-levels. In conclusion, there appears to be a reduction in plasma sP-sel levels following angioplasty and stenting for PVD, suggesting alterations in platelet physiology, which may be accompanied by some alterations in the endothelium. The possibility that these changes may have pathophysiological implications for understanding platelet and endothelial reactions to angiography and associated interventions (that is, angioplasty and stent) needs to be explored.

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.