The effects of exercise stress testing on soluble E‐selectin,von Willebrand factor,and circulating endothelial cells as indices of endothelial damage/dysfunction

Background. The quantification of circulating endothelial cells (CECs) in whole blood is an increasingly recognized index of endothelial damage/dysfunction. Abnormal CECs have been linked to the severity of coronary artery disease (CAD).

Objective. We assessed the relationship of CECs to other markers of endothelial dysfunction (von Willebrand factor (vWF) and soluble E‐selectin (sEsel)) during exercise stress testing (EST) in a cohort of patients with suspected CAD.

Methods. We studied a cohort of patients referred to our chest pain clinic with a history of exertional chest pain. Treadmill EST was performed, using a full Bruce exercise protocol. Blood for CECs (immunobead method), vWF and sEsel (both ELISA) were collected immediately before (pre‐exercise), immediately following exercise, and at 30 minutes post‐EST.

Results. We studied 31 patients (84% male; mean (SD) age 58.4 (9.8) years). Of the entire cohort, 14 patients (45.2%) had a positive EST. Exercise led to significant increases in levels of CECs, sEsel, vWF, white blood cells (WBC), heart rate, mean and systolic blood pressure compared with base‐line (all P<0.05). There was a significant correlation between the change (Δ (immediate post–pre‐exercise)) in CECs and ΔvWF (r = 0.45; 95% CI 0.11–0.69: P = 0.01) and ΔsEsel (r = 0.41; 0.05–0.7: P = 0.02), as well as between ΔvWF and ΔsEsel (r = 0.55; 0.25–0.76: P = 0.001). Neither absolute nor ΔCEC counts were predictive of exercise work‐load/functional capacity, nor the presence of positive EST results.

Conclusion. EST led to a significant increase in endothelial markers (CECs, vWF, and sEsel) compared with base‐line levels. The rise in CECs correlated with the increases in other endothelial markers, but was not related to the either exercise work‐load/capacity or to the presence of a positive EST.     

Fibrinolytic function and atrial fibrillation

Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, which is associated with a substantial risk of stroke and thromboembolism. A prothrombotic or hypercoagulable state has been observed in these patients, although previous studies have mainly focused on various clotting factors, endothelial damage or dysfunction markers and platelet activation. However, fibrinolytic function has been less frequently studied, despite the fibrinolytic system playing an important role in preventing intravascular thrombosis. Indeed, increasing evidence suggests that an imbalance between the fibrinolytic function is of great importance in cardiovascular disease. This review will begin by providing a brief approach to fibrinolytic function and examine previous studies about fibrinolytic activity and atrial fibrillation.     

Anti-oxidative properties of beta-blockers and angiotensin-converting enzyme inhibitors in congestive heart failure

BACKGROUND: Chronic elevation of plasma catecholamines and sympathetic stimulation in chronic heart failure (CHF) leads to increased production of free radicals, and so possibly to endothelial damage/dysfunction and atheroma formation. Abnormal oxidative stress may therefore be related to some of the high mortality and morbidity in CHF. The objective of the present prospective open study was to compare the effects of beta-blockers and ACE inhibitors in relation to oxidative stress and endothelial damage in CHF. METHODS: We studied 66 outpatients with CHF: 46 patients were established on an ACE inhibitor and were then started on a beta-blocker, and 20 patients not previously on ACE-inhibitors were started on lisinopril. Baseline levels of the measured parameters were compared to 22 healthy control subjects. Serum lipid hydroperoxides (LHP) and total antioxidant capacity (TAC) were determined as indices of oxidative damage and antioxidant defence, and plasma von Willebrand factor (vWf) as an index of endothelial damage/dysfunction. RESULTS: Baseline indices for the measures of oxidative damage and endothelial function in the 66 CHF patients were significantly higher than healthy control subjects [median LHP 7.5 (5.9-12.6) vs. 4.8 micromol/l, P=0.0022; TAC 428 (365-567) vs. 336 Trollox Eq. Units, P=0.0005; mean vWf 134+/-27 vs. 89+/-23 IU/dl, P<0.0001]. Following 3 months of maintenance therapy with beta-blockers, there was significant reduction in LHP levels, but not TAC or vWf. ACE inhibitor therapy also significantly reduced vWf levels, but failed to have any statistically significant effects on LHP or TAC. CONCLUSION: This pilot study suggests that oxidative stress in CHF may be due to increased free radical production or inefficient free radical clearance by scavengers. beta-Blockers, but not ACE inhibitors, reduced lipid peroxidation in patients with CHF. No relation was demonstrated between a reduction in oxidative damage and endothelial damage/dysfunction.     

The role of aspirin in carcinogenesis

British Journal of Cancer (2002) 87, 1337–1338. doi:10.1038/sj.bjc.6600670 www.bjcancer.com© 2002 Cancer Research UKSirWe read with interest the excellent paper by Akhmedkhanov et al (2002) regarding aspirin use and the incidence of lung cancer. We would like to offer another possible anti-cancer property of aspirin, namely, the inhibition of phenolsulphotransferase (PST) activity.PSTs are found throughout the body, but the bowel, liver and platelets are known to contain particularly high activities of this enzyme. PSTs are cytosolic and exist in two forms: (i) P-PST, which selectively sulphates micromolar concentrations of phenols; and (ii) M-PST, which is similarly selective for aromatic amines.The main function of this sulphation is to scavenge low concentrations of endogenous and exogenous toxins from the body, but the lability of the phenolic sulphate-ester bond means it is liable to cause the formation of electrophilic free radicals. These react chemically with DNA which may cause mutations leading to neoplasia (Coughtrie, 1996).Food cooking can result in a wide variety of mutagenic compounds, including polyaromatic hydrocarbons and heterocyclic amines, especially if the food becomes charred when grilled or barbequed. Certainly, several polyaromatic hydrocarbons have been shown to be activated by hydroxylation to phenols followed by sulphation via P-PST to the final mutagenic form (Grover, 1986). P-PST has also been found to be responsible for the activation of heterocyclic amines by N-sulphation, for example, the bladder carcinogen 2-napthylamine (Hernandez et al, 1991) and a wide variety of carcinogenic N-hydroxy arylamines (Chou et al, 1995).Thus, inhibition of P-PST would block one route of activation for both main groups of carcinogen found in food. Indeed, Rao and Duffel (1991) have shown that salicylic acid, the initial breakdown product of aspirin, is a potent inhibitor of aryl sulphotransferase IV (AST IV), at least in the rat – and AST IV is the rat equivalent of human PST enzymes. Other studies (Boberg et al, 1983; Tsutumi et al, 1995) have also shown that sulphotransferase inhibitors dramatically reduces the potency of sulphation activated carcinogens in both mice and hamsters.We would therefore suggest that the action of salicylic acid on P-PST, by preventing the excessive activation of carcinogens, may represent another possible pathway by which aspirin may reduce cancer risk.     

Mutations of the slow muscle alpha-tropomyosin gene,TPM3, are a rare cause of nemaline myopathy

The alpha-tropomyosin-3 (TPM3) gene was screened in 40 unrelated patients with nemaline myopathy (NM). A single compound heterozygous patient was identified carrying one mutation that converts the stop codon to a serine and a second splicing mutation that is predicted to prevent inclusion of skeletal muscle exon IX. TPM3 mutations are a rare cause of NM, probably accounting for less than 3% of cases. The severity of cases with TPM3 mutations may vary from severe infantile to late childhood onset, slowly progressive forms.