Vascular Medicine

Hind-limb ischemia is a potent stimulus for angiogenesis. However, capillary density does not change in tibialis anterior muscle (TA) following hind-limb ischemia, despite increases in angiogenic growth factors. The objective of this study was to determine whether changes in proliferation and apoptosis occurred in the same muscle.

In total, 19 New Zealand white rabbits underwent femoral artery ligation and excision and the ischemic and contra-lateral (control) TA muscles were harvested after 1 (n = 7), 5 (n = 7) and 21 (n = 5). Terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) was used to detect apoptosis and double staining was used to identify the apoptotic cell types. Proliferation was assessed by immunohistochemistry for proliferating cell nuclear antigen (PCNA) and [³H]thymidine incorporation, in vitro.

TUNEL positive nuclei were greater in ischemic than control muscle at 1 day (1.83 0.70% vs 1.03 0.20%), 5 days (2.13 0.50% vs 1.21 0.42%) and at 21 days the difference was statistically significant (3.42 0.80% vs 0.96 0.40%, p 0.01). The majority of TUNEL positive nuclei were endothelial (Tie2 positive) cells. The number of PCNA positive cells in ischemic versus control muscle was similar at 1 day (0.71 0.20% vs 0.53 0.20%) and 5 days (1.28 0.30% vs 0.77 0.30%), but was significantly (p 0.05) reduced in ischemic muscle at 21 days (0.18 0.20% vs 1.35 0.30%) with no difference in [³H]thymidine incorporation.

Directionally opposite changes in endothelial cell proliferation and apoptosis occur in TA muscle following hind-limb ischemia. Modulating apoptosis in ischemic skeletal muscle may present a novel therapeutic target in peripheral arterial disease.

Inherited abnormalities of coagulation are increasingly recognized in patients with venous thromboembolism. Common causes of hypercoagulability, also known as thrombophilia, include factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies. Thrombophilia should be suspected in patients who develop idiopathic venous thromboembolism at a young age, recurrent thrombosis, thromboses at unusual sites, recurrent unexplained pregnancy loss, or if there is a family history of thrombotic disorders. The most cost-effective approach is to initially screen for factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies because these are the most common defects causing thrombophilia. Long-term anticoagulation is controversial but should be considered if unprovoked venous thromboembolism recurs.

To investigate the effects of non-ECG-triggered imaging during ultrasound studies of endothelial function, brachial artery diameters were measured throughout the cardiac cycle at rest, during reactive hyperemia, and after administration of nitroglycerin. R-wave-triggered imaging using a 7.5-MHz ultrasound transducer with acquisition every 41.7-66.7 ms was performed in 24 subjects. Cardiac cycle-related variation was computed as the maximum per cent change from the end-diastolic diameter. The range of possible errors in flow-mediated dilation (FMD) and nitroglycerin-mediated vasodilation that may result from ignoring cyclic variations in diameter was determined for each condition.

True FMD, true nitroglycerin-mediated vasodilation, and the maximum and minimum values that could be erroneously calculated for FMD if timing was ignored all differed dramatically (p 0.05). The range of apparent FMD values that could be measured was nearly three times the true FMD value. Ignoring temporal position within the cardiac cycle artifactually increased calculated FMD into the normal range, despite truly impaired FMD. Peak arterial dilation occurred before end-systole and greater baseline vessel compliance was associated with greater FMD.

Brachial arterial diameters vary significantly throughout the cardiac cycle. The magnitude of this variation is similar to the arterial dilation induced by reactive hyperemia and nitroglycerin, making ECG-triggered imaging mandatory for accurate and reproducible clinical and research measurements of artery diameters and FMD. Measurement of diameters at end-diastole may be preferred to other time-points in the cardiac cycle.

In a non-randomized, open-label study results after a structured institution-based peripheral arterial occlusive disease (PAD) rehabilitation program were compared with the results of training at home. Three groups were compared: group 1 (n = 19) PAD rehabilitation; group 2 (n = 19) PAD rehabilitation + clopidogrel 75 mg once daily; group 3 (n = 21) home-based training. The training period was 3 months for all groups, which was followed by a 3-month observation phase (without prescribed training). The rehabilitation program consisted of 3 training hours per week. Background variables, demographics, and baseline claudication distances were comparable between groups. After 3 months of training the absolute claudication distances (ACD) improved by 82.7%, 131.4%, and 5.4% for groups 1, 2 and 3. The initial claudication distances (ICD) changed by 163.8%, 200.6%, and 44.4%, respectively. All changes, except the ACD result for group 3, were statistically significant (p 0.05).

Structured training groups (1 and 2) performed significantly better than group 3 (p 0.05). When results from groups 1 and 2 were pooled, ACDs changed from 493.3 218.1 to 1026.0 468.9 m, 546.0 378.8 m [95% CI 417.8 - 674.2 m]; p 0.05. ICDs improved from 175.3 110.8 m to 493.1 326.7 m, 320.8 315.9 m [95% CI 213.9 - 427.7 m]; p 0.05. The difference between the pooled mean results of the structured training groups and the results of group 3 amounted to 474.3 m [95% CI 270.2 - 678.4 m] and 242.4 m [95% CI 99.0 - 385.7 m], for ACD and ICD, respectively.

Structured, supervised PAD rehabilitation is a highly efficacious treatment for intermittent claudication and may be regarded as the present gold standard among conservative treatment options.

There is growing interest in the role of matrix metalloproteinasesin vascular diseases. These conditions are often characterized by excessive tissue remodelling, and increased matrix metalloproteinase activity has been demonstrated in aneurysms, intimal hyperplasia and atherosclerotic plaque disruption. These enzymes represent a potential target for therapeutic intervention to modify vascular pathology.

The core of this review is derived from a MEDLINE database literature search. The review found that there is convincing evidence of increased matrix metalloproteinase activity in a spectrum of vascular disease. Evidence for an imbalance promoting increased matrix degradation is less well documented. However, studies of matrix metalloproteinase inhibition in vascular disease models suggest potential therapeutic benefit.

In conclusion, in vivo studies of matrix metalloproteinase inhibition are required to further study the potential for reversal or deceleration of the excessive tissue remodelling that accompanies vascular disorders.

Major advances in cardiovascular intervention for chronic disease are underway. These innovations lie at the interface of minimally invasive catheter-based technologies and biologic approaches for the management of complex cardiovasculardiseases. This review highlights key areas where such ‘biointerventional’ cardiovascular therapies are envisioned to occur: cardiac cell transplantation, myocardial gene therapy, genetic and photodynamic endovascular interventions, and vascular tissue engineering.

This study aimed to identify the role of intermittent pneumatic compression in treating peripheral arterial disease and to investigate the types of treatment programs that are most effective. Data was sourced from English-language articles which were identified by a computer search using MEDLINE from 1966 to 2001, followed by extensive bibliography review. Studies were included if they contained pertinent material involving a compression device and arterial flow dynamics in lower limbs. A total of 26 English-language studies were identified that met the inclusion criteria. The diverse patient criteria and methods used in the studies provided an opportunity to examine the effectiveness of each, but made it difficult to compare one study with another. To assist in focusing on overall trends in improvement, patient type and treatment type disparities must be identified. In conclusion, it is evident that an intermittent pneumatic compression program appears promising and may be used in patients with severe peripheral arterial disease who are not candidates for revascularization using surgery or percutaneous angioplasty. It is now the goal to establish randomized, prospective, controlled trials to clarify the most beneficial regimen for treating such disease.

Question: Among high-risk patients with vascular disease treated with aspirin, is incomplete suppression of thromboxane generation associated with an increased risk of recurrent cardiovascular events?

Population: Men and women 55 years of age who had a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes plus at least one other CV risk factor who participated in the HOPE trial which was a 2 2 factorial randomized controlled trial of ramipril and vitamin E.¹

Design and methods: Nested case-control study of the 5529 patients from the HOPE trial participants from Canada in whom a urine sample was collected at baseline. All samples were sent to a central laboratory and stored at -80°C. Only those patients who were taking aspirin were included. Cases were defined as individuals who had a confirmed MI, stroke, or CV death after randomization. Control subjects were randomly selected from aspirin-treated patients who provided adequate urine samples but did not suffer MI, stroke or CV death after randomization. Cases and controls were matched according to sex and age (5 years) in a ratio of 1:1. Urine was thawed and assayed for 11-dehydro thromboxane B₂ levels using the Caymann Chemical immunoassay.

Results: Among 488 cases and 488 matched controls, the odds of an MI, stroke or CV death increased with each increasing quartile of 11-dehydro thromboxane B₂, with patients in the upper quartile having a 1.8 times higher risk than those in the lower quartile (OR = 1.8; 95% CI: 1.2-2.7, p = 0.009).

Conclusion: Among aspirin-treated patents who have established vascular disease, urinary 11- dehydro thromboxane B₂ predicts the future risk of MI and CV death, and may reflect ‘aspirin resistance’.