Current Vascular Pharmacology - Volume 6, Issue 1, 2008

Starting in the 1970s the hypothesis that the low mortality from coronary heart disease among the Greenland Eskimos was due to their high consumption of n-3 fish oil fatty acids, initiated many studies to find if the n-3 polyunsaturated fatty acids in fish oils (PUFAs) could prevent cardiac atherosclerosis. To date this possibility has not achieved clinical recognition. The recent literature shows an increase of intervention studies to learn if the fish oil fatty acids can reduce mortality from sudden cardiac death, and the mechanism(s) of such a protective effect. Indeed the most definite beneficial cardiac action of these n-3 PUFAs seems now to be their ability in the short term to prevent sudden cardiac death. It is apparent that over long periods of time the n-3 fish oil fatty acids also prevent atherosclerosis. Definition of the fatty acids to which I will be referring in the text:n-6 (omega-6) polyunsaturated fatty acids; linoleic acid (18:2n-6, LA); arachidonic acid (C20:4n-6, AA). n-3 (omega-3) fatty acids; α-linolenic acid (18:3n-3, ALA); eicosapentaenoic acid (20:5n-3, EPA); docosahexaenoic acid (C22:6n-3, DHA). The bold, underlined abbreviation will appear in the text to identify the fatty acid being discussed.

Familial combined hyperlipidaemia (FCH) was identified in early genetic studies of populations as a dominant condition associated with mixed hyperlipidaemia and early onset coronary heart disease. Later studies extended the phenotype and noted that this genetic hyperlipidaemia was sensitive to environmental effects. This article reviews the definitions, animal models and genetics of FCH. In contrast to familial hypercholesterolaemia, which is caused by mutations in a limited number of affected genes, the genetics of FCH have remained obscure and very few definite candidate genes have been identified. A strong role for the apoA-I, A-IV, A-V, C-III cluster on chromosome 11 was identified early on and multiple associations have been found to hyperlipidaemia in this region and more strongly to adjacent sections of the chromosome. More recently quantitative trait mapping has identified a number of candidate genes including upstream transcription factor -1 (USF-1) on 1 q21 and CD- 36 on chromosome 4. Of these the strongest evidence, based on 4 analyses, links the lipid components of FCH to intronic variants in the USF-1 gene on chromosome 1q21-23. Unfortunately USF-1 yet fails to show clear associations with diabetes and the metabolic syndrome which co-map to this region and are also associated with mixed hyperlipidaemia. Large scale validation of USF-1 variants in other populations is still awaited. It is likely that FCH is a heterogeneous condition, that is subject to wide-scale environmental confounding from common traits such as obesity and the metabolic syndrome, and that the resolution of its genetics is going to prove a severe challenge.

The diabetic foot remains a major cause of morbidity worldwide. Ischaemia due to peripheral arterial disease significantly contributes to its pathogenesis and natural history. Increased revascularisation has been decisive in improving outcomes. However, there is still a need for further improvement. Advances in the treatment of ischaemia in the diabetic foot include therapeutic angiogenesis, stem cell therapy and miscellaneous modalities. Angiogenesis has yielded encouraging results in the treatment of peripheral arterial disease, but it has not been studied enough in patients with diabetes. Choice of patients, reliable study endpoints, as well as safety of growth factors in diabetic patients, who have an excess risk of widespread vascular disease, need to be addressed more convincingly. Similar improvement is required in the other emerging therapeutic options. From a practical point of view, until novel modalities are available, increased vigilance and prompt aggressive revascularisation are indispensable to reduce the rate of amputations.

The goal of acute stroke therapy is to salvage brain tissue by rapid cerebral artery recanalization to improve microcirculation. A major drawback of fibrinolysis is the activation of platelets leading to a high rate of re-occlusion. Antagonists of the platelet GPIIb/IIIa-receptor inhibit the binding of fibrinogen to platelets counteracting secondary thrombus formation. Also, they were shown to suppress thrombembolus formation and to limit lesion development in cerebral ischemia. We review the literature concerning the use of intravenously administered GPIIb/IIIa-receptor antagonists abciximab, eptifibatide and tirofiban for the treatment of patients with acute ischemic brain infarction. In multicenter, prospective, randomized and placebo-controlled trials abciximab had a higher cerebral bleeding risk, while tirofiban did not increase hemorrhage. When combined with fibrinolysis, abciximab and tirofiban were found to improve cerebral artery recanalization and tissue reperfusion resulting in reduced infarct volumes and improved neurological outcome. Thus, GPIIb/IIIareceptor antagonists have a great potential for the treatment of acute stroke.

The murine carotid artery ligation (CAL) model has been widely used in the research of intimal hyperplasia, a major pathological process in vascular diseases, such as atherosclerosis and restenosis after angioplasty. Using a variety of gene knockout or transgenic mice and different pharmacological interventions, these studies have yielded significant new findings that contribute not only to unraveling the basic molecular mechanisms involved in the pathogenesis of intimal hyperplasia, but also to the identification of novel targets for intervention of these diseases. The current review outlines the findings derived from the murine CAL model, including studies run by the authors, covering the impacts of hyperlipidemia, pro-inflammatory factors, endothelial dysfunction, protease activity and growth mediators on neointimal hyperplasia.

Despite many advances achieved to date, heart failure (HF) remains a leading cause of morbidity and mortality. There is a widely-accepted consensus that HF and diabetes are strongly linked by at least 3 mechanisms: associated comorbidities, coronary atherosclerosis or a specific diabetic cardiomiopathy. For the last 2 mechanisms, advanced glycation end-products may contribute to trigger key processes relevant to HF by affecting cardiac function through cross-linking or receptor engagement. This review focuses on the main effects of advanced glycation end-products on cardiomyocytes and endothelial cell function. Some pharmacological approaches are also discussed.

Platelet activation induces rapid thrombus formation at a ruptured atherosclerotic plaque leading to acute vessel occlusion and a fatal or non-fatal cardiovascular event. More recent evidence suggests that activated platelets play an additional central role during the initiation of atherosclerosis, essentially facilitating leukocyte adhesion and recruitment. Endothelial dysfunction is a common and early feature of cardiovascular diseases characterized by reduced bioavailability of prostacyclin and nitric oxide (NO). Subsequently impaired endogenous platelet inhibition causes platelet activation in pre-atherosclerotic vascular disease resulting in enhanced platelet susceptibility to agonists released from the inflamed endothelium. Platelet adhesion to inflammatory, dysfunctional endothelium precedes leukocyte adhesion. Indeed, adherent activated platelets are mandatory for leukocyte recruitment in the early phases of atherosclerosis under arterial flow conditions. Increased expression of chemokines in atherosclerotic plaques and the inflamed endothelium initiates and facilitates pro-inflammatory processes in leukocytes and the vascular wall. Apart from their chemotactic properties, some chemokines such as fractalkine contribute to platelet activation. Moreover, fractalkine induces leukocyte recruitment to inflamed endothelial cells under arterial flow by activating adherent platelets. An aggressive form of atherosclerosis is found in patients with diabetes. Since diabetes is currently considered as a risk equivalent for coronary artery disease, the interaction between oxidative stress, endothelial dysfunction, impaired endogenous platelet inhibition and platelet activation is discussed in the light of diabetes. Defective regulation of platelet activation/ aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke.

This article reviews randomized control trials (RCT's) published in 2006 of various medications evaluated for stroke patients. These trials were primarily efficacy studies. These included aggrenox (an antiplatelet agent), magnesium (to treat arterial spasm after an aneurysmal subarachnoid hemorrhage), NXY (a free radical trapping agent) and albumin which were both tested as a neuroprotectant, amphetamine (to aid motor recovery), fluoxetine (an anti-depressant and anxiolytic) and low molecular weight heparin (for prevention of deep vein thrombosis post-stroke).

Dyslipidaemia is a common and consistent abnormality in insulin resistant subjects with obesity and type 2 diabetes mellitus associated with increased risk of cardiovascular disease. Lipoprotein metabolism is complex and abnormal plasma concentrations can result from alterations in the rates of production and/or catabolism of diverse lipoprotein particles. Our understandings of the dysregulation and therapeutic regulation of lipoprotein transport in insulin resistant states has relied on the application of advances in stable isotope and modelling methods. Dysregulation of lipoprotein metabolism in these circumstances may be caused by a combination of overproduction of VLDL apolipoprotein (apoB) B- 100 and VLDL-apoC-III, decreased catabolism of apoB-containing particles, and increased catabolism of HDL apoA-I particles. These abnormalities may be consequent on a global metabolic effect of insulin resistance and accumulation of visceral fat. Several pharmacological treatments, such as statins, fibrates or fish oil can correct the dyslipidaemia by diverse kinetic mechanisms of action, including decreased secretion of apoB and apoC-III, and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. Newer agents, including insulin sensitizers, cholesterol absorption inhibitors, CETP inhibitors, peroxisome proliferator-activated receptor-delta agonists and endocannabinoid- 1 receptor blockers, have also been shown to improve plasma lipid and lipoprotein abnormalities in insulin resistant states; their mechanisms of action are at present being investigated. Rimonabant is the endocannabinoid receptor blocker shown to decrease cardiometabolic risk in insulin resistant subjects. The complementary mechanisms of action of different agents support the use of combination regimens in treating dyslipoproteinaemia in subjects with central obesity and type 2 diabetes.