Vascular Disease Prevention (Discontinued) - Volume 1, Issue 2, 2004

Homocysteine is a sulfur-containing intermediate aminoacid, produced by the metabolism of methionine. Circulating homocysteine can be increased by a genetic deficiency of enzymatic pathways involved in its catabolism as well as by environmental factors including nutritional deficiencies, life style factors or physiological conditions, which mainly induce deficiency of folate, vitamin B12 and vitamin B6. Homocysteine exerts a prothrombotic and proatherosclerotic effect, mainly caused by a direct deleterious effect on the endothelium. An early event of this interaction is endothelial dysfunction, characterised by a reduced nitric oxide (NO) availability due to an abnormal production of reactive oxygen species induced by homocysteine. This alteration has been confirmed in humans, either in conditions of acute or fasting chronic hyperhomocysteinaemia. When hyperhomocysteinaemia is associated with another cardiovascular risk factor such as hypertension, a further reduction of endothelial function occurs: an effect likely due to an exacerbated production of oxidative stress. Folates also exert beneficial effects on endothelial function by mechanisms independent of changes in plasma homocysteine levels, including an effect on free homocysteine, an antioxidant effect or an action on endothelial NO synthase (eNOS). Although the deleterious effect exerted by hyperhomocysteinemia on endothelial function is well recognised, its role in the pathogenesis of atherosclerotic lesions or cardiovascular events is still to be established. Finally, although available evidence suggests that hyperhomocysteinaemia could be an independent predictor of recurrent cardiovascular events, the possibility that a reduction in plasma homocysteine induced by vitamin therapy can diminish the risk of cardiovascular events is still under evaluation.

Preeclampsia has recently been suggested to be a two-stage disorder of an alteration in placental perfusion (stage 1) leading to a maternal syndrome (stage 2). However, the mechanism linking the two remains unclear. There is now cumulative evidence that platelets may be involved. Platelets are known to be activated in early normal pregnancy, and their increased activation and consumption is probably controlled by yet unknown buffering factors that maintain hemostasis and prevent further platelet activation. Further platelet activation that is affected by cytokines, especially TNF- α and by IL-1β, by currently unknown mechanisms, occurs weeks to months before the clinical appearance of preeclampsia. We found that maternal platelet function undergoes marked changes during normal pregnancy toward refractoriness to activation by IL-1β and TNF-α. In preeclampsia, this refractoriness is lost or diminished due to an intrinsic change in platelet response and, at least in the case of IL-1β, reverts toward the non-pregnant state. Failure to control the stimulatory platelet changes of pregnancy leads to platelet adhesion, aggregation, and release of thromboxane A2, which in turn, generate vasoconstriction, further aggregation, and progressive damage to endothelial cells. CD40 ligand (a transmembrane protein structurally related to TNF-α) is shed from activated platelets to directly initiate inflammation of the vessel wall. On the basis of these findings, we propose that the complex interaction between activated platelets and impaired cytokine production at the feto-maternal interface, triggered by immunological or inflammatory factors in the early stages of pregnancy, contributes to the evolution of preeclampsia.

Stroke is the third most common cause of death in Western civilizations, and the single most common cause for permanent disability. Approximately 20% to 30% of ischemic strokes are caused by high grade carotid artery stenosis, and revascularization therapy has the potential to resolve this problem. Traditionally, carotid endarterectomy (CEA) is considered the Gold standard for treatment of symptomatic and asymptomatic high-grade internal carotid artery (ICA) obstructions with a degree of stenosis above 70%. Recently, carotid artery stenting (CAS) emerged as an accepted alternative method for treatment of patients with high-grade carotid artery stenosis, who are at an increased risk for surgical carotid endarterectomy (CEA). The reported rates of neurological complications of CAS substantially decreased during the past years, and the routine use of cerebral protection devices and low profile catheter systems have further increased the procedure's safety. Provided that the ongoing randomized controlled trials comparing CAS and CEA confirm equivalence between these methods, CAS like CEA may be applicable to a more general population of patients with high grade carotid artery stenosis in the near future. The present article critically reviews the evidence that endovascular treatment of high grade carotid artery stenosis by elective CAS may be beneficial in the prevention of thromboembolic stroke.

Dexmedetomidine is a selective α2-adrenoceptor agonist, which has been shown to be neuroprotective in experimental cerebral ischemia models. Dexmedetomidine administration induces sedation and it has been used as a veterinary sedative in a racemic mixture called medetomidine and recently also clinically in the intensive care unit. Dexmedetomidine treatment has been found to be neuroprotective in cerebral ischemia and some excitotoxic models. The neuroprotective effect of dexmedetomidine could be utilised in prevention of ischemic damage and memory disturbances following by major surgery causing cerebrovascular events.

Acetaminophen (paracetamol) has been used therapeutically in Western medicine for about 110 years. Its fever-lowering and pain-relieving properties are well known, even though the specific mechanisms responsible for these actions are still uncertain. Recent and ongoing investigations have revealed previously-unpublished actions of this agent. This review focuses on heart and vasculature. For example, relative to vehicle-treated control hearts, we have found that acetaminophen improves the rate of recovery and the magnitude of ventricular function in the postischemic, reperfused mammalian myocardium. This is true whether the agent is administered before, during, or after ischemia. It is also true of the chronic administration of acetaminophen. Among other possibilities, mechanisms include antioxidation against hydroxyl radicals, hydrogen peroxide, and peroxynitrite (myeloperoxidase is likely to be added to the list in the near future). Acetaminophen also appears to be protective against myocardial infarction and necrosis (manuscript in preparation) as well as against the ventricular dysfunction caused by hypoxia / reoxygenation (manuscript in review). Moreover, it has recently been shown to block the actions of myeloperoxidase, and to attenuate the production of conjugated dienes and oxysterols, all of which are implicated in the pathogenesis of vascular disease. As these and related future results become known, acetaminophen could well be added to the list of preferential therapeutics in the management of heart and vascular disease.

Conventional coronary artery bypass grafting (CABG) is the most common cardiac surgical procedure for treating coronary artery disease (CAD). The greater saphenous vein (SV) is the most commonly used conduit material for aortocoronary grafting. During conventional harvesting of the SV graft for CABG the surrounding tissue is removed and the vein distended before implantation takes place. This results in mechanical trauma to the vascular tissue. A no-touch preparation technique for CABG has been developed where the SV graft is harvested with its surrounding tissue preserved. This functions as a protective cushion that protects against vasospasm and reduces mechanical stress. Collectively, various post-implantation studies of patients showed a significant improvement in the patency of no-touch grafts compared to conventionally harvested grafts. The aim of the present study was to examine the effects of the two harvesting techniques of SV for CABG. SV segments were prepared and their morphological features were examined with a scanning electron microscope. The results demonstrated a high degree of structural preservation of no-touch SV preparations for CABG, including the endothelium, media, and the adventitia with the vasa vasorum. In contrast, a high degree of damage due to mechanical trauma was observed in SV harvested by conventional techniques. There were structural changes to the intima of these segments. In addition, remnants of the adventitial vasa vasorum were exposed to the outer environment. The possible pathophysiological implications of conventionally prepared grafts and the beneficial consequences of using the no-touch technique, in relation to CABG history, are discussed.

Potassium selective ion channels play an important role in the regulation of vascular tone. Particularly important is the class of K+ (KATP) channels modulated by intracellular ATP, which are normally closed at physiological intracellular ATP concentrations (ATPi) but open when ATPi decreases. KATP channels play an important role in the relaxation of vascular smooth muscle, including that of coronary vessels. Recent data suggest that coronary flow under normal conditions may be tonically controlled by KATP channels. Coronary KATP channels are activated by adenosine released during exercise, hypoxia or ischemia. They also constitute the main site of action of many drugs. Physiologic regulation of these channels is not fully understood. Protein kinase C (PKC) modulates coronary flow, probably via an effect on KATP channels. Implications are that drugs interacting with the KATP channels may change basal coronary flow under normal conditions. The PKC modulation may be important, given its role in mediating the response to neurotransmitters and hormones. In addition, since PKC isoform expression and activity can be modified during disease conditions, the enzyme may be partially responsible for pathologic reduction in coronary flow.

In atherosclerosis overactivity of matrix metalloproteinases (MMPs) is thought to contribute to plaque instability. In the present study we investigated in patients with acute coronary events: a) the longitudinal course of plasma levels of MMP-9, MMP-2 and of tissue inhibitors of metalloproteinase-1 and -2 (TIMP-1, TIMP-2), b) any association between MMPs and TIMPs with soluble markers of platelet activation (sP-selectin, sCD40L) or endothelial activation (sVCAM-1), and c) any effect of statin therapy on these parameters. Forty-one men with unstable angina pectoris (n=17) or myocardial infarction (n=24) were examined during the acute phase and nine months later. Plasma levels of MMP-9, MMP-2, TIMP-1, TIMP-2, as well as sP-selectin, sCD40L and sVCAM-1 were measured. Half of the patients from both groups received statin treatment. In the acute phase upregulation of MMP-9 and TIMP-1 and downregulation of MMP-2 was observed, congruent with the pattern of inflammatory stimulation of cells in vitro. The dysregulation of MMP-2 and TIMP-1 persisted in the chronic phase. Similarly, all cellular activation markers were upregulated in acute disease and attenuated only partly in the chronic phase, indicative of a permanent inflammatory state. Statin therapy effectively lowered lipid levels, but had no impact on MMPs or cellular activation markers. MMP-9 is a sensitive marker of acute coronary disease, whereas the continuous dysregulation of MMP-2, TIMP-1 and of cellular activation markers in both acute and chronic phases of coronary disease is indicative of persisting inflammatory stimulation. Current results fail to support a relevant anti-inflammatory effect of statins in chronic coronary disease.

The radio-telemetric technology makes it possible to continuously monitor arterial pressure, heart rate and physical activity as well as their circadian rhythms and their response to therapeutics in unrestrained animals for a longer period of time. This is essential for in vivo cardiovascular research. The primary purpose of the present study was to use telemetry to characterize those physiological parameters in a rat model of heart failure post myocardial infarction. Moreover, some of the neurohormonal alterations and the hemodynamic responses to L-arginine, the substrate for nitric oxide synthase (NOS), and L-NAME that inhibits NOS activity were also evaluated. Rats with moderate and large myocardial infarction are considered to have chronic heart failure (CHF), which displayed decreased systolic and consequently decreased mean blood pressure, blunted diurnal dips in systolic, diastolic and mean blood pressure, narrowed pulse pressure and relatively reduced strength of physical activity. These telemetric alterations were accompanied by increased left ventricular end diastolic pressure, right and left ventricular hypertrophy and elevated plasma norepinephrine and tumor necrosis factor. In CHF rats, L-arginine widened pulse pressure and L-NAME caused attenuated pressor response, suggesting the presence of the general NO deficiency in this model. Thus, telemetry provides some new and unique information about CHF in rats, which is important in exploring the underlying mechanism of heart failure, but cannot be obtained by the conventional approach.

Clinical practice guidelines exist in many different forms and in a wide spectrum of therapeutic areas; some recommendations are directed at specialists and others at a primary care audience, some focus on prevention and others on treatment of disease. In all of their various guises, guidelines represent an attempt to bridge the gap between the generation and the application of scientific evidence. Successful guideline implementation should improve quality of care by expediting the utilization of effective advances in everyday practice. Guidelines for the prevention of cardiovascular disease (CVD) are particularly numerous. More so than in most therapeutic areas, scientific evidence continues to accumulate rapidly demonstrating that lifestyle interventions and the use of pharmacological therapies in patients with CVD and other selected high-risk individuals can reduce cardiovascular morbidity and mortality. However, despite widespread dissemination of comprehensive guidelines over several years, CVD remains the primary cause of mortality worldwide. It seems apparent, therefore, that there is a failure to put into action what is known about prevention. In 2003, a small group of key opinion leaders, with previous involvement in the development and / or implementation of CVD and coronary heart disease guidelines, held a series of workshops focused on current and future trends of clinical guidelines in the management of atherosclerosis. The objectives were to stimulate dialogue around the convergence / divergence of guidelines on an international basis; to discuss the practicalities of guideline implementation and to identify future trends in the evolution of guidelines. Here, we summarize the key discussions of the workshops.