Showing papers in "European Heart Journal Supplements in 1999"

Lowering heart disease risk with cholesterol reduction : evidence from observational studies and clinical trials

Abstract: In considering any food or drug that lowers serum lipid levels, the question arises as to the expected reduction in heart disease mortality given the reduction in serum total or low-density lipoprotein (LDL) cholesterol. Such quantitative assessment of the relationship between heart disease and its risk factors is best done by analysing observational and trial data in tandem, since the two are complementary in strengths and weaknesses. Estimates based on trials alone are imprecise and short term. Observational data from cohort studies show that, in absolute units, the effect of a given cholesterol difference on heart disease risk is similar whether based on LDL or total serum cholesterol levels. The relationship between heart mortality (on a logarithmic scale) and serum cholesterol (in absolute units) fits a linear model extremely well, indicating that a constant absolute decrease in cholesterol from any point on the distribution in Western countries is associated with a constant proportionate decrease in heart disease mortality. The strength of the relationship varies with age, being proportionately stronger in younger age groups. In the age group 55-64 years, trial data show little reduction in heart disease risk in the first 2 years, but a reduction from the third year onwards that is remarkably close to the cohort study estimate of 27% for a 0.6 mmol.l -1 cholesterol reduction. This result is important, showing that risk is reversed relatively quickly (after 2 years), and reinforcing the cohort study estimate of the size of the long-term effect. Therefore, a population dietary intervention that lowered serum cholesterol by 0.6 mmol.l -1 (10%) would reduce heart disease mortality after 2 years by about a quarter. Margarines containing plant sterol/stanol esters have been shown to reduce cholesterol by about this much. Such an effect is particularly important in Britain, where the population average serum cholesterol level has not changed significantly over many years. Although it might be considered preferable to direct dietary intervention to those with the highest cholesterol levels in a community, the large number of persons with cholesterol levels close to the average gives rise to many more heart disease deaths than the smaller number with relatively high levels, and reinforces the importance of a population-wide intervention.

Biochemical and pharmacological properties of clopidogrel : a new ADP receptor antagonist

Abstract: Clopidogrel is a novel platelet ADP receptor antagonist. Animal experiments have shown that clopidogrel's anti-aggregating activity is due to a short-lasting metabolite generated in the liver by a cytochrome P 450 -dependent pathway. The active metabolite of clopidogrel antagonizes a set of low-affinity ADP receptors on platelets. Thus. clopidogrel therapy inhibits adenylyl cyclase down regulation, protein phosphorylation at tyrosine residues, Gp IIb/IIIa complex activation, and fibrinogen binding, aggregation and release. This suggests that these processes are mediated by activation of the low-affinity ADP receptor. Clopidogrel therapy reduces the platelet aggregation and myointimal thickening that occur following endothelial injury of the rabbit carotid artery. The antithrombotic activity of clopidogrel is several times greater than that of ticlopidine and aspirin in animal models of arterial and venous thrombosis. Clopidogrel is more effective than aspirin and has a favourable safety and tolerability profile: thus, it is a promising and potent antithrombotic therapy.

Atherosclerosis involves more than just lipids : focus on inflammation

Abstract: Inflammation in the vessel wall is now considered to play an essential role in the initiation, progression and the final pathophysiological steps of atherosclerosis, plaque erosion, fissure and eventual rupture. Classical pathological studies have demonstrated the presence of inflammatory cells, such as monocyte-derived macrophages and T lymphocytes, at every stage of the disease. These morphological changes are preceded by dysfunction of endothelial cells, which produce adhesion molecules that interact with inflammatory cells. Yet atherosclerosis and its clinical complications are not only characterized by a local inflammation. Recent prospective studies have consistently shown that several markers of systemic inflammation may predict future cardiovascular events, not only in apparently healthy subjects but also in patients with unstable angina. Measurements of inflammatory markers add to the predictive value of total and HDL cholesterol levels in assessing long-term coronary risk. Finally, the results of recent clinical trials indicate that the proven efficacy of various compounds in primary and secondary prevention of coronary heart disease, such as aspirin and statins, may be mediated at least in part by modifying the consequences of the inflammatory response on vascular risk.

Cholesterol-lowering effects of a stanol ester-containing low-fat margarine used in conjunction with a strict lipid-lowering diet

Abstract: Aim To investigate a possible additional cholesterol-lowering effect when a plant stanol ester-containing margarine was added to a cholesterol-lowering diet. Methods and Results Moderately hypercholesterolaemic men (n=28) and women (n=33) were randomly assigned to treatment with a strictly controlled lipid-lowering diet plus a low-fat stanol ester-containing margarine, to the identical diet plus a low-fat control margarine without stanol esters, or to their usual diet plus the low-fat stanol ester margarine (reference group). The calculated intake of fat in the test diet corresponded to 8% of the total energy input (8 E%) of saturated fatty acid, 18 E% of monounsaturated fatty acid, 9 E% of polyunsaturated fatty acid, and 240 mg . day -1 of cholesterol; this was in close agreement with analysed values. The effect of the stanol ester-containing margarine on serum total and low-density lipoprotein (LDL) cholesterol was additive when given with the lipid-lowering diet. Combined use of the stanol ester test margarine and the lipid-lowering diet reduced serum total and LDL cholesterol by 15% and 19%, respectively (both P<0.001). These reductions were significantly greater than those in patients on the test diet with the control margarine (- 8% and - 12% for total and LDL cholesterol; P=0.0035 and P=0.0158, respectively), or those in the reference group (-9% and - 12%, P=0.0059 and P=0.0034, respectively). No clinically significant effects were observed on serum levels of lipid-soluble vitamins or antioxidants. No adverse effects were reported. Conclusion Dietary plant stanol esters seem to be a safe and effective dietary tool as part of a cholesterol-lowering diet, to lower elevated cholesterol levels also on a population basis.

Rationale for the use of a fixed combination in the treatment of hypertension

Abstract: There are two major reasons responsible for the increasing popularity of the combination of two or more antihypertensive drugs as a common approach to hypertension treatment. Firstly there is evidence that this allows achievement of satisfactory blood pressure control when monotherapy is partially ineffective, thereby improving patient compliance with the therapeutic regimen and enhancing the tolerance/effectiveness ratio of the treatment. The second reason relates to the fact that combination treatment allows treatment efficacy to be extended to a much larger fraction of the hypertensive population than would be achievable with monotherapy. This paper briefly reviews the theoretical background of and the practical requirements for effective combination treatment. It also discusses the priority two-drug combinations recommended by the recent WHO-ISH guidelines on the treatment of hypertension. Finally it examines the advantages and limitations of the combination treatment aimed at simplifying antihypertensive therapy and thus improving patient compliance.

The inter-relationship between hypertension and ischaemic heart disease

Abstract: Hypertension is a major risk factor for arteriosclerosis. The pathway from hypertension to coronary vascular disease probably involves two inter-related processes, hypertensive remodelling of the coronary microcirculation and the development of atherosclerotic lesions. The extent to which each of these is present determines the clinical expression of hypertensive ischaemic heart disease. Various different factors are involved in the remodelling and atherosclerotic processes; these include structural alterations of small intramural arteries and capillaries, alterations to the endothelium-mediated control of vasomotion, altered expression of adhesion molecules and endothelial permeability, and activation of the renin-angiotensin system. The extravascular component of coronary resistance (the myocardial factor) also contributes to the impaired flow reserve in chronic arterial hypertension.

Optimizing cardiac energy metabolism : a new approach to treating ischaemic heart disease

Abstract: The classic approach to treating ischaemic heart disease involves interventions aimed either at increasing oxygen supply to the heart muscle or at decreasing the oxygen demand of the muscle. A new approach to treating ischaemia involves improving the efficiency of oxygen utilization by the tissue. During and following ischaemia, high levels of circulating fatty acids effectively compete with glucose as a source of energy. This results in an accelerated acidosis in the muscle, and an increase in energy requirements for non-contractile purposes (i.e. a decrease in cardiac efficiency). Inhibiting fatty acid oxidation and stimulating glucose oxidation can significantly improve cardiac efficiency (cardiac work/oxygen consumed). A number of pharmacological and non-pharmacological approaches can be used to achieve this, including altering fatty acid and glucose supply and uptake into the heart muscle, directly inhibiting fatty acid oxidation, or directly stimulating the rate-limiting enzyme involved in glucose oxidation, pyruvate dehydrogenase. Presently, the only pharmacological agent clinically used on a widespread basis to treat ischaemic heart disease is trimetazidine, which acts by directly inhibiting fatty acid oxidation. This inhibition of fatty acid oxidation is accompanied by a significant increase in pyruvate dehydrogenase activity and an increase in glucose oxidation. This results in a decreased production of acidosis in the myocardium, which appears to account for the cardioprotective effects of trimetazidine observed in many experimental and clinical studies. As a result, optimizing energy substrate preference, as with trimetazidine, is emerging as a novel and effective approach to treating cardiovascular disease.

Contribution of fixed low-dose combinations to initial therapy in hypertension

Abstract: Fixed low-dose combinations of antihypertensive agents have several potential advances that make them suitable for frequent use in therapeutic practice even as an initial approach. In the randomized trials of antihypertensive therapy conducted during the 1970s and 1980s, in which very large doses of diuretics were employed as initial therapy, more than 50% of patients required treatment with combination therapy in order to achieve the blood pressure goal indicated in the trial protocol. This implies that an increase in the dose of the initial antihypertensive agent does not usually significantly increase the effectiveness of monotherapy. It is well known that high doses of almost all antihypertensive agents increase the risk and the severity of adverse effects. Adverse effects of drugs are the main cause of the low compliance of patients with antihypertensive therapy in practice. Essential hypertension has multiple mechanisms, and rational combination therapy allows interference with more than one of these mechanisms. Rational combination therapy not only reduces adverse effects because of the use of low doses of each combined agent, but can also take advantage of counteractions that each of the combined agents can exert on the undesirable actions of the other agent. Organ damage associated with hypertension can be more effectively prevented or reversed by combination therapy, not only because the blood pressure load is reduced to a greater extent but also because of specific actions exerted by the various agents used in the combination. Fixed dose combinations are an aid to the doctor, as the doses of the two components have been chosen on the basis of careful experimentation of various possible doses in order to obtain the greatest blood pressure decrease with the lowest incidence of adverse effects in the largest proportion of patients.

Heart rate as a cardiovascular risk factor

Abstract: Mounting evidence shows that elevated heart rate measured in resting conditions is associated with an increased risk of developing hypertension and atherosclerosis and that it is a potent predictor of cardiovascular morbidity and mortality. Several important epidemiological studies have shown that these relationships are present not only within general populations but also among hypertensive individuals, with important implications for the treatment of hypertension. The reason for the heart rate mortality association is not well understood. Because of its co-aggregation with blood pressure, obesity, metabolic disturbances and lipid abnormalities, heart rate has been overlooked as a risk factor. However, in most studies the risk related to fast heart rate remained highly significant after controlling for other major risk factors for atherosclerosis, suggesting that heart rate plays a direct role in the induction of the risk. The strong association between tachycardia and sudden death found in the Chicago People Gas Company study, the Framingham heart study and the Cardiovascular Study in the Elderly points to the effects of sympathetic overactivity and decreased vagal tone in favouring the occurrence of life-threatening arrhythmias. Moreover, experimental studies in animals suggest that the haemodynamic disturbances related to high heart rate have a direct impact on the arterial wall, thus promoting the development of atherosclerotic plaques. Preliminary results from animal models and pooled data from intervention studies in post-myocardial infarction patients suggest that drug-induced reduction of heart rate may be beneficial in several clinical conditions.

The North Karelia Project: from community intervention to national activity in lowering cholesterol levels and CHD risk

Abstract: Elevated serum cholesterol level is a major risk factor behind the epidemic of atherosclerotic cardiovascular disease. Lowering elevated serum cholesterol levels in a population calls for general changes in dietary habits. The North Karelia Project is a major theory-based national demonstration programme that was initiated in the early 1970s to see if a comprehensive community-based intervention would lead to major changes in dietary habits, in population cholesterol levels and, ultimately, in coronary heart disease (CHD) rates. In the 25 years since its inception, the mean serum cholesterol level has been reduced in the province of North Karelia by 18%. During the same period, the age-adjusted CHD mortality has declined by 73% among 35- to 64-year-old men. The North Karelia Project has contributed to a major national change process in Finland, involving intersectoral collaboration, national focal point(s), long-term nutrition education programmes, collaboration with voluntary organizations and the food industry, food labelling policies, price policy, research, demonstrations and international collaboration.

Atherothrombosis : the role of platelets

Abstract: The pathogenesis of atherosclerosis is associated with endothelial damage that may result from a variety of factors. Circulating factors, such as low-density lipoproteins or inflammatory mediators have been implicated in atherogenesis, along with physical factors, such as regions of high shear stress within the blood flow. The accumulation of lipid-laden macrophages marks progression of the disease, and may be followed by migration and proliferation of smooth muscle cells. Plaque results when lipids are released into the extracellular space, forming a lipid core that may be covered by a fibrous cap. Rupture of this fibrous cap exposes the highly thrombogenic lipids and matrix components to the flowing blood, which may trigger occlusive or non-occlusive thrombi. Injured blood vessels are gradually rendered less thrombogenic by a process termed wall passivation. The thrombogenic potential of a particular lesion may also depend on the inherent platelet reactivity of individual patients.

Differential metabolism of statins: importance in drug-drug interactions

Abstract: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is the key enzyme of cholesterol synthesis. HMG-CoA reductase inhibitors (statins) are potent, reversible inhibitors of this enzyme, which act by competing for the substrate, HMG-CoA. Six statins are now available: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin. The differences in the chemical structures of these agents are responsible for major differences in their pharmacokinetic properties. Pravastatin, a hydrophilic drug, is not significantly metabolized by the cytochrome P450 (CYP450) system, unlike the other statins, which are lipophilic. This unique quality of pravastatin affects its metabolism, potential for drug interactions, and side effect profile, compared with the other agents. The pharmacokinetic properties of the statins and how they affect the use of these agents in clinical practice are described here.

Saturated and trans fatty acids and coronary heart disease

Abstract: The epidemiological evidence linking coronary heart disease (CHD) mortality to the consumption of saturated fatty acids (SFAs) is sufficiently robust to have stimulated much research into potential mechanisms. By far, the most persuasive has been the low-density lipoprotein (LDL) cholesterol-raising effect. Although high-density lipoprotein (HDL) cholesterol levels may also increase to accommodate the need to transport more lipid, the overall effect is adverse. Most SFAs contribute to this relationship, but there is no clear consensus about whether lauric, myristic or palmitic acid has the greatest effect. Stearic acid is neutral and it is particularly interesting that recent findings have shown that even the medium-chain length SFAs raise plasma cholesterol levels. Trans fatty acids (TFAs), which may also increase CHD risk, raise LDL levels as much as do SFAs and, at higher intakes, lower HDL cholesterol. Additional mechanisms through which SFAs predispose to CHD include a potentially fatal arrhythmogenic effect on the myocardium, increasing thromboenicity of blood, predisposing to insulin resistance, raising blood pressure and causing endothelial dysfunction. The arrhythmogenic effects are persuasive in animal models; thrombogenic 4effects, although likely, are inconsistent; and the blood pressure-raising effect is seen across populations but not in intervention trials. These areas require further research to quantify their importance.

The costs of routine eptifibatide use in acute coronary syndromes in Western Europe : an economic substudy of the PURSUIT trial

Abstract: Alms To compare resource consumption and medical costs between patients with unstable angina and non-Q wave myocardial infarction randomized to eptifibatide or placebo in the Western European arm of the PURSUIT (Platelet GP IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) Trial. Methods and Results The PURSUIT trial collected medical resource consumption data for enrolled patients. Analyses of resources consumed were conducted for the 3697 patients recruited in Western Europe and for subgroups with different coronary arteriography rates. Unit costs were developed for six Western European countries using consistent bottom-up costing methods. These costs were applied to the resource consumption to estimate the medical treatment costs for patients assigned eptifibatide or placebo. Resource consumption varied across the six countries with a trend for lower rates of coronary arteriography and myocardial revascularization amongst eptifibatide patients. The mean costs of the initial hospital admission, including 526 EUROs for eptifibatide treatment, were 1.1% to 6.8% higher than placebo. The incremental costs associated with eptifibatide patients enrolled in the low and medium coronary arteriography rate countries were lower than those observed in high coronary arteriography rate countries. Conclusions In this analysis of the Western European subgroup of PURSUIT patients, resource consumption during the index hospital admission was consistently lower amongst eptifibatide-treated patients than amongst placebo-treated patients. Including an assumed cost of 526 EUROs for eptifibatide, the incremental cost of routine eptifibatide use was relatively modest, ranging from 122 EUROs to 425 EUROs per patient. Subgroup analyses suggest that in settings in which the use of coronary arteriography is discretionary, routine use of eptifibatide may reduce the requirement for invasive procedures and the overall economic costs of treatment.

Unifying concept of arterial vascular disease

Abstract: The structure of the vessels, the pathophysiology of atherosclerosis and the ischaemic consequences resulting from thrombus formation on an eroded or disrupted plaque are basically the same throughout the vasculature. Thus, the process of atherothrombosis (the formation of thrombi on atherosclerotic plaque) may simultaneously involve coronary, peripheral and cerebral vascular beds in the same individual. As a consequence, (1) patients with atherothrombotic disease often suffer subsequent ischaemic accidents in a different vascular district from the one that was first involved, and (2) the preventive modalities applied to vascular areas affected with atherothrombosis are similar. Recent advances in the understanding of arterial vascular disease pathophysiology and of the role played by platelets in its evolution have been accompanied by increasing interest in the development of drugs that inhibit platelet function.

Dietary cholesterol and the mechanisms of cholesterol absorption

Abstract: Cholesterol absorption occurs primarily in the duodenum and proximal jejunum at levels of efficiency that often vary greatly among individuals within any species. The absorption process is largely specific for cholesterol because plant sterols, although structurally similar to cholesterol, are absorbed either poorly or not at all. In adult humans consuming a typical Western diet, about one-third of the cholesterol that enters the small-bowel lumen daily is of dietary origin; the remainder is derived from bile and other endogenous sources. In the intraluminal phase of absorption, diet-derived lipids are hydrolyzed by pancreatic enzymes and cholesterol is incorporated into mixed micelles containing bile acid, phospholipid, fatty acid and mono-acylglycerol. These micelles diffuse across the unstirred water layer, a barrier that lies between the bulk water phase and the mucosal cell. At the mucosal membrane, micellar disaggregation occurs and cholesterol crosses the membrane either passively or via a membrane protein transporter. Cholesterol then traverses the cytosol to the endoplasmic reticulum where it is esterified and incorporated into apo B-containing lipoproteins. These nascent lipoproteins are then secreted into the lymph, thus completing the absorption process. It remains to be determined which of the steps is rate limiting.

Historical and scientific basis for the development of plant stanol ester foods as cholesterol-lowering agents

Abstract: Introduction of plant stanol ester foods in the 1990s is the culmination of nearly 50 years of scientific investigation. Early research investigated the efficacy of large amounts of plant sterols. Focus shifted to evaluating smaller quantities when they were shown to have an effectiveness similar to larger amounts. Studies then found that consumption of plant stanols resulted in even greater cholesterol-lowering than consumption of plant sterols because of their greater ability to reduce intestinal cholesterol absorption. Furthermore, it was shown that whereas plant stanols were virtually unabsorbed, plant sterols were absorbed to a greater degree. Therefore, the focus of research shifted from plant sterols to plant stanols because of the greater efficacy and safety of the latter. Because dietary fat appeared to be the most effective vehicle for delivery of plant stanols to the small intestine, a process was developed such that plant stanols could be esterified and solubilized in fat-based foods. Numerous studies have found that foods containing plant stanol esters, providing 2-3 g.day -1 of plant stanols, lower serum low-density lipoprotein (LDL) cholesterol levels significantly by about 14% compared with foods without plant stanols. When incorporated into diets low in saturated fat and cholesterol, mean reductions in LDL cholesterol of up to 24% have been achieved, a level comparable with that produced with low doses of cholesterol-lowering drugs. Thus, plant stanol ester foods are clinically proven, highly effective new dietary tools for managing blood cholesterol levels.

Effects of calcium antagonism and HMG-coenzyme reductase inhibition on endothelial function and atherosclerosis : rationale and outline of the ENCORE trials

Abstract: Atherosclerosis and its complications in the coronary circulation, the brain, kidney and peripheral circulation account for most cardiovascular clinical events. Endothelial dysfunction occurs as an early event in the atherosclerotic process. Thus, therapeutic interventions able to improve early endothelial dysfunction, particularly in the coronary circulation, would be most appropriate. In this paper we describe the background, rationale and design of the ENCORE trials. In ENCORE I, four groups of 100 patients each with coronary artery disease (CAD) undergoing percutaneous transluminal angioplasty (PTCA) will be recruited. After PTCA, endothelial function is assessed by intracoronary (i.c.) infusion of increasing dosages of acetylcholine in a non-obstructed coronary segment. Coronary responses to acetylcholine will be measured by quantitative coronary angiography (QCA) and Doppler flow velocity measurements. Endothelium-independent responses are tested by i.c. adenosine and nitroglycerine respectively. Patients will then be randomly assigned in a double-blind fashion to four treatment groups: placebo, nifedipine (30-60 mg . day - '), cerivastatin (400 μg. day - ') or their combination. Studies will be repeated at 6 months. This trial will determine whether or not in patients with CAD calcium antagonists and/or a statin alone or in combination improve endothelial function within 6 months. The ENCORE II trial will last 2 years, and aims at correlating endothelial function (as assessed by QCA and intravascular ultrasound; IVUS) and structural atherosclerosis in patients treated with cerivastatin, 200 receiving 200 μg. day -1 and 200 receiving 800 μg.day -1 , compared with 200 patients having a combination treatment with cerivastatin (800 μg. day - 1 ) and nifedipine (30-60mg). Endothelium-dependent responses of epicardial coronary arteries to acetylcholine at baseline as well as structural vascular changes as assessed by IVUS will be correlated and followed over 2 years. At the end of the 2 years another acetylcholine test, QCA and IVUS will be performed. These trials will give an answer to the question of whether calcium antagonists and statins alone or in combination reverse abnormal endothelium-dependent responses to acetylcholine in patients with CAD. Furthermore, the studies will allow us to determine whether endothelial dysfunction and/or its improvement is associated with progression or regression of atherosclerotic coronary artery disease and possibly clinical events.

Atherothrombosis as a marker for disseminated atherosclerosis and a predictor of further ischaemic events: A review

Abstract: Atherosclerosis and atherothrombosis are the major pathophysiological processes involved in ischaemic stroke, coronary heart disease and peripheral arterial disease. Clinical evidence of atherosclerosis in one vascular bed is widely believed to reflect more widespread atheromatous disease. This article provides a comprehensive review of epidemiological studies of atherosclerotic disease profiles at baseline and patient outcomes during follow-up in those with evidence of atherosclerosis. The data reveal that a high percentage of patients have atherosclerosis in more than one vascular territory, although the precise nature of the overlap varies with patient gender and age and the presence of cardiovascular risk factors. Patients with a previous atherothrombotic event are subject to an increased likelihood of death or morbidity not only due to a recurrent event in the same vascular bed, but also to an atherothrombotic event in any other vascular bed. Those with atherosclerotic involvement in all three vascular territories represent a particularly high-risk population. The evidence reviewed here demonstrates that atherothrombosis is a global vascular disease, requiring global assessment and global treatment. Therapeutic agents should have broad utility for the prevention of vascular ischaemic events in patients with coronary, cerebrovascular and peripheral arterial disease.

Dose responsiveness to plant stanol esters

Abstract: Dietary intake of plant stanol esters in amounts ranging from 0.8 to 4.0 g. day -1 (calculated as free stanol) reduces cholesterol absorption and causes significant reductions in serum low-density lipoprotein (LDL) cholesterol levels. Plant stanol esters are hydrolyzed in the small intestine most probably by pancreatic cholesterol esterase to free plant stanol, the form that actively reduces cholesterol absorption. Early studies with free plant sterols indicated a maximum cholesterol-lowering effect with a daily intake of 3 g. Published studies indicate that consumption of more than 2.5 g. day -1 of plant stanol taken as esters does not increase the cholesterol-lowering effect. A compilation of data from published studies indicates a curvilinear dose response with a clear leveling-off at an intake of plant stanol esters equivalent to about 2.2 g. day -1 plant stanol; this has recently been verified in a new study. Higher intakes of plant stanol esters could have effects similar to viscous dietary fibres on lipid emulsification and lipolysis due to the high viscosity of plant stanol esters. Such effects could further potentiate the cholesterol-lowering effects of plant stanol esters at higher daily intakes.

Vasovagal syncope: prevalence and presentation - An algorithm of management in the aviation environment

Abstract: Vasovagal syncope can occur in any individual, given sufficient provocation, and probably half the population suffers at least one episode during life. Often it occurs in youth and may occur in clusters. Usually there is a history of a previous episode. Prodromal symptoms include nausea sweatiness and a sensation of warmth. Diagnosis is by careful history and tilt testing. The false positive rate for passive tilt is 13% and the true positive rate is about 70% including use of nitroglycerine. A classical history and a positive tilt test obviate the need for further investigation in clinical practice, but in the context of aviation, it is wise to seek the small possibility of intermittent rhythm and/or conduction disturbance as an alternative explanation for the episode. It is, therefore, reasonable to carry out a Holter recording and exercise electrocardiogram, perhaps also echocardiography. No treatment is of much benefit, although many agents, including beta blocking drugs, have been used. Some patients have undergone permanent dual chamber pacing with some favourable results. Explanation and reassurance is important. From the licensing point of view, following investigation after an attack, consideration may be given to restricted certification with regular follow-up. Review with investigation after an event free interval, arbitrarily after 2 years, may permit full certification. Malignant vasovagal syncope with no warning of impending attack should disbar.

Atherosclerosis involves more than just lipids : plaque dynamics

Abstract: Recent studies on the cell and molecular biology of atherosclerosis have highlighted the pivotal role of inflammation in its pathogenesis and progression. Clinical studies with HMG-CoA reductase inhibitors such as simvastatin and pravastatin, have shown that they produce a substantial reduction in risk of both coronary and cerebrovascular events, yet have little impact on the size of existing lesions seen angiographically. These findings point to a plaque-stabilizing, anti-inflammatory effect which may result simply from lowering blood lipid levels, but which may in part be due to as yet poorly understood non-lipid-lowering effects of some statins.

The rationale for the Hypertension in the Very Elderly Trial (HYVET)

Abstract: The number of people over the age of 65 years continues to increase. However, in many countries the number of the 'over 80s' is increasing the most rapidly. Blood pressure (BP) increases with age and elevated levels of blood pressure are common in the elderly. The elderly are also a high-risk group for cardiovascular disease (CVD), which is the leading cause of death in European countries for both men and women aged 80 years or over. CVD represents about 30% of total mortality and morbidity in this age-group. Major outcome trials so far have either specifically excluded those over the age of 80 years or recruited too few subjects to establish the benefits of treatment or the risks in this group. Death from non-vascular disease and the inability of the very old to gain many extra years of life may lessen or negate any reduction in mortality. However, a reduction in morbidity and improvement in quality of life would be well worthwhile. This may not be achieved, however, if symptomatic problems such as increasing postural hypotension limit the benefits, or if the benefits are not large. The European Working Party on Hypertension in the Elderly Trial (EWPHE), the Medical Research Council trial of treatment of hypertension in older adults, the Systolic Hypertension in the Elderly Program (SHEP), and the SYSTolic hypertension in elderly in EURope trial (SYST-EUR) all found a reduction in cardiac mortality in the elderly that was greater than expected from the results of trials in middle-aged subjects. This may have been due to the elderly being particularly at risk of dying from congestive heart failure as a consequence of hypertension. If the latter is true, the very elderly should similarly experience a fall in cardiac mortality with antihypertensive treatment. However, no single trial has had the statistical power to show convincingly marked benefit from treatment or to establish the risks. The benefit-risk comparison from active treatment needs to be determined in the very elderly and the Hypertension in the Very Elderly Trial (HYVET) has been designed to address this issue.

Impact of antihypertensive therapy on the rate-pressure product : the role of chronotherapeutics

Abstract: Increased resting heart rate has become established as a potent predictor of hypertension and of an increased risk of cardiovascular and non-cardiovascular deaths. Moreover, heart rate, blood pressure and sympathetic activity have been demonstrated to adhere to a circadian pattern, generally exhibiting their highest levels when a hypertensive patient is awake and active. Conversely, values for these parameters ebb during sleep. Consequently, there needs to be increasing appreciation of the circadian variation in the pharmacodynamic response to antihypertensive medications and the importance of timing of drug administration to blunt the morning surge in cardiovascular risk factors while simultaneously avoiding excessive nocturnal reduction in blood pressure. The chronotherapeutic agent, controlled-onset extended-release (commercially described as COER-24 ) verapamil hydrochloride (HCI) affords the ability to match drug dosing to the circadian patterns of blood pressure, heart rate and the heart rate-systolic blood pressure product. Once-daily dosing with COER-24 verapamil HCI at bedtime provides optimal drug doses in the early morning hours when cardiovascular risk is at its highest. A comparative study of COER-24 verapamil HCI and nifedipine gastrointestinal system (GITS) found that COER-24 verapamil HCI significantly reduced early morning heart rate, while nifedipine GITS increased early morning heart rate. COER-24 verapamil HCI also significantly reduced the heart rate systolic blood pressure product compared with nifedipine GITS.

Platelets and atherosclerosis

Abstract: Arterial vascular occlusion generally occurs as a result of two processes- atherosclerosis and thrombosis, a process termed atherothrombosis Platelets play important roles in both processes through their ability to secrete growth factors, adhere to exposed subendothelial surfaces and to form platelet-to-platelet bonds in a thrombus Plaque develops from repeated endothelialization of platelets and thrombotic material adhering to the vessel wall Plaques may be subject to rupture or fissuring both of which expose subendothelial elements to the flowing blood Platelets adhere to damaged regions largely through the activity of von Willebrand factor, which binds them to exposed sub-endothelial constituents at the site of endothelial damage and then to the glycoprotein Ib receptor on platelets Von Willebrand factor is particularly important for platelet adherence and activation in regions of high shear stress Following adhesion to the vessel wall, platelets are activated enabling the platelet glycoprotein IIb/IIIa receptor to bind other platelets, so forming a thrombus P-selectin an adhesion molecule on activated platelets, binds to leukocytes bringing them into the complex process of plaque growth Alterations in platelet function may predispose susceptible individuals to the development of atherosclerosis and atherothrombosis

CardioVision 2020: A multidisciplinary cardiovascular disease prevention project

Abstract: CardioVision 2020 is a multidisciplinary project organized by the Mayo Clinic Division of Cardiovascular Diseases. The goal of the programme is to minimize the population burden of cardiovascular disease for residents of Olmsted County, MN, U.S.A., by promoting a tobacco-free environment, nutrition habits that minimize the risk of cardiovascular disease, diabetes and cancer, and a physically active lifestyle. CardioVision 2020 will provide leadership and facilitate communication to optimize lifestyle choices, risk factor levels and clinical event rates. The lay and medical communities will be provided with information about progress toward the CardioVision 2020 goals, opportunities that might be taken to speed that progress, and encouragement to adopt lifestyles that minimize the risk of cardiovascular disease. A web-based community report card will be maintained; each resident will have access to a personalized web-based expert system to support behaviour change. A cardiovascular disease event simulation programme will be developed to predict and communicate the impact of risk factor and disease treatment changes in the community. A disease register and case-management system will be implemented to assist in identification and treatment of patients with heart disease. Three major campaigns will be launched in the first year: a cholesterol-lowering challenge for parents of 5th grade students, a physical activity challenge for the entire population and a smoking cessation challenge for tobacco users. Although each campaign has a different focus, all emphasize the three main CardioVision 2020 goals. CardioVision 2020 will track and report trends in total mortality, mortality from cardiovascular diseases, coronary artery disease mortality, clinical events precipitated by cardiovascular disease, cardiovascular risk factor levels and disease-related quality of life for residents of Olmsted County. Results will be compared with state-wide and national trends to gauge programme effectiveness.