Thomas F. Whayne

Activation of lipoprotein lipase. Effects of rat serum lipoprotein fractions and heparin.

Guinea pig serum is deficient in high density lipoproteins (HDL); post-heparin lipoprotein lipase (LPL) from it hydrolyzes a triglyceride (TG) emulsion very slowly. The rate is markedly increased by the addition of rat serum and even further by rat serum plus heparin. We have studied further the activation of LPL in this system. Rat serum lipoprotein fractions were isolated by ultracentrifugation and added to guinea pig postheparin serum in the presence or absence of heparin. When added in proportion to their original serum concentrations, HDL caused the greatest increase in TG hydrolysis. When each fraction was added at equal protein concentrations, purified low density lipoproteins had almost no effect; both very low density lipoproteins and HDL were very effective in increasing the rate of hydrolysis. Rat serum or rat HDL, added to the assay system in increasing amounts, appeared to increase the effective substrate concentration. In the absence of heparin, increasing the concentration of HDL increased the reaction rate which approached a limiting velocity (Vmax) and produced a hyperbolic curve which conformed to Michaelis-Menten kinetics. In the presence of heparin, increasing the concentration of HDL produced an S-shaped curve and increased the Vmax. These data conformed to the sigmoidal kinetics described by the Hill equation. Our results suggest that (1) heparin may function as a specific ligand which acts as an allosteric modifier of LPL and alters the kinetics of interaction of LPL with the effective substrate and (2) the rate of hydrolysis of the effective TG substrate is regulated by the concentration of this substrate.

Epigenetics in the development, modification, and prevention of cardiovascular disease

Epigenetics has major relevance to all disease processes; cardiovascular (CV) disease and its related conditions are no exception. Epigenetics is defined as the study of heritable alterations in gene expression, or cellular phenotype, and goes far beyond a pure genetic approach. A more precise definition is that epigenetics represents all the meiotically and mitotically inherited changes in gene expression that are not encoded on the deoxyribonucleic acid (DNA) sequence itself. Major epigenetic mechanisms are modifications of histone proteins in chromatin and DNA methylation (which does not alter the DNA sequence). There is increasing evidence for the involvement of epigenetics in human disease such as cancer, inflammatory disease and CV disease. Other chronic diseases are also susceptible to epigenetic modification such as metabolic diseases including obesity, metabolic syndrome, and diabetes mellitus. There is much evidence for the modification of epigenetics by nutrition and exercise. Through these modifications, there is infinite potential for benefit for the fetus, the newborn, and the individual as well as population effects. Association with CV disease, including coronary heart disease and peripheral vascular disease, is evident through epigenetic relationships and modification by major CV risk factors such as tobacco abuse. Aging itself may be altered by epigenetic modification. Knowledge of epigenetics and its relevance to the development, modification, and prevention of CV disease is in a very preliminary stage but has an infinite future.

Echocardiographic evaluation of extracardiac masses

Echocardiography was performed on 5 patients with extracardiac masses. Four patients had solid tumours and the fifth had a cystic intrapericardial haematoma. Case 1 showed dense echoes anterior to the aortic root and over the right ventricle. Thoracotomy disclosed malignant infiltration ofthe anterior heart wall. The echocardiogram of case 2 showed a dense mass behind the anterior mitral leaflet, left ventricle, and the left atrium. Bronchoscopy disclosed a carcinoma of the left bronchus. An x-ray film of case 3 was suggestive of a pericardial effusion; no echoes were recordable from the left sternal border, and echocardiography from the right sternal border showed no evidence ofpericardial effusion. Necropsy showed a sarcoma which displaced the heart to the right. The ultrasound recording on case 4 in the supine position showed a dilated right ventricle and right ventricular outflow tract, and no evidence of pericardial effusion. In the left lateral position a large space in front of the right ventricle and a paradoxical decrease in right ventricular size were noted. Surgery showed an intrapericardial cystic haematoma anterior to the right ventricle. Echocardiography on case 5 showed a pericardial effusion and thickening (1.5 cm) of the anterior wall of the right ventricle. At operation a lymphoma infiltrating anterior wall of the right ventricle and a pericardial effusion were found. Careful gain control, examination of the patient in different positions, and placement ofthe transducer

Atherosclerosis: Current Status of Prevention and Treatment

The reality of regression of atherosclerotic plaques was established as long ago as 1987 by aggressive cholesterol reduction even before the era of statin therapy. Nevertheless, the most important aspect of patient benefit to prevent cardiovascular (CV) disease events is stabilization of these plaques so they will not rupture. Lowering of low-density lipoproteins is critical to this goal and can be considered the gold standard of preventive CV medicine. The major goal for the high-risk patient and the diabetic patient is lowering these harmful lipoproteins to less than 70 mg/dL. No discussion of CV disease prevention is complete without considering tobacco abuse and its elimination. Even secondhand smoke has been established as harmful. Control of hypertension is another major aspect of CV disease prevention, and a blood pressure less than 120/80 mm Hg is ideal. With obesity a major problem in the developed world, its role in the metabolic syndrome is of major significance as is the high prevalence of this so-called syndrome versus collection of specific risk factors in a population with poor health habits. Control of diabetes mellitus has established benefit from the standpoint of CV disease prevention except that some problems have been reported with extremely tight blood sugar control. Exercise was long considered good but now there are evidence-based reasons to recommend it as essential in CV disease prevention. There are many unforeseen frontiers in CV disease prevention but, for now, everything points to elevation of high-density lipoproteins as the next focus of this prevention.

Statin Myopathy: Significant Problem With Minimal Awareness by Clinicians and no Emphasis by Clinical Investigators

High cardiovascular risk patients need reduction of low-density-lipoprotein cholesterol (LDL-C) to <70 mg/dL (1.8 mmol/L). Statins are optimal treatment but myopathy can be a limitation to their use. The incidence of statin-related myopathy is difficult to determine but up to 10.5% appears an appropriate estimate. Short-term trials report lower incidence than long-term trials. Statin-related myopathy may be influenced by genetics and tends to be dose-dependent. Ezetimibe can contribute to LDL-C reduction allowing a lower dose of statin to be used. Another approach is to administer rosuvastatin twice weekly. Statins have been shown to interfere with the cellular role of coenzyme Q10. Coenzyme Q10 supplementation may decrease or prevent statin myopathy, but this has not been proven. The occurrence of the most serious complication of myopathy—rhabdomyolysis—is very rare, but awareness of the problem, risks, and prevention are essential.

Reflex Cardiovascular Responses to Simulated Diving

Submersion produces profound cardiovascular responses in diving mammals and birds. This &dquo;diving reflex&dquo; consists of bradycardia, decreased cardiac output and a marked decrease in peripheral blood flow.’ Studies of land mammals such as man suggest these mammals possess a modified diving reflex. In man, the method of study have been necessarily limited. We have taken advantage of two techniques to assess more thoroughly the diving reflex in man. First is the method of Whayne and Killip which allows diving to be simulated by a cold

A Review of the Role of Anticoagulation in the Treatment of Peripheral Arterial Disease

Peripheral arterial disease (PAD) is a major medical/surgical problem associated with high risk for coronary heart disease (CHD). Anticoagulation plays a significant role in the management of the PAD patient. However, evidence-based medicine supports only select anticoagulants, mainly antiplatelet agents. The available anticoagulant classes, their individual medications, and the mechanisms of action are described. Dextran 40, platelet glycoprotein (GP) IIb/IIIa receptor antagonists, direct thrombin (factor IIa, FIIa) inhibitors, and factor Xa (FXa) inhibitors do not, at this juncture, appear to have a significant role to play in the PAD patient. Aspirin has been used in PAD patients for a few decades, as has warfarin, but the role of warfarin is very limited. An attempt has been made to place each medication and its function in context all the way to the present with oral direct thrombin (FIIa) and FXa inhibitors described. These inhibitors may ultimately play an, as yet, undefined role in PAD. Specific use of anticoagulants in PAD patients is described and aspirin still stands out as a fundamental therapy. The thienopyridines, especially clopidogrel, have their established place and there is some evidence for benefit from the use of clopidogrel in dual therapy with aspirin. Dipyridamole, especially with aspirin as dual therapy, and cilostazol also have their evidence-based niches. The main role played by warfarin is for the patient with a vein graft in the arterial circulation. Heparin retains significant procedural importance. For now, Class I, Level of Evidence A center around aspirin for the PAD patient with clopidogrel, an alternative agent.

Peripheral Arterial Disease Implications Beyond the Peripheral Circulation

Peripheral arterial disease (PAD) affects a considerable percentage of the population. The manifestations of this disease are not always clinically overt. As a result, PAD remains underdiagnosed and undertreated. PAD is not just a disease of the peripheral arteries, but also an indication of generalized vascular atherosclerosis. PAD patients also have a high prevalence of other arterial diseases, such as coronary/carotid artery disease and abdominal aortic aneurysms. PAD is also a predictor of increased risk of lung and other cancers. The most often used examination for the establishment of the diagnosis of PAD, the ankle-brachial pressure index (ABPI), is also a predictor of generalized atherosclerosis, future cardiovascular events and cardiovascular mortality. Several markers that have been linked with PAD (e.g. C-reactive protein, serum bilirubin levels) may also have predictive value for other conditions besides PAD (e.g. kidney dysfunction). The management of PAD should therefore not be restricted to the peripheral circulation but should include measurements to manage and decrease the systemic atherosclerotic burden of the patient.

Cardiovascular Medicine at High Altitude

Altitude physiology began with Paul Bert in 1878. Chronic mountain sickness (CMS) was defined by Carlos Monge in the 1940s in the Peruvian Andes as consisting of excess polycythemia. Hurtado et al performed studies in the Peruvian Andes in the 1950s to 1960s which defined acclimatization in healthy altitude natives, including polycythemia, moderate pulmonary hypertension, and low systemic blood pressure (BP). Electrocardiographic changes of right ventricular hypertrophy (RVH) were noted. Acclimatization of newcomers to altitude involves hyperventilation stimulated by hypoxia and is usually benign. Acute mountain sickness (AMS) in travelers to altitude is characterized by hypoxia-induced anorexia, dyspnea, headache, insomnia, and nausea. The extremes of AMS are high-altitude cerebral edema and high-altitude pulmonary edema. The susceptible high-altitude resident can lose their tolerance to altitude and develop CMS, also referred to as Monge disease. The CMS includes extreme polycythemia, severe RVH, excess pulmonary hypertension, low systemic BP, arterial oxygen desaturation, and hypoventilation.

Women, the menopause, hormone replacement therapy and coronary heart disease.

Purpose of review Cardiovascular disease considerations are associated with the menopause. Despite a misconception that women have a minimal risk for coronary heart disease (CHD), it is the major cause of female deaths. This review highlights issues of hormone replacement therapy (HRT) and CHD in women. Recent findings A woman under age 60, who suffers a myocardial infarction (MI), has a 2-year post-MI mortality of 28.9%; it is 19.6% in men. CHD and MI in women are subtle. In addition, female mortality from CHD increases after the menopause. The increased inflammatory risk factor status of women plays a role in development of atherosclerosis, before and after the menopause. Until after the menopause, women overall have a lower CHD mortality rate. Menopause is associated with unique symptoms, especially vasomotor ones; preexisting cardiovascular disease further exacerbates problems associated with the menopause. Use of HRT after the menopause is a major issue. Early menopause at age 39 years or younger and late menopause at age 56 years or older increase cardiovascular risk. HRT should not be prescribed for cardiovascular risk prevention, but when less than 10 years from menopause at a normal age, women can be reassured that cardiovascular risk from HRT is very low. Summary Prescription of HRT should never be made only for cardiovascular risk reduction. However, when symptom-related and other indications are present, HRT is appropriate and well tolerated in the early years after menopause with onset at a normal age.