Biomedical Base
Harvard Clinical Nutrition Research Center
Biomedical Base
Lipid Metabolism and Cardiovascular Disease
Following are the primary investigators of this theme and a brief discussion of their work.
Alexander Leaf
At age 86, Dr. Leaf continues as a Senior Investigator in the HCNRC. He has previously supported Dr. Jing Kang, a P/F awardee and Associate Investigator, and conducted clinical studies with Dr. Nathan in the GCRC at MGH. Dr. Leaf’s laboratory studies the effects of the feeding of n-3 polyunsaturated fatty acids (PUFAs) to animals to prevent ischemia-induced fatal cardiac arrhythmias. They have confirmed this with a concentrate of fish oil fatty acids and with pure a-linolenic acid (C18:3n-3 ALA), pure eicosapentaenoic acid (C20:5n-3, EPA), or pure docosahexaenoic acid (C22:6n-3, DHA) administered intravenously just prior to occlusion of a coronary artery in a surgically prepared, conscious, exercising dog. The mechanism of the antiarrhythmic action of PUFAs has been studied in spontaneously contracting, cultured neonatal rat cardiac myocytes. Adding arrhythmogenic toxins to the medium perfusing the myocytes will cause tachycardia, contracture and fibrillation of the cultured myocytes. Adding n-3 PUFAs to the superfusate prior to the addition of the toxins will prevent the expected tachyarrhythmias. The basis for this antiarrhythmic action of these PUFAs is that they stabilize electrically every myocyte in the heart. He has also conducted a clinical trial to test the efficacy of the n-3 PUFAs in preventing fatal arrhythmias in humans.
Frank Sacks
Dr. Sacks continues as an Investigator in the HCNRC renewal. His research program is a combination of laboratory research on human lipoproteins and clinical trials in nutrition prevention of cardiovascular disease. The laboratory research is at HSPH. It concerns the acute and long‑term effects of diet on the kinetics of lipoproteins in plasma, and the identification of new lipoprotein subspecies as risk factors for cardiovascular disease. The kinetic studies are determining the influence of apolipoproteins AII, CI, CII, CIII and E on the metabolic pathways for VLDL, IDL and LDL in plasma. The metabolic pathways are being investigated in hypertriglyceridemia and normolipidemia, in the fasting and postprandial states, and with high carbohydrate and high unsaturated fat diets. The lipoprotein species that are being investigated metabolically are also being studied in relation to risk of cardiovascular disease in several large cohorts, including the Cholesterol and Recurrent Events cohort of survivors of myocardial infarction, the Nurses Health Study, and Health Professionals Follow-up Study. The results show major effects of the apolipoproteins on both metabolism and risk of cardiovascular disease. He was PI or Chair of several multicenter trials that have affected clinical practice to prevent and treat cardiovascular disease. He chaired the study design committee for the DASH trial (Dietary Approaches to Stop Hypertension) which demonstrated that a dietary pattern that is high in fruits, vegetables, nuts, fish and low-fat dairy products substantially reduced blood pressure in patients with hypertension or high normal blood pressure. In the weight loss field, he was PI of a 2.5 year study that found that a Mediterranean style, high‑monunsaturated fat diet had better long-term results than a conventional low‑fat approach for treatment of obesity. He is also PI of a new NIH multicenter trial to determine optimal proportions of fat, protein and carbohydrate for weight loss and its long-term maintenance.
Jane Newburger
Dr. Newburger continues as an Investigator in the HCNRC renewal. Her overall goal is to better understand the relationship between elevated levels of inflammatory markers in childhood and proven cardiovascular risk factors, by describing inflammatory makers and known cardiovascular risk factors in children with parents or grandparents who have premature atherosclerotic disease (cases) as defined by the National Cholesterol Education Program and the American Academy of Pediatrics and controls without such a family history. Cases and controls will be further divided into groups with and without hyperlipidemia to allow clarification of interaction between hyperlipidemia and family history of early atherosclerosis. Her clinical research and specific goals are as follows: Aim 1 (Primary Study Aim) - To compare cases to controls with respect to serum levels of inflammatory markers. Aim 2 - To explore the relationship between inflammatory markers in cases and controls to other known cardiovascular risk factors. Aim 3 - To assess in children the intra-person variability in inflammatory marker levels over time. Aim 4 - To examine the relationship between inflammatory profiles of children and their parents or grandparents.
Ellis Neufeld
Dr. Neufeld, an outstanding physician-scientist, continues as an Investigator with the Center with the renewal application. Trained as a Pediatric Hemologist, his research interest extend from basic science to clinical investigation. The nutrition oriented projects are in two areas. (1) Genetics and biochemistry of thiamine-responsive anemia syndrome. Thiamine-responsive megaloblastic anemia with diabetes and deafness (TRMA, Rogers Syndrome) is an autosomal recessive disorder of childhood onset. In addition to the clinical triad for which the syndrome is named, several patients have had early stroke or optic atrophy. The pathophysiology of the syndrome is obscure We have used homozygosity mapping to localize the TRMA gene to a 4 cM region on chromosome 1q23.2-23.3 and obtained a YAC contig spanning the region. Studies in fibroblasts from patients reveal absence of high-affinity thiamine uptake (at 30 nM thiamine, the uptake rate is one tenth that of control cells). Mutant fibroblasts are uniquely sensitive to lethality in thi-medium. The goal of this product is to identify the TRMA gene and investigate the role of the gene product in normal thiamine transport. A P/F award in the previous research period has lead to RO1 funding for this project. (2) Genetics of low HDL-cholesterol: Pediatric Lipid Clinic study. High density lipoprotein (HDL) cholesterol levels are inversely correlated with early atherosclerotic coronary disease. Familial hypoalphalipoproteinemia (low HDL-c) is prevalent among survivors of early myocardial infarction. Low HDL in adults is commonly associated with smoking, obesity and diabetes, obscuring genetic contribution to this phenotype. However, in the pediatric lipid clinic setting, his group has often seen young persons with pure low HDL, or with familial lipid disorders, including low HDL. Obesity, smoking and diabetes are very common for this setting. They have therefore undertaken to ascertain families with (a) at least one child with low HDL-C (less that 35 mg/dl), and (b) at least one first or second degree with early onset of coronary artery disease or stroke. In collaboration with Millennium Pharmaceuticals, Inc., they will use linkage analysis to investigate the role of known genes related to HDL-C metabolism, and to scan for novel genes. To date, approximately 50 families have been ascertained and samples collected. The study began a multicenter phase to ascertain further families. His interest in inherited lipid disorders will entail use of the GCRC at Children’s Hospital.
Ernst Schaefer
Dr. Schaefer continues as an Investigator in the HCNRC renewal application. He provides an ever increasing association with the Tufts USDA Center of Nutrition for Aging. The major research focus of his laboratory is to define the interrelationships between lipoprotein metabolism, nutrition (specifically different types of dietary fatty acids and cholesterol as well as other constituents in the diet), genetics and aging. An additional research focus is to identify lipid and lipoprotein abnormalities and genetic mutations associated with CHD, stroke and dementia risk. The final major aim of his laboratory is to develop nutritionally-adequate optimal diets in terms of fatty acids, cholesterol and other dietary constituents in the elderly to minimize the risk of cardiovascular disease and dementia. His laboratory staff has documented that lipoprotein (a) cholesterol, remnant lipoprotein cholesterol, homocysteine, apoE genotype and lipoprotein lipase genotype, in addition to the standard risk factors are important in determining CHD risk. He has defined the type and prevalence of familial lipoprotein disorders in patients with CHD. They have determined, as is apoE-4 genotype, and that both apoE and apoA-IV genotype determine responsiveness in terms of LDL cholesterol lowering to diets restricted in saturated fat and cholesterol. They have documented that hydrogenation of oils adversely impacts on LDL cholesterol, and we are developing diets that are optimal in reducing LDL cholesterol as well as promoting weight loss while still providing sufficient essential fatty acids in the diet. His group has documented that caloric density via fat restriction can promote weight loss under ad libitum conditions. In the new application, a major theme of the HCNRC will continue to be the prevention of cardiovascular disease through diet.
Francine Welty
Dr. Welty, a previous P/F awardee in the first granting period (1994-1999), has continued as an Investigator in the HCNRC renewal application. She is an outstanding physician/scientist. Her research includes: 1) Evaluation of the effect of dietary soy on blood pressure, lipid levels, inflammatory markers of atherosclerosis, adhesion molecules, C-reactive protein, hemostatic risk factors, brachial artery reactivity, biochemical markers of bone turnover and menopausal symptoms is underway in postmenopausal women. She has recently shown that soy lowers systolic and diastolic blood pressure in hypertensive and normotensive postmenopausal women, lowers LDL-cholesterol (LDL-C) and apolipoprotein (apo) B in hypertensive women, lowers C-reactive protein and VCAM-1 and decreases hot flashes. An area of vascular biology that she would now like to explore is the mechanism of the reduction in blood pressure which could be related to nitric oxide and/or other signaling mechanisms. 2) Dr. Welty has identified, cloned and sequenced 3 mutations in the human apoB gene that cause very low levels of LDL-C. One mutation, the apoB-67 mutation, also causes high levels of HDL-C. Mechanisms for the low levels of LDL cholesterol and high levels of HDL cholesterol in human subjects with the apoB-67 mutation are being examined using stable isotopes. As part of this, she has established baseline kinetics for apoB and apoA-I kinetics in human subjects using stable isotopes. Physical and chemical characterization of HDL lipoprotein particles in the apoB-67 mutation is also ongoing. Kindreds with the apoB-67 mutation, which is a founder mutation in the Amish, are being extended to determine if the mutation predisposes to longevity and protects against cancer and atherosclerosis. Magnetic resonance imaging of the liver in these subjects is underway to determine if a higher content of fat in the liver predisposes these subjects to insulin resistance and diabetes. Dr. Welty has established a DNA database for the Amish to search for genes in complex traits, familial combined hyperlipidemia, both high and low blood pressure, type 2 diabetes and bone density and to study the genetics of biological aging.
Jing Kang
Dr. Kang joins the HCNRC renewal application as a new Investigator after having been an Associate Investigator and a former P/F awardee. He now has a laboratory independent of Dr. Leaf. His laboratory studies the health benefits of omega-3 polyunsaturated fatty acids and the mechanisms of their action. He is particularly interested in the beneficial effects of these lipids on cardiovascular disease, cancer and inflammatory diseases. His ongoing studies focus on identification of the factors/ pathways that mediate the protective effects of omega-3 fatty acids, aiming at elucidation of the molecular mechanism of their action. Dr. Kang has recently initiated a new project to explore the feasibility of modifying fatty acid composition of mammalian cells (i.e. increasing the content of beneficial omega-3 fatty acids and decreasing the level of omega-6 fatty acids) using a genetic knockout approach. (So far the only possible way to enrich the tissues with omega-3 fatty acids in mammals has been dietary provision of omega-3 fatty acids). By using viral strategies, he has demonstrated that gene transfer of C. elegans omega-3 fatty acid desaturase into mammalian cells, which lack this enzyme, rendered cells capable of converting n-6 fatty acids to corresponding n-3 fatty acids, leading to a balanced omega-6/omega-3 fatty acid ratio and beneficial effects on cell function, with no need of supply of exogenous fatty acids (APPENDIX Section C1 – representative reprints). He is currently evaluating the utility of this gene transfer as a novel means to provide the preventive and therapeutic effects of omega-3 fatty acids. In addition, he has recently created transgenic mice expressing the omega-3 desaturase. He will use the transgenic animals to address the importance of omega-3 fatty acids and omega-6/omega-3 ratio in disease-prevention and treatment. This model also provides a new strategy for producing omega-3-enriched foodstuff (e.g. meat, milk and eggs) by generating large transgenic animals (e.g. cow, pig, sheep and chicken) with the n-3 desaturase gene.
Biographical sketch forthcoming.