Table Of ContentNUTRITION AND
BIOTECHNOLOGY IN
HEART DISEASE AND
CANCER
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
DAVID KRITCHEVSKY, Wistar Institute
ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research
RODOLFO PAOLETTI, University of Milan
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NUTRITION AND
BIOTECHNOLOGY IN
HEART DISEASE AND
CANCER
Edited by
John B. Longenecker
University of North Carolina
Chapel Hill, North Carolina
David Kritchevsky
Wistar Institute of Anatomy and Biology
Philadelphia, Pennsylvania
and
Marc K. Drezner
Duke University Medical Center
Durham, North Carolina
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Cataloging in Publicatio n Data
On file
Proceedings of a conference on Nutrition and Biotechnology in Heart Disease and Cancer,
held December 5-7, 1993, in Research Triangle Park, North Carolina
ISBN 978-1-4613-5804-6 ISBN 978-1-4615-1957-7 (eBook)
DOI 10.1007/978-1-4615-1957-7
© 1995 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1995
Softcover reprint of the hardcover 1st edition 1995
10 9 8 7 6 5 4 3 2 1
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any
means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written
permission from the Publisher
PREFACE
There is a unique nutritional commonality developing in research relating to coronary
heart disease and cancer. The primary aim of this conference was to provide a forum for
the leading researchers, clinicians, educators and administrators in these two fields to
present a program on heart disease and cancer which included a) the major historical
milestones, b) the present areas of greatest interest in research and therapy, c) the latest
nutritional, molecular, and biotechnological advances, and d) a perspective on the most
promising areas for future research and therapy.
Scientists have long contended that research marches on the feet of methodology.
Thus there are numerous examples of research fields opening secondary to methodological
advances. Some examples are: 1) thin layer and gas-liquid chromatography which, along
with high pressure liquid chromatography have broadened the line of advances in lipid
research and 2) peR and the resultant impact on molecular biological approaches to several
fields of science. The organizers of this conference thought the time was propitious for
bringing together knowledge on newer aspects of molecular biological research with current
advances in the two major areas of degenerative disease--coronary heart disease and
cancer.
Our knowledge of these "killer diseases" has expanded greatly in the past few years
and the advance has been catalyzed by use of an array of molecular biological techniques.
Thanks to these, medical thinking in these areas is changing from considerations of
treatment to strategies for prevention.
This conference has been successful in presenting the most advanced knowledge to an
audience of interested participants who will be able to use what they learned for the
advancement of their own research. Undoubtedly the same will be true for those who read
these proceedings. It is our hope that future advances will make it possible to find the
critical answers in the fight against these two perplexing diseases.
The Editors
v
ACKNOWLEDGMENT
We wish to sincerely thank the Institute of Nutrition of the University of North
Carolina, the Sarah W. Stedman Center for Nutritional Studies of Duke University Medical
Center and the North Carolina Biotechnology Center for co-sponsoring the conference and
the Nabisco Biscuit Company, Coca Cola Company, Johnson & Johnson, Procter &
Gamble, Hoffman-LaRoche Inc., and Glaxco Inc. Research Institute for their financial
support.
We gratefully acknowledge the efforts of the members of the Program Committee
and the dedication and cooperation of the staff members of the Institute of Nutrition of the
University of North Carolina, the Sarah W. Stedman Center for Nutritional Studies, and the
University of North Carolina Continuing Education Center.
PROGRAM COMMITTEE
Chair John Longenecker Institute of Nutrition, University of North Carolina
Co-chair Connie Bales Tlte Sarah W. Stedman Center for Nutritional Studies,
Duke Unil'ersity Medical Center
Betsy Baker North Carolina American Cancer Society
Terry Bazzare American Heart Association
Mark Failla University of North Carolina at Greensboro
Charles Hamner Nortlt Carolina Biotechnology Center
David Kritchevsky The Wistar Institute
Gilbert Leveille Nabisco Biscuit Company
DavidUbhy Nortlt Carolina A& T State University
Robert Maier East Carolina Unil'ersity
Donald McCormick Emory University Medical School
Bob Sanders Tlte University of Texas at Austin
Jason Shih North Carolina State University
Tom Staga MD. Anderson Cancer Research Center
Steven Zeisel The University of North Carolina at Chapel Hill
VII
CONTENTS
HEART DISEASE
Historical Review of Research on Atherosclerosis ..................................................... .
Gardner C. McMillan
Nutrition and Coronary Heart Disease Epidemiology................................................. 7
Herman Tyroler
Obesity, Fat Patterning and Cardiovascular Risk........................................................ 21
June Stevens
The Role of Lipoproteins in Atherogenesis ................. ................. .................... .......... 29
John R. Guyton
Role of Oxidized LDL and Antioxidants in Atherosclerosis........................................ 39
Daniel Steinberg
Signal Transduction in Atherosclerosis: Second Messengers and Regulation of
Cellular Cholesterol Trafficking........................................................................ 49
Kenneth B. Pomerantz, Andrew C. Nicholson and David P. Hajjar
Genetic Determinants of Myocardial Infarction.......................................................... 6S
Jan L. Breslow and Marilyn Dammerman
Gene Therapy in Heart Disease.................................................................................. 79
Louis C. Smith, Randy C. Eisensmith and Savio L. C. Woo
Possible Role of Viruses in Atherosclerosis................................................................ 89
Jason C. Shih and Donald W. Kelemen
Impact of Biotechnology in the Diagnostic and Therapeutic Management of
Cardiovascular Disorders.................................................................................. 99
Jawed Fareed, Debra Hoppensteadt, Lalitha Iyer, Michael Koza,
Jeannie M. Walenga and Edward Bermes, Jr.
CANCER
Nutrition and Carcinogenesis: Historical Highlights and Future Prospects.................. III
R. K. Boutwell
ix
Epidemiology of Anticarcinogens in Food.................................................................. 125
Lenore Kohlmeier
Dietary Effects on DNA Methylation: Do They Account for the Hepatacarcinogenic
Properties ofLipotrope Deficient Diets? ........................................................... 141
Judith K. Christman
Cholesterol, Cholesterogenesis and Cancer................................................................ 155
Marvin D. Siperstein
Inhibition of the Induction of Cancer by Antioxidants ................................................ 167
Tom J. Slaga
Nutrients, Signal Transduction and Carcinogenesis.................................................... 175
Steven H. Zeisel
Nutrition, Immunology and Cancer: An Overview..................................................... 185
Bob G. Sanders and Kimberly Kline
Anemia of Malignancy ............................................................................................... 195
Rodger L. Bick
HEART DISEASE AND CANCER
Diet in Heart Disease and Cancer............................................................................... 201
David Kritchevsky
Carcinogens in Foods: Heterocyclic Amines and Cancer and Heart Disease ............... 211
Richard H. Adamson and Unnur P. Thorgeirsson
Genetic Engineering of Foods to Reduce the Risk afReart Disease and Cancer......... 221
Vic C. Knauf and Daniel Facciotti
NIH INITIATIVE
New Directions in Dietary Studies in Cancer: The National Cancer Institute.............. 229
Peter Greenwald, Carolyn Clifford, Susan Pilch,
Jerianne Heimendinger and Gary Kelloff
New Directions in Dietary Studies and Heart Disease; The National Heart, Lung
and Blood Institute Sponsored Multicenter Study of Diet Effects on
Lipoproteins and Thrombogenic Activity.......................................................... 241
Henry N. Ginsberg
APPENDIX
Abstracts of Poster Sessions ............................................................................... . 249
Index ....................................................................................................................... . 265
x
HISTORICAL REVIEW OF RESEARCH ON
ATHEROSCLEROSIS
Gardner C. McMillan
5305 Burling Terrace
Bethesda, MD 20814
INTRODUCTION
Atherosclerosis in humans can have severe clinical sequellae such as heart attack,
stroke and peripheral vascular disease. These diseases are common and they have their
own research histories, but it is the history of the underlying atherosclerosis or hardening
of the arteries about which I shall speak. I have listed several sources for this paper and
they have extensive bibliographies for specific points of reference.
It is possible to comment on several interwoven histories depending on whether the
research viewpoint emphasizes the pathological, the biochemical, the metabolic, the
epidemiological, the nutritional and recently the mechanistic and molecular biological.
PATHOLOGICAL RESEARCH AND DEFINITIONS
I shall begin with the pathological because it is by far the oldest, but touch on the
others as needed to develop an outline that I hope will be useful background for you.
Even today, the definition of atherosclerosis as a space occupying lesion or plaque of the
inner coat of larger arteries that is focal, has a pattern of occurrence, is composed of an
excess of fat, of an increased number of artery wall and inflammatory cells and their
connective tissue products, and that may show calcification and ulceration, narrows the
arterial lumen, may obstruct blood flow through the artery and may be associated with a
local thrombus is a definition that uses the terms of classical pathology. In view of what
we know today, a more etiological and mechanistic definition could be formulated, but,
in fact we generalIy use a descriptive definition like the foregoing and add to it etiological
associations and mechanistic cartoons as suits our purpose.
The first formal description of atherosclerosis was due to Fallopius in 1575 who
described a degeneration of arteries into bone. Four hundred years ago educated
physicians were aware of ossification of arteries. In 1695, that is three hundred years
ago, we find the aorta of a 75 year old physician Johann Jakob Wepfer pictured and
described. "The internal coat in several places was ruptured, lacerated and rotten like
fruit and hurt the fingers when thrust into it, from the roughness of the bone". That the
Nutrition and Biotechnology in Heart Disease and Cancer
Edited by J.B. Longenecker et aI., Plenum Press, New York, 1995
disease is much older has been shown by autopsies on Egyptian mummies dating from
1580 B. C. to 523 A D. and reported before World War 1. One specimen was from
Menephtah who was the Pharaoh of the Exodus.
During the 1700's descriptions improved and there were even some mechanistic
discussions. Joseph Hodgson in 1815 gave an excellent gross description and included a
chemical analysis of the arterial calcification and concluded it was not true bone. Most
importantly he thought atherosclerosis was a disease process and not an effect of ageing.
Jean-Fredrich Martin Lobstein coined the term arteriosclerosis in Strassbourg in
1829. Our preferred term of atherosclerosis was proposed and justified in 1904 by Felix
Marchand of Leipzig Meanwhile, mechanistic ideas were proposed including focal
inflammation and deposition of material from the blood onto the lining as an encrustation
that was changed into plaque. The first detailed microscopic studies were those of
Virchow (1858). He thought that the plaque began in rather than on the intima as a
proliferation of cells with formation of cell products. Fatty changes followed. There were
some elements of inflammation and lesions tended to locate where there was pressure
from the blood stream. He noted that cholesterol was present but considered it
secondary.
The descriptions of atherosclerosis became more refined and precise. A major
addition was the so-called fatty flecks or streaks of the arteries of children which were
described in detail in a large autopsy series in 1925 and suggested as the origins of the
more advanced plaques ~ a thesis still under review to-day. Great improvements in
technique and methodology have advanced us into the modern era when we can apply
electromicroscopy, microchemistry, immunohistology and protein identification to follow
cell lineage, cell kinetics, biochemical composition and apocrine and paracrine controlled
cellular activity and metabolism in plaque formation.
RESEARCH ON CHOLESTEROL AND EXPERIMENTAL ANIMAL MODELS
But there are other aspects of the history of research on atherosclerosis. One of
these deals with cholesterol and through it leads to experimental animal work, nutrition
and metabolism.
The first recognition of cholesterol in plaques was by Vogel in 1843 and a
suggestion of some connection between blood and tissue cholesterol was made two years
later. Its prominence in plaques was emphasized by Aschoff in 1906 and in 1910
Windaus, a chemist working with Aschoff compared the cholesterol content of plaque
and nonplaque tissue. Windaus found striking increases of free and esterified cholesterol
in plaque. That blood cholesterol and clinical disease might be related was reported in
1913 when 13 patients with atherosclerotic disease were found to have elevated blood
cholesterol
This state of knowledge coincided with nutritional animal experiments in which a
rabbit model of atherosclerosis was developed in Russia between 1908 and 1913. This
began with an experiment by Ignatowski who fed rabbits a diet rich in animal protein in
the form of milk, eggs and meat. The idea, derived from Metchnikov, was that protein
breakdown products would be toxic. The diet was atherogenic. The experimental result
was confirmed by Fahr and in 1912-13 Stuckey and also Wessel kin showed that the
atherogenic effect resided in the fatty aspect of the diet rather than its animal protein
components. It remained for Anitschkow and Chalatow to produce in 1912-13
atherosclerosis in rabbits by feeding cholesterol dissolved in olive oil.
A huge literature of animal experimentation takes its origin from Anitschkow's
finding. Other animal models were developed including dogs, chickens, pigs, nonhuman
primates and even cell and tissue culture surrogates. Investigators used the model to
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