Table Of ContentHOMOCYSTEINE AND VASCULAR DISEASE
Developments in
Cardiovascular Medicine
VOLUME 230
Homocysteine and
Vascular Disease
edited by
KILLIAN ROBINSON
Department of Cardiology,
The Cleveland Clinic Foundation,
Cleveland, Ohio, U.S.A.
SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.
A C.I. P. Catalogue record for this book is available from the Library of Congress.
ISBN 978-90-481-5431-9 ISBN 978-94-017-1789-2 (eBook)
DOI 10.1007/978-94-017-1789-2
Printed an acid-free paper
AII Rights Reserved
© 2000 Springer Science+Business Media Dordrechl
Originally published by Kluwer Academic Publishers in 2000
Softcover reprinl of Ihe hardcover 1s i edilion 2000
No pari of the material protected by this copyright notice may be reproduced or
utilized in any form or by any means, electronic or mechanical,
including photocopying, recarding ar by any infarmation storage and
retrieval system, without written permission from the copyright owner.
TABLE OF CONTENTS
Foreword by James D. Finkelstein IX
Editor's Historical Preface Xl
List of Contributors XV
Note on Nomenclature XIX
Dedication XX
1. Introduction
Ian Graham and Killian Robinson
2. Historical Aspects of the Relationship Between
Homocysteine and Vascular Disease
David E.L. Wilcken 5
3. Biochemistry and Metabolism
Donald W. Jacobsen 15
4. Reference Ranges for Homocysteine Concentrations
Johan B. Ubbink and Rhena Delport 41
5. Determinants of Plasma Homocysteine
Per Magne Ueland, Helga Refsum, and J0m Schneede 59
v
VI Table o/Contents
6. Epidemiology of Homocysteine Levels and Relation to Vitamins
Peter W.F. Wilson and Paul F. Jacques 85
7. Vascular Pathology ofHyperhomocysteinemia
Kilmer S. McCully 97
8. Vascular Complications of Homocystinuria: Incidence,
Clinical Pattern and Treatment
Paolo Rubba, Giovanni Di Minno and Generoso Andria 117
9. Homocysteine as a Risk Factor for Peripheral Vascular Disease
Ahmed M. Abou-Zamzam, Jr., Gregory L. Moneta,
John M. Porter, and Lloyd M. Taylor, Jr. 135
10. Homocysteine as a Risk Factor for Cerebrovascular Disease
and Stroke
Ivan 1. Perry 151
11. Homocysteine as a Risk Factor for Coronary Artery Disease
P. Barton Duell and M. Rene Malinow 173
12. Homocysteine and Family History of Coronary Artery Disease
Jacques Genest, Jr. 203
13. Homocysteine as a Risk Factor for Cardiovascular Disease
in Women
Petra Verhoef 217
14. Homocysteine and Venous Thrombosis
Martin den Heijer 239
15. Homocysteine and Renal Disease
Killian Robinson and Vincent W. Dennis 253
16. Molecular Biology of Methylenetetrahydrofolate Reductase
(MTHFR): Interrelationships with Folic Acid, Homocysteine
and Vascular Disease
Rima Rozen 271
17. Molecular Biology of Methionine Synthase: Interrelationships
with Homocysteine and Vascular Disease
Ruma Banerjee 291
Table o/Contents VII
18. Molecular Biology of Cystathionine ~-Synthase: Interrelation
ships with Homocysteine, Pyridoxine, and Vascular Disease
Warren D. Kruger and Brian Fowler 313
19. Homocysteine and Cholesterol: Basic and Clinical Interactions
Henk 1. Blom 335
20. Homocysteine and Coagulation Factors: Basic Interactions
and Clinical Studies
Ralph Green 349
21. Homocysteine and Endothelial Dysfunction
Robert T. Eberhardt and Joseph Loscalzo 371
22. The Treatment of High Homocysteine Concentrations in
Homocystinuria: Biochemical Control in Patients
and their Vascular Outcome
Godfried H.J. Boers, Sufin Yap, Eileen Naughton and
Bridget Wilcken 389
23. An overview of the homocysteine lowering clinical trials
Robert Clarke 413
24. Summary and Future Directions for Epidemiological, Preventive and
Basic Research
Steven P. Fortmann, Amo G. Motulsky and Barry Shane and 431
Index 437
FOREWORD
This is an important and timely volume. The history of research in
homocysteine metabolism can be divided into three periods. The first phase
was the exploration of the individual reactions and metabolites that
characterize the transmethylation and transsulfuration sequences. The former
originated with his description of the biosynthesis of methylpyridine and
culminated in the work of Cantoni and Axelrod. Similarly the finding that
insulin contained cystine was a potent catalyst for the metabolic and nutritional
studies of Rose and du Vigneaud.
The description and the definition of homocystinuria, a rare inherited meta
bolic disorder, marked the beginning of the second historical period. Where
previously there had been few laboratories located largely in the United States
soon there were numerous research groups representing many nationalities.
The more intense focus led to major advances, both in the laboratory and in the
clinics. Studies of afflicted individuals, when combined with investigations in
experimental animals, provided the basis for a concept of methionine metabo
lism that encompassed both transmethylation and transsulfuration. The central
role of homocysteine was apparent.
Conversely, the early clinical observations of these patients opened a new
area for investigation -the relationship between biochemical abnormalities and
several significant pathologies. Researchers sought explanations for the mental
retardation, skeletal abnormalities and thrombovascular disorders. Although
the first two areas remain relatively unexplored, studies of vascular dysfunc
tion have proliferated following the suggestion that disordered homocysteine
metabolism might explain vascular diseases in a population broader than those
with the rare genetic defects. Thus it remains for the next generation of inves
tigators to tell us whether lower levels of hyperhomocysteinemia, have the
same vascular toxicity that occurs at the much higher levels found in homo
cystinuria. Furthermore they must define the pathochemical mechanisms.
Lastly, we must know whether reduction of plasma homocysteine concentra
tions halts and/or reverses the vascular pathology.
Thus this volume rests comfortably on the border between the second and
third periods of homocysteine study. It will prove to be an invaluable road map
- providing a comprehensive review of the earlier work while offering us an
outline for future expectations.
James D. Finkelstein, M.D.
February 1999
IX
EDITOR'S HISTORICAL PREFACE
In 1959, Claude Field, a pediatrician at Belfast City Hospital, was referred a 6
year old girl for evaluation of convulsive episodes for which no cause could be
found. Patricia, aged 6 years, was a first child, and the mother had had two pre
vious miscarriages. Patricia had a younger sister of almost identical appearance.
She was a premature infant of 1023 gms, due to pre-eclamptic toxemia. She sat
up at 10 months and walked at 18 months. At three years she was thought to be
quite fit, although still slow to develop mentally. Talking began at five years.
She was placid, plump and obviously mentally backward. She was at the 50th
percentile for height and 75th percentile for weight. She had fine, dry, sparse
blond hair and blue eyes showing iridodonesis due to bilateral posterior disloca
tion of the lenses. Her complexion was fair with bright pink patches of colour
on each cheek. Her skin elsewhere was covered with erythematous blotches
resembling the pattern of erythema ab igne. She had genu valgum and pes ca
vus. Her liver was enlarged. The Babinski responses were equivocal on the right
side and extensor on the left. She had about a dozen words of speech. She was
cooperative and could obey simple commands. Later that month, her sister Pau
line was brought to hospital by request. She was four years old, birth had been
normal, she had walked at 15 months and had not yet started to speak. She had a
major motor seizure in July 1959 lasting two hours. Her height and weight were
at the 3rd and the 25th percentiles respectively. Her liver was not enlarged.
Extensive investigations, including chromosome analysis, were performed
but revealed nothing untoward. Samples of urine were sent to Nina Carson and
Desmond Neill at the Royal Victoria Hospital, Belfast, who were studing meta
bolic abnormalities in the mentally handicapped. The cyanide nitroprusside test
for cystine was positive and amino acid screening showed a spot in the cystine
position. However, as this was not accompanied by the other amino acids found
in cystinuria, further urine specimens were sent to Professor Charles Dent at
University College Hospital, London. In his laboratory, amino acid chromatog
raphy on these, and subsequent 24 hour specimens, appeared to show that the
amino acid was not cystine but homocystine.
Simultanously, another group had been working in Wisconsin, in the United
States. At that time, development of amino acid analysis in physiological fluids
had reached the stage where, in different laboratories all over the world, quali
tative information was obtained by (2-dimensional) paper chromatography
and/or electrophoresis, and quantitative data by ion-exchange column chroma
tography. Thus, essential amino acids and other ninhydrin-positive compounds
acting as intermediates in different metabolic pathways could be analysed.
Xl
Description:This is an important and timely volume. The history of research in homocysteine metabolism can be divided into three periods. The first phase was the exploration of the individual reactions and metabolites that characterize the transmethylation and transsulfuration sequences. The former originated w
