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Atlas of - - -
HEART DISEASES
Hypertension:
Mechanisms and Therapy
THIRD EDITION
volume editor
NORMAN K. HOLLENBERG, MD, PHD
Professor of Radiology
Harvard Mcdlc.J1 School
DireClor. Physiologic Research
Department of Medlcin!;!
Brigham and Woml.'n's Hospilal
BasIon, fI:lassachusctts
Se ri es edito r
EUGENE BRAUNWALD , MD, MD (HON), SeD (HON)
Vice President for Academic Programs. Partners t-IcallhCarc System
Distinguished I h:rscy Profcssor of the Theory .:md Practice of ""Icdiclnc
Faculty Dcan for ,\eademlc Programs
Brigham .:md Women's Hospllal and Massachus('IIS Gener.11 lIospital
H.lrvard Medical School
Basion. MJssilchusctls
With 22 Contributors
eM
nJRR~
Ml.DICINl.
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Hypertension: mechanisms andt herapy / volume editor, Norman K. Hollenberg. - 3rd ed.
p. ; cm. - (Alias of heart d iseases)
Includes bibliographic references and i ndex.
1. Hypertcnsion-Atlases. 1. Hollenberg, Norman K. II. A lais of heart diseases
(Unnumbered)
IDNLM: 1. Hypertension-physiopathology-allases. 2.
Hypertension-therapy-atlases. WG 17 H998 20001
RC685.H8 H825 2000
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for library of Congress 00-023233
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ISBN 978-1-4684-6911-0 ISBN 978-1-4684-6909-7 (eBook)
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() Copyright 2001 by Springer Science+Business Media New York. AII rights reserved. No part
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Originally published by Current Medicine in 2001
Softcover rellrint or the hardcover 3rd edition 2001
1098 76543
"
CONTRIBUTORS
R. WAYNE ALEXANDER, MD, PHD WILLIAM J. ELLIOTT, MD, PHD
R. Brllce Logue Professor of Medicillf! Professor
Director of Cardiology Department of Preventive Medicine
Emory Ulliversity Rush Medical College
Atfa/lfn, Georgia Attending Pllysiciall
Rllsh-Presbyteriall-St. Luke's Medical Center
JOHN AMERENA, MBBS, FRACP
Chicago, lllillois
SCllior Lectllrer
Depar/me,,! of Medicille KATHY K. GRIENDLlNG, PHD
University of Melbourne Professor of Medicille
Gee/OIlg Hospital Department of Medicille/Cardiology
Gee/ollg, Australia Emory Ulliversity
Atlanta, Georgia
HENRY R. BLACK, MD
Charles f. mId Margaret Roberts Professor and CARLENE MINKS GRIM
Cltainl1{1ll Shared Care Researdl alld Educatioll
Departmellt of Preventive Medicine Torrallce, Califomia
Rush Medical College
CLARENCE E. GRIM
Associate Vice Presidellt for Rl..'Search
Professor
RlIs},-Presbyleriml-Sf. Luke's Medical Cellter
Departmellt of Cardiovascular Medicille
Chicago, Illillois
Medical College of Wisconsi"
EMMANUEL L. BRAVO, MD Milwaukee, Wiscollsi/l
Department of Nephrology a/ld Hypertellsion
RANDOLPH A. HENNIGAR, MD, PHD
The Cleveland Clillie FOIlI1dntioll
Associate Professor of PatilOlogy
Cleve/alld, Ohio
Departmellt of Pathology
HANS R. BRUNNER, MD Emory University
Professor of Medicine Atlallta, Georgia
Dillisioll of HypertcIIsioll
NORMAN K. HOLLENBERG, MD, PHD
La/lSl1//lfC University
Professor of Radiology
Ulliversity Hospital
Departmel/t of Medici/Ie
WI/sa/me, Switzer/fl/ld
Harvard Medical School
Director, Physiologic Researdl
ROBERT M. CAREY, MD
Professor of Medicine Brig/mill alld Women's Hospital
BostOll, Massad/llsetts
Dean, SeI/Ool of Medicillc
U"iversily of Virgil/in Health Sciences Cellter
Clmrlottesville, Virginia
"'
STEVO JULIUS, MD, SeD HELMY M. SIRAGY, MD, FRACP
Profi'~sor of lull'rIml Medicine "lid Plty:;;ology Professor of Medicil/e
Frede,;ck C.L. H,lehllel/ Professor Dl'pnrtmel/t of Medicil/e
of Hyperle1lsioll Ullilll'rsity of Virgil/ia
Departlllellt of '"/ernal Medicine CJmrlottesuille, Virgil/in
Ulliversity of Miclligall
BERNARD WAEBER, MD
AIIII Arbor, Middgn"
Professor of Medicille
WILLIAM B. KANNEL, MD, MPH DepnrtmC'I/t of Medici/Ie
Professor of Medici"e "lid Pllhlic Health wI/Sflm/C' UIlil.lCrsity
Bostoll U"iversity School of Medicille Ulliuersity Hospital
LaIlSflmIe, Switzer/mId
Boslol/, Massad/lise/Is
SmioT Investigator
ALAN B. WEDER, MD
Frnm;IIgllflm Study
Professor of Medicine
Framillglmm, Massad/usetls
Department of 11111..'",01 Medicine
BARRY j. MATERSON, MD, MBA rhe U"iuersity of Michigan Medical CClfter
Professor of Medici"e An" Arbor, Micltigall
Depur/mell' of Medicine
MATIHEW R. WEIR, MD
Ulliversi/y of Miami
Professor of Medicine
Miami, Florida
Director, Division of Nephrology and Clillical
Research Unit
JAMES A. SCHOENBERGER, MD
Department of Medicil/e
Emeritlls Proft!ssor of Medicille
Divisioll of Nephrology
Drpar/mel//s of Medicille nlld Preve1ltive
Medicine Ulliversity of Maryla/ld School of Medicille
RIIsh-Presbyleriall-St. Lllke's Medical Cellier Baltimore, Marylalld
Cllicngo, Illinois
GORDON H. WILLIAMS, MD
DOMENIC A. SICA, MD Professor of Medicille
Professor Departmellt of Medici"e
Harvard Medical ScI,ool
Depar/mt'''' of Medicine alld Plmrmacology
Chief, Endocrille-Hypertensiotl Division
CllI7irmflll. Clinical Pharmacology fwd
Hypertellsioll Brigham and Womeu's Hospital
Medical College of Virgil/in 80stOIl, Massachusetts
RiclllllOlld, Virginia
iv
PREFACE
Although It '-;('Cms like only yesterday, it ha ... banded out...tanding units devoted to the
oc'Cn 6 year. .. .,ince the first edition wa ... pre development of antihyperten~ives. ThoM.'
pared, and almost 3 years since the <;ccond. who ignored the conventional wisdom, as is
The atlas format, applied to the problem of often the case, prospered.
hypertenSion, has proven to be very attractive This created a problem. How could we
to readers of both the first and second edition. develop a detailed overview on the Angll
We have learned a lot while preparing the Antagonist class, vasopcptidasc inhibitors,
Atlas, and we are confident that readers of the and new ilgents available for blocking aldos
third edition will find it to be improved. terone-with all of their therapeutic implica
Cardiovascular medicine is moving at a tions-without distorting and overloading a
vcry rapid pace, and hypertension is no chapter on drug therapy, prepared so well by
exception. All of the chapters have been Drs. Wncber and Brunner? The solution was
updated and incorporate new information. to have Drs. Wacher and Brunner focus on
The new figures and legends have not simply therapeutics, while maintaining their empha
been added to the end of the chapters, as a sis on the agents that have been available for
kind of caboose, but rather have been fitted some time. They added new information 011
into the narrative in what we hope is a seam the newer drugs that have reached what
less manner. might be called "therapeutics." Dr. Domcnic
Additionally, we have included two new Sica contributed the second new chapter,
chapters. Dr. Clarence Grim pointed out that which places emphasis on the pharmacology,
an atlas of hypertension ought to include at clinical pharmacology, and early therapeutics
least something on blood pressure measure in the arca of the new drug classes. We believe
ment. He was, of course, absolutely correct, this solution not only divides the workload,
and has contributed a new chapter that pro but also makes it easier for the physician to
vides detailed information on the "how to" of find the information that he or she needs.
correct blood pressure measurement. One hope expressed in the preface to the
While considering the second new chapter, first edition, and echoed in the preface to the
we faced another fundamental issue in plan second, is that a single chapter on pathophys
ning this edition. The area of drug therapy has iology would be all that would be required
shown continued, major growth. This is par because our understanding of pathogenesis
ticularly interesting in view of the widely held had become so complete. Alas, that wish has
conventional wisdom of the early 1990s that not been met. Perhaps in the next edition ... ?
patients with hypertension were already well
served, and there would be little advance in
drug therapy. Indeed, some companies dis· Norman K. Hollenberg, MD, PhD
v
CONTENTS
CHAPTER 1
Pathogenesis of Hypertension: Genetic and Environmental Factors
Alall B. Werler .............. ,., ........................... .. . ...... ..... . . 1 - 33
CHAPTER 2
Role of the Nervous System in Human Hypertension
}olm Amerr1la (Iud Stevo jll/iIlS . ... .. .... .. , .... .. ... .. ..... .... ,. , ..... . ... 34 - 58
CHAPTER 3
Hypertension: Kidney, Sodium, and the Renin-Angiotensin System
Helmy M. Siragy and Robert M. Carey .... .... ... .. .. .. ..... ... .............. 59 - 79
CHAPTER 4
Pathogenesis of Hypertension
Kathy K. GriclIdl;lfg, R. WaYlle Alexander, alf(l Randolph A. Hennigar .......... .. 80 - 99
CHAPTER 5
Cardiovascular Risk Assessment in Hypertension
William 8. Kannel .............................. , ............•........ . . 100 - 117
CHAPTER 6
Secondary Hypertension: Adrenal and Nervous Systems
( ""'Wlllle! L. Bravo ... ... .. ..... .................. .. .......... .. .. ...... 118 - 143
CHAPTER 7
Antihypertensive Agents: Mechanisms of Drug Action
Benlaril Waeber and Harts R. Brullller ............ ........... . ..... ..••.... 144 - 161
CHAPTERS
The Therapeutic Trials
lames A. Schoenberger ....... .•• •. ..••••.. ... •.. ....••......•.......... . 162 - 184
vi
CHAPTER 9
Antihypertensive Therapy: Patient Selection and Special Problems
Barry ,. Materso" .... . .. .. . .. .. . ...... . .. .. ... .. .. .... . .. . .. ........ . .. . 185 - 207
CHAPTER 10
Antihypertensive Therapy: Progression of Renal Injury
Matthew R. Weir ... ..... ..... ....... ..... ......... ......... .••••....... 208 - 236
CHAPTER 11
Antihypertensive Therapy: Compliance and Quality of life
Gordon H. Williams .... ...... ........ ...... ....... .. ..... ....... ....... 237 - 251
CHAPTER 12
Special Situations in the Management of Hypertension
William J. Elliott and Henry R. Black .......... ............ .....••... •..... 252 - 274
CHAPTER 13
Recommendations of the American Diabetes Association and Summary
of the Joint National Committee ONC)-V and Who/International Society
of Hypertension (ISH) Special Reports
Nannan K. Hollenberg ..... .. ... .. .. .. .. . .. ... .. .... .. . .. ... .. .. .. ... .. .. 275 - 292
CHAPTER 14
Newer Antihypertensive Agents: Angiotensin-Receptor Antagonists
and Dual Metalloproteinase Inhibitors
Domen;c A. Sica .. .. ... .. ... .. .. .... . ....... ....... .. ..... .. ... .. .. .. ... 293 - 313
CHAPTER 15
Accurale and Reliable Blood Pressure Measurement in the
Clinic and Home: The Key to Hypertension Control
Clarence E. Grim and Carlene Minks Grim .. . ..... .. .. ... .. .. ... .. .. .•.. ... . 314 - 324
vii
PATIIOGENESIS OF HYPERTENSION:
GENETIC AND ENVIRONMENTAL FACfORS
Alan B. Weder
Like obesity and diabetes, essential hypertension is one of the
"diseases of civilization" that results from the collision of a
modem Lifestyle with Paleolithic genes.
Genetic analyses of communities, families, twins, and
individuals aU support the tenet of a genetic contribution to blood
pressure regulation, but the identification of specific genes that
cause hypertension has only just begun. The use of segregating
populations derived from inbred hypertensive and normotensive
animals, which permits tracing the linkage of genetic markers
with blood pressure, has led to the detection of several genes that
may contribute to hypertension. It was hoped that such studies
would identify candidate genes that cause essential hypertension,
but none of the specific genes identified in rat models has been
proven to cause disease in humans. The applicability of congenic
and transgenic methods to rats has permitted studies of candidate
loci and individual genes in relatively well-defined settings, and it
is hoped that such models will define the effects of mutant genes
on the control of blood pressure.
It should not be assumed that the effects of single-gene insertions
or knockouts of candidate alleles will always have straightforv.rard
phenotypic effects. An example is the hypertensive rat created by
insertion of the mouse renin gene. These rats are characterized by
low levels of plasma renin and renal renin gene expression but also
by high adrenal renin gene expression and fulminant hypertension.
Such unpredictable phenotypic effects arising from seemingly
"simple" genetic manipulations serve to emphasize the complexity
of genomic dynamiCS.
The task of identifying genes that contri.bute to essential
hypertension in humans is a great challenge, and the genetic
architecture of human hypertension is only dimly perceived.
Several notable successes have been achieved recently, however.
The rare mendelian-dominant hypertensive syndrome of gluco
corticoid~remediable hyperaldosteronism has been proven to
result from a genetic chimerism of the genes for l1~~hydroxylase
and aldosterone synthase, and i.t is likely that other mendelian
defects associated with hypertension can be approached through
use of similar methods. The more difficult problem of essential
hypertension has also witnessed progress lately with the recently
described link between the angiotensinogen gene and both
essential hypertension and hypertension of pregnancy. A major
problem in defining the genetics of essential hypertension is
heterogeneity of the phenotype, and further advances may depend
on refinements in subtyping hypertension. In addition to classic
characterizations based on measurements of biochemical
regulators of cardiovascular function, promising approaches factors can rightly focus on factors that are universally
include subtyping by membrane transport character active in societies (eg, high salt intake, calorie excess, and
istics and definitions based on multivariate hypertension social stress) as well as specific factors (eg, alcohol excess)
related syndromes. whose impacts are limited to at-risk individuals. There may
Regardless of its genetic substrate, hypertension is clearly be genetic subtypes of hypertensive individuals who are
an ecogenic disease, that is, environmental factors interact particularly sensitive to specific environmental factors, for
with genes to result in high blood pressure. Because the example, dietary sodium and calcium, although inter
prevalence of hypertension is directly related to the mean ventional studies have not yielded conclusive evidence on
blood pressure of the population, studies of environmental which to base preventive approaches to hypertension.
.. { w;~~{~;: ': ~
GENETIC FACTORS IN HYPERTENSION J.~.~. .(.. ~
.~:...v .
-..~~"" .
FIGURE 1-1. A model indicating the
mechanisms by which essential hyper
Determinants of hypertension
tension could result from the combined
GRA
effects of individual major genes that have
Angiotensin
a large impact on blood pressure, blended
Diabetes Major genes
Kallikrein polygenes with small individual contribu
Obesity
Na-Li counter- Polygenes Race tions, and environmental effects operating
transport?
Blood pressure on individuals or within families. FCHL
Haptoglobin
Major gene traits: familial combined hyperlipidemia; FDH
MN blood type
RBC Na Background familial dyslipidemic hypertension; GRA
Combination
Na-K cotransport? glucocorticoid-remediable aldosteronism.
FDH? FCHL? (Courtesy of Roger R. Williams, MD.)
Nonmodulation?
i Sympathetics? Environment Individual
Others? Shared
Diet Oral contraceptives
Na Pb Physical inactivity
K Fat Stress
CI Calories Lower education
Ca Alcohol Small family size
Mg Caffeine
FIGURE 1-2. From the late 1940s through the
1960s, Sir George Pickering and Lord Platt of
Grindleford debated the nature of the genetic
Plan Pickering
basis of human essential hypertension. Platt,
a prominent English irttemist, poirtted to
~ormotensives
what he believed to be discontinuities in the
Normotensives
~ distribution of blood pressure values irt
~~rtensives
families of hypertensive individuals and
-
postulated the existence of a major gene for
, \ "I,
hypertension, transmitted as a mendelian
:: '\., "" '-\ ,, ,' -I~, dominant trait [1]. Pickering, who mam
, tairted that hypertensives have blood pres
:" '\ ',., ' '., . ,, , , , sures irt the upper end of a continuous,
,,, ',, ,' \, ,, smooth distribution, argued that hyperten
, , \. ' sion is a multigenic disease [2). In such a
,I ," ,\. , ,, , , construct, each gene has a small effect on a
,
,
~/A trait (intermediate phenotype) that contri
butes to irtcreased blood pressure; the sum
of all the trait effects, when sufficient to
zz elevate blood pressure to some arbitrarily
Major Major AA aa BB bb zz
gene gene Trait A Trait B Trait Z high value, is the genetic basis of essential
hypertension. The consensus now supports
Intermediate phenotypes
Pickering's view, but the debate was of most
importance because it sparked interest irt the
genetic basis of human essential hypertension.
H
YPERTENSION: MECHANISMS AND THERAPY
2
