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THIRD EDITION

HYPERTENSION
A Companion to Braunwald’s Heart Disease

George L. Bakris, MD, FAHA, FASN, FASH

Professor of Medicine
Director, ASH Comprehensive Hypertension Center
Section of Endocrinology, Diabetes and Metabolism
University of Chicago Medicine
Chicago, Illinois

Matthew J. Sorrentino, MD, FACC, FASH

Professor of Medicine
Section of Cardiology
University of Chicago Medicine
Chicago, Illinois
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

HYPERTENSION: A COMPANION TO BRAUNWALD’S HEART DISEASE,

THIRD EDITION ISBN: 978-0-323-42973-3

Copyright © 2018 by Elsevier, Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, elec-
tronic or mechanical, including photocopying, recording, or any information storage and retrieval
system, without permission in writing from the publisher. Details on how to seek permission, further
information about the Publisher’s permissions policies and our arrangements with organizations
such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our
website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the
Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experi-
ence broaden our understanding, changes in research methods, professional practices, or medi-
cal treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described herein.
In using such information or methods they should be mindful of their own safety and the safety
of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check
the most current information provided (i) on procedures featured or (ii) by the manufacturer of
each product to be administered, to verify the recommended dose or formula, the method and
duration of administration, and contraindications. It is the responsibility of practitioners, rely-
ing on their own experience and knowledge of their patients, to make diagnoses, to determine
dosages and the best treatment for each individual patient, and to take all appropriate safety
precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,
assume any liability for any injury and/or damage to persons or property as a matter of prod-
ucts liability, negligence or otherwise, or from any use or operation of any methods, products,
instructions, or ideas contained in the material herein.

Previous editions copyrighted 2013 and 2007.

Library of Congress Cataloging-in-Publication Data

Names: Bakris, George L., 1952- editor. | Sorrentino, Matthew J., editor.
Title: Hypertension : a companion to Braunwald’s heart disease / [edited by]
George L. Bakris, Matthew J. Sorrentino.
Other titles: Hypertension (Black) | Complemented by (expression):
Braunwald’s heart disease. 10th edition.
Description: Third edition. | Philadelphia, PA : Elsevier, [2018] |
Complemented by: Braunwald’s heart disease / edited by Douglas L. Mann,
Douglas P. Zipes, Peter Libby, Robert O. Bonow, Eugene Braunwald. 10th
edition. 2015. | Includes bibliographical references and index.
Identifiers: LCCN 2016054229 | ISBN 9780323429733 (hardcover : alk. paper)
Subjects: | MESH: Hypertension
Classification: LCC RC681 | NLM WG 340 | DDC 616.1/2--dc23
LC record available at https://lccn.loc.gov/2016054229

Content Strategist: Dolores Meloni

Senior Content Development Specialist: Marybeth Thiel
Publishing Services Manager: Catherine Jackson
Senior Project Manager: Daniel Fitzgerald
Designer: Renee Duenow

Printed in China.

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 Contributors

Ailia W. Ali, MD Athanase Benetos, MD, PhD

Fellow, Sleep Medicine, Division of Pulmonary, Allergy, and Head, Geriatric Medicine, Université de Lorraine, Nancy,
Critical Care Medicine, University of Pittsburgh, Pittsburgh, France
Pennsylvania, United States
Kenneth E. Bernstein
Radica Z. Alicic, MD, FHM Director of Experimental Pathology, Professor of Biomedical
Associate Director for Research, Providence Health Care, Sciences, Pathology and Laboratory Medicine, Cedars-Sinai
Clinical Associate Professor of Medicine, University of Medical Center, Los Angeles, California, United States
Washington School of Medicine, Spokane, Washington,
United States Deepak L. Bhatt, MD, MPH
Executive Director of Interventional Cardiovascular
Laurence Amar, MD, PhD Programs, Brigham and Women’s Hospital Heart and Vascular
Hypertension Unit, Hôpital Européen Georges Pompidou, Center; Senior Physician, Brigham and Women’s Hospital;
Assistance Publique-Hôpitaux de Paris, Paris-Descartes Senior Investigator, TIMI Study Group, Professor of Medicine,
University, Paris, France Harvard Medical School, Boston, Massachusetts,
United States
Saif Anwaruddin, MD
Assistant Professor of Medicine and Co-Director, Italo Biaggioni, MD
Transcatheter Valve Program, Cardiovascular Medicine, Professor of Medicine and Pharmacology, Associate Director,
University of Pennsylvania School of Medicine, Philadelphia, Clinical Research Center, Vanderbilt Autonomic Dysfunction
Pennsylvania, United States Center, Division of Clinical Pharmacology, Vanderbilt
University School of Medicine, Nashville, Tennessee,
Lawrence J. Appel, MD, MPH United States
C. David Molina Professor of Medicine, Johns Hopkins
University School of Medicine; Director, Welch Center for Roger S. Blumenthal, MD
Prevention, Epidemiology and Clinical Research, Johns Kenneth Jay Pollin Professor of Cardiology and Director,
Hopkins University, Baltimore, Maryland, United States Johns Hopkins University School of Medicine and Ciccarone
Center for the Prevention of Heart Disease, Baltimore,
Phyllis August, MD, MPH Maryland, United States
Ralph A. Baer MD Professor of Research in Medicine,
Nephrology and Hypertension, New York Presbyterian/Weill Guillaume Bobrie, MD
Cornell Medicine, New York, New York, United States Hypertension Unit, Hôpital Européen Georges Pompidou,
Assistance Publique-Hôpitaux de Paris, Paris, France
Michel Azizi, MD, PhD
Hypertension Unit, Hôpital Européen Georges Pompidou, Robert D. Brook, MD
Assistance Publique-Hôpitaux de Paris, Paris-Descartes Professor of Internal Medicine, Division of Cardiovascular
University, Paris, France Medicine; Director, ASH Comprehensive Hypertension Center,
University of Michigan, Ann Arbor, Michigan, United States
George L. Bakris, MD, FAHA, FASN, FASH
Professor of Medicine, Director, ASH Comprehensive J. Brian Byrd, MD, MS
Hypertension Center, Section of Endocrinology, Diabetes Assistant Professor of Medicine, Division of Cardiovascular
and Metabolism, University of Chicago Medicine, Chicago, Medicine, University of Michigan, Ann Arbor, Michigan,
Illinois, United States United States

José R. Banegas, MD Barry L. Carter, PharmD, FCCP, FAHA, FASH, FAPHA

Professor of Preventive Medicine and Public Health, Patrick E. Keefe Professor of Pharmacy, Department of
Universidad Autónoma de Madrid⁄IdiPAZ–CIBERESP, Madrid, Pharmacy Practice and Science, College of Pharmacy;
Spain Professor, Department of Family Medicine, College of
Medicine, University of Iowa, Iowa City, Iowa, United States
Robert L. Bard, MA
Research Associate, Division of Cardiovascular Medicine, Debbie L. Cohen, MD
University of Michigan, Ann Arbor, Michigan, United States Associate Professor of Medicine, Perelman School of
Medicine—Renal, Electrolyte and Hypertension Division,
Orit Barrett, MD University of Pennsylvania, Philadelphia, Pennsylvania,
Senior Resident, Department of Medicine D, Soroka United States
University Medical Center, Faculty of Health Sciences,
Ben-Gurion University of the Negev, Beer Sheva, Israel

v
 vi
William C. Cushman, MD Philip B. Gorelick, MD, MPH, FACP, FAAN, FANA,
Chief, Preventive Medicine, Medical Service, Veterans Affairs FAHA
Medical Center; Professor, Preventive Medicine, Medicine, Medical Director, Mercy Health Hauenstein Neurosciences;
Contributors

and Physiology, University of Tennessee Health Science Professor, Department Translational Science & Molecular
Center, Memphis, Tennessee, United States Medicine, Michigan State University College of Human
Medicine, Grand Rapids, Michigan, United States
Peter Wilhelmus De Leeuw, MD, PhD
Professor of Medicine, Department of Medicine, Maastricht Elvira O. Gosmanova, MD
University Medical Center, Maastricht, Netherlands; Nephrology Section Chief, Medical Service, Samuel S Stratton
Department of Medicine, Zuyderland Medical Center, VA Medical Center, Associate Professor of Medicine, Division
Geleen/Heerlen, The Netherlands of Nephrology, Department of Medicine, Albany Medical
College, Albany, New York, United States
Georg B. Ehret, MD
Médecin Adjoint Agrégé et Chargé de Cours, Cardiology, Carlene M. Grim, BSN, MSN, SpDN
Department of Specialities of Medicine, Geneva University Founder and President, Shared Care Research and Education
Hospitals, Geneva, Switzerland; Research Associate, Consulting, Inc., Stateline, Nevada, United States
McKusick-Nathans Institute of Genetic Medicine, Johns
Hopkins University School of Medicine, Baltimore, Maryland, Clarence E. Grim, MS, MD, FACP, FAHA, FASH
United States Owner, High Blood Pressure Consulting, Stateline, Nevada;
Senior Consult, Shared Care Research and Education
William J. Elliott, MD, PhD Consulting, Inc., Stateline, Nevada; Retired (Semi) Professor
Professor of Preventive Medicine, Internal Medicine and of Medicine, Medical College of Wisconsin, UCLA, and
Pharmacology, Pacific Northwest University of Health Indiana U.; Board Certified Internal Medicine, Geriatrics,
Sciences, Chair, Department of Biomedical Sciences; Chief, Hypertension Specialist, United States
Division of Pharmacology, Pacific Northwest University of
Health Sciences, Yakima, Washington, United States Rajeev Gupta, MD, PhD
Chairman, Preventive Cardiology & Internal Medicine, Eternal
Michael E. Ernst, PharmD, FCCP Heart Care Centre and Research Institute, Jaipur, India
Professor, Department of Pharmacy Practice and Science,
College of Pharmacy; Professor, Department of Family John E. Hall, PhD
Medicine, College of Medicine, University of Iowa, Iowa City, Arthur C. Guyton Professor and Chair, Department of
Iowa, United States Physiology and Biophysics; Director, Mississippi Center of
Obesity Research, University of Mississippi Medical Center,
Muhammad U. Farooq, MD, FACP, FAHA Jackson, Mississippi, United States
Division of Stroke and Vascular Neurology, Mercy Health
Hauenstein Neurosciences, Grand Rapids, Michigan, Michael E. Hall, MD, MS
United States Assistant Professor of Medicine, Division of Cardiology,
Department of Medicine, University of Mississippi Medical
Anne-Laure Faucon, MD Center, Jackson, Mississippi, United States
Hypertension Unit, Hôpital Européen Georges Pompidou,
Assistance Publique-Hôpitaux de Paris, Paris-Descartes Coral D. Hanevold, MD
University, Paris, France Clinical Professor of Pediatrics, University of Washington,
Seattle Children’s Hospital, Division of Nephrology, Seattle,
Lauren Fishbein, MD, PhD Washington, United States
Assistant Professor of Medicine, University of Colorado
School of Medicine, Department of Medicine, Division of David G. Harrison, MD
Endocrinology, Metabolism and Diabetes, Aurora, Colorado, Betty and Jack Bailey Professor of Medicine, Clinical
United States Pharmacology, Department of Medicine, Vanderbilt
University, Nashville, Tennessee, United States
Joseph T. Flynn, MD, MS
Chief, Division of Nephrology, Seattle Children’s Hospital; Qi-Fang Huang, MD, PhD
Professor, Department of Pediatrics, University of Research Associate, The Shanghai Institute of Hypertension,
Washington School of Medicine, Seattle, Washington, Shanghai, China
United States
Alun Hughes, BSc, MB, BS, PhD
Toshiro Fujita, MD, PhD Professor of Cardiovascular Physiology and Pharmacology,
Chief, Division of Clinical Epigenetics, Research Center for Institute of Cardiovascular Science, Faculty of Pop
Advanced Science and Technology, The University of Tokyo, Health Sciences, University College London, London,
Emeritus Professor, The University of Tokyo, Tokyo, Japan United Kingdom

Mary G. George, MD, MSPH, FACS Philip Joseph, MD

Senior Medical Officer and Deputy Associate Director for Assistant Professor of Medicine, McMaster University,
Science, Division for Heart Disease and Stroke Prevention, Hamilton, Ontario, Canada; Investigator, Population Health
Centers for Disease Control and Prevention, Atlanta, Georgia, Research Institute, Hamilton Health Sciences & McMaster
United States University, Hamilton, Ontario, Canada
 vii
Kazuomi Kario, MD, PhD Juan Eugenio Ochoa, MD, PhD
Professor & Chairman, Division of Cardiovascular Medicine, Researcher, Department of Cardiovascular, Neural and
Department of Medicine, Jichi Medical University School Metabolic Sciences, S. Luca Hospital, IRCCS, Istituto

Contributors
of Medicine, Tochigi, Japan Auxologico Italiano, Milan, Italy

Kunal N. Karmali, MD, MS Takeyoshi Ota, MD, PhD

Clinical Instructor, Department of Medicine, Division of Associate Professor of Surgery, Department of Surgery;
Cardiology, Northwestern University Feinberg School of Co-Director, Center for Aortic Diseases, Section of Cardiac
Medicine, Chicago, Illinois, United States & Thoracic Surgery, The University of Chicago, Chicago,
Illinois, United States
Anastasios Kollias, MD, PhD
National and Kapodistrian University of Athens Clinical Christian Ott, MD
Fellow, Hypertension Center STRIDE-7, National and Assistant Professor, Department of Nephrology and
Kapodistrian University of Athens, Third Department of Hypertension, Friedrich-Alexander University
Medicine, Sotiria Hospital, Athens, Greece Erlangen-Nürnberg, Erlangen, Germany

Luke J. Laffin, MD Gianfranco Parati, MD

Cardiology Fellow, Department of Medicine, The University Professor of Cardiovascular Medicine, Department of
of Chicago, Medicine & Biological Sciences, Chicago, Illinois, Medicine and Surgery, University of Milano-Bicocca; Head,
United States Department of Cardiovascular, Neural and Metabolic
Sciences, S. Luca Hospital, IRCCS, Istituto Auxologico
Lewis Landsberg, MD Italiano, Milano, Italy
Irving S. Cutter Professor of Medicine, Northwestern
University, Feinberg School of Medicine, Chicago, Illinois, Carl J. Pepine, MD
United States Professor of Medicine, Division of Cardiovascular Medicine,
University of Florida College of Medicine, Gainesville, Florida,
Donald M. Lloyd-Jones, MD, ScM, FACC FAHA United States
Chair and Eileen M. Foell Professor, Preventive Medicine,
Northwestern University Feinberg School of Medicine, Vlado Perkovic, MBBS, PhD, FRACP, FASN
Senior Associate Dean for Clinical & Translational Research, Executive Director, George Institute, University of Sydney,
Northwestern University Feinberg School of Medicine, Sydney, Australia
Chicago, Illinois, United States
Tiina Podymow, BSc, MDCM
Anne-Marie Madjalian, MD Associate Professor, Department of Nephrology, McGill
Hypertension Unit, Hôpital Européen Georges Pompidou, University, Montreal, Canada
Assistance Publique-Hôpitaux de Paris, Paris-Descartes
University, Paris, France Kazem Rahimi, FRCP, DM, MSc, FESC
Associate Professor of Cardiovascular Medicine, University
Line Malha, MD of Oxford; Deputy Director, The George Institute for Global
Instructor in Medicine, Nephrology, Hypertension, and Health, James Martin Fellow in Healthcare Innovation, Oxford
Transplantation Medicine, Weill Cornell Medicine, Martin School; Honorary Consultant Cardiologist, Oxford
New York, New York, United States University Hospitals NHS Trust, The George Institute for
Global Health, Oxford Martin School, University of Oxford,
Giuseppe Mancia, MD Oxford, United Kingdom
Emeritus Professor of Medicine, University of
Milano-Bicocca, Milano, Italy Luis Miguel Ruilope, MD, PhD
Chief of Hypertension and Cardiovascular Risk Group,
John W. McEvoy, MB BCh BAO, MHS Institute of Research i+12, Hospital 12 de Octubre,
Assistant Professor, Division of Cardiology, Johns Hopkins Madrid-28009; Professor of Public Health & Preventive
University School of Medicine and Ciccarone Center for Medicine, Public Health, Universidad Autonoma, Madrid,
the Prevention of Heart Disease, Baltimore, Maryland, Spain
United States
Gema Ruiz-Hurtado, PhD
George A. Mensah, MD, FACC, FCP(SA) Hon Laboratory Head of Hypertension and Cardiovascular
Director, Center for Translation Research and Risk Group, Hypertension Unit, Institute of Research i+12,
Implementation Science, NIH/National Heart, Lung, and Hypertension and Cardiovascular Risk Group, Hospital
Blood Institute, Acting Director, Division of Cardiovascular Universitario 12 de Octubre, Madrid, Spain
Sciences, NIH/National Heart, Lung, and Blood Institute,
Bethesda, Maryland, United States Roland E. Schmieder, MD
Professor of Medicine, Department of Nephrology and
Ross Milner, MD, FACS Hypertension, Friedrich-Alexander University
Professor of Surgery, Department of Surgery, Director, Erlangen-Nürnberg, Erlangen, Germany
Center for Aortic Diseases, Section of Vascular Surgery and
Endovascular Therapy, The University of Chicago, Chicago, Shigeru Shibata, MD, PhD
Illinois, United States Associate Professor, Division of Nephrology, Department of
Internal Medicine, Teikyo University, School of Medicine;
Jiangyong Min, MD PhD Project Lecturer, Division of Clinical Epigenetics, Research
Division of Stroke and Vascular Neurology, Mercy Health Center for Advanced Science and Technology, The University
Hauenstein Neurosciences, Grand Rapids, Michigan, of Tokyo, Tokyo, Japan
United States
 viii
Steven M. Smith, PharmD, MPH, BCPS Ji-Guang Wang, MD, PhD
Assistant Professor of Pharmacy and Medicine, Departments Director, Centre for Epidemiological Studies and Clinical
of Pharmacotherapy & Translational Research and Trials; Professor, Shanghai Key Laboratory of Hypertension;
Contributors

Community Health & Family Medicine, Colleges of Pharmacy Director, The Shanghai Institute of Hypertension; Director,
and Medicine, University of Florida, Gainesville, Florida, Department of Hypertension; Professor, Ruijin Hospital;
United States Professor, Shanghai Jiaotong University School of Medicine,
Shanghai, China
Matthew J. Sorrentino, MD, FACC, FASH
Professor of Medicine, Section of Cardiology, University of Seamus P. Whelton, MD, MPH
Chicago Medicine, Chicago, Illinois, United States Pollin Cardiology Fellow in Preventive Cardiology, Johns
Hopkins University School of Medicine and Ciccarone Center
George S. Stergiou, MD, FRCP for the Prevention of Heart Disease, Baltimore, Maryland,
Professor of Medicine and Hypertension, Hypertension United States
Center STRIDE-7, National and Kapodistrian University of
Athens, Third Department of Medicine, Sotiria Hospital, William B. White, MD
Athens, Greece Professor of Medicine and Division Chief, Division of
Hypertension and Clinical Pharmacology, Calhoun Cardiology
Hillel Sternlicht, MD Center, University of Connecticut School of Medicine,
Fellow in Hypertension, ASH Comprehensive Hypertension Farmington, Connecticut, United States
Center, The University of Chicago Medicine and Biological
Sciences, Chicago, Illinois, United States Bryan Williams, MD
Department of Medicine, Institute of Cardiovascular Sciences,
Patrick J. Strollo, Jr., MD, FACP, FCCP, FAASM University College London, London, United Kingdom
Professor of Medicine and Clinical and Translational
Science; Chairman of Medicine VA Pittsburgh Health System; Talya Wolak, MD
Vice Chair of Medicine for Veterans Affairs, University of Head of Hypertension Services, Soroka University Medical
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, Center, Faculty of Health Sciences, Ben-Gurion University of
United States the Negev, Beer Sheva, Israel

Sandra J. Taler, MD Hala Yamout, MD

Professor of Medicine, Division of Nephrology and Department of Internal Medicine (Nephrology), Saint Louis
Hypertension, Mayo Clinic, Rochester, Minnesota, University, John Cochran Division, Veterans Affairs St. Louis
United States Health Care System, St. Louis, Missouri, United States

Akiko Tanaka, MD, PhD Clyde W. Yancy, MD, MSc, MACC, FAHA, MACP, FHFSA
Aortic Fellow, Department of Cardiothoracic and Vascular Vice Dean, Diversity & Inclusion, Magerstadt Professor
Surgery, The University of Texas, Austin, Texas, of Medicine, Professor of Medical Social Sciences;
United States Chief, Division of Cardiology, Northwestern University,
Feinberg School of Medicine; Associate Director, Bluhm
Stephen C. Textor, MD Cardiovascular Institute, Northwestern Memorial Hospital;
Professor of Medicine, Division of Nephrology and Deputy Editor, JAMA Cardiology, Chicago, Illinois,
Hypertension, Mayo Clinic, Rochester, Minnesota, United States
United States
William F. Young, Jr., MD, MSc
Raymond R. Townsend, MD Tyson Family Endocrinology Clinical Professor, Professor of
Professor of Medicine, Perelman School of Medicine, Medicine, Mayo Clinic College of Medicine, Division
University of Pennsylvania, Philadelphia, Pennsylvania, of Endocrinology, Diabetes, Metabolism, and Nutrition,
United States Mayo Clinic, Rochester, Minnesota, United States

Katherine R. Tuttle, MD, FASN, FACP Salim Yusuf, DPhil, FRCPC, FRSC, OC
Executive Director for Research, Providence Health Care, Professor of Medicine, McMaster University, Hamilton,
Regional Principal Investigator and Clinical Professor Ontario, Canada; Executive Director, Population Health
of Medicine, Institute of Translational Health Sciences, Research Institute, Hamilton Health Sciences & McMaster
University of Washington School of Medicine, Spokane, University, Hamilton, Ontario, Canada
Washington, United States
 Foreword

Hypertension has been recognized as an important cardiovas- Drs. George Bakris and Matthew Sorrentino have accepted
cular disorder since the dawn of the 20th century, when Riva- the baton and have brilliantly edited the third edition. They
Rocci and then Korotkoff described the sphygmomanometric have selected internationally recognized authorities as
method of measuring arterial pressure. Despite intense study authors, who have summarized the important research car-
since then, hypertension currently presents an extraordinary ried out in the last 5 years. This edition also includes rigorous
opportunity and challenge for investigators, teachers, health comparisons among the classes of antihypertensive drugs.
officials, and clinicians in the field. Hypertension has spread The volume also presents revised practice guidelines that
to the developing world and is reaching pandemic propor- synthesize much useful information for clinical practice. This
tions. More inclusive definitions as well as more accurate and comprehensive book will be of great value and interest to cli-
detailed measurements of blood pressure indicate that the nicians, investigators, and trainees in this important subspe-
prevalence and health threat of hypertension worldwide are cialty of cardiology.
even greater than previously thought.
The Companions to Heart Disease: A Textbook of Eugene Braunwald
Cardiovascular Medicine aim to provide cardiologists and Douglas P. Zipes
trainees with important additional information in critically Peter Libby
important segments of cardiology that go beyond what is Robert O. Bonow
contained in the “mother book,” thereby creating an exten- Douglas L. Mann
sive cardiovascular information system. The first two editions Gordon F. Tomaselli
of Hypertension, edited by Drs. Henry R. Black and William J.
Elliott, clearly accomplished this goal.

ix
 Preface

There have been many books published dealing with the topic quelling a silent killer, hypertension. There are chapters in
of hypertension across a spectrum of diseases. However, it is the book that address some of these issues, but the only real
rare to find one source that has an encyclopedic and timely solution is a multipronged approach involving governmental
spectrum of topics across the disease spectrum with a focus policy makers, the pharmaceutical industry, payers, and the
on hypertension. This third edition of Hypertension has medical professionals. We hope you will find the book a valu-
expanded the topic variety from previous editions and pres- able resource to address a spectrum of questions surrounding
ents novel topics of emerging areas of hypertension. Examples the disease of hypertension.
include a chapter dealing with hypertension as an immune The book is divided into multiple parts including epide-
disease with a pathophysiology based on immune changes miology, mechanisms of hypertension, pathophysiology of
relating to inflammation rather than hemodynamic changes. disease, pharmacology of antihypertensive drugs, clinical
There is also a focused chapter dealing with sleep disorders, outcome trials, and guideline discussions focusing on process
not just sleep apnea, as a major cause of hypertension. Lastly, rather than what was produced.
there is a novel chapter on environmental pollution and its
contribution to endothelial dysfunction. In addition to these ACKNOWLEDGMENTS
new chapters, all other chapters have been consolidated and
updated with the latest information sourced from basic sci- We would like to thank our families and our wives especially
ence to clinical trials and guidelines so that information is for being supportive through this editing and writing process.
applicable to the clinician. We are especially thankful to all the authors that contributed
Although there are now more than 125 different antihy- time and effort and produced excellent chapters for your
pertensive medications, blood pressure control rates around reading knowledge and pleasure.
the world vary from as low as 15% in some Southeast Asian
countries to over 50% in North America. Clearly, this does George L. Bakris, MD, FASN, FAHA, FASH
not relate to the price of medication but rather to individual Matthew J. Sorrentino, MD, FACC, FASH
patients, understanding, attitudes, and behaviors toward

xi
 Braunwald’s Heart Disease Family of Books

BRAUNWALD’S HEART DISEASE

COMPANIONS
ISSA, MILLER, AND ZIPES ANTMAN AND SABATINE
Clinical Arrhythmology Cardiovascular
and Electrophysiology Therapeutics

BALLANTYNE MCGUIRE AND MARX

Clinical Lipidology Diabetes in
Cardiovascular Disease

xv
 xvi
KORMOS AND MILLER MANN AND FELKER
Mechanical Circulatory Heart Failure
Support
Braunwald’s Heart Disease Family of Books

BLUMENTHAL, FOODY, DE LEMOS AND

AND WONG OMLAND
Preventive Cardiology Chronic Coronary Artery
Disease

CREAGER, BECKMAN,
OTTO AND BONOW
AND LOSCALZO
Valvular Heart Disease
Vascular Medicine
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 xvii
KRAMER AND HUNDLEY BHATT
Atlas of Cardiovascular Cardiovascular Intervention
Magnetic Resonance

Braunwald’s Heart Disease Family of Books

Imaging

MORROW
Myocardial Infarction

BRAUNWALD’S HEART DISEASE REVIEW

AND ASSESSMENT
LILLY ISKANDRIAN AND GARCIA
Braunwald’s Heart Disease Atlas of Nuclear Cardiology
Review and Assessment
 xviii

BRAUNWALD’S HEART DISEASE IMAGING COMING SOON!

COMPANIONS
SOLOMON
Braunwald’s Heart Disease Family of Books

TAYLOR Essential Echocardiography

Atlas of Cardiovascular
Computer Tomography
 section I
Epidemiology

1 General Population and Global

Cardiovascular Risk Prediction
Donald M. Lloyd-Jones
EPIDEMIOLOGY AND RISK FACTORS, 1 SEQUELAE AND OUTCOMES WITH IMPORTANCE OF PREVENTING THE
HYPERTENSION, 6 DEVELOPMENT OF ELEVATED BLOOD
PREVALENCE AND SECULAR TRENDS, 1 PRESSURE, 12
RISK FACTOR CLUSTERING, 11
RISK FACTORS FOR HYPERTENSION, 3 SUMMARY, 13
GLOBAL RISK ASSESSMENT AS A STRATEGY
CLASSIFICATION OF BLOOD PRESSURE, 5 FOR HYPERTENSION TREATMENT, 12 REFERENCES, 13

Systemic arterial hypertension is the condition of persistent, that the prevalence of hypertension among adults 18 years
nonphysiologic elevation of systemic blood pressure (BP). It of age and older in the U.S. was 29%, or nearly one in three
is typically defined as a resting systolic BP (SBP) 140 mm Hg adults, with 30% of men and 28.1% of women affected.3
or higher, or diastolic BP (DBP) 90 mm Hg or higher, or receiv- In the context of the entire population, approximately 80
ing therapy for the indication of BP-lowering.1 Hypertension million U.S. adults are estimated to have hypertension.
afflicts a substantial proportion of the adult population world- Despite significant advances in our understanding of the
wide, and a growing number of children. Numerous genetic, risk factors, pathogenesis, and sequelae of hypertension,
environmental, and behavioral factors influence the develop- and multiple trials over the past 5 decades indicating the
ment of hypertension. In turn, hypertension has been identi- benefits of antihypertensive therapy, hypertension remains
fied as one of the major causal risk factors for cardiovascular a significant public health problem. Although there were
disease (CVD), including heart disease, peripheral vascular steady and significant reductions over the last 4 decades
disease and stroke, as well as renal disease. An understand- in population levels of BP and prevalence of hypertension
ing of the basic epidemiology of hypertension is essential for in the U.S., recent data indicate a plateau in these favor-
effective public health and clinical efforts to prevent, detect, able trends. Between the late 1970s and the mid-1990s, the
treat, and control this common condition. prevalence of hypertension in the U.S. declined from about
32% to 25%.4,5 However, more recent survey data indicate
EPIDEMIOLOGY AND RISK FACTORS that there was an increase in prevalence between 1988 to
1994 and 1999 to 2002. The prevalence appears to have
An epidemiologic association between a proposed risk factor been stable from 1999 to 2014, however, at approximately
and a disease is likely to be causal if it fulfills the following 29%.3,6 The current pandemic of obesity and aging of the
criteria: (1) exposure to the proposed risk factor precedes population are likely to increase rates of hypertension sub-
the onset of disease; (2) there is a strong association between stantially over the next decades.
exposure and incidence of disease; (3) the association is dose- Huffman et al examined trends in SBP levels in the U.S. from
dependent; (4) exposure is consistently predictive of disease 1991 to 2008.7 They observed that SBP levels declined in US
in a variety of populations; (5) the association is independent adults during this time period. However, there were significant
of other risk factors; and (6) the association is biologically and differences noted when stratified by age group in men and
pathogenetically plausible, and is supported by animal experi- women. In the overall population, SBP declined significantly
ments and clinical investigation.2 In addition, more definitive only in those older than 60 years of age, from an average of
support for a causal association between a proposed risk fac- 139 to 133 mm Hg, whereas in younger and middle-aged indi-
tor and disease may arise from clinical trials in which inter- viduals, SBP levels were essentially unchanged. Patterns were
vention to modify or abolish the risk factor (by behavioral or similar among untreated individuals, with untreated men over
therapeutic means) is associated with a decreased incidence age 60 years experiencing an 11 mm Hg decline and women a
of the disease. As discussed later, hypertension fulfills all of 6 mm Hg decline in mean SBP from 1991 to 2008, and stable
these criteria, and represents an important target for inter- mean SBP in younger individuals. Among treated individu-
vention in reducing the population and individual burden of als, mean SBP levels declined from 1991 to 2008 in men and
CVD and renal disease. women of all age groups.7
African Americans, and especially African-American
PREVALENCE AND SECULAR TRENDS women, have a prevalence of hypertension that is among the
highest in the world. Currently, it is estimated that 41.2% of
Data from recent United States National Health and Nutrition non-Hispanic African-American adults have hypertension
Examination Surveys (NHANES) from 2011 to 2014 indicated (including 40.8% of men and 41.5% of women), compared with

1
 2

TABLE 1.1 Trends in Prevalence, Awareness, Treatment and Control of Hypertension in the United States, From the
I National Health and Nutrition Examination Surveys
Epidemiology

NHANES II NHANES III NHANES III NHANES NHANES NHANES

1976-1980 1988-1991 1991-1994 1999-2000 2007-2008 2011-2012
Prevalence 31.8% 25.0% 24.5% 28.7% 29.6% 29.1%
Awareness 51% 73% 68% 69% 80.6% 82.7%
Treatment 31% 55% 54% 60% 73.7% 75.6%
Control to <140/ 10% 29% 27% 30% 48.4% 51.8%
<90 mm Hg
NHANES, National Health and Nutrition Examination Surveys.

28% of non-Hispanic whites, 24.9% of non-Hispanic Asians,

and 25.9% of Hispanic Americans.3 Asian Americans and most Hypertensive
other ethnic groups tend to have similar BP levels and hyper- n = 80 million
tension prevalence as whites. Trends in the prevalence of
hypertension have followed a similar pattern in all ethnicities Aware Unaware
from the 1990s to the present.5 Prevalence rates are similar 83% 17%
between men and women, but they increase dramatically with
age, from 7.3 to 32.2 to 64.9% among those aged 18 to 39, 40 to
59 and 60 years or older, respectively.3 Treated Untreated
There have been substantial improvements in aware- 76% 7%
ness, treatment, and control of hypertension over the last 2 38 million
decades, but the number of hypertensive individuals who are Controlled Uncontrolled
aware of their hypertension, receiving treatment, or treated 52% 24%
and controlled remains well below optimal levels (Table 1.1).
Data from NHANES 2011 to 2012 indicate that 82.7% of hyper- FIG. 1.1 Number and percentage of Americans who are aware of their hyperten-
tensive individuals were aware of their elevated BP, 75.6% of sion, treated, and controlled to goal levels from the National Health and Nutrition
Examination Surveys 2007-2008. (Data from references 6, 8, 27)
them were receiving antihypertensive therapy, but only 51.8%
had a BP of less than 140/90 mm Hg, the level considered to
be “controlled” or at goal.8 These data reflect a significant
increase in treatment and control rates from approximately TABLE 1.2 Awareness, Treatment and Control of
60% and 30%, respectively, in 2000, to the current levels of Hypertension in the United States, 2011-12, by Sex and
treatment and control. Nonetheless, extrapolating these data Race/Ethnicity
to the current estimate of 80 million Americans with hyperten- PREVALENCE
sion,9 there are still over 38 million hypertensive individuals AWARENESS OF ANTIHYPER- CONTROL
who are unaware of their diagnosis, aware but untreated, or OF HYPER- TENSIVE TO <140/
treated but uncontrolled (Fig. 1.1). TENSION TREATMENT <90 MM HG
Rates of awareness, treatment, and control of BP tend
Men 80.2% 70.9% 49.3%
to differ by age, sex, and race/ethnicity. After years of rela-
tive stagnation, trends in awareness, treatment, and control Women 85.4% 80.6%a 55.2%a
have shown remarkable progress in the last decade among
all age, sex, and race groups.6 Overall, awareness of elevated
Age 18-39 years 61.8% 44.5% 34.4%
BP increased significantly from 69.6% to 80.6% between 1999
and 2008, with women and non-Hispanic black adults being Age 40-59 years 83.0%b 73.7%b 57.8%b
more likely to be aware, and Mexican Americans being the Age ≥60 years 86.1%b 82.2%b 50.5%b
least likely to be aware of their hypertension.6 Currently,
Non-Hispanic 82.7% 76.7% 53.9%
women are somewhat more likely than men to be aware of white
their hypertension, to receive treatment with antihyperten-
sive drug therapy, and to be at goal BP (Table 1.2). Individuals Non-Hispanic 85.7% 77.4% 49.5%
black
with hypertension aged 18 to 39 years are far less likely to be
aware, treated, or controlled compared with middle-aged and Non-Hispanic 72.8%c 65.2%c 46.0%
older individuals. Compared with other race/ethnic groups, Asian
non-Hispanic Asians are significantly less likely to be aware of Hispanic- 82.2% 73.5% 46.5%
their hypertension or to have it treated, but control rates are American
similar across all race/ethnic groups (see Table 1.2).8 aSignificantly different compared with men
There is also substantial geographic variation in the epide- bSignificantly different compared with ages 18-39 years
miology of hypertension in the U.S. Prevalence of hyperten- cSignificantly different compared with all other race/ethnic groups

sion is highest in the southeastern U.S., but so are awareness, Data from Nwankwo T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the
treatment and control of hypertension. Areas of the south- United States: National Health and Nutrition Examination Survey, 2011–2012. NCHS
data brief, no 133. Hyattsville, MD: National Center for Health Statistics;2013.
western U.S. in New Mexico, Colorado, and Texas have some
of the lowest rates of awareness, treatment and control.10
of diseases.11,12 Fig. 1.2 reveals the estimated proportion of
deaths attributable to high systolic blood pressure by country
Global Burden of Hypertension across the globe. There is substantial variation globally and
International data indicate that hypertension is even more regionally, with the lowest proportion of deaths attributable
prevalent in other countries, including developed countries. to high systolic blood pressure in Chad, at 3.8%, and the high-
Hypertension is also the leading single cause of global burden est in Georgia, at 40.4%.13
 3

General Population and Global Cardiovascular Risk Prediction

4% 5% 10% 15% 20% 25% 30% 35% 40%

FIG. 1.2 Percentage of deaths attributable to high systolic blood pressure worldwide for both sexes and all ages. Global Burden of Diseases study 2013. (Data from Institute for
Health Metrics and Evaluation [IHME]. GBD Compare. Seattle, WA: IHME, University of Washington, 2015. Available from http://vizhub.healthdata.org/gbd-compare/. Accessed
April 20, 2016.)

Although data from low-income and middle-income coun- practice guidelines have typically recommended higher BP
tries around the world had been sparse, in recent years the thresholds before initiation of drug therapy, causing even
scope and trends in the global burden of hypertension have lower rates of treatment and control of BP.14,16 Of the European
become clearer. Danaei and colleagues14 described the cur- countries studied, Italy had the lowest prevalence (38%),
rent levels and trends in SBP for adults 25 years and older whereas Germany had the highest (55%).15 The increase in BP
in 199 countries using data from published and unpublished and in prevalence of hypertension with age has been steeper
health examination surveys and epidemiologic studies includ- in European countries compared with the U.S. and Canada.
ing 5.4 million participants. In 2008, age-standardized mean The correlation between hypertension prevalence and stroke
SBP worldwide was 128.1 mm Hg in men and 124.4 mm Hg mortality rates is very strong (r = 0.78), with a stroke mor-
in women. The investigators estimated that between 1980 tality rate of 27.6 per 100,000 in North America and 41.2 per
and 2008, global SBP decreased by 0.8 mm Hg per decade 100,000 in European countries.15 Furthermore, treatment
in men and 1.0 mm Hg per decade in women. There was sig- rates in Europe have been substantially lower, in association
nificant regional variation in SBP trends over time. Female with higher BP thresholds for treatment in clinical practice
SBP decreased by 3.5 mm Hg or more per decade in Western guidelines promulgated in Europe and Canada until recently.
Europe and Australasia. Male SBP fell most, by 2.8 mm Hg per Among 35- to 64-year-old hypertensives, over half (53%) were
decade in high-income North America. SBP rose in Oceania, treated in the U.S., compared with 36% in Canada and 25%
East Africa, and South and Southeast Asia for both sexes, and to 32% in European countries. The associated differences in
in West Africa for women. Female SBP was highest in some levels of BP control were dramatic, with 66% of U.S., 49% of
East and West African countries, with means of 135 mm Hg Canadian, and 23% to 38% of European hypertensives con-
or greater. Male SBP was highest in Baltic and East and West trolled to BP levels of less than 160/95 mm Hg, and 29%, 17%,
African countries, at 138 mm Hg or more. Men and women in and 10% or lower, respectively, controlled to levels of less
Western Europe had the highest SBP in high-income regions. than 140/90 mm Hg.16
SBP is currently highest in low-income and middle-income
countries overall, creating a substantial burden of disease in RISK FACTORS FOR HYPERTENSION
these countries.14
Surveys of the prevalence of hypertension indicate a grow- Hypertension is a complex phenotype with multiple genetic
ing global burden. Using data from the 1990s, the prevalence and environmental risk factors, as well as important
of hypertension in adults aged 35 to 74 years in Canada has gene-environment interactions. Age, with its concomitant
generally been similar to that of the U.S. (at approximately changes in the vasculature, and demographic and socio-
28%), and concurrent data from six European countries economic variables are among the strongest risk factors for
revealed an overall prevalence of 44%.15 In Europe, clinical hypertension.
 4
Age hypertension among obese individuals, with a body mass
I The prevalence of hypertension increases sharply with index (BMI) 30 kg/m2 or higher, is 42.5%, compared with 27.8%
advancing age: although only 8.6% of men and 6.2% of women for overweight individuals (25 to 29.9 kg/m2), and 15.3% for
Epidemiology

ages 20 to 34 years are affected, 76.4% of men and 79.9% of individuals with BMI less than 25 kg/m2.23 Comparing NHANES
women aged 75 years and over have hypertension (Fig. 1.3).9 1988-1994 with NHANES 1999-2004, Cutler et al found an over-
Thus, in older patients, hypertension is by far the most preva- all increase in the prevalence of hypertension by 13% in men
lent risk factor for CVD. About 81% of hypertensive individu- and 24% in women. After adjustment for BMI, there was no
als in the U.S. are aged 45 years and older, although this group statistically significant change in hypertension in men, indi-
comprises only 46% of the U.S. population.17 With the aging of cating that the increase in BMI accounted for nearly all of the
the population, the overall prevalence of hypertension in the increase in hypertension in men. For women, after adjust-
population is sure to increase. ment for BMI, there continued to be large relative increases
Viewed from another perspective, hypertension already in the prevalence of hypertension, indicating that some of the
affects more individuals during their lifespan than any other trait increases in hypertension in women were attributable to fac-
or disease studied to date. The concept of the “lifetime risk” of a tors other than their increases in BMI in the recent NHANES
given disease provides a useful measure of the absolute burden period.
and public health impact of a disease, as well as providing an Data from Framingham also reveal marked increases in risk
average risk for an individual during his or her lifetime. Lifetime for development of hypertension with higher BMI. Compared
risk estimates account for the risk of developing disease dur- with normal weight adult men and women, the multivariable-
ing the remaining lifespan and the competing risk of death from adjusted relative risks for development of hypertension in
other causes before developing the disease of interest. Data from long-term follow up were 1.48 and 1.70 for overweight men
the Framingham Heart Study (FHS), a longstanding study of CVD and women, and 2.23 and 2.63 for obese men and women,
epidemiology, indicate that, for men and women free of hyper- respectively.24
tension at age 55, the remaining lifetime risks for development Numerous studies have also demonstrated the important
of hypertension through age 80 are 93% and 91%, respectively. role of weight gain in BP elevation and weight reduction in
In other words, more than 9 out of 10 older adults will develop BP lowering. As discussed above, SBP and DBP tend to rise
hypertension before they die. Even those who reach age 65 free with age beginning at around age 25 years in most adults.19,20
of hypertension still have a remaining lifetime risk of 90%.18 However, recent data indicate that these “age-related”
In Western societies, SBP tends to rise monotonically and increases in SBP and DBP may be avoided in young adults who
inexorably with advancing age. Conversely, DBP levels rise maintain stable BMI over long-term follow up. In the Coronary
until about age 50 to 55 years, after which there is a plateau Artery Risk Development In young Adults (CARDIA) study,
for several years and then a steady decline to the end of the those who maintained a stable BMI at all six examinations
usual lifespan.15,19,20 A variety of factors, particularly related over 15 years had no significant changes in either SBP or DBP,
to changes in arterial compliance and stiffness,21,22 contribute whereas those who had an increase in their BMI of 2 kg/m2 or
to the development of systolic hypertension and to decreas- more had substantial increases in BP.25
ing DBP with age. Both of these phenomena contribute to a The influence of weight gain on BP, and the benefits of
marked increase in pulse pressure (PP), defined as SBP minus maintaining stable weight or losing weight extend down even
DBP, after age 50 years. Thus, hypertension, and particularly to young children. One large birth cohort study of children
systolic hypertension, is a nearly universal condition of aging, examined BMI at ages 5 and 14 and the association with SBP
and few individuals escape its development. Only in societies and DBP at age 14. Children who were overweight at age 5 but
where salt intake is low, physical activity levels are very high, had normal BMI at age 14 had similar mean systolic and dia-
and obesity is rare, are age-related increases in SBP avoided. stolic BP to those who had a normal BMI at both time points.
Conversely, children who were overweight at both ages, or
who had a normal BMI at age 5 and were overweight at age
Weight 14, had higher systolic and diastolic BP at age 14 than those
Increasing weight is one of the major determinants of who had a normal BMI at both ages, even after adjustment for
increasing BP. In recent NHANES surveys, the prevalence of potential confounders.26

100 Other Risk Factors

Men As discussed above, sex influences the prevalence of hyperten-
Women sion in an age-dependent fashion. Until about the sixth decade
79.9
80 76.4 of life, men have a higher prevalence, after which women pre-
Percent with hypertension

67.8 dominate increasingly (Fig. 1.3). Overall, more women than

62 men are affected by hypertension, in part because of their
60 54.6 53.7 longer life expectancy.
Race/ethnicity has also been shown to be significantly
associated with hypertension. Although non-Hispanic white
40 36.8 persons make up about two-thirds of the U.S. adult hyperten-
32.7
sive population, this is consistent with their representation
22.6 in the overall population. African Americans are dispro-
18.3
20 portionately affected, and have among the highest rates
8.6
6.2
of hypertension in the world, with mean systolic BP levels
approximately 5 mm Hg higher than whites, and prevalence
0 rates at least 10% higher than whites.27,28 Other racial/eth-
20–34 35–44 45–54 55–64 65–74 75 nic groups in the U.S., including Hispanic Americans, have
Age (years) a prevalence of hypertension similar to whites.17,19,27-29
Education status also influences rates of hypertension,
FIG. 1.3 Prevalence of hypertension among men and women aged 18 years and over,
from National Health and Nutrition Examination Surveys 2005-2008. (Data from Mozaf-
with lower education levels being strongly associated with
farian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2016 update: A hypertension. However, much of this inverse association of
report from the American Heart Association. Circulation. 2016;133:e38-60.) education with BP appears to be explained by differences in
 5

diet and in BMI between less educated and more educated CLASSIFICATION OF BLOOD PRESSURE
individuals.30 1
Among dietary influences on BP level, high dietary sodium Formal classification of BP stages by consensus panels

General Population and Global Cardiovascular Risk Prediction

intake has consistently been related to rates of hypertension began to take shape in the early 1970s with the first National
in numerous populations and cohort studies. Conversely, Conference on High Blood Pressure Education. The first
higher potassium, calcium, and magnesium intakes appear report of the Joint National Committee (JNC) was published in
to be associated with lower rates of hypertension in various 1977 and has been followed by six subsequent reports in 1980,
populations.31 Patients with omnivorous diets have higher BP 1984, 1988, 1993, 1997, and 2003. The seventh report (JNC 7,
levels than those who are vegetarian, but the types of dietary published in 2003)1,35 was the clinical standard for the preven-
fat do not appear to influence BP levels directly (with the tion, detection, evaluation and treatment of hypertension in
possible exception of mild lowering by omega-3 fatty acids). the U.S. until recently. Current U.S. and international guide-
The evidence linking heavy alcohol intake to hypertension is lines still use the same classification system. JNC 7 recognized
unequivocal. More than 50 epidemiologic studies have dem- several important concepts that have evolved in our under-
onstrated an association between intake of 3 or more drinks standing of hypertension over the past decades. First, systolic
per day and hypertension, although regular alcohol intake is hypertension confers at least as much, and usually greater,
associated with a lower risk of atherothrombotic CVD events. risk for adverse events as diastolic hypertension, which was
not fully appreciated in the first four JNC reports. Thus, the
JNC report recommends that for middle-aged and older hyper-
Genetic Factors tensives (who represent the vast majority of hypertensives in
Numerous studies have examined potential genetic suscepti- the population), SBP should be the primary target for staging
bilities for hypertension. Data consistently indicate that BP of BP and initiation of therapy. Second, hypertension rarely
levels are heritable. Using data from the multigenerational occurs in isolation, and is usually present in the context of one
FHS cohorts, Levy et al estimated that heritability for single- or more other CVD risk factors. Therefore, in recommending
examination measures were 0.42 for SBP and 0.39 for DBP. treatment for hypertension, the JNC 7 report recommended
Using data from multiple examinations, long-term systolic and some consideration of global risk for CVD.
diastolic BP phenotypes had high heritability estimates, at It has long been recognized that BP confers risk for CVD
0.57 and 0.56, respectively.32 beginning at levels well within the clinically “normal” range,
The availability of high-throughput technology has recently with risk increasing in a continuous, graded fashion to the
allowed for genome-wide association studies to be performed highest levels, as discussed in detail later. Thus, although
in large pooled cohorts to assess for linkage between identi- clinical practice guidelines impose certain thresholds for con-
fied areas of the genome and BP levels. A large consortium sidering individuals to be hypertensive, and for initiation of
of studies33 tested 2.5 million genotyped and imputed single- therapy, this conception is an artificial construct designed to
nucleotide polymorphisms (SNPs) across the genome for asso- assist clinicians and patients with treatment decisions.
ciation with systolic and diastolic BP levels in 34,433 subjects The current scheme for classifying BP stages is shown
of European ancestry and followed up findings with direct in Table 1.3. Although BP lower than 120/80 had previously
genotyping in 71,225 participants of European ancestry and been termed “optimal,” it is now termed “normal.” A category
12,889 of Indian Asian ancestry. They also performed in silico of “prehypertension” is defined, including individuals with
comparison in another large consortium (n = 29,136). This untreated SBP 120 to 139 or DBP of 80 to 89 mm Hg. The prior
group identified associations between systolic or diastolic BP classification of Stage 3 hypertension was dropped because of
and common variants in eight genomic regions near a number its relatively uncommon occurrence, and all individuals with
of potential genes of interest: CYP17A1 (p = 7×10−24), CYP1A2 SBP 160 mm Hg or higher or DBP 100 mm Hg or higher are now
(p = 1×10−23), FGF5 (p = 1×10−21), SH2B3 (p = 3×10−18), MTHFR classified as having Stage 2 hypertension.1
(p = 2×10−13), c10orf107 (p = 1×10−9), ZNF652 (p = 5×10−9) and Individuals are classified into their BP stages on the basis of
PLCD3 (p = 1×10−8) genes. All variants associated with continu- both systolic and diastolic BP levels. When a disparity exists
ous BP were associated with the phenotype of dichotomous between SBP and DBP stages, patients are classified into the
hypertension as well. The authors concluded that these asso- higher stage. Several studies36-38 have examined this phenom-
ciations between common variants and BP and hypertension enon of “upstaging” based on disparate systolic and diastolic
could offer mechanistic insights into the regulation of BP and BP levels. In one study,36 64.6% of subjects had congruent
may point to novel targets for interventions to prevent cardio- stages of systolic and diastolic BP, 31.6% were upstaged on the
vascular disease.33 basis of SBP, and only 3.8% on the basis of DBP. Thus, among
Updates to these genome-wide association studies continue
to appear with the addition of more cohorts and refined geno-
TABLE 1.3 Blood Pressure Staging System of the Seventh
typing methods.34 To date, more than 60 loci (many in novel
Report of the Joint National Committee on Prevention,
or unexpected genes) have now been associated with blood
Detection, Evaluation, and Treatment of High Blood
pressure phenotypes or the diagnosis of hypertension, with
Pressure
similarities noted in diverse race/ethnic groups.34 Similarly,
rare inherited genetic syndromes are associated with hyper- JNC 7 BLOOD BLOOD PRESSURE
tension, including Liddle syndrome and 11β-hydroxylase and PRESSURE STAGE RANGE
17α-hydroxylase deficiencies. However, because hypertension Normal Untreated SBP <120 and
is a complex phenotype, and BP levels are determined by the DBP <80 mm Hg
complex interactions of multiple neurologic, renal, endocrino-
logic, cardiac and vascular processes, as well as environmen- Prehypertension Untreated SBP 120-139 or
DBP 80-89 mm Hg
tal and behavioral factors, there have not been any single-gene
polymorphisms discovered that explain more than a small Stage 1 hypertension SBP 140-159 or DBP 90-99 mm Hg
fraction of hypertension alone or jointly in the population Stage 2 hypertension SBP ≥160 or DBP ≥100 mm Hg
at large. The study of rare and low-frequency genetic poly-
morphisms, gene-gene interactions, gene-environment inter- DBP, Diastolic blood pressure; JNC, Joint National Committee; SBP, systolic blood
pressure.
actions and epigenetics is likely to lead to novel insights on Reused with permission from Chobanian AV, Bakris GL, Black HR, et al. Seventh
blood pressure regulation, and may provide potential future Report of the Joint National Committee on Prevention, Detection, Evaluation, and
targets for prevention or treatment of hypertension. Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.
 6

all participants, 96% were correctly classified by knowledge risks for all manifestations of CVD, but its relative impact is
I of their SBP alone, whereas only 68% were correctly classified greatest for stroke and HF (Fig. 1.5). Because CHD incidence
by knowledge of the DBP alone. Thus, SBP elevation out of is greater than incidence of stroke and HF, however, the abso-
Epidemiology

proportion to DBP is common in middle-aged and older per- lute impact of hypertension on CHD is greater than for other
sons, and SBP appears to play a greater role in the determina- manifestations of CVD, as demonstrated by the excess risks
tion of BP stage and eligibility for therapy.36 Among younger shown in Fig. 1.5.
individuals, upstaging because of DBP is somewhat more To illustrate the importance of hypertension as a risk
common. However, after the age of 50 years, which includes factor, let us consider the case of HF. Between 75% and 91%
the vast majority of hypertensives, upstaging because of SBP of individuals who develop HF have antecedent hyperten-
clearly occurs for an overwhelming proportion of the popula- sion.41,42 In a study from the FHS, hypertension conferred a
tion and determines hypertensive status and/or eligibility for hazard ratio for the development of HF of approximately 2 for
therapy.38 men and 3 for women over the ensuing 18 years.42 As shown
Isolated systolic hypertension in older people reflects in Fig. 1.6, the hazard ratios for HF associated with hyper-
progressive large artery stiffening seen with aging. In tension (2 to 3) were far lower than the hazard ratios for HF
younger hypertensive patients, isolated diastolic hyperten- associated with MI, which were greater than 6 for both men
sion (SBP <140 and DBP ≥90 mm Hg) and systolic-diastolic and women. However, the population prevalence of hyper-
hypertension (SBP ≥140 and DBP ≥90 mm Hg) tend to pre- tension was 60%, compared with approximately 6% for myo-
dominate, whereas beyond age 50, isolated systolic hyper- cardial infarction. Therefore, the population-attributable risk
tension (ISH, SBP ≥140 and DBP <90 mm Hg) predominates. (PAR) of HF, that is, the fraction of HF in this population that
ISH is the most common form of hypertension over age 60, was because of hypertension, was 59% in women and 39% in
being present in more than 80% of untreated hypertensive men. The PARs for MI were 13% and 34% for women and men,
men and women.38 respectively.42
These observations, coupled with data on risks of systolic Investigators from the comprehensive Olmsted County
hypertension and the benefits of treating systolic hyperten- cohort in Minnesota have also estimated PARs for various
sion, prompted the National High Blood Pressure Education HF risk factors. In that study, the relative risks for HF were
Program’s Advisory Panel to recommend a major paradigm again high for CHD and DM, with odds ratios of 3.05 and
shift in 2000 in urging that SBP become the major criterion for 2.65, respectively, whereas the odds ratio associated with
the diagnosis, staging, and therapeutic management of hyper- hypertension was 1.44. However, hypertension was preva-
tension, particularly in middle-aged and older Americans.22 lent in two-thirds of the cohort. The PAR was highest for
This recommendation was incorporated into the staging CHD and hypertension; each accounted for 20% of (HF)
system and treatment guidelines for JNC 7 and subsequent cases in the population overall, although CHD accounted
guidelines.1,35 for the greatest proportion of cases in men (PAR 23% for
CHD versus 13% for hypertension) and hypertension was of
SEQUELAE AND OUTCOMES WITH greatest importance in women (PAR 28% for hypertension
HYPERTENSION versus 6% for CHD).43

Hypertension is a major risk factor for atherosclerotic

CVD (ASCVD), and almost all other manifestations of CVD. Importance of Systolic Blood Pressure
Higher BP levels generally increase risk in a continuous and It has been recognized for 4 decades that elevated SBP
graded fashion for total mortality, CVD mortality, coronary confers at least as great, and, in most groups studied,
heart disease (CHD) mortality, myocardial infarction (MI), substantially greater risk for CVD as an elevated DBP.44
heart failure (HF), left ventricular hypertrophy (LVH), atrial However, translation of this knowledge into clinical guide-
fibrillation, stroke/transient ischemic attack, peripheral lines and clinical practice was slow to evolve. In numerous
vascular disease, and renal failure. For many of these end- studies, increasing SBP has consistently been associated
points, there is effect modification by sex, with male hyper- with higher risk for adverse events than increasing DBP,
tensives being at higher absolute risk for CVD events than whether these BP variables are considered separately or
female hypertensives (HF being a notable exception). There together, and whether they are treated as linear covariates
is also substantial effect modification by age, with older or in quintiles, deciles, or JNC stages. For example, in the
hypertensives being at similar relative risk but at much Cardiovascular Health Study of older Americans (Table 1.4),
greater absolute risk than younger ones.39 As discussed a one standard deviation increment in SBP was associated
later, hypertension rarely occurs in isolation, and it confers with higher adjusted risk for CHD and stroke than was a
increased risk for CVD across the spectrum of overall risk one standard deviation increment in DBP (or PP). In mod-
factor burden, but with increasing importance in the setting els with SBP and DBP together or SBP and PP together, SBP
of other risk factors.40 consistently dominated as the greater risk factor.45 When
Absolute levels of risk for ASCVD increase substantially men who were screened for inclusion in the Multiple Risk
with increasing risk factor burden, and are augmented still Factor Intervention Trial (MRFIT) were stratified into quin-
further by elevations in BP (Fig. 1.4). As shown by the arrows tiles of SBP or DBP, risks for each SBP quintile were the
in Fig. 1.4, the slope of increasing ASCVD risk is greater with same or higher than for the corresponding quintile of DBP
increasing BP levels when the burden of other risk factors is (Fig. 1.7A).46 Similar findings were observed when MRFIT
greater. Thus, BP levels, and the risk they confer, must always screenees were stratified into deciles of SBP and DBP; at
be considered in the context of other risk factors and the every level, SBP was consistently associated with higher
patient’s global risk for ASCVD. For example, because the risk for CHD mortality than the corresponding decile of DBP
combination of hypertension and diabetes (DM) is particu- (Fig. 1.7B).47 Finally, when men were stratified by JNC level
larly dangerous, JNC 7 recommended lower goal BP levels for of SBP and DBP, SBP was associated with greater risk for
patients with DM (<130/<80 mm Hg) than for those without CHD mortality than DBP in each JNC BP stage.47
DM (<140/<90 mm Hg).1 In fact, when DBP is considered in the context of the SBP
Individuals with hypertension have a two-fold to three- level, an inverse association for DBP and CHD risk has been
fold increased relative risk for CVD events compared with observed. Franklin et al demonstrated that, at any specified
age-matched normotensives. Hypertension increases relative level of SBP, relative risks for CHD decreased with increasing
 7

80 80
1
Optimal BP (<120/<80) Optimal BP (<120/<80)

10-year predicted ASCVD risk (%)

10-year predicted ASCVD risk (%)

General Population and Global Cardiovascular Risk Prediction

Normal BP (SBP 120–129 or DBP 80–84) Normal BP (SBP 120–129 or DBP 80–84)

60 High-normal BP (SBP 130–139 or DBP 85–89) 60 High-normal BP (SBP 130–139 or DBP 85–89)
Stage 1 HTN (SBP 140–159 or DBP 90–99) Stage 1 HTN (SBP 140–159 or DBP 90–99)
Stage ≥ 2 HTN (SBP ≥ 160 or DBP ≥ 100) Stage ≥ 2 HTN (SBP ≥ 160 or DBP ≥ 100)

40 40

20 20

0 0
Total Chol 200 240 240 240 240 240 Total Chol 200 240 240 240 240 240
HDL-Chol 45 45 35 35 35 35 HDL-Chol 45 45 35 35 35 35
Diabetes – – – + + + Diabetes – – – + + +
Smoker – – – – + + Smoker – – – – + +
Anti-HTN Rx – – – – – + Anti-HTN Rx – – – – – +
A 60-Year-Old White Man B 60-Year-Old Black Man

80 80
Optimal BP (<120/<80) Optimal BP (<120/<80)

10-year predicted ASCVD risk (%)

10-year predicted ASCVD risk (%)

Normal BP (SBP 120–129 or DBP 80–84) Normal BP (SBP 120–129 or DBP 80–84)

60 High-normal BP (SBP 130–139 or DBP 85–89) 60 High-normal BP (SBP 130–139 or DBP 85–89)

Stage 1 HTN (SBP 140–159 or DBP 90–99) Stage 1 HTN (SBP 140–159 or DBP 90–99)
Stage ≥ 2 HTN (SBP ≥ 160 or DBP ≥ 100) Stage ≥ 2 HTN (SBP ≥ 160 or DBP ≥ 100)

40 40

20 20

0 0
Total Chol 200 240 240 240 240 240 Total Chol 200 240 240 240 240 240
HDL-Chol 45 45 35 35 35 35 HDL-Chol 45 45 35 35 35 35
Diabetes – – – + + + Diabetes – – – + + +
Smoker – – – – + + Smoker – – – – + +
Anti-HTN Rx – – – – – + Anti-HTN Rx – – – – – +
C 60-Year-Old White Woman D 60-Year-Old Black Woman
FIG. 1.4 Predicted 10-year risk for atherosclerotic cardiovascular disease by increasing burden of risk factors and systolic blood pressure, in a 60-year-old white man
(Panel A), African-American man (Panel B), white woman (Panel C), and African-American woman (Panel D), based on the Pooled Cohort Equations.66 ASCVD, Athero-
sclerotic cardiovascular disease; BP, blood pressure; DBP, diastolic blood pressure; HDL-Chol, high-density lipoprotein cholesterol; HTN, hypertension; SBP, systolic blood
pressure.

DBP. For example, at an SBP of 150 mm Hg, the estimated haz- the PAR for CVD conferred by SBP vastly outweighs the PAR
ards ratio for CHD was 1.8 if the DBP was 70 mm Hg, but only for DBP. Finally, lack of control to goal BP in the community
approximately 1.3 if the DBP was 95 mm Hg. The higher the appears to be overwhelmingly because of lack of SBP control
SBP level, the steeper the decline in CHD risk with increas- to less than 140 mm Hg.38,49,50
ing DBP.48 These data provide some compelling evidence for In national samples, significant cross-sectional predictors
the importance of PP as a measure of risk, because PP repre- of lack of BP control among those who are aware of their
sents the difference between SBP and DBP, and higher risk was hypertension include age 65 years or older, male sex, and no
observed in this study when the PP widened.48 Pulse pressure visits to a physician in the preceding 12 months.50 Age and the
will be discussed in greater detail later. presence of LVH likely represent higher initial SBP before ini-
The increased risks associated with SBP are clear. When it tiation of therapy and longer duration of hypertension, both
is also appreciated that systolic hypertension out of propor- of which can contribute to greater difficulty in achieving lower
tion to diastolic elevation is by far the most common form BP levels. In addition, it appears likely that clinicians are reluc-
of hypertension, as discussed earlier, it becomes clear that tant to treat older hypertensive individuals to lower BP goals,
 8

70
I

Age-adjusted biennial rate (per 1,000)

Excess risk with HTN
Epidemiology

60
Expected rate

50
36
40
23
30
21
20
29 12
10 22
14 9 5 10
9 4 5 4
3 2 5 2 4 2
0
Men Women Men Women Men Women Men Women Men Women
All CVD CHD Stroke PAD HF
Age-adjusted relative risk associated with hypertension
Men 2.2 2.0 3.8 2.0 4.0
Women 2.5 2.2 2.6 3.7 3.0
FIG. 1.5 Age-adjusted biennial rates, relative risks and absolute excess risks associated with hypertension for different cardiovascular endpoints: Framingham Study, 36-Year
follow-up, persons aged 35-64 years. CVD, Cardiovascular disease; CHD, coronary heart disease; HF, heart failure; HTN, hypertension; PAD, peripheral arterial disease.

60
Men
Population attributable risk (%)

Women
40

20

10

0
HTN MI AP VHD LVH DM
Hazards ratio for CHF
Men 2.07 6.34 1.43 2.47 2.19 1.82
Women 3.35 6.01 1.68 2.13 2.85 3.73

Prevalence (%) of each risk factor

Men 60 10 11 5 4 8
Women 62 3 9 8 3 5
FIG. 1.6 Hazards ratios for congestive heart failure associated with selected risk factors, prevalence of each risk factor, and population-attributable risk for each factor in
congestive heart failure. AP, Angina pectoris; DM, diabetes mellitus; HTN, hypertension; LVH, electrocardiographic left ventricular hypertrophy; MI, myocardial infarction; VHD,
valvular heart disease. (Data from Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996;275:1557-1562.)

TABLE 1.4 Risks for Cardiovascular Disease Associated With Different Components of Blood Pressure in the Cardiovascular
Health Study
1 STANDARD ADJUSTED HAZARDS RATIO (95% CI)
DEVIATION Myocardial Infarction Stroke
Systolic Blood Pressure 21.4 mm Hg 1.24 (1.15-1.35) 1.34 (1.21-1.47)
Diastolic Blood Pressure 11.2 mm Hg 1.13 (1.04-1.22) 1.29 (1.17-1.42)
Pulse Pressure 18.5 mm Hg 1.21 (1.12-1.31) 1.21 (1.10-1.34)
CI, Confidence interval.
Data from Psaty BM, Furberg CD, Kuller LH, et al. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality. Arch Intern Med.
2001;161:1183-1192.
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 9

4.0
1
3.5 DBP

General Population and Global Cardiovascular Risk Prediction

SBP
3.0
3.0

2.5 2.4

Relative risk
2.0 1.8
1.7
1.5
1.5 1.3
1.2 1.2
1 1
1.0

0.5

0.0
1 2 3 4 5
A Blood pressure quintile

4.0 3.82

DBP
3.5
SBP
2.9
3.0
2.71

2.5
Relative risk

2.31

1.99
2.0 1.75 1.78 1.81
3.0 1.62
1.5 1.31 1.39 1.4
1.24 1.31
1.19 1.18
1 1 1.03
1.0

0.5

0.0
1 2 3 4 5 6 7 8 9 10
B Blood pressure decile
FIG. 1.7 Relative risks for coronary heart disease mortality among men screened for the Multiple Risk Factor Intervention Trial, by quintiles (Panel A) or deciles (Panel B) of
systolic and diastolic blood pressure. DBP, Diastolic blood pressure; SBP, systolic blood pressure.

perhaps as a result of concerns over orthostasis and risk for of large epidemiologic cohorts, and including data on more
falls, polypharmacy, or the controversial observation that than 56,000 decedents, demonstrated that risks for CVD death
there may be an increase in CVD events and mortality among increase steadily beginning at least at levels as low as an SBP
the oldest hypertensives when DBP is lowered below 60 or 65 of 115 mm Hg and DBP of 75 mm Hg. When considered in isola-
mm Hg (the J-shaped curve phenomenon).51 tion, for each 20 mm Hg higher SBP and each 10 mm Hg higher
ISH has been clearly demonstrated as a risk factor for DBP, there is approximately a doubling of risk for stroke death
adverse CVD outcomes in older individuals, but there has and ischemic heart disease death for both men and women.39
been some debate as to its importance in younger adults, in Similarly, the large data set of more than 347,000 men aged
whom it was felt to represent measurement artifact or labile 35 to 57 years screened for the MRFIT provides a precise esti-
blood pressure without significant consequences. Yano et al52 mate of incremental CVD risk beginning at lower BPs. The data
recently examined 31-year follow up of 27,000 men and women from the MRFIT screenees, shown in Fig. 1.8A, confirm a con-
aged 18 to 49 years in the Chicago Heart Association Detection tinuous, graded influence of SBP on multivariable-adjusted rel-
Project in Industry. They observed that, compared with those ative risk for CHD mortality beginning at BP levels well below
who had normal BP levels, men with ISH had significant 23% 140 mm Hg.53 Men with SBP of 150 to 159 mm Hg have over
and 28% higher hazards for CVD and CHD mortality. In women three times the risk and men with SBP greater than 180 mm
with ISH, hazard ratios were 1.55 (95% confidence interval 1.18 Hg nearly six times the risk of men with SBP less than 100 mm
to 2.05) and 2.12 (1.49 to 3.01), respectively.52 These data may Hg. These data also make an important point about BP levels
cause guidelines to change their approach to ISH in the young. in the population at which the majority of CVD events occur.
In Fig. 1.8B, the numbers above each bar indicate the number
of men in that stratum of SBP at baseline. Taking into account
Risk Across the Spectrum of Blood Pressure and the number of men in each stratum and the expected rates
the Importance of Stage 1 Hypertension of CHD death, the CHD death rates observed in the MRFIT
As noted above, increasing BP is associated with increasing screenee cohort indicate excess CHD deaths occurring at
risks for CVD, beginning at levels well within the so-called the rates indicated by the line in Fig. 1.8C. The proportion of
“normal” range. The Prospective Studies Collaboration, a pool- excess CHD deaths by SBP stratum is indicated in Fig. 1.8D. As
ing study of around 1,000,000 men and women in a number shown, nearly two-thirds of excess CHD deaths occurred in
 10

6 6 3,191
I
Epidemiology

5 5
4,013

4 4
Adjusted RR

Adjusted RR
9,308
21,477
3 3
44,388

2 2 79,308
98,834
66,080
21,379
1 1

0 0
<110 110– 120– 130– 140– 150– 160– 170– 180+ <110 110– 120– 130– 140– 150– 160– 170– 180+
119 129 139 149 159 169 179 119 129 139 149 159 169 179
A SBP (mm Hg) B SBP (mm Hg)

1.3% 9.9% 20.7% 42.9% 24.1%

6 25 6 25

5 Percent of excess CHD deaths 5

Percent of excess CHD deaths

20 20

4 4
Adjusted RR

Adjusted RR
15 15
3 3
10 10
2 2

5 5
1 1

0 0 0 0
<110 110– 120– 130– 140– 150– 160– 170– 180+ <110 110– 120– 130– 140– 150– 160– 170– 180+
119 129 139 149 159 169 179 119 129 139 149 159 169 179
C SBP (mm Hg) D SBP (mm Hg)
FIG. 1.8 Relative risks for coronary heart disease (CHD) mortality among screenees for the Multiple Risk Factor Intervention Trial by level of systolic blood pressure (SBP; Panel
A), with: number of men in each stratum of SBP (Panel B); distribution of excess CHD deaths by SBP stratum (Panel C); and distribution of excess CHD deaths by Joint National
Committee stage (Panel D).

men with SBP between 130 and 159 mm Hg, relatively “mild” the DBP, the mean arterial pressure, and the SBP. As discussed
levels of elevated BP. These findings were recently replicated earlier, Franklin et al demonstrated that increasing PP was
in the more contemporary Framingham and Atherosclerosis associated with marked increases in hazard of CHD for subjects
Risk in Communities cohorts.54 with the same SBP.48 Chae et al also found that PP was an inde-
Data from the FHS also indicate that the risk associated pendent predictor of HF in an elderly cohort, even after adjust-
with BPs in the range of 130 to 139 mm Hg systolic or 85 to ment for mean arterial pressure, prevalent CHD, and other HF
89 mm Hg diastolic are substantial, despite the fact that these risk factors.57 In another study, Haider and colleagues observed
levels are not classified as “hypertension.” These levels of that SBP and PP conferred similar risk for HF.58 However, other
BP are associated with significantly elevated multivariable- studies have found that SBP confers greater risk than PP, when
adjusted relative risks for CVD of 2.5 in women and 1.6 in SBP and PP are considered separately or as covariates in the
men.55 Likewise, individuals with SBP between 120 and 139 same multivariable model.45 The aforementioned Prospective
mm Hg or DBP between 80 and 89 mm Hg have a high likeli- Studies Collaboration, which pooled data from 61 large epide-
hood of progressing to definite hypertension over the next 4 miologic studies and around 1,000,000 men and women, found
years, especially if they are age 65 or older.56 that the best measure of BP for prediction of CVD events was
the mean of SBP and DBP, which predicted better than SBP or
DBP alone, and much better than the PP.39 The recommenda-
Pulse Pressure and Risks for Cardiovascular tion of JNC 7 was that clinical focus should remain on the SBP in
Disease determining need for therapy and achieving goal BP.1
Pulse pressure is defined as the systolic minus the diastolic BP. Mosley and colleagues compared the predictive utility of
In recent years there has been intense interest in PP as a risk PP and other BP measures for diverse CVD outcomes (includ-
factor for CVD. However, various investigators have struggled ing hospitalizations and mortality from stroke, MI and HF) using
with how best to “anchor” the PP. For example, a patient with a long-term follow-up data from the Chicago Heart Association
BP of 120/60 has the same PP (60 mm Hg) as a patient with a BP Detection Project in Industry.59 Baseline BP measures were
of 150/90, although the latter patient is clearly at higher risk for assessed for predictive utility for fatal and nonfatal events over
adverse events. Different investigators have anchored the PP to 33 years. Among 36,314 participants, who were a mean age of 39
 11

years, 43.4% were women. In univariate analyses, hazards ratios Risk Group A – No risk factors, clinical CVD or target organ damage
for stroke death per one standard deviation of PP, SBP, and DBP, Risk Group B – 1 or more risk factors 1
respectively, were 1.49, 1.75, and 1.71. Multiple metrics all indi- Risk Group C – Diabetes, clinical CVD, or target organ damage

General Population and Global Cardiovascular Risk Prediction

cated better predictive utility for SBP and DBP compared with
PP. Results for CHD or HF death, and stroke, MI, or HF hospitaliza- 100%
tion outcomes were similar. PP had weaker predictive utility at
all ages, but particularly for those younger than 50 years of age.
Overall then, in this large cohort study, PP had predictive util- 80%

Percent in each risk group

ity for CV events that was inferior to SBP or DBP. These findings
tend to support the approach of current guidelines in the use of
SBP and DBP to assess risk and the need for treatment.59 60%

Renal Disease 40%

Hypertension is also a major risk factor for renal disease. Of
the estimated 93,000 cases of incident end-stage renal disease
(ESRD) diagnosed annually, it is estimated that over 25% are 20%
because of hypertension, and more than 40% because of DM.60
However, these numbers may substantially underestimate the
contribution of BP to the increasing incidence of renal disease, 0%
because these data provide only a single diagnostic cause, and SBP SBP SBP SBP ≥160
hypertension is present in the vast majority of those with DM. <130 and 130–139 140–159 or DBP ≥100
DBP <85 or DBP or DBP or treated
African Americans have approximately four times the risk of
85–89 90–99
whites of developing ESRD, in part because of their significantly
higher prevalence of hypertension.41 In addition to its contribu- FIG. 1.9 Cross-classification of risk groups and blood pressure stages among
tion to ESRD, elevated BP also occurs in and exacerbates milder 4962 Framingham Heart Study subjects. CVD, Cardiovascular disease; DBP, diastolic
blood pressure; SBP, systolic blood pressure. (Data from Lloyd-Jones DM, Evans JC,
forms of chronic kidney disease and worsens proteinuria. Larson MG, O’Donnell CJ, Wilson PW, Levy D. Cross-classification of JNC VI blood
pressure stages and risk groups in the Framingham Heart Study. Arch Int Med.
1999;159:2206-2212.)
Cognitive Function
An association between higher baseline BP levels, typically
measured at a single time point, and lower cognitive function cumulative incidence of any CVD endpoint as a first event in men
has been well established.61 Nontraditional components of BP, was 24.7%, compared with 9.8% for non-CVD death (hazard ratio,
such as the variability in BP from visit-to-visit (so-called long- 2.53; 95% confidence interval, 1.83 to 3.50); in women, the com-
term BP variability) have also been associated with cognitive peting incidences were 16.0% versus 10.1%, respectively (hazard
function in older individuals. However, long-term BP variability ratio 1.58; 1.13 to 2.20). The most common first major CVD events
throughout young adulthood to middle age has only recently among those with new-onset hypertension were CHD death or
been examined as a potential predictor of cognitive function nonfatal MI (8.2%) in men and stroke (5.2%) in women. Type
in middle age. Investigators from the CARDIA study examined and incidence of first CV events varied by age, sex and sever-
BP variability in 2326 participants across eight serial examina- ity of hypertension at onset, with stroke predominating among
tions over 25 years and the association with cognitive func- older men and women at all ages with new-onset hypertension.63
tion at an average age of 50 years. Long-term BP variability These results represent a novel approach to understanding the
over 25 years beginning in young adulthood was associated complications of hypertension and could help target therapies
with worse psychomotor speed and verbal memory tests in for patients with new-onset hypertension to optimize prevention
midlife, independent of cumulative exposure to BP during fol- strategies. For example, an older individual (>60 years) with new-
low up.61 In a parallel study, the investigators used data from onset hypertension is at greatest risk for stroke as a first event;
ambulatory blood pressure monitoring performed at an aver- BP lowering would likely be of paramount importance to prevent
age age of 35 years and linked it to the same cognitive function this. However, a younger man with new-onset hypertension is
testing in midlife.62 In this analysis, less nocturnal SBP dipping most likely to have a major CHD event first, so aspirin and statin
and higher nocturnal diastolic BP levels were associated with therapy, in addition to BP lowering, might be emphasized.
lower executive function in midlife, independent of multiple
measures of office BP during long-term follow up. Nocturnal RISK FACTOR CLUSTERING
BP was not associated with psychomotor speed and verbal
memory, suggesting that different aspects of BP exposure over Hypertension occurs in isolation very infrequently. Data from
the lifespan may affect regions of the brain differentially.62 4962 FHS subjects were used to assess the cross-classification
of JNC VI BP stages and risk groups (Fig. 1.9) in a middle-aged
and older community-based population.64 In this study, higher
Competing Outcomes With Hypertension BP stages were associated with higher mean number of risk
Individuals with hypertension are at risk for multiple poten- factors and higher rates of clinical CVD and/or target organ
tial outcomes simultaneously, including non-CVD death, CHD, damage. Overall, among those with high-normal BP or hyper-
stroke, HF, and other causes of CVD death. Traditional survival tension, only 2.4% had no associated risk factors, whereas
analysis methods typically only evaluate each of these outcomes 59.3% had at least one associated risk factor, and 38.2% had
independently, without understanding their joint probabilities of target organ damage, clinical CVD or (DM).64
occurring. A recent analysis used novel methodology to explore The current epidemic of obesity among Western societies
these competing risks among all FHS subjects who had new- has led to a greater understanding of the phenomenon of risk
onset hypertension and were initially free of CVD. There were factor clustering, and of the pathophysiologic links between
645 men and 702 women with new-onset hypertension (mean hypertension, obesity, DM and CVD risk. The cluster of risk fac-
age 57 years). Compared with matched nonhypertensive con- tors including central obesity, atherogenic dyslipidemia (with
trols, subjects with new-onset hypertension were significantly low HDL-cholesterol, high triglycerides, and small, dense LDL-
more likely to experience a CVD event first rather than non-CVD cholesterol particles), impaired glucose metabolism, vascu-
death. Among new-onset hypertensives, the 12-year competing lar inflammation, proatherogenic milieu, and elevated BP has
 12

been termed the “metabolic syndrome.” Visceral adiposity and antihypertensive therapy across strata of baseline absolute
I insulin resistance appear to play central roles in the develop- predicted 5-year CVD risk. In 51,917 participants from 11 trials
ment of MS and elevated BP is a key diagnostic feature.65 In 4167 (8%) had a cardiovascular event during a median of 4.0
Epidemiology

some ethnicities, such as African Americans, elevated BP is the years (interquartile range 3.4–4.4) of follow up. The mean esti-
most common criterion leading to diagnosis of the metabolic mated baseline levels of 5-year cardiovascular risk for each of
syndrome. Hypertension confers increased risk for CVD in the four increasing risk strata were 6.0%, 12.1%, 17.7%, and 26.8%.
absence of risk factors, but absolute risk increases dramatically In each consecutive higher risk group, blood pressure-lowering
when other risk factors are present, as shown in Fig. 1.4. treatment reduced the relative risk of cardiovascular events
by 18% (95% CI 7–27), 15% (4–25), 13% (2–22), and 15% (5–24),
GLOBAL RISK ASSESSMENT AS A STRATEGY respectively (p = 0.30 for trend). However, in terms of absolute
FOR HYPERTENSION TREATMENT risk reduction, treatment was more efficient for higher risk than
lower risk individuals. Treating 1000 patients in each group with
For many international and U.S. clinical practice guidelines, espe- blood pressure-lowering treatment for 5 years would prevent 14
cially in the area of cholesterol-lowering therapy to prevent inci- (95% CI 8–21), 20 (8–31), 24 (8–40), and 38 (16–61) cardiovascular
dent CVD, the paradigm for the past two decades has been that events, respectively (p = 0.04 for trend). Similarly, Eddy et al used
the intensity of preventive treatment should match the absolute simulation modeling to estimate that risk-based approaches to
risk of the patient for developing disease. In other words, patients treatment of hypertension would be far more efficient than cur-
at low absolute risk for having a CVD event in the near term should rent BP threshold-based decisions, treating fewer patients to pre-
pursue lifestyle modification as needed, but typically should not vent the same number of CVD events, or preventing more CVD
be treated with drug therapy, given the concomitant costs and events for the same cost as guideline-directed BP thresholds.68
potential side effects. Patients at high enough risk should pursue
both lifestyle modification and drug therapy when their risk is IMPORTANCE OF PREVENTING THE
above the threshold where net clinical benefit has been demon- DEVELOPMENT OF ELEVATED BLOOD PRESSURE
strated and could be expected to accrue to the patient. In this
paradigm, guidelines use multivariable equations to predict the As noted earlier, BP levels tend to rise from young adulthood
10-year risk for CVD to estimate the risk for a given patient and to the end of life. Once hypertension has been diagnosed,
aid in decision making. In the U.S., recent cholesterol guidelines many effective lifestyle interventions and drug therapies can
in 2002 and 2013 adopted multivariable risk scores as decision lower blood pressure, with dramatic reduction in CVD risk.
aids. The 2013 American College of Cardiology/American Heart However, it has been an open question as to whether treat-
Association prevention guidelines developed and promulgated ment to lower BP once hypertension is diagnosed could
the Pooled Cohort Equations, based on data from 25,000 white fully reduce risk for CVD events to the low levels observed
and African-American men and women aged 40 to 79 years, to pre- in individuals whose blood pressure always remained low.
dict 10-year risks for CHD death, nonfatal myocardial infarction, Liu et al69 recently used data from the Multi-Ethnic Study of
or fatal or nonfatal stroke.66 These equations form the basis of the Atherosclerosis (MESA) to examine this issue. Outcomes were
data presented in Fig. 1.4, in which it is clear that BP levels (and compared between participants without or with antihyperten-
the requirement for antihypertensive therapy) contribute signifi- sive treatment at three BP levels: less than 120/80 mm Hg, sys-
cantly to the prediction of CVD risk. Gaziano and colleagues67 tolic BP 120 mm Hg to 139 mm Hg or diastolic BP 80 mm Hg to
have also promulgated a risk score that does not require the use 89 mm Hg, and systolic BP 140 mm Hg or higher or diastolic BP
of laboratory-based data, such as total cholesterol levels, instead 90 mm Hg or higher (systolic BP ≥130 or diastolic BP ≥80 mm
using all clinic-based values to predict CVD risk. In those equa- Hg for participants with diabetes). Among MESA participants
tions, which have shown good predictive utility in a variety of aged 50 years or over at baseline, those with BP lower than
international settings, body mass index is substituted for choles- 120/80 mm Hg on treatment had higher left ventricular mass
terol with good maintenance of predictive utility. index, prevalence of estimated glomerular filtration rate less
BP guidelines have generally not adopted this approach, than 60 mL/min per 1.73 m2, prevalence of coronary calcium
instead continuing to use absolute BP levels, rather than abso- score greater than 100, and twice the incident cardiovascular
lute levels of CVD risk, as thresholds for initiation of drug disease rate over 9.5 years of follow up than those with BP
therapy. However, increasing data suggest that risk-based lower than 120/80 mm Hg without treatment. At higher levels
treatment approaches may have a role for BP management as of BP, those who were treated to a given BP level also tended
well. Sundstrom et al recently used data from the large Blood to be at greater risk for CVD compared with those whose
Pressure Lowering Treatment Trialists’ Collaboration to exam- BP was at the same level without treatment (Table 1.5).69
ine the relative and absolute risk reductions associated with The data suggest that, based on the current approach,

TABLE 1.5 Multivariable–Adjusted Hazard Ratios for all Cardiovascular Disease, Coronary Heart Disease, Heart Failure
and Stroke, Stratified by Baseline Blood Pressure and Antihypertensive Treatment Status in 5798 Multi-Ethnic Study of
Atherosclerosis Participants
MULTIVARIABLE-ADJUSTED HAZARD RATIO (95% CI)
BP <120/<80 MM HG SBP 120-139 OR DBP 80-89 MM HG SBP ≥140 OR DBP ≥90 MM HG
AT BASELINE AT BASELINE AT BASELINE
NO. OF Treated and Well Treated and Treated and
OUTCOME EVENTS Untreated Controlled Untreated Controlled Untreated Uncontrolled
CVD 603 1.0 (ref) 2.19 (1.56, 3.07) 1.42 (1.03, 1.95) 2.21 (1.60, 3.05) 2.76 (2.04, 3.72) 2.96 (2.20, 3.97)
CHD 423 1.0 (ref) 2.02 (1.37, 2.97) 1.29 (0.89, 1.86) 2.09 (1.45, 3.03) 2.28 (1.60, 3.25) 2.52 (1.79, 3.55)
HF 226 1.0 (ref) 1.70 (0.92, 3.12) 1.41 (0.80, 2.51) 2.42 (1.40, 4.19) 2.43 (1.42, 4.15) 3.04 (1.83, 5.04)
Stroke 171 1.0 (ref) 2.56 (1.25, 5.28) 1.76 (0.90, 3.45) 3.13 (1.62, 6.09) 4.20 (2.27, 7.76) 4.67 (2.55, 8.56)
BP, Blood pressure; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; DBP, diastolic blood pressure; HF, heart failure; SBP, systolic blood pressure.
Data from Liu K, Colangelo LA, Daviglus ML, et al. Can antihypertensive treatment restore the risk of cardiovascular disease to ideal levels? The Coronary Artery Risk
Development in Young Adults (CARDIA) Study and the Multi‐Ethnic Study of Atherosclerosis (MESA). J Am Heart Assoc. 2015;4: e002275.
 13

antihypertensive treatment that is begun after significant BP 23. Wang Y, Wang QJ. The prevalence of prehypertension and hypertension among US
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1
cardiovascular disease risk to ideal levels. Emphasis should 24. Wilson PWF, D’Agostino RB, Sullivan L, Parise H, Kannel WB. Overweight and obesity

General Population and Global Cardiovascular Risk Prediction

as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med.
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to further reduce cardiovascular disease morbidity and 25. Lloyd-Jones DM, Liu K, Colangelo LA, et al. Consistently stable or decreased body
mass index in young adulthood and longitudinal changes in metabolic syndrome com-
mortality. ponents: the Coronary Artery Risk Development in Young Adults Study. Circulation.
2007;115:1004-1011.
26. Mamun AA, Lawlor DA, O’Callaghan MJ, Williams GM, Najman JM. Effect of body mass
SUMMARY index changes between ages 5 and 14 on blood pressure at age 14: findings from a birth
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dietary and personal habits, as well as societal issues, must 29. CDC Health Disparities and Inequalities Report—United States, 2013. Atlanta, GA: Centers
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control individual patients’ BPs, particularly SBP. Major public 30. Stamler J, Elliott P, Appel L, et al. Higher blood pressure in middle-aged American
adults with less education-role of multiple dietary factors: the INTERMAP study. J Hum
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Study. Hypertension. 1991;17(Suppl 1):I9-I15.
Newer research understanding the genetic underpinnings 32. Levy D, DeStefano AL, Larson MG, et al. Evidence for a gene influencing blood pressure
of hypertension and important gene-environment interac- on chromosome 17. Genome scan linkage results for longitudinal blood pressure pheno-
types in subjects from the framingham heart study. Hypertension. 2000;36:477-483.
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Applied Informatics. 2015;2:1-20.
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36. Lloyd-Jones DM, Evans JC, Larson MG, O’Donnell CJ, Levy D. Differential impact of sys-
are needed, but a greater focus on primordial prevention of tolic and diastolic blood pressure level on JNC-VI staging. Hypertension. 1999;34:381-385.
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Other documents randomly have
different content
Scripture prononceth him accursed, that doeth the work of the Lord
negligently, that cometh not forth to the helpe of the Lord aganist
the mightie. If wee haue beine forward to assist our nighbour
kingdomes, shall wee neglecte to defend our owen? or shall the
enimey of God be more actiue aganist his causse, then his
couenanted people for it; God forbid! If the worke shall now
miscarey and faill in our handes, throughe our wnfaithfullnes, our
auen consciences shall condeme ws, and posterity shall cursse us.
Who knowes, bot if wee stand stoutly and steadfastly to it, the Lord
may zet command our deliuerance, and shew ws his saluation.
Lett all sortes, both of heighe and low degree, in this kingdome,
call to mynde ther soleme couenants; and namlie, that artickell of
our national couenant, wich oblidgethe ws not to stay or hinder aney
such resolution as by comon consent shall be found to conduce for
the endes of the couenant, bot by all meins to further and promoue
the same; wich layeth as a bond vpone peoples consciences, reddely
to obey suche orders as by the publicke resolutione of the
parliament, and Commissione of the Generall Assembley, are found
necessarey for the prosecutione of the warr; and that artickell of the
soleme leauge and couenant, wich oblidgethe ws not to suffer
ourselues, directly nor indirectly, by quhatsomeuer combination,
persuasione, or terror, to be dewydit and withdrawin from this
blissed wnion and coniunction, or to make defectione to the
contrarey pairt, or to giue ourselues ouer to a detestable neutrality
in the causse; according to wich artickell, mens reality and integrity
in the couenant will be manifest and demonstrable, als weill by ther
omissions as commissions: by ther not doing good, as by ther doing
euill. He that is not with ws, is aganist ws, and he that gathreth not
with ws, scattereth. Since euerey mans not adwenturing his persone,
not sending out thesse that are wnder his power, according to
publicke order and appoyntment, and not paying the contribution
imposed for mantinence of the armey, haue beine formely esteimed
a ground of judgeing men enimies, malignants, and couenant
breakers, wee vishe it may be the caire of all to shune the wayes
that may bring them wnder thesse foull charecters, and quherby
they may rune themselues wnder the hazard of the displeasure of
God, and censures of the kirke, and no doubt of ciuil punishment
also to be inflicted by the stait.
Lett ministers, an the messingers of the Lord, sture vpe others,
both publickly, by free and faithfull preaching, and priuatly, by
admonishing eurey one of his deutey, as ther shall be occasione,
considringe, that silence in the publicke causse, especially in publicke
fastis not laboring to cure the dissaffectione of people; not vrging
them to constancie and patience in bearing of publick burdens, nor
to forwardnes in the publicke causse; that speaking ambigouslie,
inclyning to justifie the wicked causse, wtring wordes wiche sauor of
disaffection, complaining of the tymes in suche a way as may steall
the heartis of people from being good instruments in this worke, and
consequently from Gods causse; that some reiding publicke orders,
and speckes aganist them in priuat conferences, are reckoned vpe
amongest the enormities and corruptiones of ministers in ther
callings. By the Generall Assembley, 1646, sess: 4.
And becausse the Commissione of the Generall Assembley, in ther
remonstrance to the Conuention of Estaites, 6 Julij, 1643, teaching
all trew patriotts and professors of the reformed religion, that they
may learne to know and descerne the enimies of the kirke,
amongest other markes of malignancey giue this ther offring to
presbeteries, in all the quarters of the kingdome, papers contrarey to
the declarations of the Commissioners of the Generall Assembley.
The Generall Assembley, 1645, in ther seasonable warning, 12
Februarij, gaue thesse characters of secrett malignants and
discouenanters, ther slighting or censuring of the publicke
resolutions of this kirke and stait; ther laboring to raisse jelosies,
diuisions, to retarde or hinder the executione of quhat is ordained by
the publicke judicatories; ther censuring and slighting of thesse
quhom God hath wsed as his cheiffe instruments in this worke; ther
drawing of parties and factions for weakning of the comon vnion;
ther endeworing informations and sollicitations, tending to weakin
the hartis and handes off others, and to make them withold ther
assistance from this worke; enioyning such to be weill marked, tymly
discovered, and cairfully awoyed, lest they infusse ther counsells into
the mynds of others, quherin they requyre ministers to be faithfull,
and presbeteries to be vigilant and impartiall, as they will anssuer
the contrarey to God, and to the Generall Assembly, or ther
Commissioners. The Generall Assembley, 1646, sessio 10, ordaines,
that besydes all vther scandels, silence and ambiguous speaking in
the publicke, muche more detracting and disaffected speiche, be
seasonablie censured. The Generall Assembley 1647, sessio 27,
doeth, in the name of God, inhibit the spreding and dispersing of
erronious books or papers, pamphletts, lybills and letters, requyring
all ministers to warne ther flockes aganist suche bookes in generall
and particular; and particularly aganist suche as are most plausable,
insinuatting and dangerous; and ordaines presbeteries and synodes
to tray and processe suche as shall trangresse; recommending to
ciuile magistrats, that they may be pleassed to be assisting to
ministers and presbeteries in the execution of this acte, and to
concurre with ther authority for that effecte.
Therfor, for execution of the forsaids actes of Assembley, and
preuining the emminent danger of religion, the people of God, and
the kingdome, by practisses leading to encourage the heartis and
strenthen the handes of enimies, in prosecutting ther wicked
practisses and purposes, to make fant the heartis and enfeeble the
handes of Gods people, and to seduce ther myndis with diuisiue and
seperating counsells and principalls, according to the power and
trust committed to ws, and according to the practisses of former
Commissions of the Generall Assembley: Wee doe, in the name of
God, inhibit and discharge all ministers to preache, and all ministers
and professors to detracte, speike or wreatt aganist the lait publicke
resolutions and papers of the Commissione of the Generall
Assembley, in order to the calling furth of the people for the
necessarey defence of the causse and the kingdome aganist the
uniust invasione of thosse enimies to the kingdome of God, and to
the gouernment of this kirke and kingdome; ore to spred and
disperse letters, informations, or aney other papers aganist the
same; or in aney other way to obstructe that seruice, tending to the
preseruation and defence of religione, King and kingdome: requyring
ministers to warne ther flockes of thesse papers in generall, and
particularly suche as are most plaussible, insinuating and dangerous;
and wee doe seriously recommend to presbeteries, that with all
vigilancey, they take special notice and trayell of such persons within
ther bounds, wither suche as haue ther station ther, or suche as, in
this troublesome tyme, haue ther present residence, ministers ore
others, and impartially proceid aganist them, as they will be
anssuerable; and to report ane accompt of ther diligence herin to
this commissione, from tyme to tyme.
Thoughe our difficulties be maney and growing, zet quhen wee
looke backe vpone the grate thinges wich God hath done for ws and
for our predecessors, and our manifold deliuerances out of seuerall
dangers and difficulties wich appeired insuperable, experience
breides hope. Our fathers trusted in God; they trusted in him, and
he did deliuer them; they crayed wnto him, and wer deliuered; they
trusted in him, and wer not confounded. Let ws wait vpon him, quho
hydeth himselue from the housse of Iacob; let ws cray wnto the Lord
of Hostis, quho hathe deliuered ws, and doeth deliuer ws; and in
him lett ws trust that he will zet deliuer ws; though for a small
moment he hath forsaken ws, zet with grate mercies he will gather
ws. He quho hath shewed ws grate and sore troubles, shall quicken
ws againe, and shall bring ws upe again from the deipthes of the
earthe; he shall encrease our strenthe, and comfort ws on eurey
syde, aganist our feares one eaurey syde; onlie be stronge, be of
good courage, be of one mynde, and according to the worke of the
Lord, and the God of love and peace shall be with you.
Sic subscribitur, W. Ker.
[20 Martij.]—Ordred that it be putt one the Commissione of the
Generall Assembley, that Stirling receaue no præiudice by Guthrie
and Bennitt, ther preaching, or ther being ther.
[21 Martij.]—Ordred that a barrone and a burgesse goe with the
Earle of Eglinton to the Commissione of the Kirke, and enquyre for
ther anssuer to the quere proposed by the parl: to them.
 [22 Martij.]—The Com: of Generall Assemblies anssuer to the
parliaments quere, reed; being a delay of a full anssuer to the said
quere, wntill ther be a more frequent meitting of the said
commission; zet in ther paper, they desyre the King and parl: to
admitt vpone ther counsells, all bot some few as haue beine pryme
actors aganist the stait, &c.
Saterday, 29 Martij. 14 dies parl: Rege presente.—Ordred that my
Lord Chanceler and my Lord Balcarras draw vpe a letter to be sent
to the Commission of the Generall Assembley, that they wold haist
ther meitting for remouing that obstikelle and scruple of taking in all
remoued by the acts of classis; and that ther may be a generall vnity
in the kingdome.
The anssuer of the Commission of the Generall
Assembley to the paper sent to them for the King
and parliament, concerning Mr James Guthrie and
Mr Dauid Bennett.
Perth, 18 Martij, 1651.
The Commissione of the Generall Assembley hauing receaued first
from Mr James Guthrie and Mr Dauid Bennett, ministers at Stirling,
and afterward from the Kings Maiestie and parliament, tuo
protestations made by thesse brethren aganist the proceidinges of
his Maiestie and the Committee of Estaits with them, in relatione to
the securing of Stirling from aney danger wiche might ensew
therinto, by the doctrine and carriage of the said brethren, contrair
to the present publicke resolutions, in relation to acting for defence
of the kingdome and causse against the publicke enimey; and being
desyred by his Maiestie and parliament to giue ther adwisse and
oppinione, wither the Committee of Estaits, in ther proceiding with
ther brethren, hes done aney thing preiudiciall to the preuiledges
and liberties of the kirke; to vindicat the publick resolutions of kirke
and stait, in order to acting aganist the enemie, from the
imputatione layed therone in the forsaid pretestations; to giue ther
oppinione, wither the Committee of Estaits hes wronged ther
brethren, contrair to the law of nature, the law of God, and the
lawes of the land, by ordring them to remaine at Perth or Dundie,
wntill his Maiesties returne from Aberdeine; that in a more full
meitting of the committee it might be determined quhat should be
done further with them, in relatione to the saftie of Stirling; and
finally, to giue ther adwice quhat now shall be done further to the
presenters of the forsaid protestations, for the securing of the
garisons of Stirlinge. Therfor the commission, hauing takin to ther
consideratione the forsaid protestations, and being informed of the
proceidinges of the committee with the presenters therof, haue
thought fitt, in obedience to the desyre of the King and parliament,
and for the discharge of the trust comitted to them, to giue this
declaratione and anssuers followeth:—
1. That they find it a thing lawfull for ministers, citted and
compeiring befor the ciuile magistrate, vpone matters relatinge to
ther doctrine and carriage in ther ministeriall dewties, to protest,
that ther compirance be with preseruation, and without all preiudice
of the liberties and preuelidges of the kirke and of the ministers of
Christ, in thesse thinges that relate to the doctrine and deuties of
ther ministeriall function; and that the forsaid brethren compiring,
vpone matters of that kind, befor the committee, had no wayes
faylled in doing so, had they contented themselues with a simple
protestation to this purposse.
2. That they doe not find that the Kinges Maᵗⁱᵉ and Committee of
Estaits, in requyring the forsaid brethren to compeir befor them, or
the Committee of Estaits, in ordaining them to stay at Perth or
Dundie, wntill a fuller meitting of the committee, haue not trenched
or incroched vpone the liberties or preuilidges of the kirke, or
wronged the same in aney wayes; for, first, quheras, in the first
protestatione, made vpone the King and committees requyring the
brethren to compeir, and ther compirance, the ground of the
protestation is layed doune to be, that they wer citted vpone a
naratiue relating to ther doctrine and ministeriall dewties, and that
the judicatories of the kirke are the only and competent judges of
thesse thinges. These is so far from evidencing aney incrochment
made by the King and committee vpon the preuilidges of the kirke,
that one the contrarey, as thus layed doune, without aney
qualificatione, it importeth a grate wronging of the iust right of the
ciuill magistrat, as if it wer not proper to him in aney caisse to judge
of thesse matters, which is contrair to the doctrine of the quhole
Reformed Kirke in generall, and particularlie of this Kirke of Scotland;
to witt, that the ciuill magistrat hes power and authoritie, and is
oblidged, in his ciuill and coerciue way, to censure and punishe
idolatrie, schisme, vnsound doctrine, ministers neglecte or
perwersues in doing ther ministeriall deuties and functions: and if he
may and ought to censure and punishe thesse thinges, may he not
citte ministers to compeir befor him, vpone ane naratiue relating to
thinges of that kynd, without encrotching or wronging the liberties
and preuelidges of the kirke?
The Generall Assembley of this Kirke, in Aᵒ 1647, in ther
approbatione of the 8 heades of the 3 propositions, (wich wer
recommended to be examined by the theologicke faculties for a
more particular approbatione of the assembley) holdeth furthe, that
notwithstanding the ecclesiasticke gouerniment is intrusted and
committed by Chryste to the Assemblies of the Kirke, &c. &c. zet the
ciuill magistrat ought to suppresse, by corporall or ciuile punishment,
suche, as by spreding errors or heresies, or by fomenting schisime,
gratly dishoners God, dangerously hurte religion, and disturbe the
peace of the kirke; and the same propositions proposed, holdethe
furthe, that the orthodox kirkes beleiue, and doe willinglie
acknouledge, that eurey lawfull magistrate, being appoynted the
keper of bothe the tables of the law, may, and ought, cheifflie to
take caire of Gods glorie, &c.; as lykwayes, to punnishe als weill
atheists, blasphemers, heretickes, and schismaticks, as troublers of
justice and ciuile peace; and propo: 63, the same sin, in the same
man, may be punished one way by the ciuile magistrat, and ane
vther way by the ecclesiasticke power; by the ciuile power, wnder
the formalitie of a cryme, with corporall or pecuniall punishment; by
the ecclesiasticke pouer, wnder the notion and nature of a scandall,
with spiritual censure, euen as the same ciuill questione is one way
handled by the magistrat in the senat, and ane other way by the
ministrie in the presbeterie. See also the lait Confessione of Faith, in
the head of the ciuile magistrat, and Didoclauius, in his Altare de
primatu regio; and Mr Rutherfurd, in his dew right of presbeteries, is
werey full and cleir; as page 287, A pouer external obiectiue about
kirke matters, as to causse kirkmen doe ther dewtie, is proper to the
magistrat; page 393, in his 3d conclusione, especially 394, The King
is not only to punishe quhat is contrair to externall quietnesse, bot
also quhat is contraire to supernaturall happinesse of the kirke; for
he is to take vengance vpone blasphemers, idolators, profest
vnbeleiuers, neglecte of religious administratione of sealls, and the
eatting and drinking damnation at the Lords table; and page 397,
The King, as a nursinge father, aught to see that the chyldes milke
be good and quholsome, thoughe it come not out of his auen breist,
so that it seimeth werey strange that the magistratts requyring
thesse brethren to compeir vpone a narratiue relatinge to ther
doctrine, &c.; and the alledgeance that the magistrat is no proper
iudge in suche matters, should be made the ground of the
protestation, as if the magistrat could in no wisse lawfully, as a
judge, interposse himselue in matters of that kynd. If to all this the
brethreen should say, that quhat they seike of being citted vpone a
narratiue relatting to ther doctrine and ministeriall dewties, &c. and
the King and committee as not being proper judges in thesse
thinges, as the ground of ther protestatione, they meane it in a way
antecedent to the kirkes judgeing. To this it is ansuered, that it is
trew indeid that the magistrat ought not to judge ministers in the
matters of ther doctrine and ministeriall dewties, by ane antecedent
judgement; bot first, ther is not one sylable of this qualification
wssed in all the first protestatione made vpone the citatione and
compirance befor the committee. Secundo, the committee hes not
proceided with them in a way antecedent to the kirke judicatorey,
quich is the cheiffe thing to be obserued for cleering bothe the
requisition and the committees ordinance for ther abyding in this
toune or at Dundie from the imputatione of incrotching vpone the
liberties and præuilidges of the Kirke; for quheras the Commission of
the Generall Assembley hes not only giuen ther judgment in poynt of
conscience concerning the coursse to be takin for acting aganist the
publicke enimey oppressing the land by wniust violence, bot also
finding that thesse brethreen wer preaching aganist that publicke
resolutione, to the hindring and obstructing therof, and making a
dangerous diuision in the kirke and kingdome; and being desyred by
the last sessione of the parliament to take some coursse for
preuenting the danger, by vssing diligence to satisfie the brethreen,
and inducing them to concurre, at least not to hinder the publicke
resolution. The commission had accordingly, at St Andrewes, takin
paines for satisfing them; and not hauing obteined that, had
judicially desyred the brethreen not to speike or doe aney thing to
the hindering or obstructing acting according to the publick
resolution; and quheras the brethreen had protested aganist that
desyre of the commission, and appealled to the Generall Assembley;
and the commission, according to the command of the parliament,
had made knouen to the Committee of Estaits the quhole proceiding
at St Andrewes: how can it be said that the committee hes takin
aney antecedent judgement vpone them in this matter? or how can
it be sayed that ther hes not preceidit ane antecedent judgement of
the kirke, so far as is sufficient for the magistrat, in ane orderly way,
to interposse his authority, that the brethreen may not, by ther
preaching and doing contrair to the publicke resolution, make aney
diuisione in the kirke and kingdome, or endanger the same, to the
violence of the enimey? Tertio, lett it be considered, that the Kinges
Maiestie being bound to follow, not only the judgement of the
Generall Assembley in maters that concern religione, bot also of the
commissione in the interwalls of the Assembleis; and now, quhill in
prosecution of the aduice of the commissione, he and the estaits are
follouing ane necessarie dewtie for preseruation of the kirke,
kingdome, liberties, liues, and all that is deire wnto ws; and they
find the commissions desyre to thosse brethreen aganist ther
preaching, to the obstruction of the publicke bussines and
resolutions, protested and appealled from, and a publicke profession
made by the brethreen of ther purpois to continew still preaching,
contrair to ther resolutions, to the slakining of the hands of the
people of God in the land, and strenthining of the handes of the
enimey; shall it be judged wnlawfull for the King and the estaits, or
counted ane encrotching vpone the liberties and preuilidges of the
kirke, to doe so much as requyre thosse brethreen to compeire befor
them, or to ordaine them to abyde some tyme at distance from ther
chairge, for restraining this euill, and preuenting so grate a danger
as might ensew vpone it? Nay, certainlie wee cannot bot conceaue it
rather ane adding of the magistrats auxiliatorie and cumulatiue
power, for strenthning the kirke judicatorey. As to that, the brethreen
sayes they haue not bein befor conveined befor aney ecclesiastick
judicatorey, nor conwicted for breache of aney ecclesiastick acts; for
the first, wee say, tho they wer not conveined by a summonds, a
more tender respecte being hade towardes them, yet wer they delt
with by a kirke judicatorey vpone the matter in hand.
And for the second, lett it be considered, if ther publicke
acknouledgement of preaching against the publicke resolution of the
commission, and protestation aganist the commissions desyre to
absteine therfra, and professed resolutione to continew therin, to the
dewyding of the people of God in this land, and obstructing the
seruice for defence of the kingdome and causse, be not equivalent.
Tertio, The commission does find that the brethreen, in ther first
protestation, renewed and owned againe, in the quhilke they make a
profession of ther willingnes to render a resson for ther wretting to
the commission, &c. a foull and most wniust aspertione to charge
the commissione in going in a contrarietie to the word of God, to the
soleme leauge and couenant, our wowes, engagements,
declarations, fastinges, in a coursse destructiue to the couenant and
causse of God, and prouoking of the eyes of the Lordes glorie.
2. The chairge is most wniust, for how shall it be made out that
the resolutione of the commission involued a coniunctione with a
malignant partey, wiche alledgeance is the fundatione of all the rest?
Does not the resolutione of the commissione expressly except suche
as continew obstinat enimies to the couenant and causse? that is,
suche as continew in malignancey, or are aney quho haue beine one
malignant coursses, admited to our knowledge, or with our
approbatione, bot suche as giue satisfaction for ther offence; and
how can or aught men, renuncing ther malignancey, satisfing for
ther offence, giuing therby, according to the ordinances and reuells
of the Generall Assembley, be still reput malignants? and how can a
coniunction with them, after suche satisfactione, be counted a
coniunction with malignants, or the malignant partie? Quhay should
the Gen: Ass: prescriued reuells for receauing such as haue beine
vpone malignant courses, if the purposse of the kirke was not to
admitt them to repentance, and if to repentance, certainly to all the
ordinances; and if to ordinances, quhat shadow of reason can ther
be not to admitt them to fight for ther liues, religion, King and
countrie? especially one of the particulars prescriued in receauing of
them, be the renewing of the leauge and couenant, wich layeth
vpon them to defend religion, &c. all persons that hes beine in a way
of malignancey, will ather satisfie not. If they satisfie according to
the acte of the Assembley, they must reneu the leauge and
couenant, and be admitted to the ordinances; and so, by far grater
resson, to fight in defence of the kingdome, &c. If they satisfie not,
(as they will neuer be accounted to satisfie by the commissione,
wnlesse they doe it according to the reuells of the assembley,) they
are to be excommunicat, and so are excludid by the resolutione of
the commission.
Tertio. This aspertione heire is cast vpone the commission vithout
aney necessity; ther protestatione wold haue beine full and compleit
aneuche, tho nothing of this had beine insert; for quheras the letter
of the King and committee sent to the brethren, requyring them to
compeire at Perth, makes relatione to ther wretting a letter to the
commission contrair to the publicke resolution, and ther protesting
against, and appealling from the commission at St Andrewes, (in
order to wich relatione, the brethreen takes occasion to insert all this
protestation,) that was not intendit as a matter they wer to be
challenged vpone by the Committee of Estaits, bot only sett doune
as a ground quhervpone the committee perceaued they wer
resolued to continew in ther preaching aganist the publicke
resolution; and that therfor the committee behoued to see to the
securing of Stirling, from the danger wich might ensew vpone ther
protestation; bot to cast ane aspertion vpone the commissione, in all
papers that should flow from them, vpone the proceidinges of the
kirke and estaits with them.
Quarto. That wee not being judges in ciuile matters, cannot
determine wither the Committee of Estaits, in ther order of
proceiding with the brethren, and ordaining them to abyde at Perth
or Dundie, wntill a fuller meitting of the committee, hes wronged
them in aney preuiledge dew to the subiects, by the law of nature
ore the lawes of the land; and wee doubte not bot the Committee of
Estaits will endeuore to cleire ther auen proceidinges.
 Quinto. That nather is it competent to ws to giue ane adwysse
quhat should be furder done by the King and committees in relation
to ther forsaid brethreen, for securing of Stirling from the danger
that may ensew vpone ther opposing the publicke resolutions; onlie
wee expecte, and are confident, that his Maiestie and estaits, as
they haue begune, so they will continew to deall with thesse
brethreen with all tendernes, in sua far as may consist with the
security of that place wherin they shall be, and preseruation of the
causse and kingdome.
Sic subscribitur, A. Ker.
1 Maij.—The parliament that wes adiorned wntill the 17 of Apryle
this zeire, wes adiorned againe wntill Wedinsday, the 21 of Maij.
In Apryle, this zeire, the Commiss: of the Generall Assembley mett
at Falkland; they wrett letters to the Committees of Estait and for
the Armey, that they wold now leaue the particulare intrests, and
joyne cordially aganist the publicke enimey, and emitted a
declaration for that purpois; and appoynted a meitting at Stirling,
one Tuesday the 13 of Maij, to giue their oppinion anent the
lawfulnes of the acte of classis, and if without sin it might be
reschindit or not.
The 6 of Maij, ther was a grate meitting of the Committee of
Estaits at Stirling, quherin the electing of the Earle of Calender to be
Felte Marishall of the Armey, that had now ioyned himselue to the
Campbells, wes waued and putt offe; and 2 Generall Maiors of
Footte chosen, viz. Collonell Pitscottey, and Dalzell of Binns. At this
meitting, lykwayes, it was ordained that the Committee of Estaits
shoulde not medle with the adiorning of the parliament, wntill the
20th of Maij instant, at wich tyme ther was a frequent meitting of
the said committee appoynted; and then the Commission of the
Generall Assembley wold present ther oppinion anent the acte of
classis....
Oliuer Cromwell, with his armey, being at this tyme in Glasgow,
had a conference with 8 ministers, anent the lawfulnes of his
engagement aganist this countrey and kingdome; he gaue them
some papers, wich they anssuered ex tempore, and proued to his
face his periurey and breache of couenant and leauge, and his sinfull
rebellion and murther, contrair to [the] expresse word of God, and
leauge and couenant suorne by himselue and most of his complices.
He toke the morrow at 3 in the afternoone to his furder conference
with them; and maney of his cheiffest officers did openly
acknouledge, they were conuinced in reson, and neuer till now did
see the weeknes of ther auen grounds. In place of keiping the
appoynted meitting, (seing a fyre to begin to kindle amongest his
auen) aboute midnight that same day, he commands all his armey
presently to marche, wnder the paine of death, backe towardes
Edinbrughe; and empties all his garisons be west Linlithgow; sends
his horses towardes the Border, and with grate haist, with his footte,
returns to Edinbrugh and Leith; and is now bussie in repairring the
breaches of Edinbrughe castle.

Mr Robert Blair, his animadwersions one the remonstrance emitted

by the vesterne forces, Octob: 1651.
Ther is no questione maney sade truthes ar layed doune in the
remonstrance, vsse quherof wold be made, and remeid therof wold
be sought in a right way; bot wnder the pretext therof to make a
secessione from the publicke counsells and forces of the kingdome,
and to gratifie the wicked inwader of the land, by laing opin the
nakednesse of the reulers, exageratting eurey miscarriage or
appeirance, as if they had bein hyred by our enimies to agent ther
bussines, cannot be bot greiuous to the godlie, quho are not
preocupied with preiudices; and this so much the more greiuous,
that the cuning slight of some malcontents, weill acquanted with
publicke consultations, hath intangled not a few gentlemen, werey
worthey, whosse constancey in the causse of God is weill knowen.
The continuers and penners of this peice, perceauing quhat strange
and vnbeseiming language they wer wttering, saw it necessarey to
take away maney obiections that lay in ther way; and that both in
the entrey and closse therof, assining that successe had not altered
ther mynd. That they iudge not themselues free of the causes of the
prowoking calamities. That in vttering thesse thinges, they haue not
beine led with the spirit of bitternes ore desyre to discouer the
nakednes of wthers; and that they haue not the least deseinge to
follow the foottsteps of the sectarian partie, they may weill say (I
mein the continuers of the remonstrance) they had not the least
dessinge; for in that essay they haue out-acted the sectaries. Thesse
men did much in order to publicke good, befor they spake biglie; bot
done nothing since, saue that they haue drawin away considerable
forces, raissed at wast charges for the publicke defence. This
speaketh nothing lesse then abandoning to carrie one ther deseinge
in the last wordes of ther paper; and that ther discoursse may be
the more taking, they put one the persons of thesse quho are
speaking ther last wordes, being zet far eneuch from all danger. It is
hard to aney man to judge with quhat heartes and intentions thesse
things wer contriued. I speake not of the gentlemen and ministers
quhom I durst absolue; bot of the proiecters and penners of this
remonstrance. Bot lett ther auen spiritts judge, if the most reall and
cordiall enimies our causse had, wold haue acted wtherwayes, to
pour contempte one ws, and to heatin wndertakings against ws. Iff
ze be all constant in the causse, quhat meinethe the loud bleatting
queries sent to our aduersaries, ane odious cryme, audacious to
priuat persons to correspond withe ane opin enimey, quho haue
shed the blood of Gods people, and receaue anssuers to the same?
Iff this concearne not them all, how is it that they quho are constant
and faithfull, declaire not against suche quho haue falsified ther
trust, and quheat ther tounge against King and committee, quhom
they should obey in the Lord?
17 Julij.—Cromuell past ouer a grate pairt of his armey from
Lothean to Fyffe one Thursday the 17 day of Julij, 1651, at the
neucke below the Queinsferrey, and fortified himselue one the hill
betuix the Ferrey and Innerkethen. He landit without aney
oppositione at all in effecte.450
 3d September.—K. Charles the Seconds armey wes routted and
defaitt at Worchester, in England, one Wedinsday the 3d of
September this zeire.
* * * *
Mercurius Scoticus, his diurnall to the 28 of Octob: hes in it this
passage anent the laitt meitting of the remonstrant ministers at
Edinbrughe, this same mounthe:—The meitting of the ministers at
Edinbrugh is dissolued; ther was 66 of them in all. After they had
made a kynd of auricular confession, eurey man for his auen sinns;
some for idolizing the couenant too muche, others for complyance
with the King, &c. ther pryde, ambitione, and other sins, they haue
dissolued; and haue sent some of ther nomber to Glasgow, quher
they intend a prouinciall meitting, in a judiciall way, and will emitt
some declaration or warning. They are werey muche troubled they
cannot haue that power in ciuill thinges, in ordine ad spiritualia,
wiche they wer wount to haue in this natione; wnder wiche
pretence, they gett all ciuell pouer quhatsomeuer in ther handes....
In Nouember this zeire, the ministers of the west, that had made
and still manteined a werey grate schisme in the churche, and
disawoved the last Generall Assembley, holdin at St Andrewes and
Dundie, sett out at this tyme a pamphlett called, a Discouery after
some search of the sinnes of the ministers; wich is dewydit in 9
sections, and printed in Aᵒ 1651, by the brethren of the presbytery
of Kilmarnock. Thir westland renters of the churche held a meitting
at Edinbrughe, about the letter end of this mounthe, by the name of
the Commissione of the Kirke; the pryme actors in it wer the tuo
fyrebrands, Mr James Guthrie and Mr Patricke Gillespie, both of them
depriued by the lait General Assembley at Dundie; to quhom,
amongest maney other of the lyke nature, wes presented by a godly
brother, (as they name him,) this famous paper, consisting of 12
heads:—
1. Our soleme ingagements to dewties, ather out of dark zeall or
policy; and it is conceaued much of both thesse will, after deepe
searche, be found in al our couenant ingagements.
 2. The taxing of ourselues, by soleme couenants and othes, to the
perpetuall mantinence of some thinges for wich ther is no warrant
from the word: as perpetuall adherence to monarchy in such a line,
and constant mantinence of the priuilidges of parliament; at least
the clauses of our taxes thesse thinges so ambigously conceaued,
that maney sueare them in the formentioned sense.
3. A fleschly zeall and policy in pursewing and carring one the
couenant and leauge by creuell oppressions, making actes for
constraning all sortes of persons, als weill men of tender consciences
as the most prophaine and grosslie ignorant in the land, to take the
couenant, wnder the hazard of incurring the heighest censures both
of churche and stait.
4. Our preiudices; and that vpon our passinat and bitter
invections, by word and wreatt, publicke and priuat, aganist suche of
the people of God in England, quho had some differences of
judgment from ws, not vsing the gospell way alloued by God for
gaining others, houever carried away with errors; and therfor in the
grate justice of God, his people in the land, quho wer formerlie one,
are now so far dewydit in judgments and affections, that grounds of
persecutione are layed doune and begune by the one aganist the
other.
5. The espousing of the malignant quarrells, not only by our own
coniunction with, and intrusting the malignant party, bot also by
intending and concluding a trettey with the Kinge, putting him in the
actuall exercisse of his power, and owning his intrest, albeit all the
tyme of the trettey, and after it als weill as befor it, he did palpably
euidence his disaffectione to the couenant and endes therof; wherby
it hath come to passe, that the quarrell wich the Lord did formerly
plead aganist the King, seimeth to be now tabled at the dore of
churche and staite.
6. The pollutting of the Lords housse and ordinances, by
continuing the vilest of men to be churche members, and to partake
of the holy ordinances of Jesus Christ; so that all the people of the
nation are members of the Churche; quherby the churche of
Scotland is become lyker to a feild of thorns and briars then the
wyneyaird of the Holy One of Israel. Nather could the remoueall of
persons scandalows from a sacrament (wich also is much neglected,)
be a sufficient remedy of this euill, seing beare negatiues are not
sufficient to putt a man in a capacitie to be a churche member,
muche lesse to partake of the sacraments; but besydes are requyred
positiue euidences of grace, so far as to ground a judicious
judgement of charity: and from this error of the actuall constitutione
of this churche flowes the sinfull coniuctions with the malignant
party in counsell and armies; for how can thosse, vpone aney
groundes of conscience, be debarred from ciuill fellowschipe, quho
may and ought to be admitted to churche fellowschipe? and therfor,
though our disease may be skinned, zet neuer cured, till the present
constitutione of the churche be helped.
7. The idolizing of men, and receauing doctrines from them
implicitly, not bringing them to the ballance of the sanctuary:
ministers medling with ciuill affaires, both in priuat and judicatories,
quherby they lord it ouer the estaites, and tyranized ouer the
consciences of men; though it is not denayed bot they may and
ought to reproue sin, and that in all sortes of persones, so far as
they haue varrant from word of God.
8. Our not cleiring, bot wreasting the trew staite of the quarrell,
with a vilfull reiecting of all meines for prewenting the sheding of
blood; whill treaties and conferences were not only requyred, bot
refussed, though desyred and offred by the Englishes; throughe
wiche it appeirethe, that the guilte of much blood shed in the lait
warre, may be justly layed to the charge bothe of kirke and stait.
9. The smothring of light, and withdrawing from dewties, wpone
the apprehensione of said euents.
10. Pitching vpone our forme of presbyteriall gouerniment, as the
vtermost attainable perfectione of reformatione.
11. The grate neglecte and creuell oppression of the comons and
poore people of the land, neuerthelesse of our obligations and tayes,
in the couenant, of mutuall aid and assistance one of another.
12. Laboring to carrey one a worke of reformation with so
corrupte and vnsuttable instruments; yea the continuance of persons
scandalous, in eminent places of trust, after ther was cleir euidence
that they wer suche.
1652.
This day, (viz. Friday) 2do Jarij: did brecke vpe the meitting of
some presbeterians, who did meitt at Edinbrughe, in reference to
the satlement of present affaires. It was composed of them quho
[are] called ministers and laymen, quherof Mr James Guthrie was
moderator; who, as he was chosen to moderat, so in his olde
wounted presbeterian zeall wold proceed in nothinge, till first he
knew wither aney wer present who wer accessorey to the sheding of
the blood of the saintes. Quasi wero, he had bein free of aney such
thing; thoughe most instrumentall in drawing one ane ingagement at
Dumbar, he may remember his accession to his spilling of blood at
Hamilton; bot wee know the pharisies can bewaill the death and
suffringes of the prophetts, thoughe apte to persecute Christe and
his disciples. It is remarkeable, this meitting was not called without
cuninge, for wpeholding the presbeterian intreste. The matter is this;
about 8 weekes agoe and aboue, some godlie and weill affected
men in this land, taking a coursse (besyde the preists not heeding
them in the bussines) in order to the good of the nation, vith no
lesse purpois then to remonstrat and petitione (quhosse
proceidinges as zet wee houpe shall take effecte) aganiste coerciue
restrainte, and for incorporatting the tuo nations into one comon
wealthe. Bot the presbeterian ministers, with ther grandee,
Wareston, finding this præiudiciall to ther crafte, Demetrius lyke,
called togidder such as wer of ther auen stampe; cuningly breking of
the meittinges of thosse quho intended to bring to naught ther
crafte, in making siluer shrynnes for ther presbeterian Diana, did
withdraw themselues altogider from suche meittinges: the result of
wich is confusione; for nothing is now to be hard after this
conuocatione, bot craying out, “Grate is the Presbetery.”
 Now they haue drawin vpe a letter, thoughe with grate debait, not
knowing weill to quhom to send it, ore how to call thosse to quhom
they should directe it, and are aboute to send it to the Generall;
testifing aganist all our proceidinges, and with a full pretence (I
should say, purposse) of suffringe, doe earnistly bege religion in
Scotland may be preserued, and established according to the
couenant, wich in ther accompte is nothing bot presbeterey. Marke
ther ingenuity; they resolue to suffer, and zet wold haue pouer to
persecute. Werily, I thinke, they are justly sufferers, quho goe
aboute to be persecutters. In the interim, I supposse they shall not
receaue a satisfactorey anssuer in petitioning him (viz. Cromwell)
aganist quhom they testifie; this bewrayethe ther policey, thoughe
presbeterey be wsullay attendit therwith. Howsoeuer, as they
conueined cuningly, with a full purposse to manteine their crafte,
that ther idol presbeterey perishe not, so they are dismissed
confusedly, craying out, “Grate is the Presbeterey.” We haue only to
adde to it that Warrestone, in face of the meitting, contrarey to
experience, with a full purposse to deceaue the simple, (Ex vngue
Leonem) denayed aney trettey to haue beine offred by the Englishe,
befor Dumbar, to the Scotts. Bot wee know it is a Matchiuelian
policey, fortiter calumniarij.
 1652.

Acts of the Assembly 1652, and other Documents,

extracted from the Controversial Pamphlets of the
Time, but never recognised or printed among the
Acts of the Church since the Revolution.451
 No. I.

Propositions which were offered to the Meeting of

Ministers and others, appointed to be keeped at
Edinburgh, July 21, 1652.

Wheras we, and many of the godly in the Land have been really
scandalized and stumbled at their late Acts and Proceedings, relating
to Publick Resolutions concerning the same in the nature and
Intention of the Work, to have obstructed and shaken the Work of
Reformation, (although we think honourably of diverse Godly and
Learned men who have been concurring in the same, and dare not
judge their Intentions to be such as we think their Work hath been,
and do allow charity to others.) Therefore for satisfaction of our
conscience, and for securing the Work of Reformation, for purging
the Church, and for promoving the power of godlinesse, and for
removing of these sad differences, and for attaining and preserving
a good understanding, We desire,
That they give evidence and assurance, that they approve of, and
will adhere unto the solemn Publick Confession of sins and
engagement to duties, and all the Acts of the uncontroverted
Assemblies of this Church, concerning the Work of Reformation, in
the literal and genuine sense and meaning thereof. And that in
dispensing of the Ordinances, censuring of scandalous persons,
receiving of Penitents, trying, admitting, removing, and deposing of
Church-Officers, they will walk according to the same. That it be laid
seriously to heart before the Lord, how after such a defection, and
so sad judgments for it, the Lord may be restored to his honor, the
Land to his favor, and the like defection prevented in time coming.
That as we are ready to our station, to follow all religious and
conscionable means and Overtures for securing and guarding the
Cause and Work of God against Error, Heresie, and Schism on the
one hand, so they would hold out to us a solid way for securing the
same against dangers from Malignancy on the other. And we would
know what shall be the Characters in time coming, by which
Malignancy may be known and judged.
That a reall and effectuall course be taken, according to the
established rules of this Kirk, for purging out, and holding out all
such Church-Officers as have not the Position, and qualifications
required in the Word of God, and Acts of this Kirk, particularly, where
Ministers deposed by lawfull Assemblies, have intruded themselves,
or have been unwarrantably restored by Synods and Presbyteries to
their Charges, contrary to the form and order prescribed in the Acts
of Assemblies, be removed, and condign censures inflicted, and that
sufficient Provision be made for preventing the like in time coming.
That after means be fallen upon and followed for censuring of all
scandals and scandalous persons, and casting out of these who shall
be found grosly and obstinatly scandalous or ignorant, after they are
made inexcusable by sufficient means and pains taken for their
instructing and reclaiming.
That some course more effectuall than any hath been fallen upon
hitherto, may be condescended upon, for putting in execution the
Acts of this Kirk, anent debarring from the Lord’s Table such persons
who are found not to walk suteably to the Gospel, and have not
knowledge to examine themselves, and to discerne the Lord’s Body.
That in the receiving of Penitents, care may be had that none be
admitted to the publick Profession of repentance, or reconciled to
the Church, but these who are found to give such evidence of their
repentance, as is exprest in the Acts of the Assemblies, concerning
the receiving of Penitents.
That an effectual course may be taken for securing of the Work
and People of GOD from the harm and evill consequences which
hath already, and may further ensue from the late pretended
Assemblies at S. Andrews and Dundee, and the Acts thereof.
 No. II.

Reasons why the Ministers, Elders, and Professors,

who protested against the Pretended Assemblies
at St Andrews, Dundee, and Edinburgh, cannot
agree to the Overtures made unto them at the
Conference, upon the 28 and 29 of July, 1652, &c.

Albeit the Essayes and Endeavors which were used by us, before
our coming hither, for removing of Differences, and attaining of
Union and Peace, upon such grounds as might (indeed) bring forth a
discovery of our, and the Lands Sin, and contribute for removing the
guilt thereof, and for securing and promoving the Work of
Reformation amongst us, might in a great part have acquited our
consciences, and cleared us before the world; yet the deep sense
that we had of the many and great prejudices which do ensue to the
Work and People of God, by our continued Divisions, and our ardent
desire of Peace and Union, upon the grounds foresaid, constrained
us to lay hold upon the opportunity of your meeting together at this
time, and to represent unto you, some necessary and just
Propositions, as a fit subject of our conference; and that we were
willing to hear what should be offered by you to us, in order to these
ends; and, that therefore you would forbear to assume unto your
selves the power of, or constitute your selves into a Gen. Assembly.
And when we found this ineffectual, and our Union rendred more
hopeless, by your denying a desire so just and reasonable, and so
agreeable to the practice of former Assemblies, as was instanced
before you by these who knew the records: Nevertheless upon a
surmise of a purpose in you to confer with us, we did for divers
dayes wait upon you, being desirous to have seen upon your part,
some serious applying of your selves to the real means of healing,
and to have found solid satisfaction unto the things contained in the
Propositions offered to you by us: But in place of this, the Brethren
who were appointed by you to confer with some of our number, did
intimate unto us, that all which they had in Commission to make
offer of, was, That ye were willing to take off the Censures inflicted
by the former Assembly at St Andrews and Dundee, and the
Censurableness that persons, who have transgressed against the
Acts thereof might be liable unto: Providing, that these Brethren
censured, and deserving Censure, should pass from their
Protestation against the former and present Assemblies, and
judicially before their Presbyteries and Synods, engage themselves
under their hands, not hereafter to deliver their Judgments in
Preaching or Writing, or any way else to hold up the late differences.
Which Overture when it was earnestly desired by these of our
number to be given to them in writing according to their
Instructions, not only because it was divers wayes represented by
such of your number as did confer with them, but also that they
might the more perfectly and better understand the same, and be
able to make an exact report thereof to these who sent them, and
mistakes thereupon might be Prevented: It was most peremptorily
refused, albeit most earnestly urged and desired during the whole
time of the Conference: Therefore having set down the same as
truely and impartially as our judgments and memories could attain;
We do for our own vindication, and satisfaction of others, give these
Reasons following, why we cannot accept thereof.
“I. Because there is hereby no remedy at all offered for the course
of defection involved in the Publick Resolutions, nor for preventing
the like for time to come, which is the main ground of difference;
but upon the contrary we are required upon the matter to retract
our Testimonies thereanent, and judicially to give Bonds and
Engagements hereafter to be silent concerning the sin and guilt
thereof.
“II. Because our passing from our Protestation doth import a real
acknowledgement of the lawfulness and freedom of the Assemblies
in regard of their constitution, and of power in them to inflict and
take off Censures, and so by our own consent, doth not only retract
and condemn the testimony which we formerly gave against the
same, But also obstructeth the remeading of what is past, and the
attaining a lawful, free, General Assembly for the time to come, and
so wreaths about our own neck, and the necks of the Lords People,
the yoke of unfree, corrupt, and unlawful Assemblies.
“III. Because the offer which is made, though it contains
Immunity in regard of these who have not acquiesced unto, or
opposed these Acts for the time past, yet the Acts of themselves do
notwithstanding thereof, still stand in force, as a ground of
persecution against all these Ministers and Professors, who shall not
accept of the conditions contained in this offer, or thereafter fail in
performance of the same.
“IV. Because this offer is so far from reaching satisfaction to all, or
most part of the Propositions offered by us, that it doth not give
satisfaction to any one of them, but pitcheth upon a particular, which
ought to be of least consequence with us, (as importing but our
personal suffering) without taking notice of the Lands defection, and
of those things which do concern the Kingdom and Interest of Jesus
Christ, and the purging of his House; and what a sin and
provocation should it be against the Lord, and what a stumbling and
grief of heart unto the godly who have concurred in these
Propositions, and after such a defection, do expect repentance and
reformation, and the purging of his House of corrupt Officers and
Members, if we should make such a transaction, as seems to
promise present security to our selves, but doth not contribute for
preserving of the Truth, and attaining a solid Peace and Union in the
Lord.
“V. We cannot see how the passing from these Propositions, and
the taking upon us such Engagements for the time to come as are
desired, should not involve us in the condemning of our own
judgments, and in the acknowledgment of a sin and offence in
making these Protestations, and bearing testimony against the
Publick Resolutions, and import that what is done by you in taking
off of Censures and censurableness (as you term it) is an Act of
meer favour and grace upon your part, unto Delinquents, upon their
repentance. And though we hope that we shall never be ashamed,
but esteem it our mercy and glory to acknowledge any thing
whereby we have provoked the Lord, or offended others, yet being
more and more convinced in our consciences, that what we did in
these things was a necessary duty, we dare not purchase immunity
and exemption from Censures at so dear a rate, as to deny the
same, we shall rather choose still to be sufferers, and to wait upon
the issue that the Lord shall give, then to provoke the eyes of his
Glory, grieve the spirits of his People, and wound our own
Consciences, by so unsatisfying and so sinful a transaction.”
And conceiving that, we shall not have the opportunity to speak
unto you hereafter, as being now about to dissolve our Meeting; We
do from the zeal that we owe to the honour of God, and from the
tender respect we owe to you as Brethren, and for exonering our
own Consciences, most earnestly beseech and obtest you, by your
appearing before the Lord Jesus Christ, to give your selves unto
Prayer, and searching of your own hearts and way, in Order to
Publick Resolutions and Actings, untill each of you finde out wherein
ye have turned aside from the straight way of the Lord, and
imployed your gifts and power not for Edification, but for grieving
the spirits of many of the Godly, and strengthening of the hands of
the wicked, and to Repent thereof, and to do no more so, least
wrath be increased from the LORD, the Godly of the Land more
offended, and our breach made wider, and our wound more
incurable. If both you and we might obtain mercy of the Lord to
know our trespasse, and why he contends, and to accept the
punishment of our iniquity, and humble our selves before hime, who
knoweth but that he might yet have compassion upon us, and
pardon our sins, and heal our Land.
 July the 28. Ante merid. 1652.

Mr Andrew Cant, Mr Samuel Rutherford, Mr James Guthry, My

Lord Waristoun, Mr Robert Trail, Mr John Nevay, Mr James Nasmith,
being nominated to meet and confer with some Brethren, Members
of the present pretended Assembly, the Instructions following were
given them, and the Meeting doth require and expect, that they will
walk according thereto.
I. That they shall declare to the Brethren with whom they are to
meet, That as they do adhere to the Protestations formerly and
lately given in, so they do protest, that they do not meet nor confer
with them, nor receive any Papers from them, as being in the
capacity of Commissioners of a General Assembly, but onely as sent
from a meeting of Ministers and Elders, Wanting any such Authority.
II. That whatever be offered by the Brethren with whom they do
confer, they desire to get it in writing from them, as the mind of the
Meeting whereof they are Members; That it being communicated to
us, Answer may be given thereunto by our whole Meeting.
III. That they do not engage in Conference with them at first
about the matter of Censures; It being neither the chief nor only
ground of our grievance; and because with us things of that nature,
and any thing of personal concernment, ought to be of the smallest
value, while there are many things in question betwixt them and us,
of far higher consequence to the Kingdom of Christ and his Interest,
as anent the causes of Gods controversie with the Land, and the
way of remedy and cure of the former and late defection, and the
way of preventing the like in time coming. The establishing and
promoving the Work of Reformation, and the purging of the Kirk,
and the like, as are laid before them in our Propositions given in to
their Meeting; And that they do intimate to the Brethren foresaid,
that we cannot look upon an offer relating onely to the Censures,
upon some of our number, as satisfaction to them or us, and that
(besides what we have said) for other reasons to be communicated
in due time to their Meeting. And that therefore they shall offer to
these Brethren, and desire of them, that if there be any Conference
at all, the subject matter of it may be upon the whole Propositions in
the order as they stand.
IV. That in case of their refusing the latter part of the former
Article, they shall require and demand from the Brethren of the
other Meeting, That they would declare whether we may expect,
that these from whom they were sent, will either by the said
Brethren, or any other way, give answer and satisfaction to us anent
the Propositions, and what is their sense and meaning of the Publick
Resolutions, and anent the Constitution, Acts, and Proceedings of
the Meeting at Dundee, and of this at Edinburgh, and what they
minde to do in reference to the same.
V. That in case there be not satisfaction obtained in these so just
and necessary things, They do professe their own and our dis-
satisfaction with any thing that hath been offered by them to us, or
answered to our desires first or last. And that they protest for
themselves and us, That as we have sought Peace, and pursued it
by all lawfull and possible means, though much in vain on their part.
So we are henceforth free from the guilt and blame of the sad
prejudices and evil consequences whatsomever, which may follow
upon their present way, and their former and future actings of that
nature, so contrary and destructive to Edification and Peace.

Right Reverend,
We have now for these fourteen dayes past, been imployed in
using our best endeavours, and waited for Overtures from you, for
healing the breach, and, removing the differences that are amongst
us; And now there being no ground of hope given us, nor any desire
made unto us for continuing the Conference, whereby a better
understanding might be attained, We have thought good before our
parting from this place, to send unto you this inclosed Paper,