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 SECON D E DITION

Manual of
Hypertension
of the European Society of Hypertension
EDITED BY
Giuseppe Mancia • Guido Grassi • Josep Redon
SECON D E DITION

Manual of
Hypertension
of the European Society of Hypertension
SECON D E DITION

Manual of
Hypertension
of the European Society of Hypertension
EDITED BY
Giuseppe Mancia , Professor
University of Milano-Bicocca, Istituto Auxologico Italiano, Milano, Italy

Guido Grassi , Professor

Director of Clinical Medica Department of Health Science,
University of Milano-Bicocca, San Gerardo Hospital Milan, Italy

Josep Redon , Professor

Scientific Director INCLIVA Research Institute
University of Valencia, Spain

Boca Raton London New York

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 Contents

Prefacexi
Contributors  xiii

section 1: Background, History, and Epidemiology

1. Epidemiology of Hypertension 1
Renata Cífková

2. The Total Cardiovascular Risk 13

Claudio Borghi, Arrigo Francesco Giuseppe Cicero, and Ettore Ambrosioni

section 2: Associated Risk Factors

3. Classical and New Risk Factors 21
Manolis S. Kallistratos and Athanasios J. Manolis

4. Pulse Pressure as a Cardiovascular Risk Factor 29

Athanase Benetos

5. Clinical Significance of High Heart Rate in Hypertension 35

Paolo Palatini and Guido Grassi

6. Obesity and Obstructive Sleep Apnea 47

Marzena Chrostowska, Anna Szyndler, Jacek Wolf, and Krzysztof Narkiewicz

7. Diabetes Mellitus 61
Peter M. Nilsson

8. Stress-Related, Psychosocial, and Other Risk Factors in the

Hypertensive Patient67
Philippe van de Borne
 vi Contents

9. Blood Pressure Variability: Methodological Aspects, Physiology, and

Clinical Implications 73
Gianfranco Parati, Juan Eugenio Ochoa, and Grzegorz Bilo

10.
Antihypertensive Treatment Strategies 93
Giuseppe Mancia and Peter A. van Zwieten

section 3: Etiological and Pathophysiological

Aspects
11.
Hemodynamics of Hypertension 101
Per Omvik and Per Lund-Johansen

12.
Genetic Basis of Blood Pressure and Hypertension 115
Sandosh Padmanabhan, Mark Caulfield, and Anna F. Dominiczak

13.
Structural Cardiovascular Changes in Hypertension 129
Harry A.J. Struijker-Boudier

14.
Impaired Autonomic Cardiovascular Control in Hypertension 135
Guido Grassi, Gianmaria Brambilla, Raffaella Dell’Oro, and Gino Seravalle

15.
The Renin–Angiotensin–Aldosterone System 141
Ulrike M. Steckelings and Thomas Unger

16.
Etiological and Pathophysiological Aspects of Hypertension:
Other Humoral–Endocrine Factors 149
Michel Burnier

section 4: Target Organ Damage:

Measurements/Clinical Importance
17.
Cardiac Damage and Progression to Heart Failure 159
E. Agabiti Rosei, M.L. Muiesan, and R.E. Schmieder

18.
Brain Damage 177
Cristina Sierra and Antonio Coca

19.
Large Artery Damage: Measurement and Clinical Importance 191
Stéphane Laurent and Michel E. Safar

20.
Small Artery Structure and Function in Hypertension 203
Anthony M. Heagerty, Sarah B. Withers, Ashley S. Izzard,
Adam S. Greenstein, and Reza Aghamohammadzadeh
 Contents vii

21. Endothelial Damage: Measurement and Clinical Importance 211

Lorenzo Ghiadoni, Agostino Virdis, and Stefano Taddei

22.
Renal Damage and Hypertension: Mechanisms of Renal End-Organ
Damage223
Hermann Haller

23.
Retinal Changes in Hypertension 229
Martin Ritt, Enrico Agabiti-Rosei, and Roland E. Schmieder

section 5: BP Measurements and Other

Diagnostic Procedures
24.
BP Measurements and Other Diagnostic Procedures 237
Jean-Philippe Baguet, Jean-Michel Mallion, and Denis L. Clement

25.
Blood Pressure Response to Acute Physical and Mental Stress 249
Robert Fagard and Guido Grassi

26.
Central Blood Pressure 257
Cristina Giannattasio and Stéphane Laurent

27.
The Diagnostic Approach in Uncomplicated and
Complicated Hypertension  269
Athanasios J. Manolis and Costas Tsioufis

section 6: Therapeutic Aspects

28.
Blood Pressure Targets of Antihypertensive Treatment 277
Giuseppe Mancia and Guido Grassi

29.
Interventional Trials in Hypertension: What Have We Learned and
What Remains to Be Learned? 283
Alberto Zanchetti

30.
The Nephroprotective Effect of Antihypertensive Treatment 293
Luis M. Ruilope and Julian Segura

31.
Nonpharmacological Interventions 299
Stefan Engeli and Jens Jordan

32.
Medical Treatment of Hypertension: Monotherapy and
Combination Therapy309
M. Burnier, G. Wuerzner, and B. Waeber
 viii Contents

33.
Emerging Antihypertensive Drugs 319
Massimo Volpe and Giuliano Tocci

34.
The Polypill 329
Marie Briet and Michel Azizi

35.
Invasive Procedures 337
Roland E. Schmieder

section 7: Special Conditions

36.
Clinical Management of Patients Presenting with Hypertension and
Peripheral Artery Disease 351
Denis L. Clement

37.
Resistant and Malignant Hypertension 357
Josep Redon, Fernando Martinez, and Gernot Pichtler

38.
Hypertensive Emergencies and Urgencies 367
Cesare Cuspidi and Achille C. Pessina

39.
Secondary Hypertension: Diagnosis and Treatment 373
Peter W. de Leeuw

40.
Hypertension in Diabetes Mellitus 383
Peter M. Nilsson

41.
Hypertension in Children and Adolescents 395
Empar Lurbe

42.
Hypertension in Pregnancy 405
Renata Cífková

43.
Posttransplant Hypertension 415
Martin Hausberg and Karl Heinz Rahn

44.
Hypertension in Patients with Renal Parenchymal Disease,
Chronic Renal Failure, and Chronic Dialysis 423
Jose L. Rodicio and Jose A. García-Donaire

45.
The Metabolic Syndrome in Hypertension 433
Josep Redon, Fernando Martinez, and Maria Jose Fabia

46.
White-Coat and Masked Hypertension 443
Robert Fagard

47.
Secondary Prevention of Stroke 449
Miguel Camafort, Monica Doménech, and Antonio Coca
 Contents ix

48.
Hypertension and Atrial Fibrillation: Modern
Epidemiologic, Pathophysiologic, and Therapeutic Aspects 457
Athanasios J. Manolis, Leonidas E. Poulimenos, and John B. Kostis

49.
Management of Perioperative Hypertension 467
Paul E. Marik

section 8: Economic and Organizational Issues

50.
Pharmacoeconomic and Cost–Benefit Aspects 473
Ettore Ambrosioni and Claudio Borghi

51.
How to Organize and Run a Hypertension Center 479
Csaba Farsang and Margus Viigimaa

section 9: Current Problems

52.
Blood Pressure Control in Europe 483
Bernard Waeber, François Feihl, and Giuseppe Mancia

53.
Hypertension in the Very Elderly 497
Nigel S. Beckett

54.
Hypertension in Acute Stroke 511
Terence J. Quinn, John A. Goodfellow, and John L. Reid

55.
Cardiovascular Risk of Nonsteroidal Anti-Inflammatory Drugs 525
Csaba Farsang

56.
Compliance to Treatment in Hypertension 529
Serap Erdine and Margus Viigimaa

57.
Antihypertensive Treatment in Patients with Heart Failure 537
Nisha B. Mistry, Sverre E. Kjeldsen, and Arne S. Westheim

58.
Residual Risk and Resistance to the Benefits of
Antihypertensive Treatment543
Alberto Zanchetti

59.
A Commentary on The 2013 ESH/ESC Guidelines for the Management
of Arterial Hypertension553
Michael A. Weber

Following the successful first edition, it is a great pleasure
to present to readers the second edition of the Manual of
Hypertension of the European Society of Hypertension. The
new edition updates the chapters that are part of the
first manual, based on the additional ­scientific evidence
that has been gained in recent years. It also includes
new chapters that address the ­ e merging interesting
aspects of the pathophysiology, epidemiology, diagno-
sis, and treatment of hypertension and related disorders.
Attention has also been given to the practical aspects of
the management of hypertensive patients in an attempt
to make the book useful not only to investigators with an
Preface
in-depth involvement in the basic and clinical problems
in this field of m
­ edicine but also to physicians for whom
­hypertension is an important ­component of their daily
professional activity.
On behalf of the European Society of Hypertension, we
wish to express our gratitude to our colleagues who have
contributed to the book. We are confident that readers
will appreciate their contributions and regard the book
as useful in helping to successfully cope with a risk factor
that, despite decades of research, continues to remain the
number-one cause of death as well as the most important
burden of disease worldwide.
 Contributors

Enrico Agabiti-Rosei Grzegorz Bilo

Department of Medical and Surgical Sciences Department of Cardiology
University of Brescia S. Luca Hospital
Brescia, Italy IRCCS Istituto Auxologico Italiano
Milan, Italy
Reza Aghamohammadzadeh
Institute of Cardiovascular Sciences Claudio Borghi
University of Manchester Department of Medical and Surgical Sciences
Manchester, England, United Kingdom University of Bologna
Bologna, Italy
Ettore Ambrosioni
Department of Medical and Surgical Sciences
University of Bologna Gianmaria Brambilla
Bologna, Italy Università Milano-Bicocca
Ospedale S. Gerardo
Monza, Italy
Michel Azizi
Hôpital Européen Georges Pompidou
Paris, France Marie Briet
Hôpital Européen Georges Pompidou
Jean-Philippe Baguet Paris, France
Department of Cardiology
Grenoble University Hospital
Michel Burnier
Grenoble, France
Division of Nephrology and Hypertension
Department of Medicine
Nigel S. Beckett Lausanne, Switzerland
Imperial College London
Department of Medicine
and Miguel Camafort
Guys and St. Thomas’ NHS Foundation Trust Hypertension Unit
London, England, United Kingdom Department of Internal Medicine
Institute of Medicine and Dermatology
Athanase Benetos Hospital Clinic (IDIBAPS)
Head of the Geriatric Department University of Barcelona
University Hospital of Nancy Barcelona, Spain
Nancy, France
 xiv­ Contributors

Mark Caulfield Anna F. Dominiczak

William Harvey Research Institute Regius Professor of Medicine
Barts and the London School of Medicine and Dentistry Vice-Principal and Head of College of Medical, Veterinary
Queen Mary University of London and Life Sciences
London, England, United Kingdom University of Glasgow
Glasgow, Scotland, United Kingdom
Marzena Chrostowska
Hypertension Department Stefan Engeli
Medical University of Gdansk Institut für Klinische Pharmakologie
Gdansk, Poland Medizinische Hochschule Hannover
Hannover, Germany
Arrigo Francesco Giuseppe Cicero
Department of Medical and Surgical Sciences Serap Erdine
University of Bologna Hypertension Unit
Bologna, Italy Department of Cardiology
Cerrahpasa School of Medicine
Istanbul University
Renata Cífková Istanbul, Turkey
Center for Cardiovascular Prevention
Charles University in Prague
Maria Jose Fabia
First Faculty of Medicine and Thomayer Hospital
Hypertension Clinic
Prague, Czech Republic
Internal Medicine
Hospital Clinico
Denis L. Clement Research Institute INCLIVA
Deparment of Cardiology and Angiology CIBERObn Health Institute Carlos III
University Hospital Madrid, Spain
and and
Department of the Dean University of Valencia
Ghent University Hospital Valencia, Spain
Ghent, Belgium
Robert Fagard
Antonio Coca Hypertension and Cardiovascular Rehabilitation Unit
Hypertension Unit Department of Cardiovascular Diseases
Department of Internal Medicine KU Leuven University
Institute of Medicine and Dermatology Leuven, Belgium
Hospital Clinic (IDIBAPS)
University of Barcelona Csaba Farsang
Barcelona, Spain St. Imre Teaching Hospital
Budapest, Hungary
Cesare Cuspidi
Department of Clinical Medicine and Prevention François Feihl
University of Milano-Bicocca and Policlinico di Monza Division of Clinical Pathophysiology
Monza, Italy University Hospital
Lausanne, Switzerland
Peter W. de Leeuw
Department of Internal Medicine José A. García-Donaire
University Hospital Maastricht Fundación para la Investigación Biomédica Unidad de
Maastricht, The Netherlands Hipertensión
Hospital Clínico San Carlos Avda
Raffaella Dell’Oro Madrid, Spain
Clinica Medica
Università Milano-Biococca Lorenzo Ghiadoni
Milan, Italy Department of Clinical and Experimental Medicine
University of Pisa
Monica Doménech Pisa, Italy
Hypertension Unit
Department of Internal Medicine Cristina Giannattasio
Institute of Medicine and Dermatology Università Milano-Bicocca and Cardiologia Iv
Hospital Clinic (IDIBAPS) Dipartimento Cardiotoracovascolare “A.Degasperis”
University of Barcelona Ospedale Niguarda Ca Granda
Barcelona, Spain Milano, Italy
 Contributors xv

John A. Goodfellow Sverre E. Kjeldsen

Institute of Neurological Sciences Department of Cardiology
Southern General Hospital Ullevaal University Hospital and Faculty of Medicine
Glasgow, Scotland, United Kingdom University of Oslo
Oslo, Norway
Guido Grassi and
Università Milano-Bicocca Division of Cardiovascular Medicine
Ospedale San Gerardo University of Michigan
Monza, Italy Ann Arbor, Michigan
and
Istituto di Ricerca a Caratttere Scientifico Multimedica John B. Kostis
Milan, Italy John G. Detwiler Professor of Cardiology
and
Adam S. Greenstein Professor of Medicine and Pharmacology
Institute of Cardiovascular Sciences and
University of Manchester Associate Dean for Cardiovascular Research
Manchester, England, United Kingdom and
Director, Cardiovascular Institute
Robert Wood Johnson Medical School
Hermann Haller
Rutgers University
Department of Internal Medicine
New Brunswick, New Jersey
Hannover Medical School
Hannover, Germany
Stéphane Laurent
Department of Pharmacology and INSERM U970
Martin Hausberg Hôpital Européen Georges Pompidou
Department of Medicine I
Université Paris-Descartes
Karlsruhe General Hospital
Paris, France
Karlsruhe, Germany
and
Empar Lurbe
Department of Medicine D
Department of Pediatrics
University of Muenster
Consorcio Hospital General
Muenster, Germany
University of Valencia
Valencia, Spain
Anthony M. Heagerty and
Institute of Cardiovascular Sciences CIBERObn Fisiopatología de Obesidad y Nutrición
University of Manchester Instituto de Salud Carlos III
Manchester, England, United Kingdom Madrid, Spain

Ashley S. Izzard Jean-Michel Mallion

Institute of Cardiovascular Sciences Department of Cardiology
University of Manchester Grenoble University Hospital
Manchester, England, United Kingdom Grenoble, France

Per Lund-Johansen Athanasios J. Manolis

Department of Clinical Science Cardiology Department
University of Bergen Asklepeion General Hospital
Bergen, Norway Athens, Greece

Jens Jordan Paul E. Marik

Direktor, Institut für Klinische Pharmakologie Department of Medicine
Medizinische Hochschule Hannover Eastern Virginia Medical School
Hannover, Germany Norfolk, Virginia

Manolis S. Kallistratos Fernando Martinez

Cardiology Department Department of Internal Medicine
Asklepeion General Hospital Hypertension Clinic
Athens, Greece Hospital Clinico
University of Valencia
Valencia, Spain
 xvi­ Contributors

Nisha B. Mistry Gernot Pichtler

Department of Cardiology Department of Internal Medicine
Ullevaal Hospital Hypertension Clinic
University of Oslo Hospital Clinico
Oslo, Norway University of Valencia
Valencia, Spain
M.L. Muiesan
Dipartimento di Scienze Cliniche e Sperimentali Leonidas E. Poulimenos
Università di Brescia Department of Cardiology
Brescia, Italy Asklepeion General Hospital
Voula, Athens, Greece
Krzysztof Narkiewicz
Hypertension Department Terence J. Quinn
Medical University of Gdansk Division of Cardiovascular and Medical Sciences
Gdansk, Poland University of Glasgow
Glasgow, Scotland, United Kingdom
Peter M. Nilsson
Department of Clinical Sciences Karl Heinz Rahn
Lund University Department of Medicine D
University Hospital University of Muenster
Malmö, Sweden Muenster, Germany

Juan Eugenio Ochoa Josep Redon

Department of Health Sciences Hospital Clinico
University of Milano-Bicocca University of Valencia
and Valencia, Spain
Department of Cardiology
S. Luca Hospital John L. Reid
IRCCS Istituto Auxologico Italiano Division of Cardiovascular and Medical Sciences
Milan, Italy University of Glasgow
Glasgow, Scotland, United Kingdom
Per Omvik
Martin Ritt
Department of Clinical Science
Department of Nephrology and Hypertension
University of Bergen
University of Erlangen-Nürnberg
Bergen, Norway
Erlangen, Germany
Sandosh Padmanabhan Jose L. Rodicio
BHF Glasgow Cardiovascular Research Centre
Professor Emeritus of Medicine
Institute of Cardiovascular and Medical Sciences
Universidad Complutense
University of Glasgow
and
Glasgow, Scotland, United Kingdom
Chief of Nephrology and Hypertension Department
Clinica la Luz
Paolo Palatini Madrid, Spain
Department of Medicine
University of Padova Luis M. Ruilope
Padova, Italy Hypertension Unit
Hospital 12 de Octubre
Gianfranco Parati Madrid, Spain
Department of Health Sciences
University of Milano-Bicocca Michel E. Safar
and Hôtel-Dieu de Paris
Department of Cardiology Assistance-Publique Hôpitaux De Paris
S. Luca Hospital Paris, France
IRCCS Istituto Auxologico Italiano
Milan, Italy Roland E. Schmieder
Department of Nephrology and Hypertension
Achille C. Pessina University of Erlangen-Nürnberg
Department of Internal Medicine Erlangen, Germany
University of Padova
Padova, Italy
 Contributors xvii

Julian Segura Thomas Unger

Hypertension Unit Department of Cardiovascular and Renal Research
Hospital 12 de Octubre University of Southern Denmark
Madrid, Spain Odense, Denmark
and
Gino Seravalle CARIM School for Cardiovascular Diseases
Istituto di Ricerca a Caratttere Scientifico Multimedica Maastricht University
Sesto San Giovanni Maastricht, The Netherlands
Milan, Italy
Philippe van de Borne
Cristina Sierra Hypertension Clinic
Hypertension Unit Department of Cardiology
Department of Internal Medicine Erasme Hospital
Institute of Medicine and Dermatology Brussels, Belgium
Hospital Clinic (IDIBAPS)
University of Barcelona Peter A. van Zwieten
Barcelona, Spain Departments of Pharmacotherapy, Cardiology, and
Cardiothoracic Surgery
Ulrike M. Steckelings Academic Medical Centre
Department of Cardiovascular and Renal Research Amsterdam, The Netherlands
University of Southern Denmark
Odense, Denmark Margus Viigimaa
Centre of Cardiology
Harry A.J. Struijker-Boudier North Estonia Medical Centre
Department of Pharmacology Tallinn, Estonia
Maastricht University
Maastricht, The Netherlands Agostino Virdis
Department of Clinical and Experimental Medicine
Anna Szyndler University of Pisa
Hypertension Department Pisa, Italy
Medical University of Gdansk
Gdansk, Poland
Massimo Volpe
Division of Cardiology
Stefano Taddei Department of Clinical and Molecular Medicine
Department of Clinical and Experimental Medicine Faculty of Medicine
University of Pisa University of Rome “Sapienza”
Pisa, Italy Sant’Andrea Hospital
Rome, Italy
Giuliano Tocci and
Division of Cardiology IRCCS Neuromed
Department of Clinical and Molecular Medicine Pozzilli (IS), Italy
Faculty of Medicine
University of Rome “Sapienza”
Bernard Waeber
Sant’Andrea Hospital
Department of Medicine
Rome, Italy
Centre Hospitalier Universitaire Vaudois
and
Lausanne, Switzerland
IRCCS Neuromed
Pozzilli, Italy
Michael A. Weber
Costas Tsioufis Division of Cardiovascular Medicine
Department of Cardiology State University of New York
University of Athens Downstate College of Medicine
Hippokration Hospital Brooklyn, New York
Athens, Greece
Arne S. Westheim
Department of Cardiology
Ullevaal Hospital
Faculty of Medicine
University of Oslo
Oslo, Norway
 xviii Contributors

Sarah B. Withers G. Wuerzner

Institute of Cardiovascular Sciences Department of Medicine
University of Manchester Centre Hospitalier Universitaire Vaudois
Manchester, England, United Kingdom Lausanne, Switzerland

Jacek Wolf Alberto Zanchetti

Hypertension Department Istituto Auxologico Italiano and Centro Interuniversitario di
Medical University of Gdansk Fisiologia Clinica e Ipertensione
Gdansk, Poland Università di Milano
Milan, Italy
 EPIDEMIOLOGY OF
HYPERTENSION
INTRODUCTION
Blood pressure (BP) is a quantitative trait with a normal,
continuous, bell-shaped (Gaussian) distribution p ­ attern,
skewed to the upper end in any general population
(Figure 1.1), and hypertension represents a clinical defini-
tion of the upper part of the distribution curve. Figure 1.1
shows a distribution curve for diastolic BP plotted using
BP measurements in 158,906 individuals aged 30–69 years
screened for the Hypertension Detection and Follow-up
Program in the United States (1).
The final BP value is the result of the interaction of
genetic and environmental factors (Figure 1.2). The divid-
ing line between normotension and hypertension is purely
arbitrary and, in fact, artificial.
Hypertension is the most prevalent cardiovascular (CV)
disorder, affecting 20%–50% of the adult population in
developed countries (2). The prevalence of hypertension
increases with age, rising steeply after the age of 50 years
and affecting more than 50% of this population.
BP AS A RISK FACTOR FOR CV DISEASES
Elevated BP has been identified as a risk factor for coronary
heart disease (CHD), heart failure, stroke, peripheral arte-
rial disease, renal failure, and atrial fibrillation in both men
and women in a large number of epidemiological studies
(Figure 1.3) (3–7). Observational evidence is also avail-
able that BP levels correlate inversely with cognitive func-
tion and that hypertension is associated with an increased
incidence of dementia (8). Historically, diastolic BP was
long considered a better predictor of cerebrovascular dis-
ease and CHD than systolic BP. This was reflected in the
design of major randomized controlled trials of hyperten-
sion management, which used diastolic BP as an inclusion
criterion until the 1990s (9). Individuals with isolated sys-
tolic hypertension were excluded from such trials by defi-
nition. Nevertheless, a large compilation of observational
data before (3) and since the 1990s (10) confirms that both
systolic and diastolic BP show a continuous, graded, inde-
pendent relationship with the risk of stroke and coronary
events (Figures 1.4 and 1.5). Data from observational stud-
ies involving one million individuals have indicated that
death from both CHD and stroke increases progressively
and linearly from BP levels as low as 115 mmHg systolic
and 75 mmHg diastolic upward (10). The increased risks
are present in all age groups ranging from 40 to 89 years
old. For every 20 mmHg systolic or 10 mmHg diastolic
1
Renata Cífková
increase in BP, there is a doubling of mortality from both
CHD and stroke.
In addition, longitudinal data obtained from the
Framingham Heart Study indicated that BP values in the
130–139/85–89 mmHg range are associated with a more
than twofold increase in relative risk from CV diseases
(CVDs) compared with BP levels below 120/80 mmHg
(Figure 1.6) (11).
The apparently simple direct relationship between
increasing systolic and diastolic BP and CV risk is con-
founded by the fact that systolic BP increases throughout
the adult age in the vast majority of populations, whereas
diastolic BP peaks at about age 60 years in men and
70 years in women and falls gradually thereafter (12).
This observation helps to explain why a wide pulse pres-
sure (systolic BP − diastolic BP) has been shown in some
observational studies to be a better predictor of adverse CV
outcomes than either systolic or diastolic BP individually (13)
and to identify patients with systolic hypertension who are at
especially high risk (14). However, the largest meta-analysis
of observational data in one million patients in 61 studies
(70% of which had been conducted in Europe) (10) showed
that both systolic and diastolic BP, more so than pulse pres-
sure, were independently predictive of stroke and CHD
mortality. This meta-analysis also confirmed the increasing
contribution of pulse pressure after age 55 years.
It has been shown that, compared to normotensive indi-
viduals, those with an elevated BP more commonly have
other risk factors for CVD (diabetes, insulin resistance, and
dyslipidemia) (5,15–17) and various types and degrees of
target organ damage. Because risk factors may interact posi-
tively with each other, total CV risk in hypertensive patients
is not infrequently high when the BP elevation is also only
mild or moderate (5,11,18). In a study by Anderson et al. (19),
686 treated hypertensive men, followed up for 20–22 years,
had a significantly increased CV mortality, especially from
CHD, compared with nonhypertensive men from the same
population. These differences were observed during the
second decade of follow-up. The high incidence of myocar-
dial infarction was related to organ damage, smoking, and
cholesterol at the time of entry to the study and to achieved
serum cholesterol during follow-up.
POPULATION IMPACT
The impact of hypertension on the incidence of CVD in the
general population is best evaluated from the population-­
attributable risk or, more correctly, the population-­
attributable burden, which is the proportional reduction
 2 Manual of Hypertension of the European Society of Hypertension

20 CHD Stroke PAD Heart

failure
18 Prevalence of hypertension 50
45
16 by different DBP levels
% of screened population

40

Numbers/1,000, adj. for age

14
12 ≥90 = 25.3%
30
Normal BP
10 ≥95 = 14.5% 23
Hypertension
21
8 ≥100 = 8.4% 20
14
12.4
6 ≥105 = 4.7% 9.5 10 M = Males
10 7.3 F = Females
4 ≥110 = 2.9% 6.2 5
6.3
≥115 = 1.4% 3.3 2.4 2
3.5
2
2 0
0 Odds ratio: 2.0 2.2 3.0 2.6 2.0 3.7 4.0 3.0
M F M F M F M F
50 60 70 80 90 100 110 120 130
DBP (mmHg) Figure 1.3 Risk of cardiovascular events related to
hypertension and normotension. Abbreviations: BP, blood
Figure 1.1 Frequency distribution of diastolic blood
pressure; CHD, coronary heart disease; PAD, periph-
pressure (DBP) measured in 158,906 individuals aged
eral arterial disease. (Adapted from Kannel WB. Blood
30–69 years, screened for the Hypertension Detection
­pressure as a ­cardiovascular risk factor: prevention and
and Follow-up Program. (Adapted from Hypertension
treatment. JAMA 1996; 275(20):1571–6.)
Detection and Follow-up Program Cooperative Group.
The Hypertension Detection and Follow-up Program.
A progress report. Circ Res 1977; 40(Suppl 1):1106–9.) general population comes from those with relatively mild
BP elevation (22). About half of the CV events in the gen-
eral population occur at BP levels below those recom-
“Polygenic inheritance” mended for treatment with antihypertensive medications.
About 54% of stroke and 47% of ischemic heart disease
Gene+ worldwide were attributable to high BP in 2001 (23). This
Epistasis Gene– equates to approximately 7.6 million premature deaths
(13.5% of the global total) and 92 million DALYs (1 DALY
Gene+ Gene+
[disability-adjusted life year] is 1 lost year of healthy life;
6.0% of the global total). This indicates a need for vigor-
ous nonpharmacological treatment of individuals with
Gene– Blood pressure Gene+ high-normal BP and for initiating drug treatment in the
vast majority of patients with mild hypertension based on
their total CV risk.
Others
Salt intake

Stress Diet POPULATION STRATEGY

Smoking
“Environmental interaction”
Figure 1.2 Multifactorial nature of blood pressure. Blood
pressure is controlled by both genes and environment,
with both epistatic and gene–environment interactions.
in average disease risk over a specified time interval that
would be achieved by eliminating the exposure of interest
from the population, while the distribution of other risk
factors remains unchanged (20). For BP, attributable bur-
den can therefore be defined as the proportion of disease
that would not have occurred if BP levels had been at the
same alternative distribution (21). The statistics take into
account both the prevalence of the risk factor (hyperten-
sion) and the strength of its impact (risk ratio) on CVD.
Because of the high prevalence and risk ratio of hyper-
tension in the general population, approximately 35% of
atherosclerotic events are attributable to h ­ ypertension.
The odds ratio, or the relative risk to the individual,
increases with the severity of hypertension, but the attrib-
utable risk is greatest for mild hypertension because of its
greater prevalence in the general population. Therefore,
the burden of CVD arising from hypertension in the
In the past, most treatment efforts were aimed at the group
with the highest levels of BP. However, this “high-risk”
strategy, effective as it may be for those affected, does little
to reduce total morbidity and mortality if the “low-risk”
patients, who make up the largest share of the population
at risk, are ignored (24).
Most people with mild hypertension are now being
treated with antihypertensive drugs. However, as empha-
sized by Rose (25), a more effective strategy would be to
lower the BP level of the entire population, which might
be accomplished by reduction of sodium intake. Rose esti-
mated that lowering the entire distribution of BP by only
2–3 mmHg would be as effective in reducing the overall risk
of hypertension as prescribing current antihypertensive drug
therapy for all individuals with definite hypertension. This
has been further elaborated by Stamler et al. (26) who made
the assumption that a reduction in systolic BP by 2 mmHg
may lead to a 6% reduction in stroke mortality, 4% reduc-
tion in CHD mortality, and 3% reduction in total mortal-
ity (Figure 1.7). The following environmental factors affect
BP: diet, physical activity, and psychosocial factors. Dietary
factors have a prominent and likely predominant role in
BP homeostasis. In nonhypertensive individuals, includ-
ing those with high-normal BP, dietary changes that lower
 Epidemiology of Hypertension 3

Age at risk: Age at risk:

256 256 80–89
80–89
years years

128 128 70–79

70–79
years years

64 64
60–69 60–69
years years

(floating absolute risk and 95% Cl)

(floating absolute risk and 95% Cl)

32 32
50–59 50–59
years years
Stroke mortality

Stroke mortality
16 16

8 8

4 4

2 2

1 1

120 140 160 180 70 80 90 100 110

Usual systolic blood Usual diastolic blood
pressure (mmHg) pressure (mmHg)

Figure 1.4 Stroke mortality rate in each decade of age plotted for the usual systolic (left) and diastolic (right) blood pres-
sure at the start of that decade. Data from one million adults in 61 prospective studies. (Adapted from Lewington S, et al.
­Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults
in 61 prospective studies. Prospective Studies Collaboration. Lancet 2002; 360:1903–13.)

BP have the potential to prevent h ­ ypertension and, more
broadly, to reduce BP, thereby lowering the risk of BP-related
clinical complications (27). Lifestyle modifications, which
may induce more reductions in BP at the population level,
include weight reduction in overweight or obese individu-
als, lower sodium intake, consumption of diets rich in
fruits and vegetables and rich in low-fat dairy products,
and reduced intake of saturated fat and cholesterol (Dietary
Approaches to Stop Hypertension [DASH]-like diet) (28).
Redon et al. published a study showing differences in BP
control and stroke mortality across Spain. Poor hyperten-
sion control and prevalence of ECG left ventricular hyper-
trophy were the main factors related to stroke mortality
rates (29). Cooper, in an editorial commentary, suggests
that we can begin to consider stroke as a surveillance mea-
sure that indicates the quality of hypertension control (30).
Several decades ago, there was general agreement that
medical care did not have a sufficiently widespread effect
on population health (e.g., life expectancy or m ­ ortality),
which was considered to be influenced only by living
­conditions and nutrition.
However, a analysis suggests that medical care may
not have a sufficiently widespread effect on p­ opulation to
make a significant contribution to extending life expec-
tancy in the United States (31). In fact, pill taking to
prevent CV events has become a mass phenomenon, with
more than half of the U.S. population over 60 years of
age taking antihypertensive medication alone. Long-term
therapy has thus become a public health intervention and
can be considered a bridge between clinical medicine and
traditional population-wide preventive measures.
GLOBAL BURDEN OF HYPERTENSION
Overall, 26.4% (26.6% in men and 26.1% in women) of
the world adult population in 2000 had hypertension, and
29.2% (29.0% in men and 29.5% in women) were predicted
to have hypertension in 2025 (32). Regions with the highest
estimated prevalence of hypertension had roughly twice the
rate of regions with the lowest estimated prevalence. The
highest estimated prevalence of hypertension for men was
found in the regions of Latin America and the Caribbean,
and that for women was found in the former socialist econ-
omies, represented in Kearney’s paper by Slovak data from
1978 to 1979. The lowest estimated prevalence of hyperten-
sion for both men and women was found in the region of
Asia represented by Korea, Thailand, and Taiwan. Although
hypertension is more common in developed countries
 4 Manual of Hypertension of the European Society of Hypertension

Age at risk:
Age at risk:
256 80–89 256
years 80–89
years

128 70–79 128

years 70–79
years
64 60–69 64
years 60–69
years

(floating absolute risk and 95% Cl)

(floating absolute risk and 95% Cl)

32 50–59 32
years 50–59
years
IHD mortality

IHD mortality
16 16
40–49
40–49
years
years
8 8

4 4

2 2

1 1

120 140 160 180 70 80 90 100 110

Usual systolic blood Usual diastolic blood
pressure (mmHg) pressure (mmHg)

Figure 1.5 Ischemic heart disease (IHD) mortality rate in each decade of age plotted for the usual systolic (left) and ­diastolic
(right) blood pressure at the start of that decade. Data from one million adults in 61 prospective studies. (Adapted from
Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data
for one million adults in 61 prospective studies. Prospective Studies Collaboration. Lancet 2002; 360:1903–13.)

Men Women
14 10
High normal
12 High
Cumulative incidence (%)

Cumulative incidence (%)

8 normal
10 Normal
8 6

6 Optimal 4 Normal
4
2
2 Optimal

0 0
0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14
Time (yr) Time (yr)

No. at risk No. at risk

Optimal 1005 995 973 962 934 892 454 Optimal 1875 1867 1851 1839 1821 1734 887
Normal 1059 1039 1012 982 952 892 520 Normal 1126 1115 1097 1084 1061 974 649
High normal 903 879 857 819 795 726 441 High normal 891 874 859 840 812 722 520

Figure 1.6 The cumulative incidence of cardiovascular events in men and women enrolled in the Framingham Heart
Study with initial blood pressure classified as optimal (<120/80 mmHg), normal (120–129/80–84 mmHg), or high normal
(130–139/85–89 mmHg) over a 12-year follow-up. (Adapted from Vasan RS, et al. Impact of high-normal blood pressure on
the risk of cardiovascular disease. N Engl J Med 2001; 345:1291–7.)

After intervention Before intervention
Reduction in BP
Reduction in BP % Reduction in mortality
mmHg Stroke CHD Total
2 –6 –4 –3
3 –8 –5 –4
5 –14 –9 –7
Figure 1.7 Estimated effects of population-wide shifts
in systolic blood pressure distribution on mortality.
Abbreviations: BP, blood pressure; CHD, coronary heart
disease. (Adapted from Stamler J, et al. Blood pressure,
systolic and diastolic, and cardiovascular risk: US popula-
tion data. Arch Intern Med 1993; 153:598–615.)
(37.3%) than in developing ones (22.9%), the much larger
population of the developing countries results in a consider-
ably larger absolute number of individuals affected. The pro-
jection of the number of individuals with hypertension for
2025 is probably an underestimate as it does not account for
the rapid changes in lifestyle and concurrent increase in the
risk of hypertension taking place in these countries.
BP AND AGE
The relationship between age and BP has been demon-
strated in a number of cross-sectional studies conducted in
populations with different economic status. A remarkable
finding is the consistent relationship between BP and age
in developed countries.
CHILDHOOD AND ADOLESCENCE
Perhaps the most valuable data for this population are con-
tained in the Second Task Force on Blood Pressure Control
in Children (33). Data were obtained by BP measurements
in over 70,000 children enrolled into nine cross-sectional
studies in the United States and the United Kingdom.
BP was determined in the sitting position, using a mercury
sphygmomanometer (Doppler ultrasound in infants). In
an effort to maintain a uniform methodology that would
allow pooling of data, only the first measurement was
used for analysis. In children aged 3–12 years, Phase IV
Korotkoff sounds were recorded, while in adolescents aged
13–18 years, both Phase IV and V Korotkoff sounds were
recorded. While at birth, mean BP levels are 70/50 mmHg,
systolic BP starts to increase soon after birth reaching a
mean value of 94 mmHg by the first year of life. In contrast,
the increase in diastolic BP is a mere 2 mmHg. Systolic
and diastolic BP levels do not change substantially over
the next 2–3 years. After this period, that is, from 4 years
of age onward, there is a tendency toward a progressive
increase with age throughout childhood and adolescence
(Figure 1.8). The increase in systolic BP tends to be some-
what more rapid (1–2 mmHg/year) than that in diastolic
Epidemiology of Hypertension 5
Boys
Girls
120
110
100
BP (mmHg)
90
80
70
60
50
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)
Figure 1.8 Mean systolic (above) and diastolic (below)
blood pressure (BP) of boys (bold line) and girls (­dotted
line) from birth to 18 years. Diastolic BP reflects the use
of Phase IV Korotkoff sounds. (Adapted from Report
of the Second Task Force on Blood Pressure Control in
Children—1987. Task Force on Blood Pressure Control
in Children. National Heart, Lung, and Blood Institute,
Bethesda, Maryland. Pediatrics 1987; 79:1–25.)
BP (0.5–1 mmHg/year). The rate of BP increase is about
the same for both sexes up to 10 years of age, with the
curve becoming flatter for girls in the ensuing period. In
adolescence, the mean (particularly systolic) BP of boys
is higher than that of girls. As a result, systolic BP of boys
aged 18 years is 10 mmHg higher than that of girls, with
the respective difference between both sexes in diastolic
BP being 5 mmHg. No systematic differences have been
reported for different ethnicities (blacks, Caucasians,
Hispanic Americans) in childhood and adolescence.
The Second Task Force Report on Blood Pressure Control
in Children was updated in 1996 (34). The main change
was the recommendation to adjust BP not only for the
child’s sex and age but also for height, which became the
third criterion for BP assessment. This new criterion helps
to eliminate bias in assessing BP in children with extreme
values of body height, that is, in those small and tall for
age. The recommendation for the recording of Phase V
Korotkoff sounds was extended to include children up to
13 years of age.
ADULTHOOD AND OLD AGE
In adulthood, systolic and diastolic BPs tend to increase
with age. The increase is somewhat greater in systolic
BP rising up to 80–90 years of age, whereas diastolic BP
remains almost unaltered from age 50 years upward.
Aging results in a progressive increase in pulse pres-
sure (difference between systolic and diastolic BPs). In
adults, systolic and diastolic BPs are higher in men than
in women (e.g., 1 ­20–130/75–80 mmHg in 20-year-old
men and 1 ­ 10–120/70–75 mmHg in women of the same
age). However, the BP increase in adulthood is steeper in
 6 Manual of Hypertension of the European Society of Hypertension
Males
160
140
BP (mmHg)
120
100
80
60
20 30 40 50 60
Age (yrs)
Figure 1.9 Age–blood pressure (BP) relationship by ethnicity and sex for systolic (above) and diastolic (below) BP in the general
population of the United States, 1976–1980. (Adapted from National Center for Health Statistics. Drizd T, Dannenberg AL,
Engel A. Blood pressure levels in persons 18–74 years of age in 1976–80, and trends in blood pressure from 1960 to 1980 in the United States.
Vital and Health Statistics, Series 11, 234, DHHS Pub No (PHS) 86–1684. Washington DC: US Government Printing Office; 1986.)
women than in men (0.6–0.8 mmHg/year in women and
0.33–0.5 mmHg/year in men between 20 and 70 years of
age). As a result, systolic BP of women aged 70 and over
is equal to or higher than that of men. Data regarding
BP in the elderly are limited. However, several studies of
questionable reliability have suggested that systolic BP
of women in their late 80s or 90s is 10–20 mmHg higher
than their male counterparts. The gender difference may
be partly explained by different survival rates. Male hyper-
tensive patients are more likely to die from CVD.
As mentioned earlier, both blacks and whites show s­ imilar
BP levels in childhood and adolescence. Among the ­20- to
30-year-olds, mean BP is higher in blacks than in whites,
and the difference continues to grow in the ­ensuing 10-year
periods. The National Health and Nutrition Examination
Survey I reported mean differences of 4 ­ .1–10.6/3.5–7.0 and
5.3–17.7/3.4–10.9 mmHg between 30- and 70-year-old
males and females, respectively (Figure 1.9) (35).
The age-related increase in systolic BP is primarily
responsible for an increase in both the incidence and
prevalence of hypertension with increasing age (36). The
impressive increase in BP to hypertensive levels with age
is also illustrated by the Framingham data, indicating
that the 4-year rates of progression to hypertension are
50% for those aged 65 and older with BP in the 130–139/­
85–89 mmHg range and 26% for those with BP in the
120–129/80–84 mmHg range (36).
BP TRACKING
Several longitudinal studies have shown that essential
hypertension in adults is associated with high BP levels in
childhood. The concept that BP rank is established early
in childhood has received increasing attention because
early detection and prevention of high BP levels in child-
hood may reduce the incidence of adult hypertension. The
tendency for individuals to stay roughly in the same rank
Females
160
140
BP (mmHg)
120
100
80
60
70 20 30 40 50 60 70
Age (yrs)
Blacks
Whites
of the BP distribution as they age is known as “tracking.”
It means that individuals from the lower part of the distri-
bution curve tend to have the smallest BP increases with
age (i.e., they continue to remain in the lower part of the
distribution curve).
While BP tracking is generally believed to exist within
populations, long-term prediction for a specific individual
is fairly unreliable (37).
BP tracking is most relevant in childhood, as it allows
identification of individuals likely to develop hyperten-
sion during their lifetime.
POPULATIONS WITH A LOW BP
A constant finding in all populations who do not develop
hypertension and whose mean BP does not tend to increase
with age is a low salt intake. The relationship seems to be a
causal one. A case in point are some African tribes retain-
ing their original lifestyle without exposure to excessive
salt intake. Changes in lifestyle and eating habits are usu-
ally associated with a higher prevalence of all risk factors
for hypertension (increase in body mass index [BMI],
increased salt intake, and decreased potassium intake).
It is generally believed that BP levels and hypertension
prevalence are lower in the rural population than in the
urban one forced to quit its hitherto traditional, simple life-
style. A substantially greater increase in BP occurs during
migration to another continent (Japanese to Hawaii and fur-
ther onto the United States, blacks migrating to Europe) (38).
AGE AND GENDER DIFFERENCES
Global estimates of BP by age, sex, and subregion
show considerable variation in estimated levels (analy-
ses based on data from about 230 surveys including

660,000 participants) (39). Age-specific mean systolic
BP values ranged from 114 to 164 mmHg for females
and from 117 to 153 mmHg for males. Females typi-
cally had lower systolic BP levels than males in the 30- to
44-year-old groups, but in all subregions, systolic BP levels
increased more steeply with age for females than for males.
Therefore, systolic BP levels in those aged ≥60 years tended
to be higher in females.
PREVALENCE OF HYPERTENSION
Whenever comparing the prevalence of hypertension, one
should be aware that this is heavily dependent on the defi-
nition of hypertension, population examined, number of
BP readings taken on each occasion, and, finally, on the
number of visits.
The prevalence of hypertension reported by Kearney
et al. (2) varies widely, with rates as low as 3.4% in rural
Indian men and as high as 72.5% in Polish women. In
developed countries, the prevalence of hypertension ranges
between 20% and 50%.
REGIONAL DIFFERENCES
INTERCONTINENTAL AND WITHIN-EUROPE
DIFFERENCES
Subregions with consistently high mean systolic BP levels
include parts of Eastern Europe and Africa. Mean systolic
BP levels are the lowest in Southeast Asia and parts of the
western Pacific.
A comparative analysis of hypertension prevalence and
BP levels in six European countries, the United States,
and Canada, based on the second BP reading, showed a
60% higher prevalence of hypertension in Europe than
in the United States and Canada in population samples
aged 35–64 years (40). There were also differences in
the prevalence of hypertension among European coun-
tries, with the highest rates in Germany (55%), followed
by Finland (49%), Spain (47%), England (42%), Sweden
(38%), and Italy (38%). Prevalence rates in the United
States and Canada were half those in Germany (28% and
27%, respectively). The differences in prevalence cannot
be explained by differences in mean BMI (North America,
27.1 kg/m2; Europe, 26.9 kg/m2).
Findings from the World Health Organization
MONItoring trends and determinants in CArdiovascular
diseases (MONICA) Project showed a remarkably higher
prevalence of hypertension in Eastern Europe and virtu-
ally no difference in the rates of controlled hypertension
among Eastern and Western populations (41).
REGIONAL DIFFERENCES WITHIN A COUNTRY
Regional differences in BP levels have been observed in a
number of developed countries. Differences were reported
between urban and rural populations, with a tendency
toward higher BP levels in urban areas. In a number of
areas, regional variations in BP levels are closely related to
CV mortality. This is the case, for example, in Japan where
Epidemiology of Hypertension 7
mean BP levels are the highest in the northeast part of the
largest island (Tohoku), also known for high stroke-related
mortality rates.
Minor differences in mean BP levels have been reported
in the United States, with the highest in the south and the
lowest in the west. This is consistent with regional differ-
ences in stroke-related mortality (42).
Marked geographic differences in CV mortality have
also been noted in the United Kingdom. The lowest rates of
death from CVD and stroke have been reported in south-
east and eastern England. CV mortality tends to increase
west- and northward, reaching the highest rates in the val-
leys of southern Wales, northern England, and Scotland.
The results of the British Regional Heart Study (43) and
the Nine Towns Study documented geographic variation
related to different CV mortality rates. While some of
the variations could be attributed to factors such as body
weight and alcohol and sodium–potassium intake, most
of the variations remain unexplained (44).
ETHNIC DIFFERENCES
Prevalence of hypertension varies among different racial
groups within the population. An excellent database is pro-
vided by the National Health and Nutrition Examination
Survey (NHANES), which used stratified multistage prob-
ability samples of the civilian, noninstitutionalized U.S.
population. The age-adjusted prevalence of hypertension
is the highest in non-Hispanic blacks, followed by non-
Hispanic whites and Mexican Americans (45).
TRENDS IN THE PREVALENCE OF
HYPERTENSION
The prevalence of hypertension in the United States
declined uniformly across all population groups between
NHANES I and NHANES II, with an additional and
greater decline between NHANES I and the first two
phases of NHANES III. However, the NHANES survey
of 1­ 999–2000 reported an increase in the prevalence of
hypertension (46). No significant increase in the overall
prevalence of hypertension was detected at the last survey
performed in 2003–2004 (45).
A significant decrease in the prevalence of hypertension
was reported in Australia, with three surveys performed
as part of the National Heart Foundation’s Risk Factor
Prevalence Study in 1980, 1983, and 1989 (47).
Two Health Surveys for England conducted in 1994
and 1998 reported a similar prevalence of hypertension
(38% and 37%, respectively) (48), which was also the case
in Greece, where surveys were performed between 1979
and 1983 and in 1997 (49,50).
A significant decline in the prevalence of hypertension
was found in the Belgian (51), Finnish (52), and Czech (53)
populations, whereas a slight increase was observed in
the MONICA Augsburg Project in Germany (54). An
increase in the prevalence of hypertension was reported in
China (55), Singapore (56), and India (57–61).
In conclusion, over the past one to two decades, the
prevalence has remained stable or decreased in developed
countries and has increased in developing countries.
 8 Manual of Hypertension of the European Society of Hypertension
AWARENESS AND TREATMENT OF
HYPERTENSION
Awareness and treatment of hypertension varies considerably
between countries and regions (2). In developed countries,
there are approximately one-half to two-thirds of hyperten-
sive patients in the general population aware of their diagno-
sis, and one-third to one-half receiving treatment. The levels
of awareness and treatment in most developing countries
tend to be lower than those reported in developed countries.
TRENDS IN AWARENESS AND TREATMENT OF
HYPERTENSION
There are only few countries having data on longitudi-
nal trends reported. During the 12-year interval between
NHANES II and III, the proportion of hypertensive patients
aware of their condition increased from 51% to 73% (46).
Increases in awareness were higher for women than for men,
among both blacks and whites. The Health Survey for England
reported increased hypertension awareness and treatment
from 46.0% and 31.6% in 1994 to 52.2% and 38.0% in 1998,
respectively (48). In Germany, from 1984/1985 to 1994/1995,
awareness remained at 50% in men and 60% in women. The
proportion of hypertensive patients receiving drug treatment
increased by 7.9% in men and 4.1% in women (62).
An enormous increase in the awareness of hypertension
was reported in Finland (from 54.5% to 75.9% in men
and from 72.8% to 84.3% in women) between 1982 and
1997 (52). In the Czech Republic, there was an increase
in the awareness (from 49.5% to 69.7%) and treatment
(from 29.3% to 58.5%) of hypertension from 1985 to
2007/2008 (53).
HYPERTENSION CONTROL
Hypertension is poorly controlled worldwide, with less
than 25% controlled in developed countries and less than
10% in developing countries (2). Hypertension control rates
also vary within countries by age, gender, ethnicity, socio-
economic status, education, and quality of health care (63).
While awareness of hypertension has improved in the
United States and other Western countries over the past
decade, hypertension control remains inadequate as only a
portion of those who are aware of their diagnosis are treated,
and an even smaller number of those receiving treatment are
treated adequately. However, the most important parameter
likely to have an impact on public health is neither the num-
ber of those who are aware of their hypertension nor the
number taking steps to improve it but, rather, the percentage
of those whose BP is under control (64).
ENVIRONMENTAL FACTORS
AIR TEMPERATURE AND SEASONAL
VARIATION IN BP
A number of reports have pointed out that a lower air
­temperature is associated with a higher mean BP. As air
temperature is lower in Scotland and northern England
than in southern England, the differences in air temper-
ature may be theoretically responsible for some regional
differences in BP across the United Kingdom.
A seasonal effect on BP was first described by Rose (65),
analyzing measurements in 56 men observed for 1–3 years
at a clinic for ischemic heart disease. The Medical Research
Council’s trial of mild hypertension found that systolic
and diastolic BP levels were higher in winter than in sum-
mer. The seasonal variation in BP was greater in older than
in younger individuals and was significantly related to
maximum and minimum daily air temperature measure-
ments but not to rainfall (66).
SOCIAL STATUS
The British Regional Heart Study and the Nine Towns Study
reported a lower systolic BP in white-collar workers com-
pared with blue-collar workers (44,67). Individuals with a
lower level of education also show a higher prevalence of
other risk factors, in particular, obesity and lower physical
activity. An inverse relationship between education and BP
has been shown in many adult populations (68). In the
less educated populations, BMI levels and more adverse
intake patterns of multiple macro- and micronutrients
account substantially for their higher BP levels (69).
BODY WEIGHT AND PHYSICAL ACTIVITY
BP and BMI are closely interrelated. The relative risk (odds
ratio) for the development of hypertension increases
markedly with increasing BMI (70). The importance of
this relationship is reinforced by the high and increasing
prevalence of overweight and obesity worldwide (71–73).
A variety of epidemiological studies have documented
an inverse correlation between the level of physical activ-
ity and BP levels. Prospective cohort studies have reported
a higher incidence of hypertension in individuals with
lower levels of physical activity and lower cardiorespira-
tory fitness (74). Randomized controlled studies have fur-
nished evidence of a beneficial effect of physical activity
on BP. A meta-analysis of randomized controlled trials
has shown that aerobic endurance training reduces rest-
ing systolic and diastolic BP by 3.0/2.4 mmHg overall and
even by 6.9/4.9 mmHg in hypertensive participants (75).
Even regular physical activity of lower intensity and dura-
tion has been shown to be associated with about a 20%
decrease in mortality in cohort studies (76).
SODIUM AND POTASSIUM INTAKE
In most populations, there is a correlation between normal
dietary sodium intake (usually expressed as 24-hour urinary
sodium excretion) and mean BP (77). However, 24-hour
urinary sodium output is biased by large intraindividual
variability. In most populations, the age-related increase in
BP is significantly associated with sodium intake (78).
There are major differences in the individual response
of BP to salt intake. Afro-Americans, the middle-aged, the
elderly, patients with diabetes, and people with hypertension
respond more sensitively to changes in salt intake compared

with the general population. These groups tend to have a less
responsive renin–angiotensin–aldosterone system (79). The
usual salt intake is between 9 and 12 g/day in many coun-
tries, and it has been shown that reduction to about 5 g/day
has a modest (1.5 mmHg) systolic BP-lowering effect in nor-
montesive individuals and a somewhat more pronounced
effect in hypertensive individuals. A daily intake of 5–6 g of
salt is thus recommended for the general population (80).
Individuals on a predominantly vegetarian diet show
lower BP levels, and their BP increases less with increasing
age compared with those on diets of animal origin (81).
Vegetarians have lower BP levels than the nonvegetarian
population, even in developed countries (82). The low-
est levels of BP in industrialized nations were reported in
strict vegetarians not consuming virtually any products of
animal origin. Their diet includes whole-grain products,
lots of green-leaved vegetables, pumpkins, and root veg-
etables. A diet rich in potassium and polyunsaturated fat
and containing little starch, saturated fat, and cholesterol
correlated inversely with BP levels in a large population
of men in the United States (83). Over the past decade,
increased potassium intake and dietary patterns based on
the DASH trial (a diet rich in fruit, vegetables, and low-fat
dairy products, with a reduced content of dietary choles-
terol as well as saturated and total fat) (84) have emerged
as effective strategies that also lower BP.
ALCOHOL CONSUMPTION
Observational studies and clinical trials have documented
a direct, dose-dependent relationship between alco-
hol intake and BP, particularly as the intake of alcohol
increases above approximately two drinks per day (85,86).
Importantly, this relationship has been shown to be inde-
pendent of potential confounders such as age, obesity, and
salt intake (87). Although some studies have shown that
the alcohol–hypertension relationship also extends into
the light drinking range (≤2 drinks per day), this is the
range in which alcohol may reduce CHD risk.
A meta-analysis of 15 randomized controlled trials
reported that decreased consumption of alcohol (median
reduction in self-reported alcohol consumption: 76%;
range: 16%–100%) reduced systolic and diastolic BP by 3.3
and 2.0 mmHg, respectively. The BP reductions were simi-
lar in normotensive and hypertensive individuals; there
was a dose-dependent relationship between reduction in
alcohol consumption and decline in BP (86).
Table 1.1 Rates of progression to hypertension in the Framingham Heart Study
Percentage of 4-year progression to hypertension
Blood pressure (BP) Men (age:
category 35–64 years)
Optimal BP 5 15
Normal BP 18
High-normal BP 37
Source: Adapted from Franklin SS, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study.
Circulation 1997; 96:308–15.
Epidemiology of Hypertension 9
A reduction in alcohol consumption is associated with a
decrease in BP (a decrease in alcohol consumption by one
alcoholic drink results in decreases in both systolic and
diastolic BP by about 1 mmHg).
Women and lean individuals absorb larger amounts
of ethanol than men (88); consequently, their daily con-
sumption should not exceed 20 mL of ethanol.
Excessive alcohol intake is a major risk factor for the
development of hypertension and may be responsible for
resistance to antihypertensive therapy (89).
DIETARY FACTORS WITH LIMITED OR
UNCERTAIN EFFECT ON BP
Several, predominantly, small clinical trials and meta-
analyses of these trials (90–92) have documented that
high-dose omega-3 polyunsaturated fatty acid (commonly
called fish oil) supplements can lower BP in hypertensive
individuals with BP reductions occurring at relatively high
doses (≥3 g/day). In hypertensive individuals, average sys-
tolic and diastolic BP reductions were 4.0 and 2.5 mmHg,
respectively (92).
Overall, data are insufficient to recommend an increased
intake of fiber alone (93,94), supplemental calcium, or
magnesium (95,96) as means to lower BP. Additional
research is warranted before specific recommendations
can be made about how the amount and type of carbohy-
drates (97,98) affect BP.
INCIDENCE OF HYPERTENSION
There are much lesser data about the incidence, that is,
newly developed cases, of hypertension than about
its prevalence. The incidence of hypertension in the
Framingham cohort over 4 years was directly related to
the prior level of BP and to age, with similar rates in men
and women (37). Obesity and weight gain also contrib-
uted to the progression of hypertension. A 5% weight gain
after 4 years was associated with 20% increased odds of
hypertension (Table 1.1). Another longitudinal database
is provided by the NHANES study, which found mini-
mal differences in the incidence of hypertension between
men and women for all age groups. Incidence rates for
blacks were at least twice the rates of whites for almost
every age–sex group (99).
Men (age: Women (age: Women (age:
65–74 years) 35–64 years) 65–74 years)
5 16
25 12 26
47 37 49
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 sketch of, 309, 310;
selected by Hamilton and King as Federalist candidate for President, in
1796, 310.

Pintard, John, chief of Tammany Society, 148.

Porcupine’s Gazette, active in urging war with France, 350-60;

publishes Martin’s attacks on Jefferson, 352, 353;
abusive to Democrats, 354, 355;
on Lyon-Griswold fight in House, 361.

Powell, Mrs. Samuel, aunt of Mrs. William Bingham, 132.

Priestley, Joseph, English liberal, addresses Tammany and other

‘Democratic Societies’ in New York, 259.

Randolph, Edmund, Attorney-General under Washington, considers

Hamilton’s Bank Bill unconstitutional, 77;
on reception of Genêt, 215;
succeeds Jefferson as Secretary of State, 239;
and French Minister Faucet, 285;
is dismissed from Cabinet, 286.

Read, Jacob, Senator from South Carolina, denounced in Charleston for

supporting Jay Treaty, 281.

Reign of Terror, Alien and Sedition Laws produce, in 1798, 380-82;

continued through two years, 383;
riotings, 384;
victims, 386-93, 398-406.

Report on Manufactures, Hamilton’s, 161;

newspaper comments on, 161.

Report on the Public Credit, Hamilton’s, 43-68;

debated in Congress, 44.
Reynolds, James, seeks to blackmail Hamilton, 187.

Ricketts, John, proprietor of the Circus, Philadelphia, 138.

Rights of Man, by Thomas Paine, copy lent by printer to Jefferson, 82;

in returning borrowed copy to printer Jefferson writes note commending
pamphlet, 83;
Jefferson’s note used by printer as preface, 83;
effect of publication, 83, 84;
newspaper controversy over, 83, 84.

Rittenhouse, David, scientist and friend of Jefferson, 149;

and Jefferson in library of Philosophical Society, Philadelphia, 156;
aids in preparations for reception of Genêt, 219;
president of Democratic Club of Philadelphia, 223.

Rochefoucauld-Liancourt, Duc de La, on Philadelphia, 124, 125;

in Philadelphia, 135.

Rush, Dr. Benjamin, writes letters to Maclay against Assumption, 61;

on Paine’s Rights of Man, 84;
letter to Burr, 147;
Jefferson’s friend, 149;
in yellow fever epidemic in Philadelphia, 237.

Rutledge, John, denounces Jay Treaty, 280;

appointment as Chief Justice not confirmed, 289.

Saint Cecilia Society, Democratic Club in Charleston, 223.

St. Clair, General Arthur, failure of expedition against Indians made issue
by Jeffersonians in campaign of 1792, 175.

Schuyler, Philip, father-in-law of Hamilton, elected Senator from New

York, 36;
 letter of Hamilton to, on Washington, 41, 42;
and the Assumption Bill, 62.

‘Scrippomony,’ Jefferson on, 87.

Sedition Bill, purpose to crush Jeffersonian press, 376, 377;

debates on, in Congress, marked by disorder, 378;
passed by small margin, 380.

Sedgwick, Theodore, speculator in public securities, defends Funding Bill,

48, 49;
on funding of debt, 48, 49, 50;
on Madison’s plan to amend Funding Bill, 55;
speech on the Assumption Bill, 62;
and Excise Bill, 72;
and amendment to Excise Bill, 73;
on Giles’s resolutions attacking Treasury management, 201;
recommended Adams’s nomination as Vice-President, in 1789, 325;
on results of 1798 elections, 383.

Sedgwick, Mrs. Theodore, 134.

Sherman, Roger, Representative and Senator from Connecticut, on titles, 3.

Sign of the Sorrel Horse, Philadelphia tavern, 119.

Smith, Mrs. Margaret Bayard, on Jefferson, 92, 93.

Smith, Samuel, on Madison commerce resolutions, 241.

Smith, Jeremiah, on Philadelphians, 116.

Smith, William, Representative from South Carolina, on Madison’s

amendment to Funding Bill, 55;
chosen director of Bank of United States, 90;
on Giles’s resolutions attacking Treasury management, 201, 203;
on Madison’s commerce resolutions, 240, 242.
Southwark Theater, Philadelphia, 137.

Speculation, in government securities, 44-47;

members of Congress involved, 46-48;
in stock and scrip, 87;
fraud and counterfeiting, 88;
Hamilton shocked and concerned, 88;
bubble bursts in 1792, 176;
Hamilton’s policies charged as cause of panic, 177;
newspaper comments on, 177.

Spooner’s Vermont Journal, on the Jay Treaty, 283.

Steele, John, North Carolina, 181.

Stewart, Mrs. Walter, daughter of Blair McClenachan, social leader of

Philadelphia, 132.

Strong, Caleb, Senator from Massachusetts, 9;

and the Assumption Bill, 62.

Sullivan, James, lawyer, pamphleteer, and orator for the Democrats, 145.

Tammany, Sons of, rival organization to Society of the Cincinnati, 148;

at first non-partisan, then fervid Jeffersonians, 148.

Tariff, in First Congress, 19;

in Second Congress, 161;
Hamilton’s Report on Manufactures excites little attention, 161.

Taylor, John, of Caroline, a Jeffersonian leader in Virginia, 149, 150;

Jeffersonian leaders confer at home of, 205;
pamphlet analyzing vote in Congress vindicating Hamilton, attributed to,
205, 206;
introduces Virginia Resolutions in Legislature, 409.
Tilley, Count, 135.

Treaty with the Southern Indians, Washington’s attitude on presentation to

the Senate, 21, 22.

Trumbull, John, paints portrait of Hamilton, 162.

Tucker, George, editor of Blackstone’s Commentaries, 169.

Twining, Thomas, in Philadelphia, 120.

United States Chronicle, on Freneau’s attacks on Hamilton, 164.

Venable, Abraham B., of deputation from Congress to Hamilton on the

Reynolds charges, 187.

Vermont Journal, on Hamilton’s Passaic Falls scheme, 162.

Vining, John, Representative from Delaware, and Assumption, 61;

Maclay on, 61.

Virginia Resolutions, written by James Madison, and introduced in

Legislature by John Taylor of Caroline, 409;
contemporary opinions of, 409-11.

Wadsworth, Jeremiah, Representative from Connecticut, speculator in

certificates, 47 n.;
sneers at soldiers of Revolution, 55, 56;
elected director of Bank of United States, 90.

Warville, Brissot de, and Mrs. Bingham, 128, 129.

Washington, George, reception on arrival in New York, 6, 7;

 inaugurated President, 7;
bored by dignities and ceremonial of office, 16, 17;
his solemn dinners, 18;
presents in person treaty with Southern Indians for ratification by Senate,
20;
annoyed by proposal to refer treaty to committee, 21;
rents house of Robert Morris in Philadelphia, 119;
endeavors, unsuccessfully, to effect reconciliation between Jefferson and
Hamilton, 171;
Hamilton refuses to discontinue attacks in Fenno’s Gazette, 172;
and the French Revolution, 214;
issues Neutrality Proclamation, 216;
and Jefferson in the case of the Little Sarah, 228;
reluctantly accepts Jefferson’s resignation, 233, 234;
appoints Jay special envoy to Great Britain, 247;
attacks Democratic Societies in Message, 261;
delays signing Jay Treaty, 285;
his prestige used to make Treaty more acceptable, 286;
is attacked by Democratic press, 286-88;
refuses to comply with request of House for papers pertaining to Jay
Treaty, 298;
refuses to be a candidate for a third term, 308;
accepts chief command of army in prospective war with France, 413;
selects Hamilton, Pinckney, and Knox as major-generals, 413.

Washington City, new capital, in 1800, 486-89;

‘city of magnificent distances,’ but mud roads, 487.

Whiskey Boys, the. See Whiskey Insurrection.

Whiskey Insurrection, the, 250-56;

grew out of enforcement of Excise Law, 251;
Hamilton active in suppressing, 254-56;
ringleaders arrested, harshly treated, and jailed, 255;
most of prisoners acquitted on trial, 255;
two convicted, but pardoned by Washington, 256;
tempest in a teapot, 256.
Williamson’s Gardens, New York City, 10.

Willing, Thomas, business partner of Robert Morris, elected director of

Bank of United States, 90.

Wingate, Paine, on Federal Hall, 2.

Witherspoon, John, president of Princeton, 157.

Wolcott, Mary Ann, sister of Oliver Wolcott, afterward Mrs. Chauncey

Goodrich, 134.

Wolcott, Oliver, of Connecticut, on Hamilton’s religious views, 41;

mouthpiece for Hamilton, 59, 60;
on Philadelphians, 116;
on demonstrations against Jay Treaty, 275;
Adams’s Secretary of the Treasury, sketch of, 331-34.

Wolcott, Mrs. Oliver, called ‘the magnificent,’ 134.

Wythe, George, Virginia lawyer and politician, 96;

presides at meeting in Richmond denouncing Jay Treaty, 282.

X Y Z papers, Federalists familiar with, before publication, 364;

Hamilton sees trump card in them for war party, 364;
Jeffersonians kept in ignorance, 364;
excitement intense on publication, 365, 366;
‘millions for defense, but not one cent for tribute,’ a clarion call, 366;
rioting in Philadelphia, 367.

Yellow Cat, the, Philadelphia tavern, 120.

Yellow fever, in Philadelphia, 237, 238;

in New York, Boston, and Philadelphia, 380.
FOOTNOTES:
[1] Pickering (Wingate to Pickering), II, 447.
[2] Ames, I, 31.
[3] Writings, I, 450.
[4] Ames, I, 31, 32.
[5] Pickering (Wingate to Pickering), II, 447.
[6] Ames, I, 31; Pickering, II, 447.
[7] Republican Court, 120-22; Story of a Street, 101.
[8] Ames, I, 32-34.
[9] Writings, I, 450.
[10] Ames (to Minot), I, 41-42.
[11] Republican Court, 122, note.
[12] Adams’s explanation, Works, VIII, 511-13.
[13] Maclay, 2-3.
[14] Maclay, 7-10.
[15] Ibid., 22-24.
[16] Ibid., 25-27.
[17] Maclay, 37.
[18] Writings, I, 470-71.
[19] Ames, I, 46.
[20] June 3, 1789.
[21] Maclay, 31.
[22] Daily Advertiser, April 24, 1789.
[23] Ibid.
[24] Story of a Street, 221.
[25] Maclay, 7-10.
[26] Ibid.
[27] Gazette of the United States, May 2, 1789.
[28] Ibid.
[29] Ibid, May 8, 1789.
[30] Daily Advertiser, May 8, 1789.
 [31] Daily Advertiser, May 8, 1729.
[32] Gazette of the United States, May 9, 1789.
[33] Governor Page complained bitterly of hogs and mud. Memorial History, III,
48.
[34] The Daily Advertiser advertises the specifications April 13, 1789.
[35] Maclay, 90.
[36] Gazette of the United States, June 27, 1789.
[37] Memorial History, III, 47.
[38] Daily Advertiser, March 6, 1789.
[39] Memorial History, III, 45.
[40] Daily Advertiser, April 15, 1789.
[41] New York in 1789, 117.
[42] Memorial History, III, 65; New York in 1789, 117-20.
[43] New York in 1789, 172-75.
[44] Ibid., 176.
[45] Ibid., 178.
[46] May 9, 1789.
[47] Gazette of the United States, May 13, 1789.
[48] Maclay, 31.
[49] Gazette of the United States, June 6, 1789.
[50] Ibid., September 19, 1789.
[51] Story of a Street, 112.
[52] Gibbs, I, 22.
[53] Ibid., I, 43.
[54] New York in 1789, 19.
[55] Ibid., 119.
[56] Warville, 96-97.
[57] Republican Court, 210, note.
[58] Brooks, Knox, 217-18.
[59] Mrs. Iredell; McRee, Iredell, II, 296-97.
[60] Gazette of the United States, May 16, 1789.
[61] Ibid., May 30, 1789.
[62] Daily Advertiser, June 19, 1789.
 [63] Gazette of the United States, April 15, 1789.
[64] Maclay, 257-58.
[65] Wharton, Salons, Colonial and Republican, 53.
[66] Maclay, 266.
[67] Ibid., 73-74.
[68] Story of a Street, 112, 114-17, 121.
[69] Richmond Hill, at present site of Charlton and Varick Streets.
[70] Letters of Mrs. Adams (to Mrs. Shaw), II, 201; (to Thomas Brand-Hollis), II,
205.
[71] Ames (to Minot), I, 34; Maclay, 375; Familiar Letters, 86-89.
[72] Adams, Works, VIII, 491-92.
[73] Thayer’s Washington, 180-81.
[74] Gazette of the United States, May 6, 1789.
[75] Republican Court, 149, note.
[76] Autobiography, Ford, I, 171.
[77] Maclay, 138.
[78] Iredell, II, 138.
[79] Maclay, 138.
[80] Ibid., 138, 206.
[81] Ibid., 101.
[82] Maclay, 38.
[83] Ibid., 50.
[84] Bassett, The Federalist System.
[85] Gerry, Annals, May 20, 1789.
[86] Writings (to Randolph), I, 471-73.
[87] Jackson, Annals, I, 486-89.
[88] Page, Annals, I, 548-52.
[89] Maclay, 128-31.
[90] Iredell (Lowther to Iredell), II, 258-59.
[91] Writings, I, 471-73.
[92] Warville, 102.
[93] Familiar Letters, 236-37.
[94] Oliver, 114.
[95] Gibbs, I, 22.
[96] Autobiography, 278.
[97] Morris, Diary, II, 456.
[98] Oliver, 15.
[99] See Appendix, Lodge, Alexander Hamilton.
[100] Works, IX, 405-06; letter to brother.
[101] Ibid., X, 109.
[102] Intimate Life, 3.
[103] Life, by son, I, 4.
[104] Fiske, I, 104-05.
[105] Life, by son, I, 10.
[106] Ibid., 22.
[107] Ibid., 263-74.
[108] Payne’s Journalism, 191-92.
[109] Works, I, 202.
[110] Ibid., I, 213-39.
[111] Ibid., I, 243-87.
[112] Life, by son, II, 277.
[113] Ibid., I, 69.
[114] Works, VI, 276.
[115] Life, by son, I, 69.
[116] Ibid., I, 318.
[117] Ibid.
[118] Lodge, 26.
[119] Oliver, 27.
[120] Intimate Life, 47.
[121] Oliver, 161-62.
[122] Lodge, 177-78; Oliver, 163-64.
[123] Oliver, 86.
[124] Ibid., 263.
[125] Ibid., 376.
[126] Works, VI, 457.
[127] Oliver, 149.
 [128] Fiske, 120; Lodge, 58.
[129] Beck, 75.
[130] Oliver, 156.
[131] Works, I, 347-69.
[132] Beck, 76.
[133] Life, by son, II, 487.
[134] Ibid., 487.
[135] Ibid., 488.
[136] Ibid.
[137] Ibid.
[138] Ibid., 516.
[139] Lodge, 60.
[140] Works, I, 404.
[141] Gordy, I, 70.
[142] Works, I, 417.
[143] Ibid.
[144] Works, I, 420.
[145] Lodge, 62-63.
[146] Statement to Tench Coxe quoted by Jefferson, Works of Jefferson, Ford, I,
338.
[147] Letter to G. Morris, Works, X, 425.
[148] Morris, Diary, II, 456.
[149] Works, X, 480.
[150] Intimate Life, 75.
[151] Life, by son, I, 398.
[152] Parton’s Jefferson, 358.
[153] Familiar Letters, 236-37.
[154] Oliver, 177-78.
[155] Works, X, 3; letter to King.
[156] Jefferson’s Anas, I, 180.
[157] Morris, Diary, II, 456.
[158] Lodge, 156.
[159] Works, X, 354.
 [160] Morris, Diary, II, 456.
[161] Cabot, 298-300.
[162] Intimate Life, 48.
[163] Life, by son, I, 236.
[164] Ibid., 233.
[165] Lodge, 81.
[166] Ibid., 144.
[167] Oliver, 40.
[168] Works, X, 90-91.
[169] Ibid., X, 425-26.
[170] Works, X, 123-26; letter to Lloyd.
[171] Parton’s Jefferson, 355.
[172] Intimate Life, 46.
[173] Works, IX, 256-58.
[174] Familiar Letters, 236-37.
[175] Morison’s Otis (to Mrs. Otis), I, 141-43.
[176] Cabot, 204-05.
[177] Morison’s Otis, I, 141.
[178] Lodge, 272.
[179] Oliver, 76.
[180] Ibid., 381.
[181] Griswold, 173.
[182] Intimate Life, 55.
[183] Ibid., 56.
[184] Ibid., 60.
[185] Ibid., 259.
[186] Ibid., 73.
[187] Intimate Life, 17.
[188] Works, V, 61 (to Washington); X, 256 (to William Smith); X, 275 (to King);
X, 343 (to Pickering).
[189] Life, by son, reminiscences of Troup, I, 10.
[190] Ibid.
[191] Works, VI, 276.
 [192] Ibid., X, 432-37.
[193] Intimate Life, 334.
[194] Ibid., 406.
[195] Oliver and Sumner.
[196] Intimate Life, 261.
[197] Works, IX, 232-37.
[198] Ibid., X, 356-57.
[199] Daily Advertiser, October 9, 1789.
[200] Gerry and Clymer, both supporters of the Report, objected. Annals, January
9, 1790.
[201] Maclay, 177.
[202] Writings, J. Q. Adams, I, 49.
[203] Connecticut Gazette, February 19, 1790.
[204] Lodge, 90-91.
[205] Ibid.
[206] Madison’s Writings (letter to Pendleton), I, 507-09.
[207] Maclay, 179. The member of Congress who sent the vessels was Jeremiah
Wadsworth of Connecticut.
[208] Professor C. A. Beard makes a conclusive case against both in his Economic
Origins of Jeffersonian Democracy.
[209] Works of Jefferson, I, 354.
[210] Mr. Amory, H. G. Otis, and William Wetmore.
[211] Writings of J. Q. Adams, I, 56-59.
[212] Maclay, 177-78.
[213] Beard’s Economic Interpretation, 104-12.
[214] Gazette of the United States, ‘Common Sense,’ January 30, 1790.
[215] Annals, January 28, 1790.
[216] Ibid.
[217] Maclay, February 1, 1790.
[218] Maclay, 194.
[219] Annals, February 10, 1790.
[220] New York Daily Advertiser, February 13, 1790.
[221] Familiar Letters, 108.
[222] Gazette of the United States, April 15, 1790.
 [223] Fiske, 187.
[224] Ames (letter to Minor), I, 35.
[225] First Forty Years of American Society, Family Letters of Mrs. Margaret
Bayard Smith, 61.
[226] Works of Jefferson, Ford, I, 86.
[227] Mrs. Smith, 63.
[228] Annals, February 11, 1790.
[229] Madison’s Writings, I, 507.
[230] Annals, February 15, 1790.
[231] Writings (to Randolph), I, 512.
[232] White, Annals, February 16, 1790.
[233] White, Annals, February 16, 1790.
[234] Maclay, 199.
[235] Ibid., February 22, 1790.
[236] Writings, J. Q. Adams, I, 49.
[237] Gazette of the United States, June 12, 1790.
[238] Centinel, February 24, 1790.
[239] Ibid., March 20, 1790.
[240] Pennsylvania Gazette, copied in Maryland Gazette, February 26, 1790.
[241] Boston, Independent Chronicle, March 4, 1790.
[242] Boston, Independent Chronicle, March 25, 1790.
[243] Ibid., April 15.
[244] Maclay, 202.
[245] Ibid., 205.
[246] New York Advertiser, February 20, 1790.
[247] Ibid., February 22, 1790.
[248] Comptroller of the Treasury.
[249] Gibbs, I, 43.
[250] Madison’s Writings (to Jefferson), I, 511.
[251] McRee, Iredell (from Senator Johnson), II, 286; (from William R. Davie), II,
281, note.
[252] King, I, 385.
[253] Henry, II, 459.
[254] Stone of Maryland.
[255] Maclay, 203.
[256] Ibid., 209.
[257] Ibid., 212.
[258] Ibid., 214.
[259] Maclay, 227, 230.
[260] Ibid., 234.
[261] Elias Boudinot of New Jersey.
[262] Maclay, 237.
[263] Maclay, 248.
[264] Ibid., 250.
[265] Writings, I, 517.
[266] McRee, Iredell, II, 286.
[267] Lodge, Cabot, 35-36.
[268] Ibid. (to Goodhue), 37.
[269] Gazette of the United States, April 21, 1790.
[270] Ibid., April 24, 1790.
[271] Centinel, June 19, 1790.
[272] Daily Advertiser, March 24, 1790.
[273] Ames (to Dwight), I, 79-80.
[274] Maclay, 292.
[275] Ibid., 299.
[276] Maclay, 310.
[277] Works, Ford, VIII, 42-45.
[278] Ibid., VIII, 52.
[279] Writings (to Monroe), I, 522.
[280] Maclay, 332.
[281] Gazette of the United States, August 25, 1790.
[282] February 25, 1791.
[283] Brooks, Knox, 213.
[284] Maryland Journal, February 11, 1791.
[285] Josiah Parker.
[286] Annals, January 5, 1791.
[287] Samuel Livermore.
[288] Annals, January 6, 1791.
[289] Annals, January 11, 1791.
[290] Maclay, 385.
[291] Ibid., 385.
[292] Maclay, 387.
[293] Jefferson’s Works, VIII, 123.
[294] Works, III, 319-41; 342-87.
[295] Ibid., 388-443.
[296] Maclay, 364.
[297] Ibid., 369.
[298] Annals, February 2, 1791.
[299] Ames (to Dwight), I, 94.
[300] Annals, February 3, 1791.
[301] Jefferson’s Works, III, 145-53.
[302] Madison’s Writings, III, 171.
[303] Madison’s Writings, III, 171.
[304] Ames (to Minot), February 17, 1791.
[305] Madison’s Writings (to Jefferson), I, 534-35.
[306] Hamilton’s Works (letter to Carrington), IX, 513-35.
[307] Parton, II, 1.
[308] Dustin’s Freneau, 160.
[309] May 11, 1791.
[310] Gazette of the United States, April 6, 1791.
[311] Daily Advertiser, February 25, 1791.
[312] Independent Chronicle, March 10, 1791.
[313] New York Daily Advertiser, July 19, 1791.
[314] British Agent.
[315] Domestic Life, 197-98. Jefferson was living in the country.
[316] Maryland Journal, March 22, 1791.
[317] Domestic Life, 199.
[318] Ibid., 201.
[319] Jefferson’s Works, VIII, 205.
 [320] Gay’s Madison.
[321] Madison’s Writings, I, 534.
[322] Graydon, 375.
[323] McRee, Iredell, II, 335.
[324] Adams, Adams, I, 454.
[325] New York Daily Advertiser, July 8, 1791.
[326] Ibid., July 9, 1791.
[327] Ibid., July 14, 1791.
[328] Independent Chronicle, June 23, 1791.
[329] Ibid., July 7, 1791.
[330] Ibid., August 26, 1791.
[331] Ibid.
[332] Jefferson’s Works, VIII, 192.
[333] Adams, Works, VIII, 503.
[334] Ibid., 505.
[335] Madison’s Writings, I, 535.
[336] Jefferson’s Works, VIII, 223.
[337] Jefferson’s Works, VIII, 232.
[338] Madison’s Writings, I, 540.
[339] Ibid., I, 534.
[340] Madison’s Writings, I, 538.
[341] Maryland Journal, February 15, 1791.
[342] Pennsylvania Gazette, September 7, 1791.
[343] August 17, 1791.
[344] Hamilton’s Works (to King), I, 402.
[345] August 8, 1791.
[346] August 9, 1791.
[347] August 13, 1791. ‘Scrips sold last night: Cash 212-202-210-206; 10 days,
216, 217-1/2, 214; 30 days, 223, 212, 215; 45 days, 216; 60 days, 219; Sept. 10, 224;
Deliver and pay December 1, 235; Deliver October 1 and pay January 1, 242;
Monday next, 207; Tuesday, 215-1/2, 217, 210.’ (New York Daily Advertiser.)
[348] Daily Advertiser, August 15, 1791.
[349] New York Daily Advertiser.
[350] Daily Advertiser, August 17, 1791.
[351] New York Daily Advertiser, September 21, 1791.
[352] Independent Chronicle, September 1, 1791.
[353] Independent Chronicle, August 18, 1791.
[354] Maclay, 272.
[355] Familiar Letters, 148.
[356] Maclay, 272.
[357] Mrs. Smith, 6.
[358] Ibid., 6-7.
[359] Liancourt, III, 157.
[360] Parton on the Moore incident, III, 115-19.
[361] Maclay, 272.
[362] Mrs. Smith, 6-7.
[363] Maclay, 272.
[364] Familiar Letters, 149.
[365] Familiar Letters, 148.
[366] Maclay, 272.
[367] Liancourt, III, 157.
[368] Familiar Letters, 148.
[369] Mrs. Smith, 6-7.
[370] Randall, I, 14.
[371] Dodd, Statesmen of the Old South, 3-4.
[372] Ibid., 9.
[373] Dodd, Statesmen of the Old South, 23.
[374] Parton’s Jefferson, I, 27.
[375] Randall, III, 448.
[376] Autobiography, I, 77.
[377] Fiske, 148.
[378] Works (to Mrs. Trist), V, 151.
[379] Ibid. (to Bellini), V, 151.
[380] Ibid. (to Mrs. Trist), V, 81-82.
[381] Ibid. (to Bellini), V, 151-54.
[382] Morris, Diary, I, 101.
[383] Domestic Life (letter to Madison), 155; Works, I, 131-38.
 [384] Domestic Life (letter to Adams), 156.
[385] Ibid. (to Jay), 156.
[386] Ibid. (to Jay), 159.
[387] Works (letter to Lafayette), VII, 370; (to De St. Etienne), VII, 370-72; (the
Charter), VII, 372-74.
[388] Ibid., IV, 72.
[389] Ibid. (to De Unger), IV, 138-39.
[390] Autobiography, I, 72.
[391] Mrs. Wharton, 391.
[392] Parton’s Jefferson, I, 344.
[393] Vol. I, 77.
[394] Works, V, 3-4: letter to Chastellus.
[395] Ibid., VI, 428: to Warville.
[396] Randall, I, 17.
[397] Ibid., III, 556-58; letter to Rush.
[398] Ibid., 671-76.
[399] Ibid.; also see The Thomas Jefferson Bible, edited by Henry Jackson.
[400] Randall, III, 547.
[401] Dodd, Statesmen of the Old South, 36.
[402] Randall, III, 620-22.
[403] Works, VI, 11-15; to Charles Thompson.
[404] Ibid., 227-29 (to Edward Carrington); 269-71 (to J. Blair).
[405] Ibid., 296-301 (to Benjamin Hawkins and George Wythe); 231-32 (to Count
Del Vermi).
[406] Ibid., 285-89; to John Adams.
[407] Ibid., 368.
[408] Ibid., 378-83; to William Carmichael.
[409] Works, VI, 385-93.
[410] Ibid., 425-27. I have the authority of Josephus Daniels for a tradition in
North Carolina that such a letter in the hands of Willie Jones was responsible for the
failure of the first Convention there to ratify. The letter is apparently lost.
[411] Ibid., VII, 26-30; to Carmichael.
[412] Ibid., 36-39; to Colonel Carrington.
[413] Ibid., 79-88.