5 Hypertension

5: Hypertension
Overview
This chapter focuses on the important cardiovascular risk factor of hypertension. It includes hypertensive definitions,
descriptions of the pathophysiologic effects of hypertension and potential end organ damage. It explains how the history and
physical exam often contain clues to the etiology of hypertension, and reviews the critical nonpharmacologic and pharmacologic
treatments of hypertension. The final section describes how to recognize and treat secondary causes of hypertension.
Authors
Patrick T. O'Gara, MD, FACC

EditorinChief
Thomas M. Bashore, MD, FACC

Associate Editor
James C. Fang, MD, FACC

Associate Editor
Glenn A. Hirsch, MD, MHS, FACC

Associate Editor
Julia H. Indik, MD, PhD, FACC

Associate Editor
Donna M. Polk, MD, MPH, FACC

Associate Editor
Sunil V. Rao, MD, FACC

Associate Editor
5.1: Definitions, Prevalence, Etiology, Target Organs
Author(s):
Clive Rosendorff, MD, PhD, FACC
Learner Objectives
Upon completion of this module, the reader will be able to have explain the definition, prevalence, etiology, and complications of
hypertension, and its contribution to cardiovascular (CV) risk.
Introduction
CV disease (CVD), including stroke, is now the most common cause of death and disability in developed countries, and
is rapidly becoming so in developing countries as well.1 Hypertension is one of the most important modifiable risk
factors for CVD. Hypertension affects about 25% of the adult population of the world, and its prevalence is predicted to
increase by 60% to 2025, when a total of over 1.5 billion people may be affected. Primary hypertension (essential or
idiopathic hypertension) accounts for about 90% of all cases of hypertension.
Definitions
Blood pressure (BP) in human populations has a normal distribution. Accordingly,

the definitions of "normal" BP and of various forms of hypertension are arbitrary, but
are needed for practical reasons in the assessment and treatment of patients. Figure 1
Hypertension is defined as a systolic blood pressure (SBP) of 140 mm Hg or greater
and/or a diastolic blood pressure (DBP) of 90 mm Hg or greater in persons not
taking antihypertensive medication (Figure 1).
Those with a BP of 120139 mm Hg systolic and/or 8089 mm Hg diastolic are

classified as "prehypertensive," now known to increase the risk of any CV event by
two to fourfold compared with a normal BP (<120/80 mm Hg).2 Older persons, in Figure 2
whom hypertension is both more prevalent and more likely to lead to CVD
complications, are more likely to have elevations in SBP in the presence of normal
DBP (Figure 2). The positive correlation between BP and risk of CVD morbidity and
mortality is stronger for SBP than for DBP.
Ageing is associated with a progressive increase in systolic BP, a reduction in

diastolic BP, and widening of the pulse pressure. This is a reflection of a
progressive reduction in the compliance, or stiffening, of large conduit arteries. Figure 3
"Isolated systolic hypertension" (ISH), the predominant form of hypertension in the
elderly, is defined as a SBP of 140 mm Hg or greater in the presence of a DBP of 90
mm Hg or lower (Figure 3). The accuracy of diagnosis and staging of hypertension
is markedly improved by using SBP rather than DBP as the dominant criterion.
"Essential, primary, or idiopathic hypertension," defined as high BP due neither to

secondary causes nor to a Mendelian (monogenetic) disorder, accounts for 90% of
all cases. The term "primary hypertension" is preferred, since "essential
hypertension" represents an archaic misunderstanding of pathophysiology, namely
that hypertension is "essential" to maintain blood flow through severely narrowed
resistance vessels.
"Secondary hypertension" is high BP caused by an identifiable and potentially

curable disorder. "Refractory or resistant hypertension" is defined as a BP of
≥140/90 mm Hg despite three drugs of different classes at maximum approved
doses, given for at least 1 month. "Spurious hypertension (pseudohypertension)" is
artefactually elevated BP obtained by indirect cuff measurement over a rigid, often
calcified, brachial artery.
"Whitecoat hypertension" describes patients whose BP is high (>140/90 mm Hg) in

an office or clinic setting, with a normal daytime ambulatory pressure (<135/85 mm
Hg). This is a relatively benign condition with low risk of morbid events; however, the
risk may increase with longterm followup (6 years or more). Antihypertensive
medication in whitecoat hypertension patients may decrease clinic BP, but
produces little or no change in ambulatory BP; thus, drug treatment may not confer
substantial benefit.
"Masked hypertension" is the mirror image of whitecoat hypertension. Here, the

clinic BP is normal, but ambulatory or home measurements are high, and
associated with high risk. Although the prevalence of masked hypertension is low,
perhaps only 6% of the normotensive population, the absolute number in the United
States may approach 1518 million.
The term "hypertensive crisis" encompasses both hypertensive urgency and

hypertensive emergency. "Hypertensive urgency" is defined as DBP >120 mm Hg in
the absence of acute or rapidly worsening targetorgan damage (Figure 3).
"Hypertensive emergency" is defined as acute or rapidly worsening targetorgan
damage occurring in a hypertensive patient in association with elevated BP, but
irrespective of the specific BP level attained. "Malignant hypertension" is a
hypertensive emergency associated with papilledema, whereas "accelerated
hypertension" is a hypertensive emergency associated with retinal hemorrhages
and exudates.
Because of the new data on lifetime risk of hypertension and the impressive
increase in the risk of CVD complications associated with levels of BP previously
considered to be normal, the seventh report of the Joint National Committee for the
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)
introduced a new classification that includes the term "prehypertension" for those
with SBP 120139 mm Hg or DBP 8089 mm Hg (Figure 1).3
Individuals who are prehypertensive are not candidates for drug therapy on the basis
of their BP alone and should be advised to practice lifestyle modification to reduce
their risk of developing hypertension in the future. However, persons with BPs in the
prehypertensive range and high CV risk should be treated with antihypertensive
medications to a target of <130/80 mm Hg.
High CV risk is indicated by the presence of diabetes, chronic kidney disease,

coronary artery disease, coronary artery disease equivalents (stroke, carotid
disease, aortic aneurysm, peripheral vascular disease), or by a Framingham risk
score of >10%.
Classification and Management of Blood Pressure for Adults Ages 18 Years or Older
Figure 1
Reproduced with permission from Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 (Express) Report. JAMA 2003;289:256072. Copyrighted © 2003,
American Medical Association. All Rights reserved.
Changes in Systolic and Diastolic Blood Pressure With Age
Figure 2
Reproduced with permission from Lippincott, Williams, & Wilkins. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult
population. Results from the Third National Health and Nutrition Examination Survey, 19881991. Hypertension 1995;25:30513.
Other Hypertension Definitions
Figure 3
*The most frequent causes of secondary hypertension are renal parenchymal disease, renal artery stenosis, pheochromocytoma, primary
aldosteronism (Conn’s syndrome), coarctation of the aorta, and vasoconstrictor drugs. See section on Secondary hypertension.
†Orthodox definition requires a diastolic BP of >120 mm Hg, but any elevated BP may be associated with acute target organ damage, justifying
management as a hypertensive emergency.
DBP = diastolic blood pressure; HT = hypertension; SBP = systolic blood pressure.

Prevalence
Approximately 76 million Americans have hypertension, about one in three of the

adult population.4 In a study conducted in 19992000, 40% of persons were
normotensive, 30% were prehypertensive, and 30% were hypertensive. There has Figure 2
been an increase in the prevalence of hypertension in the United States from 1988
1994 (25%) to 20052008 (33%), with a consequent increase in hypertension
related mortality.4,5 The prevalence of hypertension increases with age, so that well
over 50% of the population above the age of 55 years has hypertension, and in the
75+ age group, the prevalence is 7080%.
SBP in the population increases with advancing age throughout life, whereas DBP Figure 4
tends to plateau or fall after age 60 (Figure 2). Consequently, in older persons, the
diagnosis of hypertension is more often made on the basis of SBP rather than DBP,
and the prevalence of ISH is much greater in the elderly than in middleaged and
younger individuals. A higher percentage of men than women have high BP until age
45. From age 45 to age 54, the percentages of men and women with hypertension
are similar, and after age 55, a much higher percentage of women have
hypertension than do men. The prevalence of hypertension has increased
significantly (from 25% to 30%) since the National Health and Nutrition Examination
Survey (NHANES) of 198891 in women of all age groups, most dramatically in
those ages 60 years and over.
There are some ethnic differences in the prevalence of hypertension. Hypertension

is more prevalent in nonHispanic blacks than in nonHispanic whites and Mexican
Americans (Figure 4).4,6 Overall, African Americans have a higher prevalence of
hypertension (41%) than whites (28%) or Mexican Americans (27%). In both sexes,
hypertension was associated with increasing age, black race/ethnicity, and higher
body mass index.
Changes in Systolic and Diastolic Blood Pressure With Age
Figure 2
Reproduced with permission from Lippincott, Williams, & Wilkins. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult
population. Results from the Third National Health and Nutrition Examination Survey, 19881991. Hypertension 1995;25:30513.
Hypertension Prevalence by Age and Race/Ethnicity in Men and Women
Figure 4
Reproduced with permission from Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United
States, 19882000. JAMA 2003;290:199206. Copyrighted © 2003, American Medical Association. All Rights reserved.
Hypertension and Cardiovascular Risk
Advances in diagnosing and treating hypertension have played a major role in the
dramatic declines in CHD (down 49%) and stroke (down 58%) mortality that have
occurred in the past 30 years. Major progress has been made in public awareness Figure 5
of the importance of high BP in the population. However, rates of decline of death
from CVD have slowed in the past decade, and major complications of
hypertension, including heart failure and endstage renal disease, have actually
risen over that time period. In addition to the rapidly escalating prevalence of
diabetes and obesity, a major contributor to these trends is inadequate control of BP
in the hypertensive population. Although there has been an improvement in the past
decade, still <50% of patients with hypertension have their BP controlled (Figure 5).4 Figure 6
In the elderly population, increased pulse pressure (PP) (generally a result of

decreased DBP in the presence of elevated SBP) is a predictor of CVD risk. SBP
should be stressed more than DBP in the diagnosis and treatment of hypertension
in the elderly because it plays a major role in determining risk of CVD events and
benefits of therapy. CVD, including stroke, is the most common cause of death and
disability in developed countries, and hypertension is one of the most important
Figure 7
modifiable risk factors for CVD.1 The relationship between BP and CVD mortality is
positive, strong, and continuous.
A metaanalysis of observational studies involving more than 1 million individuals

without prior histories of stroke or heart disease carried out by the Prospective
Studies Trialists' Collaboration showed that death from ischemic heart disease and
stroke increases continuously and linearly from BP levels as low as 115 mm Hg
Figure 8
systolic and 75 mm Hg diastolic upward.7
An increment of 20 mm Hg in SBP or 10 mm Hg in DBP in middleaged and elderly

persons is associated with a twofold increase in CVD (both ischemic heart disease
and stroke) mortality throughout the entire range of BP (Figures 6, 7). Likewise, a
decrease of 20 mm Hg in SBP or 10 mm Hg DBP halves CVD mortality.
Individuals with a BP in the prehypertensive range (SBP 120139 mm Hg or DBP 80

89 mm Hg) also have a significantly greater risk of developing a CV event than those
with a normal BP (<120/80 mm Hg). Data from the Framingham Heart Study showed
that the lower half of the prehypertension range (SBP 120129 mm Hg or DBP 8084
mm Hg) is associated with a doubling of risk of developing a CV event, and the
upper half of the prehypertension range (SBP 130139 mm Hg or DBP 8589 mm
Hg) is associated with a threefold increased risk, when compared to normal BP.
This demonstrates that BPs even within the prehypertensive range of 120139/8089
mm Hg are far from benign (Figure 8).8
Prevalence of Hypertension*, Prevalence of Treatment† and Control§ of Blood Pressure Among Persons With Hypertension – National Health and
Nutrition Examination Survey, United States 19992002 and 20052008
Figure 5
The prevalence of hypertension did not change significantly from 19992002 (28.1%) to 20052008 (30.9%) after adjustment for sex, age,
race/ethnicity, and povertyincome.
*Average systolic blood pressure ≥140 mm Hg, average diastolic blood pressure ≥90 mm Hg, or current blood pressure – lowering medication
use.
† An answer of “yes” to the question, “Are you currently taking medication to lower your blood pressure?” Among those with hypertension
(average systolic blood pressure ≥140 mm Hg, average diastolic blood pressure ≥90 mm Hg, or current medication use). Unadjusted prevalence.
§ Average treated blood pressure <140/90 mm Hg on examination among all persons with hypertension. Unadjusted prevalence.
¶ Test for difference in prevalence statistically significant (p<0.01) after adjustment for sex, age group, race/ethnicity, and povertyincome ratio.
Reproduced with permission from CDC. National Health and Nutrition Examination Survey Data. Hyattsville, MD: US Department of Health and
Human Services, CDC; 2010. Available at http://www.cdc.gov/nchs/nhanes.htm. Accessed October 19, 2011.
Ischemic Heart Disease Mortality Rate in Each Decade of Age Versus Usual Blood Pressure at the Start of That Decade
Figure 6
Rates are plotted on a floating absolute scale, and each square has area inversely proportional to the effective variance of the log mortality rate.
For diastolic BP, each agespecific regression line ignores the lefthand point (i.e., at slightly less than 75 mm Hg), for which the risk lies
significantly above the fitted regression line.
IHD = Ischemic Heart Disease
Reproduced with permission from Elsevier Science. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, for the Prospective Studies
Collaboration. Agespecific relevance of usual blood pressure to vascular mortality: a metaanalysis of individual data for one million adults in 61
prospective studies. Lancet 2002;360:190313.
Stroke Mortality Rate in Each Decade of Age Versus Usual Blood Pressure at the Start of That Decade
Figure 7
Rates are plotted on a floating absolute scale, and each square has area inversely proportional to the effective variance of the log mortality rate.
For diastolic BP, each agespecific regression line ignores the lefthand point (i.e., at slightly less than 75 mm Hg), for which the risk lies
significantly above the fitted regression line.
IHD = Ischemic Heart Disease
Reproduced with permission from Elsevier Science. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, for the Prospective Studies
Collaboration. Agespecific relevance of usual blood pressure to vascular mortality: a metaanalysis of individual data for one million adults in 61
prospective studies. Lancet 2002;360:190313.
Impact of Prehypertension on CV Risk
Figure 8
Normal BP: <120/<80 mm Hg
PreHypertension (1): 120129/8084 mm Hg
PreHypertension (2): 130139/8589 mm Hg
Prehypertensive blood pressure (BP) is associated with an increased risk for cardiovascular disease (CVD). The association between baseline
BP and the incidence of CVD on followup was investigated in 6,859 participants in the Framingham Heart Study who were initially free of
hypertension and CVD (Vasan et al., 2001). A stepwise increase in cardiovascular (CV) event rates was noted in subjects with higher baseline
BP levels. The 10year cumulative incidence of CVD in subjects aged 35 to 64 years with prehypertension (2) at baseline (systolic BP: 130139
mm Hg; diastolic BP 8589 mm Hg) was 4% in women and 8% in men. In older subjects (ages 65 to 90 years), the incidence was 18% in women
and 25% in men. Compared with optimal BP, prehypertension (2) was associated with a risk factor adjusted hazards ration of 2.5 in women and
1.6 in men.
Reproduced with permission from Vasan RS, Larson MG, Leip EP, et al. Impact of highnormal blood pressure on the risk of cardiovascular
disease. N Engl J Med 2001;345:12917.
Etiology
(1 of 2)
Primary hypertension, which accounts for more than 90% of all cases of
hypertension, tends to cluster in families, and represents a complex interplay of Figure 9
polygenic and acquired etiology.9 Many pathophysiologic factors have been
implicated in the genesis of essential hypertension (Figure 9). These include:
Increased sympathetic nervous system activity.

Overproduction of sodiumretaining hormones and vasoconstrictors
(endothelin and thromboxane).
Longterm high sodium intake. Figure 10
Inadequate dietary intake of potassium and calcium.
Increased or inappropriate activation of the reninangiotensinaldosterone
system (RAAS).
Deficiencies of vasodilators such as prostaglandins and nitric oxide.
Congenital abnormalities of the resistance vessels.
Diabetes mellitus.
Insulin resistance. Figure 11
Obesity.
Increased activity of vascular growth factors.
Altered cellular ion transport.
The concept that structural and functional abnormalities in the vasculature—

including endothelial dysfunction, increased oxidative stress, vascular remodeling,
and decreased compliance—may antedate hypertension and contribute to its
pathogenesis, has gained strength in recent years. This formulation has important Figure 12
implications for the targeting of antihypertensive therapy in order to achieve benefits
beyond BP lowering.
Genetics
Hypertension due to a single gene mutation is rare. In the vast majority of cases,
multiple genes contribute to hypertension, and it is likely that each of the genes
makes a small contribution to the increased BP, with the resultant hypertension
representing a complex effect of many genes and environmental influences.
Improved techniques of genetic analysis, especially genomewide linkage analysis
and gene associations, have allowed a search for genes that contribute to the
development of primary hypertension. Application of these techniques has found
statistically significant linkage of BP to several chromosomal regions, including
regions linked to familial combined hyperlipidemia. Overall, however, identifiable
singlegene causes of hypertension are uncommon, consistent with a multifactorial
cause of primary hypertension. Ultimately the goal of gene mapping is to identify
single nucleotide polymorphisms (SNPs) that alter function in such a way as to
elevate BP.
The candidate gene approach typically compares the prevalence of hypertension or

the level of BP among individuals of contrasting genotypes at candidate loci in
pathways known to be involved in BP regulation. The most promising findings of
such studies relate to genes of the RAAS, such as the M235T variant in the
angiotensinogen gene, which has been associated with increased circulating
angiotensinogen levels and BP in many distinct populations, and a common variant
in the angiotensinconverting enzyme (ACE) gene that has been associated in some
studies with BP variation in men. These variants only modestly affect BP, and other
candidate genes have not shown consistent and reproducible associations with BP
or hypertension in larger populations. Thus, genetic causes of hypertension appear
to be uncommon in general hypertensive populations. Recently, a very large
genomewide association study of seven common diseases failed to find any
significant gene associations with hypertension.10
Mutations in about 15 genes have been shown to cause Mendelian forms of human
hypertension; all of these are very rare, and most affect BP by altering renal salt
handling. These will be described more fully in the section on Secondary
Hypertension.
Sodium and Potassium
Sodium excess and potassium deficit in the diet are pivotal factors in the
pathogenesis of hypertension.11 Primary hypertension and agerelated increases in
BP are virtually unknown in populations with a sodium intake of <50 mmol/day. On
average, for each 50 mmol/day increase in sodium intake, BP increases by about
5/3 mm Hg, and if sodium intake is lowered, BP generally falls. Most processed
foods have large amounts of sodium; a fast food hamburger contains over 1 g (over
40 mmol) of sodium. It is therefore no surprise that the average salt intake in the
United States is about 10 g/day, equivalent to about 4 g or (180 mmol) of sodium per
day.
In contrast, diets containing abundant fruits and vegetables are sodium poor and
potassium rich. Lowpotassium diets also predispose to hypertension, and
inclusion of potassiumrich foods in the diet lowers BP. An example of this is the
DASH (Dietary Approaches to Stop Hypertension) diet, rich in fruits, vegetables, and
lowfat dairy products, which has been shown to reduce BP in prehypertensive
persons.
Figure 10 depicts some of the molecular mechanisms implicated in the retention of

sodium and loss of potassium by the kidneys in primary hypertension. Other
mechanisms may include a congenital reduction in the number of nephrons,
diminished renal medullary blood flow, and acquired renal injury due to ischemia or
interstitial inflammation.
The main consequence of sodium retention and potassium depletion is an increase

in vascular tone and BP. Increased vascular smooth muscle tone is generated by
changes in the transmembrane distribution of sodium, by decreasing the synthesis
of nitric oxide, and by stimulation of sympathetic outflow from the brain. These effects
can be reversed by adequate potassium repletion, and minimized by dietary sodium
reduction.
Sympathetic Nervous System
Increased sympathetic nervous system activity increases BP and contributes to the

development and maintenance of hypertension through stimulation of the heart,
peripheral vasculature, and kidneys, causing increased cardiac output, increased
vascular resistance, and fluid retention. Autonomic imbalance (increased
sympathetic tone accompanied by reduced parasympathetic tone) has also been
associated with many metabolic, hemodynamic, trophic, and rheologic
abnormalities that result in increased CV morbidity and mortality (Figure 10).
Increased sympathetic activity and/or reduced parasympathetic activity increases
heart rate, stroke volume, cardiac output, peripheral resistance, norepinephrine, and
epinephrine secretion by the adrenal medulla, and renin secretion by activation of
the βadrenergic receptors on the juxtaglomerular apparatus of the kidney. All of
these effects raise BP.
The normal response to an elevated BP is activation of baroreceptors to reflexly

lower the pressure; there is evidence that in hypertensive individuals, baroreceptor
thresholds are reset upwards and baroreceptor sensitivity reduced, blunting the
normal response to an elevated BP and allowing for the maintenance of the
hypertension. There is also an interesting interrelationship between the
sympathetic nervous system and salt and water metabolism. Increased dietary salt
will activate the anterior hypothalamus to increase central nervous system
sympathetic outflow. Renal sympathetic nerve stimulation is increased in
hypertensive patients, inducing renal tubular Na+ and water reabsorption, resulting
in intravascular volume expansion and increased BP.
BP in younger individuals tends to be more labile, with an increase in cardiac output

and systolic BP, suggesting an important role for the sympathetic nervous system in
the initiation of hypertension. Thereafter, there is a shift to an increased vascular
resistance, also contributed to by the sympathetic nervous system, with an increase
in DBP and normalization of cardiac output. Eventually, after age 50 or 60 years, ISH
again predominates, which is associated with increased central arterial stiffness.
Chronic sympathetic stimulation induces vascular remodeling and left ventricular

(LV) hypertrophy, presumably by actions of norepinephrine on its receptors, as well
as on release of various trophic factors, including transforming growth factorβ,
insulinlike growth factor 1, and fibroblast growth factors. Positive correlations
between circulating norepinephrine levels, LV mass, and reduced arterial
compliance due to vascular hypertrophy have been demonstrated. Thus,
sympathetic mechanisms contribute to the development of targetorgan damage, as
well as to the pathogenesis of hypertension.
Vascular Reactivity
Hypertensive patients manifest greater vasoconstrictor responses to infused

norepinephrine than normotensive controls. The expected downregulation of
noradrenergic receptors in response to increased circulating norepinephrine levels
does not occur in hypertensive patients, resulting in enhanced sensitivity to
norepinephrine, increased peripheral vascular resistance, and BP elevation.
Vasoconstrictor responsiveness to norepinephrine is also increased in
normotensive offspring of hypertensive parents compared to controls without a
family history of hypertension, suggesting that the hypersensitivity may be genetic in
origin and not simply a consequence of elevated BP. Centrally acting sympatholytic
agents and α and βadrenergic antagonists are effective in reducing BP in patients
with essential hypertension, thus providing indirect clinical evidence for the
importance of sympathetic mechanisms in the maintenance of hypertension.
Exposure to stress increases sympathetic outflow, and repeated stressinduced

vasoconstriction may result in vascular hypertrophy, leading to increased peripheral
resistance and BP. Persons with a family history of hypertension have augmented
vasoconstrictor and sympathetic responses to laboratory stressors, such as cold
pressor testing and mental stress, which may predispose them to hypertension.
Vascular Remodeling
In hypertension, the increase in peripheral vascular resistance can be ascribed to

both functional (vasoconstriction) and morphologic (remodeling) effects on
precapillary small arteries and arterioles. There are two types of arterial remodeling
in hypertension: 1) eutrophic inward remodeling, and 2) hypertrophic inward
remodeling. Eutrophic inward remodeling refers to a decrease in lumen diameter
without a change in the thickness of the arterial wall. In contrast, hypertrophic inward
remodeling is defined as a decrease in lumen diameter associated with an
increase in wall thickness. Elevated peripheral vascular resistance in hypertensive
patients is related to rarefaction (decrease in number of parallelconnected vessels)
and luminal narrowing of resistance vessels (Figure 11).
Mechanisms of hypertrophy and eutrophic remodeling are similar, and include

increases in intravascular pressure, sympathetic activity, angiotensin II and
endothelin1 levels, and oxidative stress, as well as nitric oxide deficiency and
genetic factors.12 Antihypertensive treatment with several classes of agents,
including ACE inhibitors (ACEIs), angiotensinreceptor blockers (ARBs), and
calciumchannel blockers (CCBs), normalizes resistance vessel structure. On the
other hand, betablocker therapy does not reverse resistance vessel remodeling
even when it effectively lowers BP. In randomized clinical trials, the major
determinant of outcome seems to be BP reduction, and diuretics and CCBs seem to
have done as well or better than RAAS blockers, at least in highrisk patients.
However, many authorities would agree that the major determinant of CV outcomes
is BP reduction, using whatever class of drugs is effective.
Arterial Stiffness
SBP and PP increase with advancing age, mainly as a result of reduced elasticity
(increased stiffness) of the large conduit arteries. Increased stiffness of these
arteries results from collagen deposition and smooth muscle cell hypertrophy, as
well as thinning, fragmenting, and fracture of elastin fibers in the media. The
distending pressure of conduit vessels is a major determinant of stiffness. The two
phase (elastin and collagen) content of loadbearing elements in the media is
responsible for the behavior of these vessels under stress: At low pressures, stress
is borne almost entirely by the distensible elastin lamellae, while at higher
pressures, less distensible collagenous fibers are recruited, and the vessel
appears stiffer. Conduit vessels are relatively unaffected by neurohumoral
vasodilator mechanisms.
In addition to these structural abnormalities, endothelial dysfunction, which develops
over time as a consequence of both aging and hypertension, contributes functionally
to increased arterial stiffness in elderly persons with ISH. Other factors that
decrease central arterial compliance by damaging the endothelium include: 1)
diabetes, 2) tobacco use, 3) high dietary salt intake, 4) elevated homocysteine
levels, and 5) estrogen deficiency.
Reduced nitric oxide (NO) synthesis and/or release in this setting contributes to
increased wall thickness of conduit vessels such as the aorta and common carotid
artery. The functional significance of NO deficiency in ISH is supported by the ability
of NO donors, such as nitrates or derivatives, to increase arterial compliance and
distensibility, and reduce SBP without decreasing DBP.
Increased arterial stiffness contributes to the wide PP commonly seen in elderly

hypertensive patients, in part by causing the pulse wave velocity to increase. With
each ejection of blood from the LV, a pressure (pulse) wave is generated and travels
from the heart to the periphery at a finite speed that depends on the elastic
properties of the conduit arteries. The pulse wave is reflected at any point of
discontinuity in the arterial tree, and returns to the aorta and LV. The timing of the
wave reflection depends on both the elastic properties and the length of the conduit
arteries.
In younger persons (Figure 12), pulse wave velocity is sufficiently slow

(approximately 5 m/sec) so that the reflected wave reaches the aortic valve after
closure, leading to a higher DBP and enhancing coronary perfusion by providing a
"boosting" effect. In older persons, particularly if they are hypertensive, pulse wave
velocity is greatly increased (approximately 1020 m/sec) due to central arterial
stiffening. At this speed, the reflected wave reaches the aortic valve before closure,
merges with the incident or antegrade wave, and produces a higher SBP (and
afterload), PP, and a decreased DBP.
This phenomenon accounts for the higher SBP and PP and the lower DBP that is
seen in the elderly population and is exaggerated in the presence of hypertension.
The increase in SBP increases cardiac metabolic requirements and predisposes to
the development of LV hypertrophy and heart failure. PP is closely related to SBP and
is clearly linked to advanced atherosclerotic disease and CVD events such as fatal
and nonfatal myocardial infarction (MI) and stroke. With aging, there is a gradual shift
in the BPrisk relationships from diastolic to systolic and PP.
Most antihypertensive drugs act on peripheral muscular arteries rather than central
conduit vessels. They reduce PP via indirect effects on the amplitude and timing of
reflected pulse waves. Nitroglycerin causes marked reductions in wave reflection,
central SBP, and LV load, with smaller changes in SBP or DBP in the periphery.
Vasodilator drugs lower BP by decreasing arteriolar tone, but some of them, like
ACEIs, ARBs, and CCBs, also reduce the stiffness of conduit arteries and therefore
pulse wave reflection, contributing to their antihypertensive effect.
Pathophysiologic Mechanisms of Hypertension
Figure 9
Red arrows show hypertensionpromoting mechanisms; gray arrows show hypertensionopposing mechanisms.
AME = syndrome of apparent mineralocorticoid excess; Ang (17) = angiotensin (17) peptide; CGRP = calcitonin generelated peptide; CNS =
central nervous system; GI = gastrointestinal; GRA = glucocorticoidremediable aldosteronism; NO = nitric oxide.
Reproduced with permission from Saunders Elsevier. Franco V, Calhoun DA, Oparil S. Pathophysiology of hypertension. In: Hypertension: A
Companion to Braunwald’s Heart Disease. Black HR, Elliott WJ. Philadelphia: Saunders Elsevier; 2007:26.
Renal Mechanisms of Sodium Retention and Potassium Loss in Primary Hypertension
Figure 10
Potassium depletion stimulated both the sympathetic nervous system and the reninangiotensinaldosterone system to enhance sodium transport
from the tubular lumen into renal tubulat cells, via the Na+K+ exchanger (NHE) in the proximal tubule, and the Na+Cl' cotransporter (NCC) in the
distal tubule. In the collecting duct, the increase in aldosterone stimulated sodium reabsorption by activating the epithelial Na+ channel (ENaC).
Removal of sodium from the tubular lumen generates a more negative intraluminal membrane voltage, which enhances potassium excretion
through the luminal K+ channel. Aldosterone also stimulates the ATPdependent Na+K+ pump on the abluminal membrane of the tubular cell,
enhancing sodium retention and potassium loss. Excess sodium upregulates the formation of an endogenous digitalislike factor in the adrenal
glands and brain, which mediates further sodium retention by increasing the expression and activity of the renal Na+K+ pump.
Adapted with permission from Adrogué HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356:1966
78.
How Remodeling Can Modify the CrossSections of Blood Vessels
Figure 11
The starting point is the vessel at the center. Remodeling can be hypertrophic (increase of crosssectional area), eutrophic (no change in cross
sectional area), or hypotrophic (decrease of crosssectional area). These forms of remodeling can be inward (reduction in lumen diameter) or
outward (e.g., increase in lumen diameter).
Reproduced with permission from the American College of Physicians. Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann
Intern Med 2003;139:7616.
Change in Aortic Pressure Profile due to AgeRelated Vascular Stiffening and Increased Pulse wave Velocity (PWV)
Figure 12
1: Increased systolic blood pressure (SBP) and decreased diastolic blood pressure (DBP) due to decreased aortic distensibility. 2: Increased
PWV as a result of decreased aortic distensibility and increased distal (arteriolar) resistance. 3: Return of the reflected primary pulse to the
central aorta in systole rather than in diastole due to faster wave travel. 4: Change in aortic pulse wave profile because of early wave reflection.
Note the summation of antegrade and retrograde pulse waves to produce a large SBP. This increases left ventricular (LV) stroke work and
therefore myocardial oxygen demand. Note also the reduction in the diastolic pressuretime (integrated area under the DBP curve). This reduction
in coronary perfusion pressure increases the vulnerability of the myocardium to hypoxia. 5: The enhanced aortic BP resulting from decreased
aortic distensibility and early reflected waves.
Reproduced with permission from Saunders Elsevier. Rosendorff C. Ischemic heart disease in hypertension. In Hypertension: A Companion to
Braunwald’s Heart Disease, eds. Black HR, Elliott WJ. Philadelphia: Saunders Elsevier, 2007:329.
Etiology
(2 of 2)
ReninAngiotensinAldosterone System
Figure 13
Figure 13 summarizes the key elements of the RAAS. The key receptor for
angiotensin II is the AT1 receptor. AT1 receptors are found in the vasculature and
many other tissues. They activate calcium channels and the G protein,
phospholipase C, diacylglycerol and inositol trisphophate transduction pathways,
thus triggering angiotensin IImediated CV events, including constriction of
resistance vessels, stimulation of aldosterone synthesis and release, renal tubular
sodium reabsorption (directly and indirectly via aldosterone), stimulation of thirst,
Figure 14
release of antidiuretic hormone, and enhancement of sympathetic outflow from the
brain. Importantly, angiotensin II also induces hypertrophy and hyperplasia of
cardiac myocytes and vascular smooth muscle cells directly and indirectly by
stimulating the release of a number of growth factors and cytokines.12
Activation of the AT2 receptor subtype stimulates a phosphatase that inactivates

mitogenactivated protein kinase, a key enzyme involved in transducing signals from
Figure 15
the AT1 receptor. Thus, activation of the AT2 receptor opposes the biological effects
of AT1 receptor activation, leading to vasodilation, growth inhibition, and cell
differentiation (Figure 14).
The physiologic role of the AT2 receptor in adult humans is unclear, but it is thought
to function under stress conditions (e.g., vascular injury, ischemia reperfusion) and
to account for some of the favorable vascular effects of the ARBs, which are selective
antagonists of AT1 receptors. When an ARB is administered, renin is released from Figure 16
the kidney due to removal of feedback inhibition by angiotensin II. This leads to
increased generation of angiotensin II, which is shunted to the AT2 receptor, favoring
vasodilation and attenuation of unfavorable vascular remodeling.
Local production of angiotensin II in a variety of tissues, including the blood vessels,

heart, adrenals, and brain, is under the control of ACE and a number of other
enzymes, including chymas. The activity of the local RAAS and alternative pathways Figure 17a
of angiotensin II formation may make an important contribution to the remodeling of
resistance vessels and the development of targetorgan damage (including
atherosclerosis, LV hypertrophy, MI, heart failure, stroke, endstage renal disease,
and arterial aneurysm) in hypertensive persons. NonACE enzymes that convert
angiotensin I to angiotensin II are responsible for the phenomenon of "angiotensin
escape," whereby the plasma and presumably the tissue concentration of
angiotensin II is never completely suppressed by ACEIs. Figure 17b
Angiotensin II and Oxidative Stress
Stimulation of reactive oxygen species production is an additional mechanism by

which angiotensin II increases CV risk (Figure 15).11 Hypertension associated with
angiotensin II administration is linked to upregulation of vascular p22phox mRNA, a
component of the oxidative enzyme NAD(P)H oxidase. AT1 receptordependent
activation of NAD(P)H oxidase is associated with enhanced formation of the oxidant
superoxide anion (O2), which reacts readily with NO to form the oxidant peroxynitrite
(ONOO). Reduction in NO bioavailability thus provides an additional mechanism to
explain the enhanced vasoconstrictor response to angiotensin II in hypertension.
NAD(P)H oxidase may also play an important role in the hypertrophic response to
angiotensin II.
Other vasculotoxic responses to angiotensin II that are linked to the activation of

NAD(P)H oxidase include the oxidation of LDL cholesterol and increased mRNA
expression for monocyte chemoattractant protein1 (MCP1) and vascular cell
adhesion molecule1 (VCAM1). ACEIs and ARBs limit oxidative reactions in the
vasculature by blocking angiotensin IIinduced activation of NAD(P)H oxidase. This
has led to the hypothesis that RAAS blockers have clinically important vasoprotective
effects beyond BP lowering.
Aldosterone
The effects of aldosterone on sodium and water reabsorption in the distal tubule of
the kidney are well known, but many of the deleterious effects of aldosterone on the
CV system are mediated via activation of mineralocorticoid receptors on
nonepithelial cells of the brain, heart, and blood vessels (Figure 16). Aldosterone
has direct effects on the brain that result in increases in salt appetite, sympathetic
outflow, and BP; effects on the heart that result in cardiac hypertrophy and fibrosis;
and direct vascular effects that result in endothelial dysfunction, renal arteriopathy
with proteinuria, and vascular inflammation with extracellular matrix deposition,
fibrosis, and increased stiffness.
These injurious effects of aldosterone often occur in the setting of hypertension; all
require salt for their full expression. Myocardial fibrosis, including both perivascular
and interstitial fibrosis, has been demonstrated in a variety of rodent models of
hypertension and shown to correlate strongly with circulating aldosterone levels.
Importantly, when salt was withheld from these animals, cardiac fibrosis did not
occur. Similarly, in humans, lowsalt diets increase aldosterone levels, but these are
not associated with cardiac or vascular pathology.
Compelling evidence indicates that aldosteroneinduced fibrosis is initiated by

vascular and perivascular inflammation. The nonselective aldosterone antagonist
spironolactone and the selective mineralocorticoid receptor antagonist eplerenone
effectively prevent or reverse expression of proinflammatory cytokines and
chemokines, and the consequent vascular and perivascular fibrosis in rodent
models. These findings are consistent with clinical evidence of an inverse
relationship between plasma aldosterone and large artery compliance in
hypertensive patients.
Spironolactone treatment of heart failure patients has also been shown to reduce
circulating levels of procollagen type II Nterminal aminopeptide, providing indirect
evidence of an antifibrotic effect on the heart. Spironolactone and eplerenone
improve outcomes in heart failure.13,14
Aldosterone excess is a more common cause of, or contributing factor to

hypertension, particularly treatmentresistant hypertension, than previously thought.
Many patients with primary hyperaldosteronism do not manifest low serum
potassium levels, and serum potassium is not an entirely reliable screening test for
aldosterone excess.
Prevalence rates between 8% and 32% have been reported on the basis of the
patient population being screened (higher in referral practices, where the patient mix
tends to be enriched with refractory hypertension, and lower in family practices or
community databases). BP in patients with aldosterone excess responds well to
treatment with a mineralocorticoid receptor antagonist. Additional clinical studies
with these agents are needed to elucidate the role of aldosterone in the
pathogenesis of primary and secondary hypertension and related targetorgan
damage in human populations.
Endothelin
The endothelins (ET1, ET2, ET3) are a family of 21 amino acid peptides with potent
biological activities. They are synthesized in several tissues, including the
endothelium (ET1) and smooth muscle cells. The production and release of
endothelin is stimulated by many factors, hormonal and metabolic, and by growth
factors, hypoxia, and shear stress.
Released endothelin binds to the endothelin receptors ETA and ETB. The ETA
receptors on vascular smooth muscle cells mediate vasoconstriction and the ETB
receptors on the endothelium are linked to nitric oxide (NO) and prostacyclin
release, thus tending to promote vasodilation. The ETA receptors activate the
phospholipase C, inositol trisphosphate, diacylglycerol pathway (as does
angiotensin II), which through an increase in cytosolic Ca2+ and protein kinase C
(PKC) causes vasoconstriction and stimulation of vascular smooth muscle growth
and proliferation.15 Thus, a complex interaction between ET1, angiotensin II, α
receptor agonists, Ca2+, and other growth factors participates in the pathogenesis of
vascular hypertrophy in hypertension.
The plasma concentration of ET1 tends to be increased in severe atherosclerotic

disease, but not consistently in hypertension. The reason for this may be that ET1 is
secreted in an abluminal direction by endothelial cells and acts in a paracrine
fashion on underlying smooth muscle cells to cause vasoconstriction and elevate
BP without necessarily reaching increased levels in the systemic circulation.
ET receptor antagonists reduce BP and peripheral vascular resistance in both

normotensive persons and patients with mild to moderate essential hypertension,
supporting the interpretation that ET1 plays a role in the control of vasomotor tone in
normal human subjects, as well as in the pathogenesis of hypertension. However,
development of this drug class for the treatment of systemic hypertension has been
plagued by toxicity issues, mainly hepatotoxicity.
The ET receptor antagonists bosentan, ambrisentan are FDAapproved for the

treatment of pulmonary, but not systemic arterial hypertension in the United States.
In a recent phase III clinical trial16 in patients with resistant systemic hypertension,
the ETAselective antagonist darusentan failed to achieve its coprimary efficacy
endpoints of a change in systolic and diastolic blood pressure after 14 weeks
compared to placebo.
Endothelial Dysfunction
Endothelial dysfunction has been implicated as both a cause and a consequence of

hypertension via mechanisms that involve reduced NO synthesis, release, and/or
bioactivity (Figures 17a, b). NO is a potent vasodilator, inhibitor of platelet adhesion
and aggregation, and suppressor of migration and proliferation of vascular smooth
muscle cells. NO is released by normal endothelial cells in response to a variety of
stimuli, including changes in BP, shear stress, and pulsatile stretch, and plays an
important role in BP regulation, thrombosis, and atherosclerosis. The CV system in
normal persons is exposed to continuous NOdependent vasodilator tone, but NO
related vascular relaxation is diminished in hypertensive persons.
It has been suggested that angiotensin II at concentrations that have a minimal

effect on BP enhances formation of the oxidant superoxide. Increased oxidant stress
and the development of endothelial dysfunction may thus predispose to the
development of hypertension. The observation that in vivo delivery of superoxide
dismutase (enzyme that reduces superoxide to hydrogen peroxide) reduces BP and
restores NO bioactivity provides further evidence that superoxideinduced oxidant
stress contributes to the inactivation of NO and the development of endothelial
dysfunction in hypertensive models.
The ReninAngiotensinAldosterone System
Figure 13
The enzyme renin, produced mainly in the juxtaglomerular cells of the kidney, cleaves the decapeptide angiotensin I from a precursor molecule,
angiotensinogen, a large globular protein derived mainly from the liver. Angiotensinconverting enzyme (ACE) is a dipeptidylcarboxypeptidase
that converts angiotensin I to the octopeptide angiotensin II, and also inactivates bradykinin, a potent vasodilator. Other angiotensin molecules are
angiotensin (17) and angiotensin IV (38), the functions of which have not yet been fully elucidated.
RAS = reninangiotensin system; ACE = angiotensinconverting enzyme; ARB = angiotensin II type1 receptor blockers; ATR = angiotensin
receptor; EP = endopeptidase; EC = endothelial cells.
Reproduced with permission from Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet 2006;368:144956.
The Angiotension II Types 1 (AT1) and 2 (AT2) Receptors Have Opposing Effects
Figure 14
The AT1 receptor mediates vasoconstriction, cell growth, and cell proliferation; the AT2 receptor has the opposite effect, stimulating vasodilation,
antigrowth, and cell differentiation. The AT1 receptor is antinatriuretic; the AT2 receptor is natriuretic. The AT1 receptor stimulation causes free
radical formation; AT2 stimulation produces nitric oxide (NO) that can neutralize free radicals. The AT1 receptor induces plasminogen activator
inhibitor1 (PAI1) and other growth family pathways; the AT2 receptor does not. The angiotensinreceptor blockers bind to and selectively block
the AT1 receptor, allowing stimulation of the receptor by angiotensin II.
Intern Med 2003;139:7616.
Mechanisms of Angiotensin II (ANG II)Dependent, OxidantMediated Vascular Damage
Figure 15
Intern Med 2003;139:7616.
Deleterious Effects of Aldosterone/Salt
Figure 16
Reproduced with permission from Bentham Science Publishers. McMahon EG. Eplerenone, a new selective aldosterone blocker. Curr Pharm Des
2003;9:106575.
Endothelial Function in the Normal Vasculature (1 of 2)
Figure 17a
Large conductance vessels (left), for example, epicardial coronary rteries, and resistance arterioles (right), are shown. In normal conductance
arteries, platelets and monocytes circulate freely, and oxidation of LDL is prevented by a preponderance of NO formation. At the level of the
small arterioles, reduced vascular tone is maintained by constant release of NO. Endothelin1 normally induces no vasoconstriction or only
minimal vasoconstriction through stimulation of type A endothelin receptors (ETA) located on smoothmuscle cells, and contributes to basal NO
release by stimulating type B endothelin receptors (ETB) on endothelial cells.
Intern Med 2003;139:7616.
Endothelial Function in the Hypertensive Vasculature (2 of 2)
Figure 17b
In the hypertensive microvasculature, decreased activity of NO and enhanced ETAmediated vasoconstrictor activity of endothelin1 result in
increased vascular tone and medial hypertrophy, with a consequent increase in systemic vascular resistance. At the level of conductance
arteries, a similar imbalance in the activity of endothelial factors leads to a proatherosclerotic milieu that is conducive to the oxidation of LDL, the
adhesion and migration of monocytes, and the formation of foam cells. These activities ultimately lead to the development of atherosclerotic
plaques, the rupture of which, in conjunction with enhanced platelet aggregation and impaired fibrinolysis, results in acute intravascular
thrombosis, thus explaining the increased risk for CV events in patients with hypertension. These mechanisms may be operative in patients with
high normal BP and may contribute to their increased CV risk.
Intern Med 2003;139:7616.
Target Organs
(1 of 2)
High BP has significance only insofar as it causes damage to target organs. The common theme in many of these
effects is inward eutrophic remodeling of small resistance arteries, increased large artery stiffness, and accelerated
atherogenesis. There is evidence that these vascular changes may precede the development of hypertension,
suggesting that these vascular effects may play a primary role in the development of hypertension or that they share a
common neurohormonal etiology with hypertension.17 This section briefly summarizes the organ damage that occurs in
response to prolonged BP elevation, including effects on the ventricular myocardium, brain, arteries, and kidney.
Hypertension and the Heart
The LV in hypertensive subjects becomes progressively less distensible in response to an increased afterload, and later
will hypertrophy. The etiology of this hypertensioninduced cardiac damage is complex, and includes pressure overload,
circulating and local factors such as angiotensin II, catecholamines, and ET1, which promote vascular and myocyte
growth, increased connective tissue deposition, and collagen crosslinking.
Increased LV stiffness and hypertrophy have several consequences: limitation of the rate at which the LV can fill during
diastole causes left atrial (LA) enlargement and thickening, with the development of a fourth heart sound or gallop and
the electrocardiographic (ECG) changes of LA abnormality (broad, notched P waves in II, biphasic P wave in V1 ), and the
characteristic echocardiographic findings of LA enlargement.
Individuals with LA enlargement are more likely to develop atrial fibrillation. LA size is important in assessing the effects
of hypertension on the heart. Newonset atrial fibrillation is more likely to develop in hypertensive patients with increased
LA size, and antihypertensive therapy is protective against this arrhythmia. Increased LV stiffness may produce the
symptoms and signs of diastolic heart failure. LV hypertrophy (LVH) also imposes an increase in myocardial oxygen
demand, which in the presence of occlusive coronary artery disease (itself accelerated by hypertension) and impaired
coronary flow reserve, makes the individual more susceptible to myocardial ischemia, infarction, or heart failure. ECG
evidence of LVH, strain pattern and prolonged QRS duration are all markers of cardiac targetorgan damage and
predictors of heart failure in hypertensive patients.18
The echocardiogram may show interventricular septal hypertrophy, hypertrophy of the LV free wall, and increased
calculated LV mass (men ≥225 g, women ≥165 g) or LV mass index (men ≥115g/m2 , women ≥95 g/m2 ).19 The
echocardiographic diagnosis of LV diastolic dysfunction due to decreased LV compliance is more complex, and is
discussed in the section on LV failure with preserved systolic function.
The prevalence of LVH in hypertensive individuals is 2535%. LVH is associated with a graded increase in the risk of
CVD, proportional to the degree of hypertrophy and over and above the risk of the hypertension per se. Patients with
hypertension and LVH are at increased risk of acute coronary syndrome due to the increased metabolic demand of the
hypertrophied myocardium, the increased output impedance of the elevated aortic BP, the impairment of myocardial
perfusion related to coronary artery disease, and the increased resistance to myocardial blood flow in the stiff LV.
Heart failure, with or without a preserved systolic function, is another frequent consequence of hypertensive and ischemic
heart disease. Many studies have shown significant regression of LVH when BP is reduced; it is not clear whether this is
simply a function of the degree of BP lowering or whether some antihypertensive drugs are better than others at doses
that are equipotent for BP reduction. ACE inhibitors, ARBs, CCBs, and diuretics all regress LVH, whereas betablockers
are less effective.
Recent data have shown that an increased nocturnal BP on ambulatory BP monitoring, especially when associated with
"nondipping" of nocturnal BP, has additional predictive value for development of congestive heart failure beyond
conventional office BP measurement.20
Hypertension and the Brain
The central nervous system complications of hypertension are stroke, hypertensive encephalopathy, and dementia.
Stroke
Hypertension is the most prevalent risk factor for cerebrovascular disease, and contributes substantially to stroke. This
may be due to lipohyalinosis or fibrinoid necrosis with associated focal damage to small resistance vessels, which may
occlude, causing lacunar infarcts, or rupture, causing hemorrhagic strokes. Hypertension may exacerbate
atherosclerosis of larger vessels, which if occluded, will cause ischemic stroke, or if ruptured, hemorrhagic stroke. Other
mechanisms of stroke include embolization of thrombus from hypertensionrelated atheroma in the carotid arteries or
ascending aorta, or from hypertensionrelated heart disease, such as atrial fibrillation, MI, ventricular dyskinesia or
aneurysm, and rarely, paradoxical emboli through a patent foramen ovale.
Most strokes have a central core of severe blood flow reduction with permanent infarction and a surrounding penumbra of
ischemic, but salvageable tissue. The purpose of prompt therapy with anticoagulants, fibrinolytics, and neuroprotective
therapies is to improve flow to the ischemic penumbra. The management of hypertension in the patient with acute stroke
is controversial. Cerebrovascular autoregulation is impaired or abolished in the ischemic penumbra because of local
hypoxia and acidosis, resulting in a passive pressureflow relationship in that region. Thus, a high perfusion pressure
(i.e., a high BP) is an advantage in acute ischemic stroke.
Current stroke guidelines from the American Heart Association and American Stroke Association reflect this concept.21
They suggest that antihypertensive medications be withheld unless the BP is very high, >220 mm Hg systolic, or BP >120
mm Hg diastolic. However, one study, CHHIPS (Controlling Hypertension and Hypotension Immediately PostStroke),22
has shown improved stroke outcomes (lower mortality and less poststroke dependency) if the BP is lowered to a SBP of
145155 mm Hg acutely. In the longerterm, there is ample evidence from many clinical trials that BP lowering is
important for the primary prevention of stroke. In patients with previous stroke, treatment of hypertension does reduce the
risk of recurrence.23
Although numerous studies have strongly supported the treatment of hypertension to prevent stroke, two large studies on
the secondary prevention of stroke have produced mixed results. The PROGRESS (Perindopril Protection Against
Recurrent Stroke Study) trial,23 showed that lowering BP (mean reduction 12.3/5.0 mm Hg) with perindopril and
indapamide in a population with a history of stroke, decreased the risk of stroke recurrence by 28% over 4 years.
On the other hand, the PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial,24 showed no benefit
of telmisartan in the secondary prevention of stroke. This may be explained on the basis that, compared to
the PROGRESS cohort, the subjects enrolled in PRoFESS had lower baseline BPs (144/84 mm Hg vs. 147/86 mm Hg),
and a lesser BP lowering during the study (4.9/2.8 mm Hg vs. 12.3/5.0 mm Hg). The need to lower BP to target values in
hypertensive patients who have had a stroke remains strong.
Target Organs
(2 of 2)
Acute Hypertensive Encephalopathy
Acute hypertensive encephalopathy is a medical emergency characterized by a very high BP (hypertensive crisis), severe
headache, and other neurologic symptoms (such as agitation, visual blurring or blindness, drowsiness, confusion,
seizures). Papilledema (malignant hypertension) is often, but not always present. In this situation, the BP in postcapillary
venules exceeds the upper limit of cerebrovascular autoregulation, causing pressurerelated dilatation with disruption of
the bloodbrain barrier and focal cerebral edema.
Factors which may facilitate the "breakthrough" of autoregulation include activation of potassium channels and of
parasympathetic nerves to cerebral vessels. Hypertensive encephalopathy is a hypertensive emergency: Patients should
be admitted to an intensive care unit for parenteral antihypertensive therapy.
Mild Cognitive Impairment and Dementia
SBP is a strong predictor of mild cognitive impairment and frank dementia, both vascular dementia (VD) and Alzheimer's
disease (AD). VD and AD have different pathogeneses; VD produces small infarcts, arteriosclerosis, particularly medial
necrosis of small penetrating arterioles (Binswanger's disease or subcortical arteriosclerotic encephalopathy), and
subcortical demyelination. The hallmark lesion of AD is the deposition of extracellular amyloid plaques and intracellular
neurofibrillary tangles. VD and AD are often not easy to differentiate clinically or by current imaging techniques, and are
often found in the same patient. Good BP control has been shown in controlled clinical trials to substantially reduce the
risk of mild cognitive impairment and dementia.
Hypertension with chronic kidney disease (CKD) is defined as the presence of longstanding injury to the kidney,
confirmed by kidney biopsy or a glomerular filtration rate (GFR) of <60 ml/min/1.73 m2 for longer than 3 months. The
clinical associations are a serum creatinine of ≥1.2 mg/dl in women and ≥1.4 mg/dl in men, and microalbuminuria (30
300 mg/day) or albuminuria (>300 mg/day). Diabetes and hypertension account for the bulk of patients with endstage
renal failure.
The key components of hypertension in patients with kidney disease include: 1) inappropriately elevated sympathetic
nervous activity, 2) activation of the RAAS, and 3) impaired sodium and water excretion by the kidney. Both sympathetic
overactivity and angiotensin II selectively constrict the efferent arterioles of the kidney, increasing glomerular filtration
pressure and therefore filtration fraction. As a consequence, the colloid osmotic pressure of the fluid leaving the
glomerular capillary to enter the peritubular network of capillaries is increased, resulting in greater sodium reabsorption
through the tubules. Both the sympathetic nervous system and the RAAS also are direct vasoconstrictors of systemic
resistance arterioles. Sympathetic nerves also stimulate renin release through activation of βreceptors, resulting in an
increase in angiotensin II.
Another stimulus to renin release is the low sodium concentration in the distal nephron, a consequence of the greater
sodium reabsorption in the proximal renal tubule. Other mechanisms include a direct effect of angiotensin II to enhance
the sodium/hydrogen antiporter, of the proximal tubule cells to increase sodium reabsorption, and the angiotensin II
mediated release of the mineralocorticoid hormone, aldosterone. Angiotensin II also causes morphologic changes in the
kidney, mesangial cell proliferation, and the activation and release of proinflammatory cytokines in the renal
parenchyma.
Hypertension is both a cause and complication of CKD, and lowering BP slows the progression of renal disease.
Patients with CKD are at increased risk of CV events. The BP goal in patients with CKD is <130/80 mm Hg. Achievement
of this level of BP control in patients with CKD is often difficult, and most patients will require 24 antihypertensive drugs in
moderate to high doses.
Both the JNC 7 and the Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney
Disease (K/DOQIBP) guidelines (http://www.kidney.org/professionals/kdoqi/guidelines_bp/index.htm) clearly state that
compelling and specific indications exist for the use of ACEIs or ARBs to lower BP in patients with either diabetes or
CKD.3 Even if the BP is normal, it is reasonable to treat diabetic patients with an ACEI or ARB, to reduce
microalbuminuria and prevent the development of diabetic nephropathy,25 as well as to slow the rate of decline of renal
function and prevent CV events in established diabetic nephropathy.26,27 The evidence for renoprotection of ACEIs or
ARBs is not as strong for hypertension as it is for diabetes, but the use of these classes of drugs are appropriate for the
firstline treatment of hypertension in patients with microalbuminuria or frank nephropathy.
It should be borne in mind that RAAS blockers reduce angiotensin IIdependent efferent arteriolar tone, thus reducing
glomerular filtration pressure and therefore GFR. The resulting increase in serum creatinine is not an indication to
discontinue the ACEI or the ARB. If the serum creatinine level increases by more than 30%, or if it continues to rise after 3
months of therapy, then volume depletion, unsuspected LV systolic dysfunction with a reduced cardiac output, or renal
artery stenosis should be suspected and the RAAS blocker should be withheld until the underlying condition can be
diagnosed and corrected.
Similarly, a rise in serum potassium should be expected with ACEI or ARB therapy; this should be a concern only if the
serum potassium rises 0.5 mEq/L or more from a baseline level of >5.0 mEq/L. Otherwise the rise in serum potassium
can be managed by educating the patient to reduce the intake of potassium.
Key Points
Hypertension is very common in nearly all populations, and is a major independent risk factor for CVD.
There is a graded relationship between BP and CV risk, with no apparent lower limit.
BP targets are <130/80 mm Hg for those with diabetes, kidney disease, and coronary artery disease.
The etiology of hypertension is multifactorial; monogenetic forms are rare. Key elements in the etiology are
activation of neurohormonal systems (sympathetic nervous system, RAAS, ET); increased oxidative stress; altered
cellular ion transport of sodium, potassium, and calcium; and abnormalities of endothelial function and vascular
reactivity, large artery compliance, and small artery/arteriolar resistance.
The main targetorgan effects and resultant CVD events are atherosclerotic vascular disease; MI, LV hypertrophy,
atrial fibrillation, heart failure; stroke, encephalopathy, dementia, and renal failure.
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25. Parving HH, Lehnert H, BrochnerMortensen J, Gomis R, Andersen S, Arner P, on behalf of the Irbesartan in
Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of
diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:8708.
26. Brenner BM, Cooper ME, de Zeeuw D, et al., on behalf of the RENAAL Study Investigators. Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861
9.
27. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensinreceptor antagonist irbesartan
in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:85160.
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5.2: Diagnosis and Management of Hypertension
Author(s):
Learner Objectives
Upon completion of this module, the reader will be able to implement current guidelines for the diagnosis and treatment of
hypertensive patients, including multiple risk factor modification.
Diagnosis of Hypertension
Hypertension should be diagnosed and treated in the context of reducing overall

cardiovascular (CV) risk and preventing morbidity and mortality from CV disease
(CVD). In most hypertensive patients, there are multiple risk factors for Figure 1
atherosclerotic disease. Therefore, comprehensive assessment and treatment of all
risk factors are essential for effective intervention. All modifiable CV risk factors (i.e.,
hypertension, hyperlipidemia, alcohol and tobacco use, obesity, sedentary lifestyle,
glucose intolerance, and insulin resistance) should be included in the initial
assessment (Figure 1), and addressed by the treatment plan. In addition, the initial
evaluation should include an accurate measurement of blood pressure (BP),
screening for secondary causes of hypertension, and assessment of targetorgan
damage.
Cardiovascular Assessment in the Hypertensive Patient
Figure 1
Reproduced with permission from Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United
States, 19882000. JAMA 2003;290:199206. Copyrighted © 2003, American Medical Association. All Rights reserved.
Blood Pressure Measurement
InOffice Blood Pressure Measurement
Except in cases of extreme BP elevation with systolic BP (SBP) >210 mm Hg, and/or Figure 2
diastolic BP (DBP) >120 mm Hg (hypertensive urgency), or elevated BP with
evidence of ongoing targetorgan damage (hypertensive emergency), hypertension
should not be diagnosed on the basis of measurements made on a single
occasion. Hypertension is diagnosed when at least two separate readings obtained
at least 12 weeks apart average ≥140/90 mm Hg.1 Procedures to ensure accurate
measurement of BP in the office setting are outlined in Figure 2.
Figure 3
Patients should abstain from tobacco use and caffeine ingestion for at least 30
minutes before the BP measurement is taken. The arm should be exposed and free
of constricting clothing. Patients should be asked to sit quietly for 5 minutes before
the BP is measured. Use of an appropriately sized cuff, in which the bladder
encircles at least 80% of the arm, is essential because a cuff that is too large or too
small will result in falsely low or falsely high readings, respectively. A common error
is to use a regular cuff on a larger arm; this will overestimate the true BP. During BP
Figure 4a
measurement, the arm should be supported with the cuff at approximately heart
level.
Determining BP accurately can be difficult in elderly patients because of stiffening of

arterial walls. The loss of arterial wall compliance can result in falsely elevated BP
measurements when a standard sphygmomanometer is used.
Pseudohypertension, a falsely elevated BP obtained by indirect cuff measurement
secondary to loss of arterial compliance or even calcification, should be suspected Figure 4b
in elderly patients diagnosed as having hypertension, but without evidence of target
organ damage.
Osler's maneuver can sometimes be used to identify this phenomenon. Inflate the
BP cuff above the level of the SBP; if the pulseless radial or brachial artery remains
palpable, stiffening of the artery may falsely elevate the BP measurement. Direct
intraarterial BP determinations may be necessary to accurately diagnose Figure 4c
hypertension in this setting.
It is now known that some classes of BPlowering drugs, such as betablockers,

may lower brachial artery systolic BP more than central aortic systolic BP, and that
the central aortic systolic BP may be a better predictor of CV outcomes.2 The
noninvasive measurement of central aortic BP involves the translation of the brachial
or radial pulse waveforms to a central aortic waveform using an experimentally Figure 4d
derived transfer function. This requires special equipment, as it is not likely to be
adopted for general use soon.
OutofOffice Blood Pressure Measurement
Home BP measurement or automated ambulatory BP monitoring often helps to

verify the diagnosis and assess the severity of hypertension. BP values obtained
outside the clinic setting are generally lower and correlate better with targetorgan Figure 5
damage and outcomes than BP measurements obtained by health care personnel
in the clinic.
The utility of home or workplace BP measurements depends on the use of accurate

and calibrated BP monitors and careful repeated instruction in good BP
measurement technique. Normal mean 24hour ambulatory BP is <125/75 mm Hg,
with a mean of <130/85 mm Hg during the day and <110/70 mm Hg at night.3 There
is normally a nocturnal "dip" in BP, which, if absent, signals an increased risk of CV
events. Obstructive sleep apnea (OSA) is associated with hypertension, and BP can
be lowered in patients with OSA by the use of continuous positive airway pressure
(CPAP) during sleep.
"White coat effect" refers to the fairly common situation in which the clinic or office BP
is higher than that at home. "Whitecoat hypertension," in which a patient's BP is in
the hypertension range when measured by health care personnel but is normal at
home, occurs in approximately 20% of hypertensive patients. It is probably an anxiety
response that may be amplified through patientphysician interactions.
Whitecoat hypertension is associated with other coronary risk factors, and is

generally thought to be associated with increased CVD risk, but not to the level
observed in fixed hypertension. In the absence of reliable prognostic data and
without prospective randomized outcome trials of antihypertensive drug treatment in
whitecoat hypertension, at a minimum, lifestyle modification should be employed
for BP control, and concomitant CVD risk factors should be treated aggressively.
Some hypertension authorities advocate antihypertensive drug therapy for these
patients.
In some patients, office BP may be significantly lower than ambulatory BP ("masked

hypertension" or "reverse whitecoat hypertension"). This may lead to a falsely low
estimate of daily BP and possible undertreatment of some patients. Patients with
masked hypertension are at increased risk of CVD, and both their BP and their
concomitant risk factors should be managed aggressively.4
History
The purpose of the history and physical examination is: 1) to determine the need for
and guide a possible evaluation of secondary causes of hypertension, 2) to
determine the presence and severity of target organ damage, and 3) to assess
overall CV risk and identify all modifiable CV risk factors (Figure 3). Patients should
also be questioned about the duration and severity of their hypertension, prior
workup of possible secondary causes of hypertension, and the efficacy and adverse
effects of previous therapies.
Clues to secondary causes of hypertension (Figures 4a, b, c, d) should be sought,

including the onset of severe hypertension at an early age, particularly in the
absence of a positive family history of hypertension, and an abrupt worsening in the
severity of hypertension in an older patient. Patients with resistant hypertension that
remains uncontrolled in the presence of an aggressive multidrug regimen should
also be worked up for secondary hypertension.
Targetorgan damage must be documented by history and physical examination. A

history of coronary heart disease (CHD), cerebrovascular disease, peripheral
vascular disease, or chronic kidney disease (CKD) suggests longstanding, poorly
controlled hypertension. In addition, prior diagnosis and treatment of other CV risk
factors (hyperlipidemia, diabetes, smoking, obesity, or sedentary lifestyle) must be
established to guide management decisions.
Risk factors for primary hypertension, such as a positive family history or pregnancy
related hypertension, should be identified. Relevant lifestyle characteristics, such as
weight gain, sedentary lifestyle, high dietary salt ingestion, and excessive alcohol
consumption should be reviewed.
Physical Examination
The physical examination should accurately determine the BP, identify signs of
secondary causes of hypertension, and document the presence and degree of
targetorgan damage. The BP determination should be the average of a minimum of
two BP readings obtained 23 minutes apart. Initially, the BP should be measured in
both arms. Although there are often small variations between arms, large
differences suggest subclavian artery obstruction. In general, the BP measurement
should be obtained from the arm that yields the higher readings. Standing BP levels
should be checked during the initial evaluation and after drug titrations to exclude
significant orthostasis.
Laboratory Evaluation
Laboratory evaluation should document targetorgan damage (Figure 5). Blood urea
nitrogen (BUN) and serum creatinine levels should be obtained to quantify renal
function. Serum creatinine can be supplemented as an index of renal function with
the calculation of estimated glomerular filtration rate (eGFR), which is derived from
an equation that includes terms for gender, race, and age.5 Urine should be
analyzed for microalbuminuria, one of the earliest signs of endothelial dysfunction
and generalized vascular disease.
CKD is both a cause and a complication of hypertension, and is defined as either: 1)
reduced excretory function with an eGFR <60 ml/min/1.73 m2 (approximately
corresponding to a serum creatinine of >1.5 mg/dl in men or >1.3 mg/dl in women),
or 2) the presence of albuminuria (>300 mg/day or >300 mg albumin/g creatinine).1
Urinary albumin excretion has diagnostic and prognostic value equivalent to reduced
eGFR. Albumin excretion can be most conveniently assessed by measuring the
albumin:creatinine ratio on a spot urine sample: A ratio of 30300 mg albumin/g
creatinine signifies microalbuminuria; >300 mg albumin/g creatinine signifies CKD.
A recent trend is to abandon the term microalbuminuria and to regard all levels of
albumin excretion above 30 mg/g creatinine as signifying CKD. Serum potassium
should be measured to rule out hypokalemia suggestive of hyperaldosteronism, or
the hyperkalemia of renal failure.
Fasting serum glucose should be assessed to exclude impaired glucose tolerance,

which occurs in as many as 50% of hypertensive patients, or frank diabetes.
Glycosylated hemoglobin can be used to confirm the diagnosis of diabetes. A
fasting lipid profile should be obtained to diagnose dyslipidemia, which is also
common in hypertensive patients. An electrocardiogram (ECG) should be obtained
to look for evidence of ischemic heart disease, left ventricular (LV) hypertrophy, or
both.
Blood Pressure Measurement
Figure 2
Evaluation of the Patient With Elevated Blood Pressure
Figure 3
Evidence of Secondary Hypertension (1 of 4)
Figure 4a
Causes of Secondary Hypertension (2 of 4)
Figure 4b
Reproduced with permission from Oparil S, Calhoun D (2000). High blood pressure. Scientific American Medicine, vol. 1, part 3, pp. 1 – 16. New
York: Scientific American.
Figure 4c
Reproduced with permission from Oparil S, Calhoun D (2000). High blood pressure. Scientific American Medicine, vol. 1, part 3, pp. 1 – 16.New
Figure 4d
Reproduced with permission from Oparil S, Calhoun D (2000). High blood pressure. Scientific American Medicine, vol. 1, part 3, pp. 1 – 16. New
Baseline Laboratory Tests
Figure 5
Benefits of Pharmacologic Treatment
Reducing BP by pharmacologic means reduces CV morbidity and mortality. In

clinical trials, antihypertensive therapy has been associated with reductions in
stroke incidence of 3540%, in myocardial infarction (MI) of 2025%, and in the Figure 6
development of congestive heart failure (CHF) of >50%.
Metaanalyses of randomized controlled trials of antihypertensive therapy have

shown outcome benefits with the major classes of antihypertensive drugs, including
angiotensinconverting enzyme (ACE) inhibitors, angiotensinreceptor blockers, and
calcium channel blockers.6,7 The evidence for betablockers and thiazidetype
diuretics for CV protection in uncomplicated hypertension is controversial, and will Figure 7
be described in the module on Pharmacologic Treatment of Hypertension in this
chapter.
Antihypertensive drug treatment also slows progression to more severe

hypertension, development of LV hypertrophy, progression of renal disease and
CHF, and reduces allcause mortality. Clinical trials in elderly patients, particularly
those with ISH, have shown even greater benefit than in younger persons.
Figure 8a
Treatment Thresholds and Goals
The ultimate goal of antihypertensive therapy is to reduce overall CV risk and thus
CV morbidity and mortality. Thus, in addition to BP reduction, treatment of other
modifiable CV risk factors should be addressed. Based on evidence from multiple
clinical trials, the seventh report of the Joint National Committee for the Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),1 Figure 8b
recommends that the threshold for the pharmacologic treatment of hypertension
should be a BP of ≥140/90 mm Hg, except in the presence of diabetes or CKD when
patients should be started on appropriate drug therapy with a goal BP of <130/80
mm Hg (Figures 6, 7).
A Scientific Statement from the American Heart Association recommends that

therapy be initiated with a goal of <130/80 mm Hg for hypertensive patients who Figure 9
have coronary artery disease (CAD), CAD equivalents (carotid artery disease, aortic
aneurysm, and peripheral artery disease), or who have a Framingham risk score of
≥10% (Figures 8a, b, 9).8
Lifestyle modification should be used as adjunctive therapy for all patients receiving
pharmacologic treatment, and for primary therapy of "prehypertensive" persons (120
129/8089 mm Hg) who do not have clinical indications for pharmacologic treatment.
An ideal BP, based on epidemiologic data, would appear to be 115/75 mm Hg.9

This has prompted many to advocate a "go as low as the patient will tolerate"
strategy of antihypertensive treatment. Expert committees and treatment guidelines
have not embraced such a radical approach, since evidence from randomized
controlled outcome trials with very low BP targets is sparse. It is not clear that
"optimal" BP achieved by pharmacologic means has a risk profile similar to naturally
occurring "optimal" BP. Further, the risks associated with antihypertensive drug
therapy in the high doses needed to reduce BP to "optimal" levels are uncertain, as
is the cost of this approach.
In the recent study, ACCORD BP (Action to Control Cardiovascular Risk in Diabetes

Blood Pressure Trial),10 in patients with type 2 diabetes at high risk for CV events,
targeting a systolic BP of <120 mm Hg, as compared with <140 mm Hg, did not
reduce the rate of a composite outcome of fatal and nonfatal CV events. A new
National Institutes of Healthsponsored trial now under way, SPRINT (Systolic Blood
Pressure Intervention Trial), will test, in nondiabetic subjects, the effects of intensive
BP lowering (to <120 mm Hg vs. <140 mm Hg) on the prevention of CVD,
progression of renal disease, and cognitive decline over 46 years.
For patients with whitecoat hypertension who have no evidence of targetorgan

damage, pharmacologic therapy is likely to be unnecessary, but this is controversial.
If, however, targetorgan damage is presentparticularly if it is progressive
pharmacologic therapy should be administered. Home BP measurement or 24hour
ambulatory BP monitoring (ABPM) is useful to avoid overtreatment of these patients.
Antihypertensive treatment is indicated in isolated systolic hypertension because

SBP is a better predictor of events (CHD, CVD, CHF, stroke, endstage renal
disease, and allcause mortality) than is DBP, especially among older persons.
Elevated pulse pressure, an indicator of reduced compliance in large vessels, is a
better marker of increased CV risk than is SBP or DBP alone, particularly in elderly
individuals. Pharmacologic therapy in patients with ISH is well tolerated and effective
in both lowering BP and reducing CV morbidity and mortality, particularly through
reductions in stroke. The goal of treatment in patients with ISH is to lower SBP to
<140 mm Hg, and to <130 mm Hg in patients with diabetes, CKD, CAD, CAD
equivalents, and with a Framingham risk score ≥10%, as defined previously.
Note, however, from Figure 9, that older men are nearly all at high risk for MI, and
should be treated if their BP is ≥130/80 mm Hg. However, if there is evidence of
myocardial ischemia, and the DBP is high to begin with, the BP should be lowered
slowly, and caution is advised in inducing falls of DBP below 60 mm Hg if the patient
has diabetes mellitus (and is therefore more likely to have significant CAD) or is over
the age of 60 years. In older hypertensive individuals with wide pulse pressures,
lowering SBP may cause very low DBP values (<60 mm Hg). This should alert the
clinician to assess carefully any untoward signs or symptoms, especially those due
to myocardial ischemia.8
Classification and Management of Blood Pressure for Adults Ages 18 Years or Older
Figure 6
Reproduced with permission from Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention,
Algorithm for Treatment of Hypertension
Figure 7
Reproduced with permission from Chobanian AV, Bakris GL, Black HR, et al. The Seventh report of the Joint National Committee on Prevention,
Calculation of a 10Year Risk for Coronary Heart Disease Using the Framingham Point Score (1 of 2) Men
Figure 8a
Reproduced from the National Heart, Lung, and Blood Institute as part of the National Institutes of Health and the US Department of Health and
Human Services. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm. Accessed 11/30/2011.
Calculation of a 10Year Risk for Coronary Heart Disease Using the Framingham Point Score (2 of 2) Women
Figure 8b
Reproduced from the National Heart, Lung, and Blood Institute as part of the National Institutes of Health and the US Department of Health and
Human Services. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm. Accessed 11/30/2011.
Data From the Framingham Heart Study Experience
Figure 9
Much of the young and middleaged population has a low to intermediate risk for hard coronary heart disease (CHD) events (myocardial
infarction or CHD death). Even up to age 80 years, more than threequarters of women experience a 10year risk of CHD that falls below 10%.
The risks are higher for men, and by age 60 the majority of men are at high risk (>10% per 10 years) for CHD. Nearly all men in the 7079 year
age group are at high risk.
Original figure courtesy of Peter W. F. Wilson, MD, Framingham Heart Study (unpublished data). Modified with permission from Pasternak RC,
Abrams J, Greenland P, et al. Task force #1—identification of coronary heart disease risk: is there a detection gap? J Am Coll Cardiol
2003;41:186374.
Lifestyle Modification
All patients with high BP should receive advice regarding lifestyle modification
(Figure 10) as either definitive therapy or as an adjunct to pharmacologic treatment.
While lifestyle modification has not been shown to reduce CV morbidity and Figure 10
mortality, it has been shown in randomized controlled trials to lower BP in both
hypertensive and highrisk prehypertensive persons, and can prevent hypertension
in the latter group. In addition, lifestyle modification can potentially reduce the
number and dosage of antihypertensive medications needed to control a patient's
high BP.
Advice on lifestyle modification should be tailored to each patient's needs. For

Figure 11a
example, emphasis should be placed on weight loss and increased physical activity
for obese patients. All hypertensive patients should be advised to adopt the following
lifestyle modifications: 1) eat a wellbalanced diet rich in fruits, vegetables, and low
fat dairy products; 2) lose weight if not at ideal body weight; 3) pursue regular
physical exercise; 4) decrease alcohol consumption to less than 23 standard
drinks a day for those who drink; 5) reduce dietary sodium; and 6) stop smoking.
Diet Figure 11b
The DASH Collaborative Research Group has provided strong evidence that total
diet is more important than individual micronutrients such as sodium in determining
BP.11 They demonstrated that the DASH eating plan, a diet high in fruits, vegetables,
and lowfat dairy products and low in saturated and total fat, lowered BP by 3.5/2.1
mm Hg in normotensive individuals, and by 11.4/5.5 mm Hg in hypertensives, even
though sodium intake and weight were held constant. Figure 12
Importantly, the DASH eating plan was particularly effective in reducing BP in the
black study participants (Figures 11a, b). The BP reduction in hypertensive blacks
was 13.6/6.1 mm Hg, an effect comparable to that achieved with many single
antihypertensive drugs. The DASH diet can be approximated by taking four servings
of fruit, four servings of vegetables, and three servings of lowfat dairy products per
day (Figure 12).
Weight Loss
Weight loss is potentially the most effective lifestyle modification for those with high
BP. The BPlowering effect of weight loss is independent of sodium restriction, and
is seen in both obese and nonobese hypertensive individuals. Clinical trial evidence
suggests that weight loss interventions produce BP benefits that persist even after
cessation of active therapy. In addition, weight loss decreases insulin resistance,
the incidence and severity of diabetes, serum cholesterol, and the prevalence of LV
hypertrophy. These effects reduce overall CV risk independent of BP. Body mass
index should be maintained between 18.5 and 24.9 kg/m2 .
Because sustained weight reduction is extremely difficult to achieve, emphasis

should be placed on prevention of weight gain, particularly in younger individuals
with prehypertension and in families with a high prevalence of hypertension. When
prescribing weight loss regimens, the clinician should avoid appetite suppressants
that contain substances known to raise BP.
Physical Activity
Regular physical activity promotes weight loss and general good health. Exercise
with a goal of achieving 4060% of maximum O2 consumption (3045 minutes of
brisk walking for most days of the week is recommended) has been shown to
decrease SBP by 49 mm Hg in both normotensives and hypertensives. In addition,
regular physical activity promotes a sense of wellbeing and decreases CV risk,
morbidity, and mortality. Exercise also reduces overall mortality and has beneficial
effects on serum lipid profiles.
Prescriptions for exercise should, as other lifestyle modifications, be tailored to each

individual patient's condition and preference. Persons with advanced or unstable
CVD may require a medical evaluation before initiation of exercise and/or a
medically supervised exercise program. Younger persons can pursue vigorous
activities, while elderly patients benefit from brisk walking for about 20 minutes every
day. Aerobic exercises such as walking, jogging, biking, and swimming are
preferred over isometric exercises such as weight lifting, as the latter can raise BP
levels.
Alcohol
Drinking alcoholic beverages increases BP both acutely and chronically. Beyond a

threshold point, the BP elevation is proportional to the amount of alcohol consumed.
Further, excessive alcohol use is a frequent cause of resistance to antihypertensive
therapy, and should be investigated in all patients failing to respond to BPlowering
medications.
Reasonable recommendations are for nondrinkers not to begin consuming alcohol

and for those who do drink to limit daily intake to 1 ounce (30 ml) of ethanol
equivalent to 2 ounces (60 ml) of 100 proof alcohol, 8 ounces (240 ml) of wine, or 24
ounces (720 ml) of beer in men and onehalf that amount in women and smaller
men. The adjustment for gender and size is necessary because women absorb
alcohol more rapidly and metabolize alcohol more slowly than men, and the effects
of alcohol are inversely proportional to body mass. Binge drinking should be avoided
because of an association with increased risk of stroke.
Sodium Reduction
High sodium intake has generally been related to BP elevation, particularly in

hypertensive individuals, and this effect appears to be augmented by concomitant
low potassium intake. When sodium restriction was added to the DASH diet in
the DASH (Dietary Approaches to Stop Hypertension) trial, the reduction in sodium
intake from the high (150 mmol/day) to the intermediate (100 mmol/day) level
reduced SBP by 2.1 mm Hg when participants were on a "usual American diet," and
by 1.3 mm Hg on the DASH diet. Reducing the sodium intake from the intermediate
to the low (50 mmol/day) level caused additional reductions of 4.6 mm Hg on the
usual diet, and 1.7 mm Hg on the DASH diet.
The largest BP effect was observed with the combination of DASH diet and low
sodium intake. While dietary sodium reduction clearly lowers BP in many
antihypertensive individuals, evidence that it can reduce CV events is sparse and
has been challenged by observational data demonstrating a direct relationship
between dietary salt intake and life expectancy. Only one study has shown a
reduction in CV events in both hypertensive and normotensive individuals who had
participated in a clinical trial of dietary sodium reduction/weight reduction many
years before.12
Based on these observations and the small but consistent BPlowering effects
observed in other clinical trials of dietary sodium reduction in hypertensive persons,
avoiding excessive sodium intake is recommended for these patients.1,13 Additional
benefits of sodium reduction include: 1) reduced diureticinduced hypokalemia and
greater ease of BP control with diuretic therapy, 2) protection from osteoporosis and
fractures by reducing urinary calcium excretion, and 3) favorable effects on LV
hypertrophy.
The JNC 7 recommends a reduction in daily consumption of sodium chloride to <6 g

and of sodium to <2.4 g. This can be achieved by avoiding obviously salty foods, not
adding salt at the table, and eating more meals cooked from natural ingredients.
Avoiding processed foods with excessive sodium content and/or reducing the
sodium content of those foods are additional strategies for reducing sodium intake.
Lifestyle Modifications to Manage Hypertension
Figure 10
Reproduced with permission from Chobanian AV, Bakris GL, Black HR, et al. The Seventh report on the Joint National Committee on Prevention,
Effect of DASH Diet on Blood Pressure by Race and Hypertension Status (1 of 2) – Systolic Blood Pressure
Figure 11a
Reproduced with permission from Svetkey LP, SimonsMorton D, Vollmer WM, et al. Effects of dietary patterns on blood pressure: subgroup
analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med 1999;159:28593. Copyrighted ©
1999, American Medical Association. All Rights reserved.
Effect of DASH Diet on Blood Pressure by Race and Hypertension Status (2 of 2) – Diastolic Blood Pressure
Figure 11b
Reproduced with permission from Svetkey LP, SimonsMorton D, Vollmer WM, et al. Effects of dietary patterns on blood pressure: subgroup
analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med 1999;159:28593. Copyrighted ©
1999, American Medical Association. All Rights reserved.
DASH Diet
Figure 12
Tips on eating the DASH Diet way:
Start small. Make gradual changes in your eating habits.

Center your meal around carbohydrates such as pasta, rice, beans, and vegetables.
Treat meat as one part of the whole meal, instead of the focus.
Use fruit, or lowfat, lowenergy foods such as sugarfree gelatin for desserts or snacks.
Key Points
There are distinct advantages and disadvantages of measuring BP at home versus the clinic or office.
Whitecoat hypertension is not benign, and should probably be treated with aggressive lifestyle modification, and
possibly with pharmacologic therapy.
In all patients, a careful history and physical examination should be directed to the following objectives: 1) to
identify secondary causes of hypertension, 2) to establish the presence and severity of hypertensive targetorgan
damage, and 3) to develop a comprehensive CV risk profile.
Laboratory evaluation should be tailored to the same objectives, and should include serum sodium, potassium,
BUN, creatinine, eGFR, fasting glucose and lipid profile, urinalysis, and measurement of the albumin:creatinine
ratio in a spot urine sample.
The threshold for pharmacologic treatment is 140/90 mm Hg, except in patients with diabetes, CKD, CAD, CAD
equivalents (cerebrovascular disease, carotid artery disease, aortic aneurysm, peripheral vascular disease) and
those with a Framingham risk score of =10%, in whom the threshold is 130/80 mm Hg.
There is clear evidence from clinical trials that changes in lifestyle, including weight loss and maintenance of
normal body weight; increased physical activity; dietary modification to include more fruits, vegetables, and low fat
dairy products; moderation of alcohol intake; and sodium reduction in saltsensitive individuals, can lower BP in
both hypertensive and prehypertensive persons, and can prevent hypertension in the latter group.
Maintenance or adoption of a healthy lifestyle is recommended for all persons irrespective of BP, and is an
important adjunct to pharmacologic therapy in patients with hypertension.
References
1. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:120652.
2. Williams B, Lacy PS, Thom SM, et al., on behalf of the CAFÉ Investigators; AngloScandinavian Cardiac Outcomes
Trial Investigators; CAFÉ Steering Committee and Writing Committee. Differential impact of blood pressure
lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function
Evaluation (CAFE) study. Circulation 2006;113:121325.
3. Kikuya M, Hansen TW, Thijs L, et al. Diagnostic thresholds for ambulatory blood pressure monitoring based on
10year cardiovascular risk. Circulation 2007;115:214552.
4. Hara A, Ohkubo T, Kikuya M, et al. Detection of carotid atherosclerosis in individuals with masked hypertension
and whitecoat hypertension by selfmeasured blood pressure at home: the Ohasama study. J Hypertens
2007;25:3217.
5. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and
antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004;43(5 Suppl 1):S1290.
6. Turnbull F, on behalf of the Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood
pressurelowering regimens on major cardiovascular events: results of prospectivelydesigned overviews of
randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet 2003;362:152735.
7. Neal B, MacMahon S, Chapman N, on behalf of the Blood Pressure Lowering Treatment Trialists' Collaboration.
Effects of ACE inhibitors, calcium antagonists, and other bloodpressurelowering drugs: results of prospectively
designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration. Lancet
2000;356:195564.
8. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of
ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood
Pressure Research and the Councils on Clinical Cardiology and Epidemiology and. Circulation 2007;115:2761
88.
9. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, on behalf of the Prospective Studies Collaboration. Age
specific relevance of usual blood pressure to vascular mortality: a metaanalysis of individual data for one million
adults in 61 prospective studies. Lancet 2002;360:190313.
10. ACCORD Study Group. Effects of intensive bloodpressure control in type 2 diabetes mellitus. N Engl J Med
2010;362:157585.
11. Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer PJ, Sacks FM. Dietary approaches to prevention and
treatment of hypertension: a scientific statement from the American Heart Association. Hypertension 2006;47:296
308.
12. Cook NR, Cutler JA, Obarzanek E, et al. Long term effects of dietary sodium reduction on cardiovascular disease
outcomes: observational followup of trials of hypertensive prevention (TOHP). BMJ 2007;334:8858.
13. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The
Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the
European Society of Cardiology (ESC). J Hypertens 2007;25:110587.
Printable PDF
5.3: Pharmacologic Treatment of Hypertension
Author(s):
Learner Objectives
Upon completion of this module, the reader will be able to identify the pharmacologic options for treating hypertensive patients,
including those with comorbid conditions.
Pharmacologic Treatment
General Considerations
Abundant clinical trial data indicate that lowering blood pressure (BP) with Figure 1
antihypertensive drugs effectively reduces the risk of a variety of cardiovascular
disease (CVD) outcomes, including CV death, as well as total mortality. Outcome
benefits have been seen with treatment based on diuretics, betablockers,
angiotensinconverting enzyme inhibitors (ACEIs), angiotensinreceptor blockers
(ARBs), and calcium channel blockers (CCBs).1,2
Most hypertensive patients require more than one drug, so the emphasis should be
Figure 2
on the choice of compatible combinations and correct doses, rather than individual
drug choices. It should be noted, also, that the eighth report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC 8) is in preparation at the time of this writing, and the
recommendations contained in this module may change as a result of JNC 8.
It is a matter of controversy whether reduction of CVD risk is simply a function of BP

lowering, or whether some classes of antihypertensive drugs have additional Figure 3
vasoprotective properties which make them more appropriate than others. Some
authorities have claimed that, for outcomes other than HF, differences in achieved
systolic BP (SBP) lowering are linearly related to the extent of risk reduction (Figure
1), and, therefore, BP reduction is everything. On the other hand, trials such as LIFE
(Losartan Intervention For Endpoint reduction in hypertension),3 ACCOMPLISH
(Avoiding Cardiovascular Events through Combination Therapy in Patients Living
Figure 4
with Systolic Hypertension),4 and ASCOTBPLA (AngloScandinavian Cardiac
Outcomes TrialBlood Pressure Lowering Arm)5 have demonstrated major
treatment advantages of one treatment over another without associated differences
in BP reduction or in attained BP. It is clear that, for hypertensive patients overall, BP
reduction is the first priority, but also that providers should be more discriminating in
their choice of antihypertensive drug, to take advantage of drug properties that are
additional to BP lowering alone.
Figure 5a
The seventh report of the Joint National Committee for the Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC 7), published in 2003,
focused its antihypertensive treatment approach on the presence or absence of
"compelling indications," that is, highrisk comorbid conditions for which clinical
trials have demonstrated benefit of specific classes of antihypertensive drugs
(Figures 2, 3).6 For hypertensive persons with compelling indications, drug
selections are dictated by the comorbid condition as well as the BP. In the absence Figure 5b
of compelling indications, JNC 7 recommends that most patients be treated with a
thiazidetype diuretic, either alone or in combination with other classes of drugs
(ACEIs, ARBs, CCBs, or betablockers) that have been shown to be beneficial in
randomized controlled outcome trials. The latest European guidelines have also
taken the view that these five classes of drugs are suitable for the initiation and
maintenance of antihypertensive treatment, alone and in combination, except that
betablockers, especially in combination with thiazide diuretics, should not be used Figure 6
in patients with the metabolic syndrome or at high risk of incident diabetes.7
AngiotensinConverting Enzyme Inhibitors and AngiotensinReceptor Blockers
ACEIs are recommended as firstline therapy for hypertension in those patients who
have left ventricular (LV) dysfunction, and should be included in the therapy of
patients with coronary artery disease (CAD) or who are at high risk for CAD. Although Figure 7
the evidence for renoprotection in patients with diabetic nephropathy is strongest for
ARBs, it is not unreasonable to use ACEIs in this situation.8 By extrapolation, ACEIs
should also be considered for hypertension treatment in patients with hypertensive
nephropathy, and in diabetes without nephropathy. If patients develop intolerance to
ACEIs, such as dry cough or angioedema, then an ARB should be substituted.
The ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril

Global Endpoint Trial) study9 showed that the ARB telmisartan was not inferior to the
ACEI ramipril in the prevention of CV events in a population of patients at high risk for
CVD. Thus, in general, an ARB can be considered a better tolerated, equivalent, and
suitable alternative to an ACEI. Surprisingly, although the BP was even lower with a
combination of ramipril and telmisartan together, there was no further improvement
with regard to the primary outcome, and there were more side effects.
The combination of a reninangiotensin system (RAS) blocker (ACEI or ARB) with a

diuretic is a logical choice for initial therapy in a wide variety of patients. The ALLHAT
(Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial)
study10 showed equal benefit between chlorthalidone, amlodipine, and lisinopril in
preventing fatal CAD events and nonfatal myocardial infarction (MI) in over 30,000
patients with hypertension, followed for a mean of just under 5 years.
Another appropriate firstline combination is a RAS blocker with a CCB.

The ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in
Patients Living with Systolic Hypertension) trial11 compared the combination of an
ACEI (benazepril) with a CCB (amlodipine) versus the same ACEI (benazepril) plus
hydrochlorothiazide. This study, in over 11,000 highrisk hypertensive patients, had
as the primary outcome a composite of death from CV causes, nonfatal MI, stroke,
hospitalization for angina, sudden cardiac arrest, and coronary revascularization.
The achieved BP was the same in both treatment groups, but there was a relative
risk reduction of about 20% in the ACEI/CCB group compared to the
ACEI/hydrochlorothiazide group.
The apparent discrepancy between ALLHAT (in which chlorthalidone was as good
as amlodipine) and ACCOMPLISH (in which hydrochlorothiazide was not as good as
amlodipine) can be resolved by the observation that these are two different diuretics.
Hydrochlorothiazide is a thiazide diuretic, whereas chlorthalidone is not. This is
discussed further later in this module.
All of these studies together would support two excellent options to combine with a
RAS blocker, namely a diuretic, or a CCB, or perhaps both for patients with resistant
hypertension.
BetaBlockers
Several metaanalyses of data from randomized controlled trials have shown that
treatment with betablockers alone, or in combination with other drug classes, is not
as effective in reducing CVD events or death as those based on other drug classes
or placebo.12,13 The result is that betablockers have lost their attractiveness as
firstline therapy for uncomplicated hypertension. The caveat to this is that nearly all
of the outcome studies of betablockers in hypertension used atenolol. It is not
known whether the newer betablockerscarvedilol, metoprolol, bisoprolol, and
nebivololwhich all improve outcomes in patients with impaired LV function, will turn
out to be more effective than atenolol in reducing other CV outcomes in patients with
hypertension. In patients with CAD, betablockers move from therapeutic limbo to
center stage; they are the drugs of first choice for the treatment of hypertension in
patients with stable angina and postMI.14
Thiazide Diuretics
The basis for the somewhat controversial recommendation of preferred status for
thiazide diuretics by JNC 7 is the favorable experience with chlorthalidone in
ALLHAT,10 as well as the fact that thiazide diuretics enhance the antihypertensive
efficacy of most other drug classes, and their low cost. Further, volume overload
related to inadequate or absent diuretic therapy is a common cause of resistance to
BP control.
At the same time, there are considerable problems with the use of thiazide diuretics
as firstline therapy in hypertension. The antihypertensive efficacy of
hydrochlorothiazide in its daily dose of 12.525 mg, as measured by headtohead
studies by ambulatory BP measurement, is consistently inferior to that of other drug
classes.15 In addition, there are significant side effects, including a decrease in
insulin sensitivity and a higher incidence of newonset diabetes mellitus,16 and an
increase in lowdensity lipoprotein cholesterol and triglycerides.17
The apparent paradox between the favorable results of ALLHAT with chlorthalidone
and the known adverse metabolic effects of hydrochlorothiazide and other thiazide
diuretics is resolved by the littleknown fact that chlorthalidone is not a thiazide
diuretic.18 This growing realization has led to an increasing utilization of
chlorthalidone in preference to hydrochlorothiazide as the diuretic of choice in the
treatment of hypertension.
Initiation of Therapy
For persons with BP >20/10 mm Hg above goal (stage 2 hypertension), initial

treatment with two drugs, usually including a thiazidetype diuretic, is recommended
by JNC 7 because of the high risk of this patient group. Randomized controlled trials
have shown that single drug treatment is not usually adequate to achieve goal BPs
in most hypertensive patients, particularly those with mainly systolic or stage 2
hypertension. For example, in the very large ALLHAT trial (n = 42,418), fewer than
30% of participants achieved goal BP (<140/90 mm Hg) on monotherapy.19
Data are similar for the LIFE,3 CONVINCE (Controlled Onset Verapamil Investigation
of Cardiovascular End Points),20 INVEST (International VerapamilTrandolapril
Study),21 and ASCOT5 trials, in which a minority of participants were on
monotherapy at the end of the followup period. In these trials, a second, third, and
even fourth drug was added in order to attain goal BPs and assure equalization of
BPs between or among treatment arms. The second, third, and fourthline active
study medications could come from a drug class other than that of a primary study
drug.
Initiating therapy with more than one agent offers the potential advantages of
achieving BP control more rapidly and avoiding doserelated adverse effects of
individual drugs by producing greater BP reduction at lower doses of the component
agents. In addition, fixeddose combinations may be more convenient, simpler to
take, and less costly than the individual components prescribed separately (Figure
4). The lowest starting dose of most fixeddose combinations is below doses used
in clinical outcome trials, and doses of these agents should be titrated upward to
achieve goal BP before adding other drugs.
The most commonly used individual antihypertensive drugs and fixeddose

combinations are listed in Figures 5a, b, and Figure 6. Common adverse effects are
summarized in Figure 7. Several additional key points should be considered when
initiating treatment with antihypertensive medication. First, treatment should always
include lifestyle modification. Longacting, onceaday agents are preferred due to
improved patient adherence and more sustained effects on BP. Continuous BP
control is especially important in preventing sudden cardiac death, MI, and stroke
precipitated by morning surges in BP. The presence of specific contraindications
and/or comorbid conditions often dictates the appropriate medication for a patient,
since 5070% of those with essential hypertension have comorbid conditions
(compelling indications) calling for specific agents (Figure 3).6
After therapy has been initiated, patients should be seen every 12 weeks
(depending on the severity of hypertension) to titrate antihypertensive drug dosage,
and every 34 months once BP control is achieved. Patients should be encouraged
to measure and record their own BPs at home or in the workplace, as an aid to
adherence and improved BP control.
Associations of Blood Pressure Differences Between Groups With Risks of Major Vascular Outcomes and Death
Figure 1
Reproduced with permission from Elsevier Science. Turnbull F, for the Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of
different bloodpressurelowering regimens on major cardiovascular events: results of prospectively designed overviews of randomised trials.
Lancet 2003;362:152735.
Algorithm for Treatment of Hypertension
Figure 2
HighRisk Conditions With Compelling Indications
Figure 3
Reproduced with permission from Lippincott, Williams & Wilkins. Franco V, Oparil S, Carretero OA. Hypertension therapyPart 2. Circulation
2004;109:30818.
Advantages of FixedDose Combination Therapy
Figure 4
Oral Antihypertensive Drugs (1 of 2)
Figure 5a
Footnote: The FDAapproved label should be consulted before any drug is prescribed.
Oral Antihypertensive Drugs (2 of 2)
Figure 5b
Combination Drugs for Hypertension
Figure 6
Common Adverse Effects of Antihypertensive Drugs
Figure 7
Reproduced with permission from Oparil S, Weber M, eds. Hypertension, Companion to Brenner and Rector’s, The Kidney. Philadelphia, PA: W.B.
Saunders Company, 2000;66274.
Resistant Hypertension
Hypertension is resistant or refractory to usual medical management in
approximately 10% of cases. Refractory or resistant hypertension is defined as a BP
that remains above goal (≥130/80 mm Hg in patients with diabetes, chronic kidney Figure 8
disease (CKD), CAD, coronary artery equivalents, and a Framingham risk score of
≥10%; otherwise ≥140/90 mm Hg) despite the concurrent use of three
antihypertensive agents of different classes.22 All agents should be prescribed at
optimal dose amounts. Causes of resistance to antihypertensive treatment include
secondary hypertension (to be described later), inadequate therapy, nonadherence
to therapy, other patientrelated factors, and inappropriate therapy (Figure 8).
Inadequate therapy is a common cause of uncontrolled BP, whether or not the high
BP is truly treatment resistant. Inadequate use of diuretic therapy as an addon is a
common culprit here, since a frequent cause of resistant hypertension in those
adherent to medical therapy is volume overload. In one study, hypertension
specialists were able to control BP in 50% of those patients whose regimens had
been considered suboptimal by adding a diuretic, increasing the dose of diuretic, or
changing the diuretic to the appropriate class for the patient's renal function.
Up to 50% of resistant hypertension is caused by nonadherence to prescribed

therapy. Clues to nonadherence include: 1) missed appointments, 2) failure to
manifest expected biological effects of medication such as decreased heart rate
with betablocker treatment, and 3) the presence of substance abuse. Various
substances, including decongestants, brochodilators, corticosteroids, and
nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin, contribute to
refractory hypertension by directly raising the BP, interfering with the actions of
antihypertensive medications, or both (Figure 8). For example, NSAIDs can raise BP
by inhibiting natriuresis and causing volume expansion, as well as by interfering
with the actions of agents such as ACEIs.
Heavy alcohol use can increase BP and make it more difficult to control, as can illicit
drugs such as cocaine and amphetamines. Abuse of alcohol and other substances
also contributes to nonadherence to therapy. Caffeine and nicotine can cause
transient refractory hypertension through their ability to temporarily raise BP.
Patientrelated factors such as obesity, hyperinsulinemia, and obstructive sleep

apnea are also associated with refractory hypertension. Obese patients (body mass
index [BMI] >30 kg/m2 ) may require more antihypertensive medications to achieve
BP control than leaner patients, and the medication requirement increases in
proportion to the elevation in BMI.
Whitecoat hypertension or spurious hypertension (pseudohypertension) can lead to

an inappropriate diagnosis of resistant hypertension. Whitecoat hypertension has
been reported in 2040% of patients with untreated hypertension. Whitecoat
hypertension should be suspected in those resistant to therapy, but without
evidence of targetorgan damage. These patients report home BP values that are
normal and much lower (<135/85 mm Hg) than those obtained in the clinic setting
(>140/90 mm Hg). Ambulatory and home BP measurements are highly useful in
diagnosing and managing whitecoat hypertension.
Patients with suspected whitecoat hypertension should be monitored carefully for

targetorgan damage and the presence of other CVD risk factors, as the presence or
absence of these plays a major role in deciding whether to treat. In general,
however, whitecoat hypertension has a more benign prognosis than true
hypertension, and there is thus less need to initiate antihypertensive medication in
patients with whitecoat hypertension than patients with true hypertension.
Nevertheless, these patients should have aggressive lifestyle modification, and if
the office BP remains elevated, drug therapy should be considered.
Spurious hypertension (pseudohypertension) most often occurs in the elderly due to

stiff, sometimes calcified arteries. It has been estimated that 57% of elderly patients
have spurious hypertension. The diagnosis is difficult to make, as the classic
physical diagnosis test, the Osler maneuver, which consists of palpating a pulse in
the radial or brachial artery while the BP cuff is inflated above the auscultated SBP,
has questionable accuracy and usefulness. Better assessment can be made with
an intraarterial BP measurement, but this is obviously unsuitable for routine use.
Causes of Refractory Hypertension
Figure 8
Barriers to Blood Pressure Control
Physicians' patterns of practice clearly contribute to the poor control of hypertension.

A national survey has shown that onethird of primary care physicians do not
recommend treatment for patients with a diastolic BP (DBP) of 90100 mm Hg, and Figure 9
an even higher proportion do not initiate or intensify treatment in patients with a SBP
of 140160 mm Hg. Other studies have shown that physicians are unlikely to
diagnose isolated systolic hypertension or treat it aggressively. In the Veterans
Affairs Hospitals, the problem has been aggressively tackled, with BP <140/90 mm
Hg, and <130/80 mm Hg in diabetics, specified as performance measures. This
has resulted in treatment success rates of over 75%, in contrast to the National
Health and Nutrition Examination Survey (NHANES) data for control rates in the Figure 10
general population of <40%.23
A second major contributor to poor control of hypertension is the high rate of

discontinuance of medications by hypertensive patients: 5070% of new treatments
are discontinued within the first 6 months in most practices. These high
discontinuance rates reflect a combination of adverse drug effects, cost of drugs,
poor efficacy, changes in provider, dissatisfaction with other aspects of care, and
Figure 3
lack of understanding of the risks of targetorgan damage. Dealing with these
barriers to adherence to prescribed therapy is the key to the successful treatment of
hypertensive patients. Maximizing adherence is clearly more important than
choosing a specific drug or regimen in achieving the desired outcome. Suggestions
for optimizing patient adherence to antihypertensive therapy are summarized in
Figure 9.
Monotherapy with most antihypertensive drugs controls BP in fewer than 50% of

patients. Randomized controlled trials in which BP has been successfully lowered to
aggressive goals have shown that three or four antihypertensive drugs are frequently
required (Figure 10). This is particularly true for highrisk patients such as those with
diabetes, renal insufficiency, or CAD. Surveys have shown that practicing physicians
commonly underprescribe antihypertensive medication: 70% of prescriptions for
antihypertensive drugs are for the starting dose, indicating failure to uptitrate doses
of individual agents. This tendency, combined with reluctance to prescribe multiple
antihypertensive drugs at up to maximum doses at frequent intervals in order to treat
to goal, as well as frequent drug discontinuations by patients, contribute to poor BP
control in practice.
Compelling Indications
Compelling indications for specific antihypertensive drug therapy include highrisk

conditions that can be direct sequelae of hypertension (heart failure [HF], CAD,
stroke, and CKD), or commonly associated with hypertension (diabetes, high CAD
risk). Therapeutic decisions in such individuals should be directed at both the
compelling indication and BP lowering (Figure 3).6,14
Suggestions for Increasing Patient Adherence to Antihypertensive Therapy
Figure 9
References:
1. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach.
National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000;36:64661.
2. Cushman WC, Ford CE, Cutler JA, et al., for the ALLHAT Collaborative Research Group. Success and predictors of blood pressure
control in diverse North American settings: the Antihypertensive LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin
Hypertens 2002;4:393404.
Average Number of Antihypertensive Agents Needed to Achieve BP Goals
Figure 10
Figure 3
2004;109:30818.
Ischemic Heart Disease
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BP Goals
Figure 11
Generally, in patients with ischemic heart disease,14 or who have coronary artery
equivalents, or who are at a high risk for developing CAD (Framingham risk score
>10%) the target BP is <130/80 mm Hg. If ventricular dysfunction is present,
consideration should be given to lowering the BP even further, to <120/80 mm Hg.14
In patients with established CAD, the BP should be lowered slowly, and caution is
advised in inducing falls of DBP below 60 mm Hg. In older hypertensive individuals
with wide pulse pressures, lowering SBP may cause very low DBP values (<60 mm
Hg). This should alert the clinician to assess carefully any untoward signs or
symptoms, especially those due to myocardial ischemia.
High Coronary Disease Risk
For the primary prevention of CV events, renal failure, and other complications of
hypertension, aggressive BP lowering is appropriate, with a target BP of <130/80
mm Hg in individuals with any of the following: diabetes mellitus; chronic renal
disease; prior stroke or transient ischemic attack, CAD; CAD risk equivalents
(carotid artery disease [carotid bruit, or abnormal carotid ultrasound or angiography,
peripheral arterial disease, abdominal aortic aneurysm), and those with a 10year
Framingham risk score of ≥10%. A target BP of <140/90 mm Hg is appropriate for
hypertensive individuals with none of the above concomitant conditions (Figure 11).
In patients with an elevated DBP and CAD with evidence of myocardial ischemia, the
BP should be lowered slowly, and caution is advised in inducing reductions in DBP
to below 60 mm Hg if the patient has diabetes mellitus or is over the age of 60
years. In older hypertensive individuals with wide pulse pressures, lowering SBP
may cause very low DBP values (<60 mm Hg). This should alert the clinician to
assess carefully any untoward signs or symptoms, especially those due to
myocardial ischemia.
In the very old, those over 80 years of age, antihypertensive therapy is effective in
reducing total mortality, stroke, and HF without major treatmentrelated adverse
effects.24 Nevertheless, caution should be used in treating very elderly patients with
orthostatic symptoms, cognitive impairment, or poor functional status, as these
individuals were excluded from the clinical trial that demonstrated treatment benefit.
The choice of drugs remains controversial. There is a general consensus that the
amount of BP reduction, rather than the choice of antihypertensive drug, is the major
determinant of reduction of CV risk; however, there is sufficient evidence in the
comparative clinical trials to support the use of an ACE inhibitor (or ARB), CCB, or
chlorthalidone as firstline therapy, supplemented by a second drug if BP control is
not achieved by monotherapy. Most patients will require two or more drugs to reach
goal, and when the BP is >20/10 mm Hg above goal, two drugs should usually be
used from the outset either as separate prescriptions or in fixeddose combinations.
Traditional betablockers should not be used as firstline therapy in uncomplicated

hypertension since randomized controlled trials have demonstrated that they are not
as good as comparator drugs and are not superior to placebo in preventing death
and CV events, including stroke.11,12 However, betablockers are indicated in
patients with CAD for both symptom relief and BP control, and the betablockers
carvedilol, nebivolol, metoprolol, and bisoprolol have improved outcomes in patients
with HF. The newer vasodilating betablockers like nebivolol and carvedilol also
have better hemodynamic and metabolic effects than the older agents. In the
asymptomatic postMI patient, a betablocker is a more appropriate choice for
secondary prevention after the infarction, and is the drug of first choice if the patient
has angina pectoris.
Once antihypertensive drug therapy is initiated, most patients should return for
followup and adjustment of medications at approximately 1 to 2week intervals until
the BP goal is reached. More frequent visits will also be necessary for patients with
stage 2 hypertension or with complicating comorbid conditions. Serum potassium
and creatinine should be monitored at least 12 times per year. After BP is at goal
and stable, followup visits can usually be at 3 to 6month intervals. Comorbidities
such as HF, associated diseases such as diabetes, and the need for laboratory
tests influence the frequency of visits.
Stable Angina and Silent Ischemia
Patients with hypertension and chronic stable angina,14,25 should be treated with a
regimen that includes a betablocker. In addition, an ACEI or ARB should be
prescribed, especially in patients with a history of prior acute coronary syndrome or
LV dysfunction. If necessary, other drugs can be added to achieve target BP. The
combination of a betablocker and ACEI or ARB should also be considered even in
the absence of a prior MI, diabetes mellitus, or LV systolic dysfunction (Figure 11).
If betablockers are contraindicated or produce intolerable side effects, a

nondihydropyridine CCB (such as diltiazem or verapamil) can be substituted, but not
if there is LV dysfunction. If either the angina or the hypertension remains
uncontrolled, either chlorthalidone or a longacting dihydropyridine CCB can be
added to the basic regimen of betablocker and ACEI or ARB. The combination of a
betablocker and either of the nondihydropyridine CCBs (diltiazem or verapamil)
should be used with caution in patients with symptomatic CAD and hypertension
because of the increased risk of significant bradyarrhythmias and HF.
As is usually indicated, the patients should also receive nitrates, antiplatelet or

anticoagulant drugs, and lipidlowering agents for the management of angina and
the prevention of coronary events. In uncontrolled severe hypertension in patients
who are taking antiplatelet or anticoagulant drugs, BP should be lowered without
delay to reduce the risk of hemorrhagic stroke.
Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: Summary of the Main Recommendations
Figure 11
Before making any management decisions, you are strongly urged to read the full text of the relevant section of the Scientific Statement.
*Diabetes mellitus, chronic kidney disease, known CAD or CAD equivalent (carotid artery disease, peripheral arterial disease, abdominal aortic
aneurysm), or 10year Framingham risk score 10% .
Weight loss if appropriate, healthy diet (including sodium restriction), exercise, smoking cessation, and alcohol moderation.
Evidence supports ACEI (or ARB), CCB, or thiazide diuretic as firstline therapy.
If anterior MI is present, if hypertension persists, if LV dysfunction or HF is present, or if the patient has diabetes mellitus.
¶If severe HF is present (New York Heart Association class III or IV, or LVEF <40% and clinical HF).
ACEI = angiotensinconverting enzyme inhibitor; ARB = angiotensinreceptor blocker; BP = blood pressure; CAD = coronary artery disease; CCB
= calcium channel blocker; DBP = diastolic blood pressure; LVD = left ventricular dysfunction; NSTEMI = nonSTelevation myocardial infarction;
SBP = systolic blood pressure; STEMI = STelevation myocardial infarction; UA = unstable angina.
Reproduced with permission from Lippincott, Williams and Wilkins. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the
prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood
Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115:27618. www.lww.com
(2 of 3)
Unstable Angina and NonSTSegment Elevation Myocardial Infarction

Figure 11
For unstable angina or nonSTelevation myocardial infarction (NSTEMI),14,26 the
initial therapy of hypertension should include an oral beta 1selective betablocker
without intrinsic sympathomimetic activity, in addition to nitrates, for symptom
control. If the patient is hemodynamically unstable, which is more commonly an
issue in STEMI than in unstable angina and NSTEMI, the initiation of betablocker
therapy should be delayed until stabilization of HF or shock has been achieved.
Diuretics can be added for BP control and for the management of HF (Figure 11). Figure 3
If there is a contraindication to the use of a betablocker, or if the patient develops

intolerable side effects of a betablocker, then a nondihydropyridine CCB, such as
verapamil or diltiazem, may be substituted, but not if there is LV dysfunction. If the
angina or the hypertension is not controlled with a betablocker alone, then a longer
acting dihydropyridine CCB may be added. Chlorthalidone can also be added for BP
control.
If the patient is hemodynamically stable, an ACEI or ARB should be added if the

patient has an anterior MI, if hypertension persists, if the patient has evidence of LV
dysfunction or HF, or if the patient has diabetes mellitus.
In addition, nitrates, anticoagulants, antiplatelet drugs, and lipidlowering agents

should be used, as indicated, for the management of acute coronary syndromes. BP
should be lowered without delay in patients with uncontrolled hypertension who are
taking antiplatelet or anticoagulant drugs, to reduce the risk of hemorrhagic stroke.
STSegment Elevation Myocardial Infarction
For STEMI,14,27,28 the principles of therapy for hypertension are similar to those for
unstable angina and NSTEMI as described earlier, with some exceptions. Initial
therapy of hypertension can include shortacting beta 1selective betablocker
without intrinsic sympathomimetic activity, usually orally but intravenously if there is
tachycardia or sustained hypertension in addition to nitrates for symptom control.
However, if the patient is hemodynamically unstable, the initiation of betablocker
therapy should be delayed until stabilization of HF or shock has been achieved.
Diuretics can be added for BP control and for management of HF.
An ACEI or ARB should be administered early in patients with STEMI and

hypertension, particularly in anterior MI, or if hypertension persists or there is LV
dysfunction, HF, or diabetes mellitus. ACE inhibition has been found to be
particularly beneficial in patients in whom the infarct is large and/or there is a history
of previous infarction, HF, and tachycardia. ACEIs and ARBs should not be given
together because there is an increase in the incidence of adverse events without
improving survival.
Aldosterone antagonists may be useful in the management of STEMI with LV

dysfunction and HF and may have an additive BPlowering effect. Serum potassium
levels must be monitored. These agents should be avoided in patients with elevated
serum creatinine levels (≥2.0 mg/dl in men, ≥1.8 mg/dl in women), creatinine
clearance of <50 ml/min, or elevated potassium levels (≥5.5 mEq/L).
CCBs do not reduce mortality rates in the setting of acute STEMI and can increase
mortality if there is depressed LV function and/or pulmonary edema. Longacting
dihydropyridine CCBs can be used when betablockers are contraindicated or
inadequate to control angina, or as adjunct therapy for BP control.
Nondihydropyridine CCBs may be used for the treatment of patients with
supraventricular tachycardia, but should not be used in patients with
bradyarrhythmias or impaired LV function.
Patients should also receive nitrates, anticoagulant and antiplatelet drugs, and lipid
lowering agents, for the management of STEMI. Uncontrolled hypertension is a
contraindication to fibrinolytic therapy because of the risk of hemorrhagic stroke. For
the same reason, BP should be lowered without delay in patients with uncontrolled
hypertension who are taking antiplatelet or antiplatelet or anticoagulant drugs.
Heart Failure
Hypertension precedes the development of congestive HF (CHF) in approximately

90% of patients, and increases the risk for CHF by twofold in men and threefold in
women. Accordingly, aggressive treatment of hypertension plays an important role in
preventing and managing CHF.14 There are compelling indications for the use of all
of the major classes of antihypertensive drugs in CHF, with the exception of the
CCBs (Figure 3). BP goals in CHF have not been specifically defined based on
clinical trial data. However, reducing SBP to the range of 110130 mm Hg appears to
be beneficial. Some experts even advocate lowering SBP to <100 mm Hg or as low
as tolerated, in part based on results of the COPERNICUS (Carvedilol Prospective
Randomized Cumulative Survival) trial.29
The treatment of hypertension in patients with HF should include behavioral

modification, such as sodium reduction, and a closely monitored exercise program.
Other nonpharmacologic approaches are the same as for patients without HF.
Drugs that have been shown to improve outcomes for patients with HF generally
also lower BP. Patients should be treated with diuretics, ACEIs (or ARBs), beta
blockers, and aldosterone receptor antagonists. Chlorthalidone is a good choice of
diuretic for BP control and to reverse volume overload and associated symptoms. In
severe HF, or in patients with severe renal impairment, loop diuretics should be
used for volume control, but these are less effective than thiazide diuretics and
chlorthalidone in lowering BP. Diuretics should be used together with an ACEI or
ARB and a betablocker.
Studies have shown equivalence of benefit of ACEIs and the ARBs candesartan or
valsartan in HF. Either class of agents is effective in lowering BP. Drugs from each
class can be used together, provided that the patient is hemodynamically stable and
not in the immediate postMI period. Among the betablockers, carvedilol, nebivolol,
metoprolol succinate, and bisoprolol improve outcomes in HF and are effective in
lowering BP.
The aldosterone receptor antagonists spironolactone and eplerenone have been

shown to be beneficial in HF and should be included in the regimen if there is
severe HF (New York Heart Association class III or IV, or LV ejection fraction <40%
and clinical HF). One or the other may be prescribed in addition to a thiazide diuretic
or chlorthalidone in patients requiring a potassiumsparing agent. If an aldosterone
receptor antagonist is administered with an ACEI or an ARB or in the presence of
renal insufficiency, the serum potassium should be monitored frequently. These
drugs should not be used, if the serum creatinine level is ≥2.5 mg/dl in men or ≥2.0
mg/dl in women, or if the serum potassium level is ≥5.0 mEq/L. Spironolactone or
eplerenone may be used together with a thiazide diuretic, particularly in patients with
refractory hypertension.
The addition of hydralazine/isosorbide dinitrate to the regimen of diuretic, ACEI or

ARB, and betablocker in AfricanAmerican patients with New York Heart Association
class III or IV HF should be considered. Others may benefit similarly, but this has not
yet been tested.
Drugs to avoid in patients with HF and hypertension are nondihydropyridine CCBs

(such as verapamil and diltiazem), clonidine, and moxonidine. Alphaadrenergic
blockers, such as doxazosin, should be used only if other drugs for the
management of hypertension and HF are inadequate to achieve BP control at
maximum tolerated doses.
Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: Summary of the Main Recommendations
Figure 11
Before making any management decisions, you are strongly urged to read the full text of the relevant section of the Scientific Statement.
*Diabetes mellitus, chronic kidney disease, known CAD or CAD equivalent (carotid artery disease, peripheral arterial disease, abdominal aortic
aneurysm), or 10year Framingham risk score 10% .
Weight loss if appropriate, healthy diet (including sodium restriction), exercise, smoking cessation, and alcohol moderation.
Evidence supports ACEI (or ARB), CCB, or thiazide diuretic as firstline therapy.
If anterior MI is present, if hypertension persists, if LV dysfunction or HF is present, or if the patient has diabetes mellitus.
¶If severe HF is present (New York Heart Association class III or IV, or LVEF <40% and clinical HF).
ACEI = angiotensinconverting enzyme inhibitor; ARB = angiotensinreceptor blocker; BP = blood pressure; CAD = coronary artery disease; CCB
= calcium channel blocker; DBP = diastolic blood pressure; LVD = left ventricular dysfunction; NSTEMI = nonSTelevation myocardial infarction;
SBP = systolic blood pressure; STEMI = STelevation myocardial infarction; UA = unstable angina.
Reproduced with permission from Lippincott, Williams and Wilkins. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the
prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood
Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115:27618. www.lww.com
Figure 3
2004;109:30818.
(3 of 3)
Diabetes
Diabetes is an independent risk factor for CVD (coronary heart disease [CHD] and stroke), and the cause of death in
approximately twothirds of persons with diabetes. Diabetes is also the most common cause of endstage renal disease
in the United States. Hypertension is common and carries a worse prognosis in diabetics.30 Randomized controlled
clinical trials have shown that rigorous treatment of BP in patients with diabetes reduces macrovascular and
microvascular disease, and that diabetic patients are particularly sensitive to small reductions in BP. The BP goal
recommended by JNC 7 in 2003 and the American Diabetes Association (ADA) in 2010 is <130/80 mm Hg.6,30
The ADA guidelines suggest that patients with an SBP of 130139 mm Hg or a DBP of 8089 mm Hg should be given a
trial of lifestyle/behavioral therapy alone, and then, if targets are not achieved, should also be treated with pharmacologic
agents. Patients with hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg) should receive drug therapy from the outset in
addition to lifestyle/behavioral therapy.
The BP target of <130/90 mm Hg has recently come into question with the publication of the results of the ACCORD BP
(Action to Control Cardiovascular Risk in DiabetesBlood Pressure) study in 2010.31 The trial showed that, in patients
with type 2 diabetes at high risk for CV events, targeting an SBP of <120 mm Hg, as compared with <140 mm Hg, did not
reduce the rate of a composite outcome of fatal and nonfatal major CV events. The conditions of the ACCORD study were
such that there was excellent glycemic and lipid control (glycated hemoglobin mean values were 7.6% and 7.5% in the
intensive and standard therapy groups; lowdensity lipoprotein cholesterol values were 98.7 and 96.8 mg/dl; and median
triglycerides were 138 and 131 mg/dl). This quality of glycemic and lipid control, which is unfortunately not common in
general clinical practice, may be the reason why the difference in BPs did not have a significant impact on outcomes. For
the vast general population of diabetic patients, with a great variation in glycemic and lipid control, it is not unreasonable
to retain the <130/80 mm Hg BP goal.
The 2010 ADA guidelines32 suggest that all patients with diabetes and hypertension should be treated with a regimen
that includes either an ACEI or an ARB. A thiazide diuretic should be added to achieve BP targets in patients with an
estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m2 and a loop diuretic in those with a lower eGFR. The
National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) 2007 guidelines33 go further; they
recommend an ACEI or an ARB in normotensive people with diabetes, who have micro or macroalbuminuria.
Other drug classes that have been shown to reduce CV events in patients with diabetes (betablockers and CCBs) can
be added as needed to achieve BP targets. However, metaanalyses have shown poorer outcomes with traditional beta
blockers, particularly atenolol, as initial therapy for patients without CAD.12,13 If ACEIs, ARB, or diuretics are used,
monitor renal function (serum creatinine, blood urea nitrogen, eGFR) and serum potassium levels for the first 3 months.
If stable, followup could occur every 6 months thereafter.
In patients with type 2 diabetes, hypertension, and microalbuminuria, ACEIs and ARBs have been shown to delay the
progression to macroalbuminuria.34 In patients with overt diabetic nephropathy, ARBs slow the decline in GFR and delay
the development of endstage renal disease.35,36 In those with type 2 diabetes, hypertension, macroalbuminuria (>300
mg/day), nephropathy, or renal insufficiency, an ACEI or an ARB is indicated as firstchoice antihypertensive therapy. If
one class is not tolerated, the other should be substituted.
Chronic Kidney Disease
CVD is the most common cause of death in persons with CKD,37 itself an independent risk factor for CVD. Persons with
eGFR <60 ml/min have an approximately 16% increase in CVD mortality, and those with eGFR <30 ml/min have a 30%
increase. CVD risk exhibits a continuous relationship with albuminuria: the presence of microalbuminuria confers a 50%
increase in risk, and the presence of macroalbuminuria confers a 350% increase.37
CKD is defined as kidney damage, as confirmed by kidney biopsy or markers of damage, or GFR <60 ml/min/1.73 m2 for
≥3 months.37,38 Using this definition, the NHANES III database and the US Renal Data System (USRDS) estimate that
approximately 11% of adults in the United States have CKD.
Hypertension is both a cause and a consequence of CKD. There is a strong, consistent relationship of higher levels of
BP to faster kidney disease progression. In part, this may be due to deleterious effects of higher intraglomerular pressure
(PGC), resulting in an elevated single nephron GFR, which in the shortterm may lead to stabilization or even increased
GFR, but in the longterm is followed by proteinuria, glomerular sclerosis, and kidney failure.
Hypertension is also a common complication of CKD, which increases the risk for the two main outcomes of CKD: loss
of kidney function, sometimes leading to kidney failure, and CVD, both associated with increased mortality. Appropriate
evaluation and management of hypertension and use of antihypertensive agents in CKD offers the opportunity to slow the
progression of kidney disease and reduce the risk of CVD. A GFR of <60 ml/min/1.73 m2 or microalbuminuria (both
criteria for the definition of CKD) are independent risk factors for CVD, and the designation of CKD is a "compelling
indication" for antihypertensive therapy at a lower BP threshold with a lower BP target (<130/80 mm Hg).
Dietary and other therapeutic lifestyle modifications are recommended as part of a comprehensive strategy to lower BP
and reduce CVD risk in CKD. A dietary sodium intake of <2.4 g/d (<100 mmol/d) should be recommended for most adults
with CKD and hypertension. Other dietary recommendations for adults should be modified according to the stage of CKD,
with the DASH (Dietary Approaches to Stop Hypertension) diet modified with protein intake 0.60.8 g/kg/d, phosphorus
0.81.0 g/d, and potassium 24 g/d for stage 34 CKD. Other lifestyle modifications include weight maintenance if BMI is
<25 kg/m2 , weight loss if overweight or obese, moderation of alcohol intake, and smoking cessation.
All antihypertensive agents can be used to lower BP in CKD. Multidrug regimens will be necessary in most patients with
CKD to achieve therapeutic goals. Patients with specific causes of kidney disease and CVD will benefit from specific
classes of agents. Target BP for CVD risk reduction in CKD should be <130/80 mm Hg.
Since angiotensin II damages the kidneys by stimulating mesangial cell proliferation, ACEIs and ARBs are the preferred
agents for diabetic kidney disease and nondiabetic kidney disease with spot urine total proteintocreatinine ratios of
≥200 mg/g. They should be used at moderate to high doses, as used in clinical trials. They can be used in combination
to lower BP or reduce proteinuria. Patients treated with ACEIs or ARBs should be monitored for hypotension, decreased
GFR, and hyperkalemia. The first agent to be added thereafter should be a diuretic.
Support for the key role of ACEIs and ARBs has come from several clinical trials. The AASK (African American Study of
Kidney Disease and Hypertension) study of 1,094 nondiabetic hypertensive AfricanAmerican individuals with CKD
demonstrated that the decline in GFR was slower in the ACEI (ramipril) group than in the BB (metoprolol) or the CCB
(amlodipine) groups, irrespective of the degree of proteinuria.39
IRMA2 (Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria),34 a trial conducted in patients with type 2
diabetes mellitus and microalbuminuria, demonstrated that the ARB irbesartan reduced the rate of progression to
proteinuria and diabetic nephropathy when compared to usual therapy, without lowering BP. The RENAAL (Reduction of
Endpoints in NIDDM with the Angiotensin II Antagonist Losartan)35 and IDNT (Irbesartan Diabetic Nephropathy Trial)36
studies were conducted in type 2 diabetics with overt nephropathy, hypertension, and serum creatinine of 13 mg/dl. In
both trials, adding an ARB reduced the incidence of a doubling of serum creatinine, compared with conventional
antihypertensive treatment, with nearly equal BP lowering in both treatment arms. In the RENAAL study, the incidence of
endstage renal disease was also lower in the losartan group compared to those on conventional hypertensive therapy.
The results of these trials strongly support the use of ACEIs and ARBs to prevent the deterioration in renal function and
progression of proteinuria, which are almost inevitable in the patient with untreated diabetic nephropathy.
The clinician should expect some initial transient decline in GFR, with an increase in serum creatinine, on initiation of
therapy with an ACEI or ARB. This is because angiotensin II constricts the efferent arterioles of the kidney more than the
afferent arterioles; inhibition of this action by an ACEI or ARB will decrease efferent arteriolar tone more that afferent
arteriolar tone, resulting in a decrease in glomerular filtration pressure, and a decline in GFR. This is the shortterm price
to pay for the longerterm renoprotective action of drugs, which block the RAS.
In most patients, the ACEI or ARB can be continued if: 1) the eGFR decline or the increase in serum creatinine over 4
months is <35% from the baseline value; or 2) serum potassium is <5.5 mEq/L. There is no cutoff value for serum
creatinine at which ACEI or ARB treatment is inappropriate. Creatinine and potassium should be measured 24 weeks
after starting therapy with an ACEI or ARB: if stable, the measurements should be repeated at 6 months and every 6
months thereafter. If there is an excessive increase in serum creatinine, the ACEI or ARB should be discontinued, and the
patient should be evaluated to assess hydration, hemodynamic status, and query use of nephrotoxic medications.
Consideration should also be given to the diagnosis of renal artery stenosis in this situation. Furthermore, in kidney
transplant recipients, ACEIs and ARBs may exacerbate hyperkalemia caused by cyclosporine or tacrolimus. Thus,
treatment of patients with CKD with ACEIs and ARBs requires knowledge of the expected benefits and risks of therapy
and careful attention to BP, renal and cardiac function, electrolyte balance, and possible drug interactions.
In most cases, a diuretic should be the second agent and a CCB the third. Thiazide diuretics or chlorthalidone given once
a day are recommended in patients with a GFR ≥30 ml/min/1.732 , and loop diuretics in patients with a GFR <30
ml/min/1.73 m2 . Loop diuretics may be given in combination with thiazide diuretics or chlorthalidone for patients with
extracellular fluid (ECF) volume expansion and edema. Potassiumsparing diuretics should be used with caution in
patients with a GFR <30 ml/min/1.732 ; in patients receiving concomitant therapy with ACEIs, ARBs, or supplemental
potassium; and in patients with additional risk factors for hyperkalemia. Patients treated with diuretics should be
monitored for volume depletion, manifested by hypotension or decreased GFR, hypokalemia, or other electrolyte
abnormalities.
Key Points
Once hypertension develops, pharmacologic treatment is needed to reduce BP and prevent CVD outcomes.
Clinical trial data indicate that lowering BP with antihypertensive drugs effectively reduces CVD outcomes,
including stroke, CHD, CHF, and CV death, as well as total mortality.
Outcome benefits have been seen particularly with antihypertensive regimens based on ACEIs, ARBs, CCBs, and
diuretics (such as chlorthalidone). Metaanalyses of data from randomized controlled trials have not shown
significant differences in total major CV events between regimens based on ACEIs, ARBs, or CCBs, and diuretics,
with traditional betablockers being less effective.
For outcomes other than CHF, differences in achieved SBP reduction have been shown in some analyses to be
related to the extent of risk reduction, independent of treatment assignment. Therefore, some would argue that, for
hypertensive patients as a whole, reduction of BP (especially SBP) is possibly more important than choice of
antihypertensive drug(s) for reducing CVD risk. However, this remains controversial.
Clinical trials have shown that in most patients, two or more antihypertensive medications are required to achieve
goal BP, namely <140/90 mm Hg in most; <130/80 mm Hg in those with diabetes, CKD, CAD, CAD equivalents,
and highrisk patients, i.e., those with a Framingham risk score of ≥10%. Accordingly, initiation of therapy with two
agents (in individual tablets or fixeddose combination) should be started in those with BP >20/10 mm Hg above
goal.
JNC 7 guidelines recommend using thiazidetype diuretics as firstline treatment in most hypertensives, and in
combination with other drug classes where multiple drugs are required. This differs from European guidelines, in
which antihypertensive drug choices are left up to the health care provider.
The American Heart Association (AHA) Scientific Statement14 on hypertension and CAD has emphasized ACEIs,
ARBs, and CCBs as the most appropriate agents, with a diuretic. The rationale for the preferred status of the
diuretics such as chlorthalidone includes: 1) the favorable outcome trial data delineating their benefits, 2) their
ability to enhance the antihypertensive efficacy of most other drug classes, and 3) their low cost. Their biochemical
adverse effects (i.e., hypokalemia, reduced insulin sensitivity) and diabetes are a concern, and may in the longer
term negate the shortterm benefit seen in the clinical trials.
A hypertensive patient may also have a highrisk condition (e.g., CAD, diabetes, CKD) that constitutes a
compelling indication for use of other antihypertensive drug classes. In that case, initial treatment should be
dictated by the compelling indication, bearing in mind that BP control is paramount. Treatment guidelines from
JNC 7, as well as the AHA, American College of Cardiology, ADA, and the NKF concur on the drugclass choices
for each compelling indication.
RAS agents have been shown to be beneficial in patients with CAD, diabetes, or CKD. In addition, betablockers
are indicated in established CAD, and CCBs can be used in patients with high CHD risk or diabetes based on
outcomes data.
Metaanalyses have shown that treatment regimens based on ACEIs, ARBs, and CCBs are superior to those
based on thiazide diuretics or traditional betablockers. The caveat is that most of these studies used
hydrochlorothiazide as the diuretic and atenolol as the betablocker. Chlorthalidone, which is not a thiazide per se,
has been shown to be effective, and is likely to supplant hydrochlorothiazide as the diuretic of choice.
Newer betablockers (carvedilol, metoprolol, bucindolol, nebivolol), lower BP and are also effective in improving
outcomes in patients with impaired LV function.
CVD is the leading cause of morbidity and mortality in developed countries, and aggressive risk factor
modification is needed to control this burgeoning public health problem. Tight BP control is fundamental for
primary and secondary prevention of CVD.
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Printable PDF
5.4: Other Special Situations
Author(s):
Learner Objectives
Upon completion of this module, the reader will be able to identify the pharmacologic options for treating special patient
populations with common comorbid conditions, hypertensive crisis, and the more common forms of secondary hypertension.
Special Patient Populations and Common Comorbid Conditions
That Influence Drug Selection
Common comorbid conditions in middleaged and elderly hypertensive patients that

may influence drug selection, either positively or negatively, are summarized Figure 1
in Figures 1 and 2. Agents that have added benefit for patients with these conditions
should be included as part of the treatment program, although additional drugs may
be needed to bring blood pressure (BP) under control. Agents that have adverse
effects on these comorbid conditions should not be selected as first or secondline
therapy, but may occasionally be needed to control BP in patients with resistant
hypertension.
Figure 2
Other special situations that affect antihypertensive drug choices or intensity of
treatment include: 1) race/ethnicity, 2) obesity or the metabolic syndrome, 3) left
ventricular (LV) hypertrophy, 4) peripheral arterial disease, 5) old age, 6) orthostatic
hypotension, 7) impaired cognitive function and dementia, 8) erectile dysfunction, 9)
pregnancy, and 10) childhood/adolescence. These special situations are described
in detail in the complete version of the seventh report of the Joint National
Committee for the Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC 7).1
Antihypertensive Drug Therapy With Potential Favorable Effects for Special Patient Populations/Comorbid Conditions
Figure 1
Antihypertensive Drug Therapy With Potential Unfavorable Effects for Special Patient Populations/Comorbid Conditions
Figure 2
Severe Hypertension
The terminology has not been standardized, so the following approach is

recommended. A "hypertensive crisis" is defined as diastolic BP (DBP) >120 mm
Hg. If the crisis is associated with acute or rapidly worsening targetorgan damage, Figure 3
it is a "hypertensive emergency"; if not, it is referred to as a "hypertensive urgency."
JNC 7 guidelines used a BP of >120 mm Hg diastolic with impending or
progressive targetorgan dysfunction as the definition of "hypertensive emergency."
However, many hypertension experts would define hypertensive emergency as the
situation in a hypertensive patient with elevated BP in which there is rapidly
worsening targetorgan damage, such as acute LV failure with pulmonary edema,
acute coronary syndrome, stroke or transient ischemic attack, encephalopathy, renal Figure 4
failure, aortic aneurysm, or severe preeclampsia, irrespective of the BP level.
"Malignant hypertension" is a hypertensive emergency associated with papilledema,
whereas "accelerated hypertension" is a hypertensive emergency associated with
retinal hemorrhages and exudates.2
The rate of rise in BP is more important than the absolute BP recorded in

determining whether the patient with severe hypertension or hypertensive urgency
Figure 5a
needs emergency treatment. Patients with chronic hypertension can tolerate much
higher BPs than previously normotensive persons. Encephalopathy, for example,
rarely develops in patients with longstanding hypertension until the DBP is ≥150
mm Hg. Conversely, a young woman with preeclampsia may become
encephalopathic with a DBP ≥100 mm Hg.
Severe hypertension occurs most commonly in patients who are noncompliant with
their prescribed antihypertensive medications or have been undermedicated. In this Figure 5b
setting, rising BP is thought to cause endothelial damage, due to the release of
vasoconstrictor substances such as norepinephrine, endothelin, and angiotensin II.
A vicious circle of release of additional vasoconstrictor substances and further
increases in peripheral resistance is initiated, which can result in lifethreatening
targetorgan damage.
The history, physical, and laboratory evaluation of a patient with severely elevated BP Figure 6a
should be directed toward identifying targetorgan damage and possible secondary
causes of the BP elevation (Figure 3). Patients with hypertensive emergency, that is
with evidence of acute targetorgan damage, require immediate BP reduction,
generally with intravenous therapy in the intensive care setting. BP should be
reduced promptly, but gradually because precipitous reductions in BP to
normotensive levels may provoke targetorgan ischemia or infarction. Reductions in
mean arterial pressure generally should not exceed 20% in the first 12 hours. Figure 6b
Further reductions should be achieved gradually over the ensuing 2448 hours.
Sodium nitroprusside is the drug of choice for treatment in most hypertensive

emergencies because of its immediate onset of action and very short halflife, which
allow for effective minutebyminute titration. Care should be taken to avoid
overshoot hypotension. Because sodium nitroprusside is both an arteriolar and
venodilator, there is a tendency to overshoot hypotension as a result of abrupt
lowering of the venous filling pressure of the right ventricle, resulting in a lower
cardiac output, especially in patients who are hypovolemic from large doses of loop
diuretics. The hypotension may also cause reflex tachycardia, which is very
undesirable if the patient has myocardial ischemia.
Other side effects include metabolic acidosis, and toxicity from thiocyanate and
cyanide (metabolites of nitroprusside), especially in patients with renal or hepatic
insufficiency. Specific hypertensive emergencies that require specialized evaluation
and treatment are summarized in Figures 4, and 5a and b. Specific parenteral drugs
for treatment of hypertensive emergencies are summarized in Figures 6a and b.
Patients who have a hypertensive crisis are more likely to have secondary
hypertension than those who do not. If the initial evaluation is not revealing, a more
extensive workup should be performed once the BP is stabilized.
Patients with severely elevated BP without evidence of targetorgan damage

(hypertensive urgency) are more likely to be harmed than helped by acute,
aggressive BP reduction. In particular, parenteral antihypertensives, or even
sublingual or oral administration of shortacting nifedipine, which can induce
dramatic BP lowering, are strongly discouraged. Allowing a patient with severely
elevated BP to sit for 2030 minutes in a quiet area will often result in a significant
BP reduction. Oral antihypertensive therapy should then be initiated in the previously
untreated patient, resumed in the noncompliant patient, or adjusted in the
undermedicated patient. Followup should be within 24 hours to ensure compliance
and ensure that the BP is not worsening. Thereafter, followup should be in days or
weeks, not months, until the BP goal is reached.
Symptoms and Signs Associated With Acute Target Organ Complications in Hypertensive Crisis
Figure 3
Diagnostic Evaluation of Specific Hypertensive Emergencies
Figure 4
BNP = Btype natriuretic peptide; BP = blood pressure; CT = computed tomography; eGFR = estimated glomerular filtration rate; JVD = jugular
venous distention; MRI = magnetic resonance imaging; TEE = transesophageal echocardiography.
Treatment Recommendations for Specific Hypertensive Emergencies (1 of 2)
Figure 5a
Treatment Recommendations for Specific Hypertensive Emergencies (2 of 2)
Figure 5b
Parenteral Drugs for Treatment of Hypertensive Emergencies (1 of 2)
Figure 6a
Modified with permission from Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection,
evaluation, and treatment of high blood pressure: JNC 7complete report. Hypertension 2003;42:120652.
Parenteral Drugs for Treatment of Hypertensive Emergencies (2 of 2)
Figure 6b
Modified with permission from Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection,
evaluation, and treatment of high blood pressure: JNC 7complete report. Hypertension 2003;42:120652.
Secondary Hypertension
(1 of 2)
Secondary hypertension, high BP caused by a specific, potentially curable disorder,

accounts for approximately 10% of all cases of hypertension (Figures 7a, b, c, d). A Figure 7a
brief description of the diagnosis and treatment of the most common forms of
secondary hypertension follows. The remaining causes of secondary hypertension
are rare and are described in standard textbooks of hypertension.35
Primary Aldosteronism
Primary aldosteronism (PA), also called Conn's syndrome, is a hypertensive

Figure 7b
syndrome that results from increased production of aldosterone, and may account
for as many as 515% of all cases of hypertension, and thus appears to be the most
prevalent form of secondary hypertension. Aldosterone excess generally results in
suppressed plasma renin activity, metabolic alkalosis, a potassiumlosing
diathesis (sometimes leading to hypokalemia; ≤3.5 mEq/L), and hypertension, but
these findings are variable. The increase in BP can be severe and resistant to
conventional antihypertensive therapy.
Figure 7c
It is important to diagnose and treat PA early because these patients may be at
higher risk than other hypertensive persons for targetorgan damage of the heart
and kidney. Further, targeted pharmacologic therapy with spironolactone or the
selective mineralocorticoid receptor antagonist eplerenone, or surgery (most
commonly laparoscopic unilateral adrenalectomy) is highly effective in lowering BP
and preventing targetorgan damage in these patients.
Figure 7d
All patients with severe or resistant hypertension (BP not at target in a patient on
three or more antihypertensive medications in adequate doses) with no other
obvious secondary cause should be considered for screening (Figure 8).
In particular, patients with spontaneous hypokalemia (serum potassium of ≤3.5

mEq/L) or inappropriate hypokalemia (serum potassium of ≤3.0 mEq/L) while on
conventional doses of diuretics or who require excessive doses of potassium
Figure 8
replacement therapy, patients with resistant or severe hypertension, as well as
patients with incidentally diagnosed adrenal tumors, should be screened for PA. It
should be noted, however, that hypokalemia is not a universal finding in patients
with PA.
The morning plasma aldosterone concentration to plasma renin activity ratio

(PAC/PRA) is the screening test of choice for PA (Figure 8). A ratio >20 with a PAC of
at least 12 ng/dl should prompt confirmatory testing. A ratio >70 with a PAC of ≥15 Figure 9
ng/dl and a PRA ≤1 ng/ml/h is virtually diagnostic of PA. The test can be performed in
patients taking all antihypertensive medications except spironolactone or
eplerenone.
If the screening test is positive, then the next step is an aldosterone suppression
test. After hypokalemia is corrected, patients are given a high sodium diet (46 g/d as
tablets) for 3 days; on day 3, a 24hour urine specimen is collected for measurement Figure 10
of aldosterone, sodium, and potassium. A 24hour urinary sodium excretion >200
mg is considered adequate documentation of sodium repletion. Urinary aldosterone
excretion >12 mcg/24 hours in this setting is diagnostic of aldosterone excess.
The remainder of the diagnostic algorithm is directed toward confirming the

existence of aldosterone excess and identifying the responsible lesion (Figure 9).
The two most common causes of PA, aldosteroneproducing adenoma and bilateral
Figure 11
adrenal hyperplasia, can be distinguished by highresolution computed tomography
(CT) of the adrenal glands. A solitary tumor >1 cm in diameter in a younger patient is
an indication for surgery, but medical therapy is also a realistic option, in part
because aldosteroneproducing adenomas very rarely undergo malignant
degeneration, and because postprocedural persistence of hypertension is common.
If there is micronodularity or bilateral masses, bilateral adrenal venous sampling (if
available) may help to determine whether the aldosterone excess originates from
one or from both adrenals.
Nonfunctioning unilateral adrenal adenomas are not uncommon in older patients,
so the mere presence of a lesion in this setting without evidence of
hyperaldosteronism ("incidentaloma") is not an indication for adrenalectomy.
Treatment for a lateralizing positive study in younger individuals can be surgical;
spironolactone or eplerenone is the treatment of choice for a nonlateralizing study
such as bilateral adrenal hyperplasia or bilateral adenomas.
Patients with atypical features or who fail to respond to aldosterone antagonists may
have one of the rarer forms of PA, such as glucocorticoidremediable aldosteronism
or adrenal carcinoma, and should be referred to a specialized center for evaluation
and treatment.
Renal Artery Stenosis
Renal artery stenosis (RAS) may result in hypertension and/or ischemic

nephropathy, eventually leading to endstage renal disease (ESRD). Although RAS
affects <5% of hypertensive patients, ischemic nephropathy accounts for 1020% of
the ESRD population. Therefore, diagnosis and treatment of RAS have important
implications for both BP control and preservation of renal function.6
RAS is due to atherosclerosis in 7090% of cases, and usually involves the ostium
and proximal third of the main renal artery and the perirenal aorta (Figure 10).
Segmental and diffuse intrarenal atherosclerosis occurs less frequently and usually
represents advanced disease. Atherosclerotic RAS, similar to other atherosclerotic
disease, occurs in middle age and beyond, and is most common in patients with
aortoiliac occlusive disease, diabetes, coronary heart disease, and/or tobacco use.
The remaining 10% or so of RAS is caused by fibromuscular dysplasia, a type of

vasculitis that affects one or more layers of the renal artery, usually including the
media. In contrast to atherosclerotic RAS, fibromuscular dysplasia more often
affects younger persons, particularly women, and involves the distal two thirds of the
renal artery (Figure 10, Panel A). Fibromuscular dysplasia is less likely to progress
than atherosclerotic RAS, although there may sometimes be dissection and
thrombosis.
Clinical features traditionally associated with hypertension due to RAS are

summarized in Figure 11. In general, the most powerful predictors of the presence
of RAS are: age, atherosclerotic cardiovascular disease elsewhere, the presence of
an abdominal bruit, recent onset of hypertension or recent loss of BP control,
unilateral small kidney, a large increase in serum creatinine after initiation of an
angiotensinconverting enzyme (ACE) inhibitor or angiotensinreceptor blocker
(ARB), hypercholesterolemia, cigarette smoking, and the absence of a family history
of hypertension.
A workup for RAS should be done only if there is resistant hypertension or if there is
worsening renal function, and if there is no contraindication to an invasive procedure
(percutaneous renal angioplasty, with or without stenting, or revascularization
surgery), and if the patient is willing to accept a more aggressive approach.
Otherwise, only medical management is advised.
Measurements of activation of the reninangiotensinaldosterone system (RAAS),

such as peripheral venous plasma renin activity (PRA) at rest or following
stimulation with an ACE inhibitor, lack the sensitivity and specificity to be useful in
screening for RAS. Moreover, in the chronic stages of hypertension, PRA may be
suppressed due to volume overload, and the hypertension may not be angiotensin
dependent.
Figure 7a
Reproduced with permission from Oparil S, Calhoun D. High blood pressure. Scientific American Medicine, vol. 1, part 3, pp. 1–16. New York:
Scientific American; 2000.
Figure 7b
Figure 7c
Figure 7d
Use of the Plasma Aldosterone Concentration to Plasma Renin Activity Ratio to Screen for Primary Aldosteronism
Figure 8
Subtype Evaluation of Primary Aldosteronism
Figure 9
Angiographic Appearance of the Two Most Common Forms of Renal Artery Stenosis
Figure 10
Panel A: The typical beaded, aneurysmal appearance of the distal right renal artery in a patient with refractory hypertension and fibromuscular
dysplasia.
Panel B: The same patient as in Panel A, after angioplasty. There was improvement in the angiographic appearance and resolution of
hypertension.
Panel C: The typical appearance of atherosclerotic renal artery stenosis, involving the ostium and proximal third of the left renal artery (arrows).
Panel D: The same patient as in Panel C, after angioplasty. There was residual stenosis, dissection, and a pressure gradient.
Panel E: Which resolved after the placement of a Palmaz stent (see arrows).
Reproduced with permission from Safian RD, Textor SE. Renalartery stenosis. N Engl J Med 2001;344:43142. Copyright © 2001, Massachusetts
Medical Society. All rights reserved.
Clinical Features Suggestive of Renovascular Hypertension
Figure 11
ACEI = angiotensinconverting enzyme inhibitor; ARBs = angiotensinreceptor blockers; BP = blood pressure.
Secondary Hypertension
(2 of 2)
Useful noninvasive tests for RAS include: radioisotope scanning with ACE inhibition
(captopril scintigraphy), Doppler ultrasound, magnetic resonance angiography Figure 12
(MRA), and CT angiography (CTA) (Figure 12). The sensitivity of these imaging
techniques varies from 8095% under optimal conditions, but each has its
advantages and limitations. Captopril scintigraphy is noninvasive and relatively
inexpensive, but is less accurate in bilateral disease or advanced renal failure
because it depends on a difference in isotope uptake between the two sides.
Doppler ultrasound is highly operator dependent, and technically difficult to perform,
especially in the presence of abdominal obesity and bowel gas. MRA and CTA Figure 13
produce excellent image quality, but are expensive. MRA produces poor images with
stents or distal stenoses (as in fibromuscular dysplasia), and CTA requires contrast
medium, often contraindicated in renal insufficiency.
Renal arteriography is the definitive diagnostic test for RAS, revealing in addition the
extent of intrarenal and associated aortic vascular disease and the dimensions of
the kidneys. If the clinical index of suspicion of RAS is high and intervention is
Figure 14
contemplated because of resistant hypertension or deteriorating renal function,
renal arteriography may be indicated in lieu of screening tests or regardless of the
outcome of screening tests.
The goals of RAS treatment are BP control and preservation of renal function. BP
control can be attempted with medical therapy alone, with percutaneous renal
angioplasty (with or without stenting), or surgery. The choice of therapy is dictated by:
1) whether the lesion is atherosclerotic or fibromuscular, 2) its proximity to the renal Figure 15
ostium, 3) the extent of renal arterial involvement, 4) the patient's comorbid medical
condition(s), 5) the ease or difficulty in controlling hypertension and preventing
progressive renal insufficiency with drugs alone, and 5) the inherent risks, as well
as the skill of available operators in performing interventional procedures. An overall
approach to the therapy of renovascular hypertension is outlined in Figures 13 and
14.
Control of BP in renovascular hypertension may be achieved in >90% of cases with

medical therapy alone, usually with a combination of antihypertensive drugs. All
classes of these drugs may be used, but because the hypertension is often the
result of activation of the RAAS, drugs that inhibit angiotensin II production or block
its receptor are particularly effective. This should be augmented with
antiatherosclerotic and antithrombotic measures such as statin therapy, smoking
cessation, and aspirin.
It should be remembered that angiotensin II has a greater vasoconstrictor effect on

the efferent arteriole than on the afferent arteriole and, thus, contributes to the
maintenance of glomerular filtration pressure, and thus glomerular filtration rate
(GFR). ACE inhibitors and ARBs, by dilating the efferent arteriole, will cause a fall in
glomerular filtration pressure and GFR and, thus, an increase in the serum
creatinine. This is a normal response to these drugs, and is not an indication to
discontinue them, unless the fall in GFR or the increase in serum creatinine is
>35% from baseline (if the baseline creatinine is ≤3 mg/dl). In rare cases, acute
(usually reversible) renal failure may occur, suggesting the presence of a highgrade
renal artery stenosis, RAS accompanied by severe renal parenchymal disease, or
volume contraction. Renal function should be carefully monitored whenever ACE
inhibitors or ARBs are used in patients with RAS, particularly when combined with a
diuretic.
Most patients with atherosclerotic RAS require medical antihypertensive therapy as

either primary treatment or following renal artery angioplasty, because the
revascularization alone is seldom sufficient to control BP in middleaged or elderly
patients with RAS. The reason for this may be residual ischemic nephropathy in the
affected kidney, maintaining the renal hypertension, restenosis of the affected
kidney, or progression of atherosclerotic disease in the contralateral kidney. In
contrast, angioplasty is the treatment of choice for patients with fibromuscular
dysplasia, and has a technical success rate of 87100%, a favorable effect on BP of
90%, a restenosis rate of only 10%, and a 10year success rate of 90%.
Surgical revascularization of the kidney is seldom indicated in fibromuscular

hyperplasia because angioplasty is so successful in this condition. Surgery is also
not recommended as initial therapy for control of BP in patients with atherosclerotic
RAS because of high rates of morbidity/mortality associated with the procedure in
these patients, and because modern medical antihypertensive therapy is so
successful. Age, coexistent atherosclerotic disease, and baseline renal function are
the major determinants of outcome. Surgical revascularization should be reserved
for patients with aortic disease or failed angioplasty with or without stenting, for
preservation of renal function and for BP control.
The success of surgical (and catheterbased) revascularization in preserving renal

function depends on the adequacy of the vasculature distal to the site of the arterial
lesion, the level of renal function at the time of intervention, and the rate at which
renal function has deteriorated prior to intervention. Best results are achieved when
the serum creatinine is <3.0 mg/dl. Risks of surgical revascularization outweigh the
benefits in patients with more advanced renal failure (serum creatinine >4.0 mg/dl)
because such patients have significant underlying irreversible renal parenchymal
disease.
In summary (Figures 13, 14), the treatment of choice for hypertension in patients
with RAS due to fibromuscular dysplasia is revascularization with angioplasty if
possible, or with surgery if angioplasty is unsuccessful or technically not feasible.
This will obviate lifelong medical therapy in these young patients. In contrast,
medical therapy is the treatment of choice for hypertension in patients with
atherosclerotic RAS, particularly if BP and renal function can be controlled or if
comorbid conditions increase the risk of intervention.
Management should include aggressive statin and aspirin treatment and smoking
cessation measures, as these may slow the progression of intrarenal
atherosclerosis. Close monitoring of renal function and kidney size is mandatory
because the progression of atherosclerosis may lead to renal functional
impairment. If there is deterioration in renal function or size, or BP cannot be
controlled with medicines, revascularization is indicated. Renal artery angioplasty,
usually with stenting, is the treatment of choice in these patients. Surgical
revascularization is indicated for complex lesions and when medical and
percutaneous approaches are unsuccessful.
It is not clear whether renal revascularization, by whatever means, changes the

natural history or mortality of patients with atherosclerotic RAS. Small prospective,
randomized trials comparing medical therapy with either surgical or endovascular
treatment have not found consistent differences in renal function or even BP control.
The severity of RAS is closely related to total atherosclerotic burden, and advanced
atherosclerosis has an overriding mortality risk that may be only minimally affected
by renal artery revascularization.
Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) is characterized by repetitive interruption of ventilation

for 10 seconds or more during sleep caused by collapse of the pharyngeal airway,
and with associated respiratory effort.7 It should be distinguished from central sleep
apnea, in which the cause of the apnea is loss of ventilatory drive, and characterized
by a ≥10 second pause in ventilation with no associated respiratory effort. The
syndrome of OSA is characterized by snoring, sleep fragmentation, daytime
hypersomnolence, and cognitive impairment. Clinical features and predisposing
factors are listed in Figure 15. Persons with hypertension and the clinical
features/predisposing factors for OSA, particularly loud snoring, daytime sleepiness,
or witnessed apneas, should undergo formal overnight sleep testing
("polysomnography") to make the diagnosis.
Approximately 50% of patients with OSA are hypertensive, and as many as 30% of
hypertensive patients are estimated to have OSA. If there is a causal relation
between the two disorders, it may be that recurrent hypoxia induced by sleep apnea
triggers sustained increases in peripheral resistance and cardiac output, in part
secondary to chronic sympathetic activation. Sleep deprivation in untreated or
inadequately treated hypertensive patients may increase sympathetic nervous
activity during the night and the following morning, leading to increased BP and heart
rate, and increased risk for both targetorgan damage and cardiovascular disease
events. Alternatively, hypertension and sleep apnea may simply share independent
risk factors, such as age and obesity.
The mainstay of treatment is weight loss, which may be curative, but is very difficult
to achieve. Behavioral therapy includes: 1) cessation of alcohol and sedative use, 2)
avoidance of sleep deprivation, and 3) sleep positioning to avoid the supine
position, in which upper airway obstruction occurs most commonly. A simple and
often effective approach is a mandibular advancement splint, a mouthguard
designed to hold the mandible slightly down and forward relative to the natural,
relaxed position. This position holds the tongue farther away from the back of the
airway, and may be enough to relieve apnea or improve breathing for some patients.
Other medical therapies include: 1) treatment of predisposing comorbid conditions,

and 2) nocturnal continuous positive airway pressure (CPAP). Surgical approaches
include uvulopalatopharyngoplasty and genioglossal/mandibular advancement in
adults and tonsillectomy/adenoidectomy in children. Uvulopalatoplasty is often
ineffective (>50% recurrence rate of OSA in 2 years), and should be used only as a
last resort, except in patients with severe specific craniofacial abnormalities.
Although CPAP lowers nighttime BP, daytime BP decreases are modest and
inconsistent, and patients with OSA should be treated according to standard
guidelines for management of essential hypertension. There is no evidence that one
class of antihypertensive agents is more or less advantageous than any other class
in patients with sleep apnea. Special attention should be paid to comorbid
conditions, and drugs that cause sedation or daytime somnolence should be
avoided.
Central sleep apnea is described in LV dysfunction and heart failure, stroke, and in
the elderly, with a prevalence in men >65 years of age of 5%. The mechanisms
underlying central sleep apnea are complex and include chemoreflexes, pulmonary
congestion, increased cardiac filling pressures, and prolonged circulation time.
Because no randomized trials of therapy for central sleep apnea in heart failure have
established a definite benefit with respect to hospitalization or mortality, there is no
consensus as to whether central sleep apnea should be treated, and if so, what the
therapeutic strategy should be. Treatments that have been assessed include drugs
that block the RAS, diuretics, theophylline, betablockers, supplemental oxygen, and
CPAP, with inconsistent results.
Noninvasive Screening Tests for Renal Artery Stenosis
Figure 12
A spiral computed tomography scan may be substituted for an MRA if there is no renal insufficiency or if an MRA is contraindicated, or both. If a
patient’s renal function significantly deteriorates or blood pressure cannot be controlled medically, proceed to angiography.
MRA = magnetic resonance angiography.
Reproduced with permission from Spitalewitz S, Reiser IW. Oparil S, Weber M, eds. Hypertension, Companion to Brenner and Rector’s, The
Kidney. Philadelphia: W.B. Saunders Co., 2000;66274.
Comprehensive Approach to the Treatment of Renovascular Hypertension (1 of 2)
Figure 13
Reproduced with permission from Reiser IW, et al. Secondary hypertension: Renal vascular causes. In: Antman E, ed. Cardiovascular
Therapeutics: A Companion to Braunwald’s Heart Disease, 2nd ed. Philadelphia: W.B. Saunders Co., 2002.
Comprehensive Approach to the Treatment of Renovascular Hypertension (2 of 2)
Figure 14
BP = blood pressure; PTRA = percutaneous renal angioplasty; RAS = renal artery stenosis.
Reproduced with permission from Reiser IW, et al. Secondary hypertension: Renal vascular causes. In: Antman E, ed. Cardiovascular
Therapeutics: A Companion to Braunwald’s Heart Disease, 2nd ed. Philadelphia: W.B. Saunders Co., 2002.
Clinical Features and Predisposing Factors Associated With Obstructive
Figure 15
Reproduced with permission from Kahn DM et al. Obstructive sleep apnea. In: Oparil S, Weber M, eds. Hypertension, Companion to Brenner and
Rector’s, The Kidney. Philadelphia, PA: W.B. Saunders Company, 2000;65762.
Key Points
"Hypertensive urgency" is the situation in which a patient's DBP is >120 mm Hg. If there is acute or rapidly
worsening targetorgan damage, then the term used is "hypertensive emergency." Hypertensive urgency can be
managed as an outpatient, but hypertensive emergency requires admission to a unit with cardiovascular
monitoring facilities, for parenteral antihypertensive therapy.
There are many causes of secondary hypertension, including primary aldosteronism and RAS. Primary
aldosteronism may be caused by an aldosteroneproducing adenoma of the adrenal gland, or by bilateral adrenal
hyperplasia. There is suppressed PRA, increased urinary potassium loss, often but not always with hypokalemia,
and hypertension. Screening for primary aldosteronism is appropriate in patients with hypertension and
spontaneous hypokalemia, or in any patient with treatmentresistant hypertension. The screening test of choice is
the morning PAC to PRA ratio, which if >20 (with a PAC of ≥12 ng/dl) is suggestive of primary hyperaldosteronism,
and if >70 with a PAC of ≥15 ng/dl and a PRA of ≤1 ng/ml/h is virtually diagnostic. Highresolution CT of the
adrenal glands completes the workup.
RAS may result in hypertension and/or ischemic nephropathy. Most cases are due to atherosclerosis, but about
10% are due to fibromuscular dysplasia, which affects younger persons, particularly women. The most powerful
predictors of the presence of RAS are: age, atherosclerotic cardiovascular disease elsewhere, the presence of an
abdominal bruit, recent onset of hypertension or recent loss of BP control, unilateral small kidney, a large
increase in serum creatinine after an ACE inhibitor or ARB, hypercholesterolemia, cigarette smoking, and
absence of a family history of hypertension.
A workup for atherosclerotic RAS should be done only if there is resistant hypertension or if there is worsening
renal function, and if there is no contraindication to an invasive procedure (renal angioplasty or revascularization
surgery), and if the patient is willing to accept revascularization. Otherwise, only medical management is advised.
Measurement of peripheral venous PRA at rest or following stimulation with ACE inhibitors lacks the sensitivity
and specificity to be useful in screening for RAS. Useful tests for RAS include radioisotope scanning with ACE
inhibition (captopril scintigraphy), Doppler ultrasound, MRA, CTA, and renal arteriography.
In atherosclerotic renovascular hypertension, BP control may be achieved in >90% of cases with medical therapy
alone, usually with a combination of antihypertensive drugs, but more invasive management is indicated if the
hypertension is refractory to medical therapy with multiple antihypertensive agents at maximum dose, or if there is
progressive deterioration of renal function. By contrast, in fibromuscular hyperplasia, renal artery angioplasty is
the treatment of choice.
OSA is characterized by repetitive interruption of ventilation for 10 seconds or more during sleep caused by
collapse of the pharyngeal airway, and with associated respiratory effort. Persons with hypertension and the
clinical features/predisposing factors for OSA, particularly loud snoring, daytime sleepiness, or witnessed
apneas, should undergo formal overnight sleep testing ("polysomnography") to make the diagnosis. Therapy is
behavioral, medical, and surgical.
References
1. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee of Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:120652.
2. Vidt DG. Treatment of hypertensive urgencies and emergencies. In: Izzo JL, Sica D, Black HR, eds. Hypertension
Primer: The Essentials of High Blood Pressure. 4th Ed. Izzo JL, Sica DA, Black HR, eds. Philadelphia: Lippincott
Williams & Wilkins; 2007: 48993.
3. Oparil S, Weber MA, eds. Hypertension: A Companion to Brenner and Rector's The Kidney. 2nd ed. Philadelphia:
W.B. Saunders Co.; 2005.
4. Black HR, Elliott WJ, eds. Hypertension: A Companion to Braunwald's Heart Disease. Philadelphia: Saunders
Elsevier; 2006.
5. Kaplan NM, Victor RG. Kaplan's Clinical Hypertension. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.
6. Elliott WJ. Secondary hypertension: renovascular hypertension. In: Black HR, Elliott WJ, eds. Hypertension: A
Companion to Braunwald's Heart Disease. Philadelphia: Saunders Elsevier; 2006: 93105.
7. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart
Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association
Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology,
Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 2008;52:686717.
Printable PDF
Chapter 5 Exam
Visit the online version of the product to see the correct answer and commentary.
1.
Which of the following statements is TRUE?
A. The term “prehypertension” is used to identify those who will develop

hypertension, but does not imply increased CV risk.
B. Hypertensive emergencies require admission to an intensive care unit,

whereas hypertensive urgencies can usually be managed in the outpatient
setting.
C. Refractory (resistant) hypertension is defined as a diastolic BP of >120 mm

Hg despite three drugs of different classes at maximum approved doses.
D. Both systolic and diastolic BP increase progressively with age, and this
increase is accelerated after age 50.
E. Above age 55, hypertension is more common in men than in women.
2.
Of the identifiable genetic causes of human hypertension, most encode genes that
do which of the following?
A. Set the level of sympathetic nervous system activity.
B. Govern insulin resistance.
C. Regulate renal handling of sodium and chloride.
D. Regulate plasma renin activity.
E. Encode the gene for endothelin.
3.
Angiotensin II receptors of the AT1 subtype do which of the following?
A. Induce hypertrophy and hyperplasia of vascular smooth muscle cells.
B. Inhibit mitogenactivated protein kinase (MAP kinase).
C. Are upregulated by chymase.
D. Inhibit aldosterone secretion.
E. Cause prostacyclin (PGI2) release in the kidney.
4.
Which of the following is a targetorgan consequence of chronically elevated blood

pressure?
A. Slowed pulse wave velocity.
B. Increased ejection fraction.
C. Impaired sodium reabsorption by the proximal renal tubules.
D. Atrophy of mesangial cells of the kidney.
E. Transient ischemic attack (TIA).
5. A 57yearold man, previously untreated, has a BP of 136/78 mm Hg on his initial

visit. He is asked to return the following week and his BP is 134/78 mm Hg. The only
significant finding on the workup is an anklebrachial index of 0.7. He is
asymptomatic, and the peripheral pulses are normal to palpation.
Which of the following is appropriate management?
A. He should be told that his BP is normal but that he may have peripheral
arterial disease, and be fully worked up for that, including MR angiography.
B. He should be treated for hypertension, including aggressive multiple risk

factor intervention and antihypertensive drug/s.
C. If the resting ECG is normal, no further interventions are necessary.
D. He should have an exercise ECG test, because peripheral arterial disease

is a marker for CAD.
E. He should be told that he is normal for his age, but that he should have
another checkup in 6 months.
6. A 67yearold woman is referred to you with a BP of 158/72 mm Hg. The history

and physical examination were unremarkable. She is currently on a thiazide diuretic,
an ACE inhibitor, and a calcium channel blocker. Laboratory tests include a
complete blood count, chest Xray, serum electrolytes, and urinalysis, all of which
were normal.
Your treatment plan is to do which of the following?
A. Order a serum creatinine, BUN, eGFR, fasting serum glucose and lipid
profile, a spot urine microalbumin:creatinine ratio, and a 12lead ECG.
B. Reassess her BP and labs in 3 months.
C. Add a betablocker to the regimen.
D. Order an echocardiogram to assess LV size.
E. Order an exercise or pharmacologic stress test
7. A 52yearold man is admitted to the coronary care unit with 8 hours of chest pain.
His ECG shows a 3 mm STsegment depression and Twave inversion in leads V4
6, and the troponin I value is clearly elevated. He is hemodynamically stable, but the
BP is 182/104 mm Hg. There is no clinical evidence of LV dysfunction.
The elevated BP should be treated initially with which of the following?
A. Intravenous sodium nitroprusside.
B. Oral ACEI and thiazide diuretic.
C. Oral betablocker.
D. Rest in a quiet room.
E. Oral nondihydropyridine CCB (diltiazem or verapamil).
8. A 77yearold man has been treated for a month with hydrochlorothiazide 25 mg

and losartan 100 mg daily with no improvement in his BP (172/78 mm Hg). He is
found to have an elevated plasma renin activity, and magnetic resonance (MR) renal
angiography reveals 90% ostial stenosis of the right renal artery. The patient
undergoes stenting of the lesion with hemodynamic success.
In addition to a followup visit in 2 weeks, which of the following instructions is most

appropriate at the time of his discharge from the hospital?
A. Discontine his antihypertensive medications.
B. Discontinue the diuretic.
C. Reduce the lisinopril and hydrochlorothiazide by one half.
D. Repeat MR angiography in 1 month.
E. Add clopidogrel to his regimen.
9.
Randomized controlled trials have shown that the benefit of antihypertensive

treatment in preventing CVD outcomes such as heart attack, stroke, and CV mortality
depends principally on which of the following?
A. Reduction in DBP.
B. Reduction in SBP.
C. Effects on plasma renin activity.
D. Effects on sympathetic neural function and circulating catecholamines.
E. All of the above.
10.
Which of the following is the drug of first choice for hypertensive type 2 diabetic
patients with microalbuminuria?
A. A diuretic.
B. An angiotensin II receptor blocker.
C. An alpha blocker.
D. A betablocker.
E. A CCB.
11.
Which of the following is the drug of first choice for hypertensive type 2 diabetic
patients without micro or macroalbuminuria and with normal renal function?
A. A diuretic.
B. An angiotensin II receptor blocker.
C. A betablocker.
D. A CCB.
E. All of the above.
12. A 64yearold man, with a history of hypertension and type 2 diabetes, but no
nephropathy, comes for a 3month followup visit. His BP at the previous visit 3
months ago was 162/92 mm Hg, and the therapy was increased to lisinopril 40
mg/d (from 20 mg/d) and hydrochlorothiazide 25 mg/d. His home fasting fingerstick
glucose has ranged from 102136 mg/dl, and in your office is 124 mg/dl. He has no
symptoms and the physical examination including fundoscopic exam reveals no
new findings; however, his BP after 15 minutes of rest in a quiet room is 212/116
mm Hg. He insists that he is taking all of his prescribed medications. The urine
dipstick is normal.
Which of the following is the next most appropriate step in his care?
A. Have him return in 1 week for a repeat BP check.
B. Add amlodipine 5 mg/d and have the patient return in 12 days.
C. Admit the patient to the intensive care unit/critical care unit for parenteral
antihypertensive therapy.
D. Refer him for an isotope (captopril) renogram to exclude renovascular

hypertension.
E. Give sublingual nifedipine 30 mg and measure the BP 15 minutes later.
13. A 56yearold female patient referred for a new evaluation is found to have a BP
of 162/88 mm Hg. She is taking losartan 50 mg/d. She is 5’8” and weighs 174 lbs.
Lab data include: white blood cell count 7300/cmm, hemoglobin 14.1 g/dl,
hematocrit 43%, serum fasting glucose 122 mg/dl, glycated hemoglobin 6.2%,
sodium 141 mEq/L, potassium 3.4 mEq/L, creatinine 1.4 mg/dl, blood urea nitrogen
33 mg/dl, PRA 0.5 ng/ml/h, and plasma aldosterone 18 ng/dl. A spot urine had a
concentration of creatinine of 250 mg/dl, and a protein concentration of 4.3 mg/dl.
Which of the following is the most likely diagnosis in this patient?
A. Hypertension due to diabetic nephropathy.
B. Renovascular hypertension.
C. Primary hypertension with no evidence of targetorgan damage.
D. Primary hypertension with hypertensive nephropathy.
E. Hypertension due to primary aldosteronism.
14. A 45yearold man comes to see you because of hypertension diagnosed

recently at his work site. On physical examination, his BP is 172/104 mm Hg. He has
evidence of LV hypertrophy on ECG. His serum creatinine is 1.5, estimated GFR by
the prediction equation is 55 ml/min; his fasting blood sugar is 200 mg/dl, and his
glycated hemoglobin is 8.0%, consistent with a diagnosis of type 2 diabetes with
nephropathy. Analysis of a spot urine sample reveals evidence of microalbuminuria.
He is on no antihypertensive medications.
Which of the following should be your treatment plan?
A. Begin an ACE inhibitor as monotherapy.
B. Begin a CCBdiuretic combination.
C. Begin an ARBdiuretic combination.
D. Begin a loop diuretic.
E. Begin triple therapy with a betablocker, diuretic, and CCB.
15. The patient described in question 3, returns after 1 month with a BP of 138/86
mm Hg and a serum creatinine of 2.0. He is on the maximum approved doses of an
ARB and diuretic.
Which of the following should be your next step in management of this patient?
A. Stop the ARB and substitute a CCB plus betablocker.
B. Add a CCB to the ARBdiuretic combination.
C. Continue current treatment and ask him to return in 1 month.
D. Switch the thiazide diuretic to a loop diuretic.
E. Refer the patient to a nephrologist in preparation for dialysis.
Please visit the online version to engage in this Exam.
1. The correct answer is B. Individuals with “prehypertension” (BP 120139/8089 mm Hg) have
a greater risk of CV events than those with a “normal” BP (<12/80 mm Hg). Refractory (resistant)
hypertension is a BP of >140/90 mm Hg despite three drugs of different classes at maximum
approved doses. While SBP continues to rise, DBP tends to decline after age 50. Above age 55,
hypertension is more common in women than in men.
2. The correct answer is C. Although rare, the genes that cause Mendelian forms of human
hypertension affect BP by altering renal salt handling.
3. The correct answer is A. MAP kinase is a transduction factor activated by angiotensin II.
Chymase is an enzyme that can generate angiotensin II from angiotensin I. Angiotensin II
stimulates aldosterone secretion. Angiotensin II activates vasoconstrictor mechanisms; PGI2 is
a vasodilator prostaglandin.
4. The correct answer is E. TIA and stroke are wellrecognized complications of chronic
hypertension. Chronic hypertension can lead to accelerated pulse wave velocity due to increased
stiffness of large arteries; ejection fraction is unchanged or diminished because of the increased
afterload on the LV, resulting in LVH and myocardial dysfunction; renal sodium reabsorption is
enhanced, and there is often mesangial cell hyperplasia.
5. The correct answer is B. He has peripheral vascular disease, which is a CAD equivalent, so
the threshold for pharmacologic therapy for hypertension is 130/80 mm Hg. The peripheral
arterial disease also mandates aggressive risk factor intervention.
6. The correct answer is A. The workup described in the scenario is incomplete, and should be
completed by the addition of the investigations listed in option A.
Option B is incorrect because her BP is uncontrolled on the present medications. Option C is

inappropriate because the BP may be controlled by uptitrating her current medications, if they are
being taken at submaximal doses, without the addition of another class of drugs.
Echocardiography and stress testing are not part of the routine workup for uncomplicated
hypertension because of the poor benefit:cost ratio.
7. The correct answer is C. If the patient is hemodynamically stable, and if there are no other
contraindications to betablockers, the initial treatment is with a betablocker. Nitrates,
intravenous or oral, are used for symptom control, but are difficult to titrate if used alone for BP
control. An ACEI (or ARB) can be added later if the BP is still elevated, the patient has an anterior
MI, there is LV dysfunction, or if the patient has diabetes. Oral diltiazem or verapamil are
appropriate alternatives to betablockers in patients intolerant to betablockers, but not if there is
LV dysfunction.
8. The correct answer is E. For the older patient with renovascular disease superimposed on a
lengthy history of essential hypertension, renal revascularization usually does not result in
normalization of BP, rapid improvement in renal function, or an immediate drastic reduction in the
need for antihypertensive therapy. Revascularization does help with preservation of renal function
and prevention of progression to endstage renal disease. Also, BP control generally becomes
easier, over the longterm facilitating a reduction in antihypertensive medication requirement.
This generally requires time, however, and in most cases, the prerevascularization medication
regimen should be maintained until the BP response to the procedure can be assessed.
9. The correct answer is B. For all CVD outcomes except HF, metaanalyses of randomized
controlled trials have shown that the benefits of any treatment compared to either placebo or an
active comparator are proportional to achieved reductions in SBP.
10. The correct answer is B. The Kidney Disease Outcomes Quality Initiative and ADA
guidelines recommend use of an angiotensin II receptor blocker or an ACEI (not included in this
list of choices) for diabetic patients with micro or macroalbuminuria or with renal insufficiency.
11. The correct answer is B. Since ACEIs and ARBs are renoprotective in patients with diabetic
nephropathy, it makes sense to regard them as the preferred antihypertensive drugs in all
diabetic patients, even those with no evidence of nephropathy. However, according to JNC 7
guidelines, diabetics without evidence of renal damage respond well to treatment with
antihypertensive drugs in all five of these classes, JNC 7 identifies no preference for one over the
others, so option E is not incorrect on that basis. Some authorities would say that options A and
C are incorrect because both thiazide diuretics and betablockers impair insulin sensitivity and
may make glycemic control more difficult.
12. The correct answer is B. Severely elevated BP without any evidence of acute targetorgan
damage is a hypertensive urgency, not an emergency. Increasing the existing therapy, or adding
another drug from another class are reasonable options, and require frequent visits to assess
efficacy and to uptitrate therapy if necessary. Hypertensive emergencies, with acute targetorgan
compromise, require admission for parenteral therapy; hypertensive urgency does not.
RAS is a possibility in this patient, but if the BP can be controlled with medical therapy, and there
is no deteriorating renal function, the diagnosis of renovascular hypertension does not contribute
substantially to the management, and the workup can be deferred. Sublingual nifedipine has
caused ischemic stroke in this situation, and should never be used.
13. The correct answer is E. The ratio of plasma aldosterone concentration to PRA is 36:1. Any
ratio >20 with a plasma aldosterone concentration of at least 12 ng/dl should prompt
confirmatory testing for primary aldosteronism. The patient does not have diabetes, because the
fasting serum glucose is <126 mg/dl, although her fasting serum glucose of 122 mg/dl puts her
in the high prediabetes range. Renovascular hypertension is always a possibility in patients with
hypertension, but there is nothing in the clinical scenario to suggest this diagnosis in particular.
There is also no evidence of renal disease; the spot urinary albumin (17.2 mg/g creatinine) is not
in the microalbuminuria range (20200 mg/g creatinine).
14. The correct answer is C. The Kidney Disease Outcomes Quality Initiative, American
Diabetes Association, and JNC 7 guidelines indicate that diabetics with nephropathy or
proteinuria should be treated with an ARB or ACE inhibitor to delay the progression of proteinuria
and the development of ESRD. In addition, guidelines indicate that patients with stage 2
hypertension (BP >160/100 mm Hg or >20 mm Hg over goal, which in this patient’s case is
130/80 mm Hg) should be started on two drugs. A logical combination would be an ARB or an
ACE inhibitor with a diuretic.
Use of an ACE inhibitor as monotherapy would not be indicated because of the severity of this
patient’s hypertension. The other combinations suggested lack a blocker of the RAAS and, thus,
would not be recommended.
References
1. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee of
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension
2003;42:120652.
15. The correct answer is B. An increase in serum creatinine of up to 35% of pretreatment

levels is an acceptable and expected response to antihypertensive treatment, particularly
treatment with an ACE inhibitor or an ARB. This is an expected response, and does not mandate
discontinuation of the drug. The patient’s serum creatinine should be monitored to ensure that it
remains stable. If it continues to rise, the patient should be evaluated for renovascular disease.
The patient is not yet at the BP goal of 130/80 mm Hg; thus, additional therapy is indicated at this
point. A calcium channel blocker would be a reasonable choice.

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5: Hypertension

Patrick T. O'Gara, MD, FACC

Thomas M. Bashore, MD, FACC

James C. Fang, MD, FACC

Glenn A. Hirsch, MD, MHS, FACC

Julia H. Indik, MD, PhD, FACC

Donna M. Polk, MD, MPH, FACC

Sunil V. Rao, MD, FACC

Blood pressure (BP) in human populations has a normal distribution. Accordingly,

Those with a BP of 120­139 mm Hg systolic and/or 80­89 mm Hg diastolic are

Ageing is associated with a progressive increase in systolic BP, a reduction in

"Essential, primary, or idiopathic hypertension," defined as high BP due neither to

"Secondary hypertension" is high BP caused by an identifiable and potentially

"White­coat hypertension" describes patients whose BP is high (>140/90 mm Hg) in

"Masked hypertension" is the mirror image of white­coat hypertension. Here, the

The term "hypertensive crisis" encompasses both hypertensive urgency and

High CV risk is indicated by the presence of diabetes, chronic kidney disease,

DBP = diastolic blood pressure; HT = hypertension; SBP = systolic blood pressure.

Approximately 76 million Americans have hypertension, about one in three of the

There are some ethnic differences in the prevalence of hypertension. Hypertension

In the elderly population, increased pulse pressure (PP) (generally a result of

A meta­analysis of observational studies involving more than 1 million individuals

An increment of 20 mm Hg in SBP or 10 mm Hg in DBP in middle­aged and elderly

Individuals with a BP in the prehypertensive range (SBP 120­139 mm Hg or DBP 80­

IHD = Ischemic Heart Disease

IHD = Ischemic Heart Disease

Increased sympathetic nervous system activity.

The concept that structural and functional abnormalities in the vasculature—

The candidate gene approach typically compares the prevalence of hypertension or

Figure 10 depicts some of the molecular mechanisms implicated in the retention of

The main consequence of sodium retention and potassium depletion is an increase

Sympathetic Nervous System

Increased sympathetic nervous system activity increases BP and contributes to the

The normal response to an elevated BP is activation of baroreceptors to reflexly

BP in younger individuals tends to be more labile, with an increase in cardiac output

Chronic sympathetic stimulation induces vascular remodeling and left ventricular

Hypertensive patients manifest greater vasoconstrictor responses to infused

Exposure to stress increases sympathetic outflow, and repeated stress­induced

In hypertension, the increase in peripheral vascular resistance can be ascribed to

Mechanisms of hypertrophy and eutrophic remodeling are similar, and include

Increased arterial stiffness contributes to the wide PP commonly seen in elderly

In younger persons (Figure 12), pulse wave velocity is sufficiently slow

Activation of the AT2 receptor subtype stimulates a phosphatase that inactivates

Local production of angiotensin II in a variety of tissues, including the blood vessels,

Stimulation of reactive oxygen species production is an additional mechanism by

Other vasculotoxic responses to angiotensin II that are linked to the activation of

Compelling evidence indicates that aldosterone­induced fibrosis is initiated by

Aldosterone excess is a more common cause of, or contributing factor to

The plasma concentration of ET1 tends to be increased in severe atherosclerotic

ET receptor antagonists reduce BP and peripheral vascular resistance in both

The ET receptor antagonists bosentan, ambrisentan are FDA­approved for the

Endothelial dysfunction has been implicated as both a cause and a consequence of

It has been suggested that angiotensin II at concentrations that have a minimal

Hypertension and the Heart

Hypertension and the Brain

Acute Hypertensive Encephalopathy

Mild Cognitive Impairment and Dementia

Hypertension should be diagnosed and treated in the context of reducing overall

In­Office Blood Pressure Measurement

Determining BP accurately can be difficult in elderly patients because of stiffening of

Those with a BP of 120139 mm Hg systolic and/or 8089 mm Hg diastolic are

"Whitecoat hypertension" describes patients whose BP is high (>140/90 mm Hg) in

"Masked hypertension" is the mirror image of whitecoat hypertension. Here, the

A metaanalysis of observational studies involving more than 1 million individuals

An increment of 20 mm Hg in SBP or 10 mm Hg in DBP in middleaged and elderly

Individuals with a BP in the prehypertensive range (SBP 120139 mm Hg or DBP 80

Exposure to stress increases sympathetic outflow, and repeated stressinduced

Compelling evidence indicates that aldosteroneinduced fibrosis is initiated by

The ET receptor antagonists bosentan, ambrisentan are FDAapproved for the

InOffice Blood Pressure Measurement

It is now known that some classes of BPlowering drugs, such as betablockers,

OutofOffice Blood Pressure Measurement

Whitecoat hypertension is associated with other coronary risk factors, and is

Targetorgan damage must be documented by history and physical examination. A

Metaanalyses of randomized controlled trials of antihypertensive therapy have

For patients with whitecoat hypertension who have no evidence of targetorgan

AngiotensinConverting Enzyme Inhibitors and AngiotensinReceptor Blockers

The combination of a reninangiotensin system (RAS) blocker (ACEI or ARB) with a

Another appropriate firstline combination is a RAS blocker with a CCB.

The most commonly used individual antihypertensive drugs and fixeddose

Patientrelated factors such as obesity, hyperinsulinemia, and obstructive sleep

Whitecoat hypertension or spurious hypertension (pseudohypertension) can lead to

Patients with suspected whitecoat hypertension should be monitored carefully for

Compelling indications for specific antihypertensive drug therapy include highrisk

Traditional betablockers should not be used as firstline therapy in uncomplicated

If betablockers are contraindicated or produce intolerable side effects, a

Unstable Angina and NonSTSegment Elevation Myocardial Infarction

If there is a contraindication to the use of a betablocker, or if the patient develops

In addition, nitrates, anticoagulants, antiplatelet drugs, and lipidlowering agents

STSegment Elevation Myocardial Infarction

Common comorbid conditions in middleaged and elderly hypertensive patients that

Patients with severely elevated BP without evidence of targetorgan damage