5 Hypertension

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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 andphysical exam often contain clues to the etiology of hypertension, and reviews the critical non-pharmacologic and pharmacologictreatments of hypertension. The final section describes how to recognize and treat secondary causes of hypertension.

Authors

Patrick T. O'Gara, MD, FACCEditor-in-Chief

Thomas M. Bashore, MD, FACCAssociate Editor

James C. Fang, MD, FACCAssociate Editor

Glenn A. Hirsch, MD, MHS, FACCAssociate Editor

Julia H. Indik, MD, PhD, FACCAssociate Editor

Donna M. Polk, MD, MPH, FACCAssociate Editor

Sunil V. Rao, MD, FACCAssociate Editor


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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 ofhypertension, and its contribution to cardiovascular (CV) risk.


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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 riskfactors for CVD. Hypertension affects about 25% of the adult population of the world, and its prevalence is predicted toincrease by 60% to 2025, when a total of over 1.5 billion people may be affected. Primary hypertension (essential oridiopathic hypertension) accounts for about 90% of all cases of hypertension.


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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, butare needed for practical reasons in the assessment and treatment of patients.Hypertension is defined as a systolic blood pressure (SBP) of 140 mm Hg or greaterand/or a diastolic blood pressure (DBP) of 90 mm Hg or greater in persons nottaking antihypertensive medication (Figure 1).

Those with a BP of 120-139 mm Hg systolic and/or 80-89 mm Hg diastolic areclassified as "prehypertensive," now known to increase the risk of any CV event by

two- to fourfold compared with a normal BP (140/90 mm Hg) inan office or clinic setting, with a normal daytime ambulatory pressure (120 mm Hg inthe absence of acute or rapidly worsening target-organ damage (Figure 3)."Hypertensive emergency" is defined as acute or rapidly worsening target-organdamage occurring in a hypertensive patient in association with elevated BP, butirrespective of the specific BP level attained. "Malignant hypertension" is ahypertensive emergency associated with papilledema, whereas "acceleratedhypertension" is a hypertensive emergency associated with retinal hemorrhagesand 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

Figure 1

Figure 2

Figure 3


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considered to be normal, the seventh report of the Joint National Committee for thePrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)introduced a new classification that includes the term "prehypertension" for those

with SBP 120-139 mm Hg or DBP 80-89 mm Hg ( Figure 1).3

Individuals who are prehypertensive are not candidates for drug therapy on the basisof their BP alone and should be advised to practice lifestyle modification to reducetheir risk of developing hypertension in the future. However, persons with BPs in theprehypertensive range and high CV risk should be treated with antihypertensivemedications to a target of 10%.


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Classification and Management of Blood Pressure for Adults Ages 18 Years or OlderFigure 1Reproduced 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 2003289:2560-72. Copyrighted 2003,

American Medical Association. All Rights reserved.


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Changes in Systolic and Diastolic Blood Pressure With AgeFigure 2Reproduced with permission from Lippincott, Williams, & Wilkins. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adultpopulation. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 199525:305-13.


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Other Hypertension DefinitionsFigure 3*The most frequent causes of secondary hypertension are renal parenchymal disease, renal artery stenosis, pheochromocytoma, primaryaldosteronism (Conns 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, justifyingmanagement as a hypertensive emergency.

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


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Prevalence

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

adult population.4 In a study conducted in 1999-2000, 40% of persons werenormotensive, 30% were prehypertensive, and 30% were hypertensive. There hasbeen an increase in the prevalence of hypertension in the United States from 1988-1994 (25%) to 2005-2008 (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 the75+ age group, the prevalence is 70-80%.

SBP in the population increases with advancing age throughout life, whereas DBPtends to plateau or fall after age 60 (Figure 2). Consequently, in older persons, thediagnosis 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 middle-aged andyounger individuals. A higher percentage of men than women have high BP until age45. From age 45 to age 54, the percentages of men and women with hypertensionare similar, and after age 55, a much higher percentage of women havehypertension than do men. The prevalence of hypertension has increasedsignificantly (from 25% to 30%) since the National Health and Nutrition ExaminationSurvey (NHANES) of 1988-91 in women of all age groups, most dramatically inthose ages 60 years and over.

There are some ethnic differences in the prevalence of hypertension. Hypertensionis more prevalent in non-Hispanic blacks than in non-Hispanic whites and Mexican

Americans (Figure 4).4,6 Overall, African Americans have a higher prevalence ofhypertension (41%) than whites (28%) or Mexican Americans (27%). In both sexes,hypertension was associated with increasing age, black race/ethnicity, and higherbody mass index.

Figure 2

Figure 4


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Changes in Systolic and Diastolic Blood Pressure With AgeFigure 2Reproduced with permission from Lippincott, Williams, & Wilkins. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adultpopulation. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 199525:305-13.


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Hypertension Prevalence by Age and Race/Ethnicity in Men and WomenFigure 4Reproduced with permission from Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the UnitedStates, 1988-2000. JAMA 2003290:199-206. Copyrighted 2003, American Medical Association. All Rights reserved.


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Hypertension and Cardiovascular Risk

Advances in diagnosing and treating hypertension have played a major role in thedramatic declines in CHD (down 49%) and stroke (down 58%) mortality that haveoccurred in the past 30 years. Major progress has been made in public awarenessof the importance of high BP in the population. However, rates of decline of deathfrom CVD have slowed in the past decade, and major complications ofhypertension, including heart failure and end-stage renal disease, have actuallyrisen over that time period. In addition to the rapidly escalating prevalence ofdiabetes and obesity, a major contributor to these trends is inadequate control of BPin the hypertensive population. Although there has been an improvement in the past

decade, still


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Prevalence of Hypertension*, Prevalence of Treatment and Control of Blood Pressure Among Persons With Hypertension National Health andNutrition Examination Survey, United States 1999-2002 and 2005-2008Figure 5

The prevalence of hypertension did not change significantly from 1999-2002 (28.1%) to 2005-2008 (30.9%) after adjustment for sex, age,race/ethnicity, and poverty-income.

*Average systolic blood pressure 140 mm Hg, average diastolic blood pressure 90 mm Hg, or current blood pressure lowering medicationuse.

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


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Ischemic Heart Disease Mortality Rate in Each Decade of Age Versus Usual Blood Pressure at the Start of That DecadeFigure 6Rates 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 age-specific regression line ignores the left-hand point (i.e., at slightly less than 75 mm Hg), for which the risk liessignificantly 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 StudiesCollaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61prospective studies. Lancet 2002360:1903-13.


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Stroke Mortality Rate in Each Decade of Age Versus Usual Blood Pressure at the Start of That DecadeFigure 7Rates 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 age-specific regression line ignores the left-hand point (i.e., at slightly less than 75 mm Hg), for which the risk liessignificantly 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 StudiesCollaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61prospective studies. Lancet 2002360:1903-13.


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Impact of Prehypertension on CV RiskFigure 8Normal BP:


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Etiology(1 of 2)

Primary hypertension, which accounts for more than 90% of all cases ofhypertension, tends to cluster in families, and represents a complex interplay of

polygenic and acquired etiology.9 Many pathophysiologic factors have beenimplicated in the genesis of essential hypertension (Figure 9). These include:

Increased sympathetic nervous system activity.Overproduction of sodium-retaining hormones and vasoconstrictors(endothelin and thromboxane).Long-term high sodium intake.Inadequate dietary intake of potassium and calcium.Increased or inappropriate activation of the renin-angiotensin-aldosteronesystem (RAAS).Deficiencies of vasodilators such as prostaglandins and nitric oxide.Congenital abnormalities of the resistance vessels.Diabetes mellitus.Insulin resistance.Obesity.Increased activity of vascular growth factors.

Altered cellular ion transport.

The concept that structural and functional abnormalities in the vasculatureincluding endothelial dysfunction, increased oxidative stress, vascular remodeling,and decreased compliancemay antedate hypertension and contribute to itspathogenesis, has gained strength in recent years. This formulation has importantimplications for the targeting of antihypertensive therapy in order to achieve benefitsbeyond 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 genesmakes a small contribution to the increased BP, with the resultant hypertensionrepresenting a complex effect of many genes and environmental influences.

Improved techniques of genetic analysis, especially genome-wide linkage analysisand gene associations, have allowed a search for genes that contribute to thedevelopment of primary hypertension. Application of these techniques has foundstatistically significant linkage of BP to several chromosomal regions, includingregions linked to familial combined hyperlipidemia. Overall, however, identifiablesingle-gene causes of hypertension are uncommon, consistent with a multifactorialcause of primary hypertension. Ultimately the goal of gene mapping is to identifysingle nucleotide polymorphisms (SNPs) that alter function in such a way as toelevate BP.

The candidate gene approach typically compares the prevalence of hypertension orthe level of BP among individuals of contrasting genotypes at candidate loci inpathways known to be involved in BP regulation. The most promising findings ofsuch studies relate to genes of the RAAS, such as the M235T variant in the

angiotensinogen gene, which has been associated with increased circulatingangiotensinogen levels and BP in many distinct populations, and a common variantin the angiotensin-converting enzyme (ACE) gene that has been associated in somestudies with BP variation in men. These variants only modestly affect BP, and othercandidate genes have not shown consistent and reproducible associations with BPor hypertension in larger populations. Thus, genetic causes of hypertension appearto be uncommon in general hypertensive populations. Recently, a very largegenome-wide 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 humanhypertension all of these are very rare, and most affect BP by altering renal salthandling. These will be described more fully in the section on SecondaryHypertension.

Figure 9

Figure 10

Figure 11

Figure 12


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Sodium and Potassium

Sodium excess and potassium deficit in the diet are pivotal factors in the

pathogenesis of hypertension.11 Primary hypertension and age-related increases inBP are virtually unknown in populations with a sodium intake of


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as on release of various trophic factors, including transforming growth factor-,insulin-like growth factor 1, and fibroblast growth factors. Positive correlationsbetween circulating norepinephrine levels, LV mass, and reduced arterialcompliance due to vascular hypertrophy have been demonstrated. Thus,sympathetic mechanisms contribute to the development of target-organ damage, aswell as to the pathogenesis of hypertension.

Vascular Reactivity

Hypertensive patients manifest greater vasoconstrictor responses to infusednorepinephrine than normotensive controls. The expected downregulation of

noradrenergic receptors in response to increased circulating norepinephrine levelsdoes not occur in hypertensive patients, resulting in enhanced sensitivity tonorepinephrine, increased peripheral vascular resistance, and BP elevation.Vasoconstrictor responsiveness to norepinephrine is also increased innormotensive offspring of hypertensive parents compared to controls without afamily history of hypertension, suggesting that the hypersensitivity may be genetic inorigin and not simply a consequence of elevated BP. Centrally acting sympatholyticagents and - and -adrenergic antagonists are effective in reducing BP in patientswith essential hypertension, thus providing indirect clinical evidence for theimportance of sympathetic mechanisms in the maintenance of hypertension.

Exposure to stress increases sympathetic outflow, and repeated stress-inducedvasoconstriction may result in vascular hypertrophy, leading to increased peripheralresistance and BP. Persons with a family history of hypertension have augmented

vasoconstrictor and sympathetic responses to laboratory stressors, such as coldpressor testing and mental stress, which may predispose them to hypertension.

Vascular Remodeling

In hypertension, the increase in peripheral vascular resistance can be ascribed toboth functional (vasoconstriction) and morphologic (remodeling) effects onprecapillary small arteries and arterioles. There are two types of arterial remodelingin hypertension: 1) eutrophic inward remodeling, and 2) hypertrophic inwardremodeling. Eutrophic inward remodeling refers to a decrease in lumen diameterwithout a change in the thickness of the arterial wall. In contrast, hypertrophic inwardremodeling is defined as a decrease in lumen diameter associated with anincrease in wall thickness. Elevated peripheral vascular resistance in hypertensivepatients is related to rarefaction (decrease in number of parallel-connected vessels)

and luminal narrowing of resistance vessels (Figure 11).

Mechanisms of hypertrophy and eutrophic remodeling are similar, and includeincreases in intravascular pressure, sympathetic activity, angiotensin II andendothelin-1 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), angiotensin-receptor blockers (ARBs), andcalcium-channel blockers (CCBs), normalizes resistance vessel structure. On theother hand, beta-blocker therapy does not reverse resistance vessel remodelingeven when it effectively lowers BP. In randomized clinical trials, the majordeterminant of outcome seems to be BP reduction, and diuretics and CCBs seem tohave done as well or better than RAAS blockers, at least in high-risk patients.However, many authorities would agree that the major determinant of CV outcomesis 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 thesearteries results from collagen deposition and smooth muscle cell hypertrophy, aswell as thinning, fragmenting, and fracture of elastin fibers in the media. Thedistending pressure of conduit vessels is a major determinant of stiffness. The two-phase (elastin and collagen) content of load-bearing elements in the media isresponsible for the behavior of these vessels under stress: At low pressures, stressis borne almost entirely by the distensible elastin lamellae, while at higherpressures, less distensible collagenous fibers are recruited, and the vesselappears stiffer. Conduit vessels are relatively unaffected by neurohumoralvasodilator mechanisms.


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In addition to these structural abnormalities, endothelial dysfunction, which developsover time as a consequence of both aging and hypertension, contributes functionallyto increased arterial stiffness in elderly persons with ISH. Other factors thatdecrease central arterial compliance by damaging the endothelium include: 1)diabetes, 2) tobacco use, 3) high dietary salt intake, 4) elevated homocysteinelevels, and 5) estrogen deficiency.

Reduced nitric oxide (NO) synthesis and/or release in this setting contributes toincreased wall thickness of conduit vessels such as the aorta and common carotidartery. The functional significance of NO deficiency in ISH is supported by the abilityof 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 elderlyhypertensive patients, in part by causing the pulse wave velocity to increase. Witheach ejection of blood from the LV, a pressure (pulse) wave is generated and travelsfrom the heart to the periphery at a finite speed that depends on the elasticproperties of the conduit arteries. The pulse wave is reflected at any point ofdiscontinuity in the arterial tree, and returns to the aorta and LV. The timing of thewave reflection depends on both the elastic properties and the length of the conduitarteries.

In younger persons (Figure 12), pulse wave velocity is sufficiently slow(approximately 5 m/sec) so that the reflected wave reaches the aortic valve afterclosure, leading to a higher DBP and enhancing coronary perfusion by providing a

"boosting" effect. In older persons, particularly if they are hypertensive, pulse wavevelocity is greatly increased (approximately 10-20 m/sec) due to central arterialstiffening. At this speed, the reflected wave reaches the aortic valve before closure,merges with the incident or antegrade wave, and produces a higher SBP (andafterload), PP, and a decreased DBP.

This phenomenon accounts for the higher SBP and PP and the lower DBP that isseen in the elderly population and is exaggerated in the presence of hypertension.The increase in SBP increases cardiac metabolic requirements and predisposes tothe development of LV hypertrophy and heart failure. PP is closely related to SBP andis clearly linked to advanced atherosclerotic disease and CVD events such as fataland nonfatal myocardial infarction (MI) and stroke. With aging, there is a gradual shiftin the BP-risk relationships from diastolic to systolic and PP.

Most antihypertensive drugs act on peripheral muscular arteries rather than centralconduit vessels. They reduce PP via indirect effects on the amplitude and timing ofreflected 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 thereforepulse wave reflection, contributing to their antihypertensive effect.


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Pathophysiologic Mechanisms of HypertensionFigure 9Red arrows show hypertension-promoting mechanisms gray arrows show hypertension-opposing mechanisms.

AME = syndrome of apparent mineralocorticoid excess Ang (1-7) = angiotensin (1-7) peptide CGRP = calcitonin gene-related peptide CNS =central nervous system GI = gastrointestinal GRA = glucocorticoid-remediable aldosteronism NO = nitric oxide.

Reproduced with permission from Saunders Elsevier. Franco V, Calhoun DA, Oparil S. Pathophysiology of hypertension. In: Hypertension: ACompanion to Braunwalds Heart Disease. Black HR, Elliott WJ. Philadelphia: Saunders Elsevier 2007:26.


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Renal Mechanisms of Sodium Retention and Potassium Loss in Primary HypertensionFigure 10Potassium depletion stimulated both the sympathetic nervous system and the renin-angiotensin-aldosterone 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 ATP-dependent 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 digitalis-like 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 Adrogu HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007356:1966-78.


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How Remodeling Can Modify the Cross-Sections of Blood VesselsFigure 11The starting point is the vessel at the center. Remodeling can be hypertrophic (increase of cross-sectional area), eutrophic (no change in cross-sectional area), or hypotrophic (decrease of cross-sectional area). These forms of remodeling can be inward (reduction in lumen diameter) oroutward (e.g., increase in lumen diameter).

Reproduced with permission from the American College of Physicians. Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. AnnIntern Med 2003139:761-6.


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Change in Aortic Pressure Profile due to Age-Related Vascular Stiffening and Increased Pulse wave Velocity (PWV)Figure 121: Increased systolic blood pressure (SBP) and decreased diastolic blood pressure (DBP) due to decreased aortic distensibility. 2: IncreasedPWV as a result of decreased aortic distensibility and increased distal (arteriolar) resistance. 3: Return of the reflected primary pulse to thecentral 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 andtherefore myocardial oxygen demand. Note also the reduction in the diastolic pressure-time (integrated area under the DBP curve). This reductionin coronary perfusion pressure increases the vulnerability of the myocardium to hypoxia. 5: The enhanced aortic BP resulting from decreasedaortic distensibility and early reflected waves.

Reproduced with permission from Saunders Elsevier. Rosendorff C. Ischemic heart disease in hypertension. In Hypertension: A Companion toBraunwalds Heart Disease, eds. Black HR, Elliott WJ. Philadelphia: Saunders Elsevier, 2007:329.


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Etiology(2 of 2)

Renin-Angiotensin-Aldosterone System

Figure 13 summarizes the key elements of the RAAS. The key receptor forangiotensin II is the AT1 receptor. AT1 receptors are found in the vasculature andmany other tissues. They activate calcium channels and the G protein,phospholipase C, diacylglycerol and inositol trisphophate transduction pathways,

thus triggering angiotensin II-mediated CV events, including constriction ofresistance vessels, stimulation of aldosterone synthesis and release, renal tubularsodium reabsorption (directly and indirectly via aldosterone), stimulation of thirst,release of antidiuretic hormone, and enhancement of sympathetic outflow from thebrain. Importantly, angiotensin II also induces hypertrophy and hyperplasia ofcardiac 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 inactivatesmitogen-activated protein kinase, a key enzyme involved in transducing signals fromthe AT1 receptor. Thus, activation of the AT2 receptor opposes the biological effectsof AT1 receptor activation, leading to vasodilation, growth inhibition, and celldifferentiation (Figure 14).

The physiologic role of the AT2 receptor in adult humans is unclear, but it is thoughtto function under stress conditions (e.g., vascular injury, ischemia reperfusion) andto account for some of the favorable vascular effects of the ARBs, which are selectiveantagonists of AT1 receptors. When an ARB is administered, renin is released fromthe kidney due to removal of feedback inhibition by angiotensin II. This leads toincreased generation of angiotensin II, which is shunted to the AT2 receptor, favoringvasodilation 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 otherenzymes, including chymas. The activity of the local RAAS and alternative pathwaysof angiotensin II formation may make an important contribution to the remodeling ofresistance vessels and the development of target-organ damage (including

atherosclerosis, LV hypertrophy, MI, heart failure, stroke, end-stage renal disease,and arterial aneurysm) in hypertensive persons. Non-ACE enzymes that convertangiotensin I to angiotensin II are responsible for the phenomenon of "angiotensinescape," whereby the plasma and presumably the tissue concentration ofangiotensin II is never completely suppressed by ACEIs.

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 withangiotensin II administration is linked to upregulation of vascular p22phox mRNA, acomponent of the oxidative enzyme NAD(P)H oxidase. AT1 receptor-dependentactivation of NAD(P)H oxidase is associated with enhanced formation of the oxidantsuperoxide anion (O2-), which reacts readily with NO to form the oxidant peroxynitrite

(ONOO-). Reduction in NO bioavailability thus provides an additional mechanism toexplain the enhanced vasoconstrictor response to angiotensin II in hypertension.NAD(P)H oxidase may also play an important role in the hypertrophic response toangiotensin II.

Other vasculotoxic responses to angiotensin II that are linked to the activation ofNAD(P)H oxidase include the oxidation of LDL cholesterol and increased mRNAexpression for monocyte chemoattractant protein-1 (MCP-1) and vascular celladhesion molecule-1 (VCAM-1). ACEIs and ARBs limit oxidative reactions in thevasculature by blocking angiotensin II-induced activation of NAD(P)H oxidase. Thishas led to the hypothesis that RAAS blockers have clinically important vasoprotectiveeffects beyond BP lowering.

Aldosterone

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17a

Figure 17b


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disease, but not consistently in hypertension. The reason for this may be that ET1 issecreted in an abluminal direction by endothelial cells and acts in a paracrinefashion on underlying smooth muscle cells to cause vasoconstriction and elevateBP without necessarily reaching increased levels in the systemic circulation.

ET receptor antagonists reduce BP and peripheral vascular resistance in bothnormotensive persons and patients with mild to moderate essential hypertension,supporting the interpretation that ET1 plays a role in the control of vasomotor tone innormal human subjects, as well as in the pathogenesis of hypertension. However,development of this drug class for the treatment of systemic hypertension has beenplagued by toxicity issues, mainly hepatotoxicity.

The ET receptor antagonists bosentan, ambrisentan are FDA-approved for thetreatment 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 ETA-selective antagonist darusentan failed to achieve its co-primary efficacyendpoints of a change in systolic and diastolic blood pressure after 14 weekscompared to placebo.

Endothelial Dysfunction

Endothelial dysfunction has been implicated as both a cause and a consequence ofhypertension via mechanisms that involve reduced NO synthesis, release, and/orbioactivity (Figures 17a, b). NO is a potent vasodilator, inhibitor of platelet adhesionand aggregation, and suppressor of migration and proliferation of vascular smooth

muscle cells. NO is released by normal endothelial cells in response to a variety ofstimuli, including changes in BP, shear stress, and pulsatile stretch, and plays animportant role in BP regulation, thrombosis, and atherosclerosis. The CV system innormal persons is exposed to continuous NO-dependent vasodilator tone, but NO-related vascular relaxation is diminished in hypertensive persons.

It has been suggested that angiotensin II at concentrations that have a minimaleffect on BP enhances formation of the oxidant superoxide. Increased oxidant stressand the development of endothelial dysfunction may thus predispose to thedevelopment of hypertension. The observation that in vivo delivery of superoxidedismutase (enzyme that reduces superoxide to hydrogen peroxide) reduces BP andrestores NO bioactivity provides further evidence that superoxide-induced oxidantstress contributes to the inactivation of NO and the development of endothelialdysfunction in hypertensive models.


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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

inhibitor-1 (PAI-1) and other growth family pathways the AT 2 receptor does not. The angiotensin-receptor blockers bind to and selectively block

the AT1 receptor, allowing stimulation of the receptor by angiotensin II.



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Mechanisms of Angiotensin II (ANG II)-Dependent, Oxidant-Mediated Vascular DamageFigure 15Reproduced with permission from the American College of Physicians. Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. AnnIntern Med 2003139:761-6.


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Deleterious Effects of Aldosterone/SaltFigure 16Reproduced with permission from Bentham Science Publishers. McMahon EG. Eplerenone, a new selective aldosterone blocker. Curr Pharm Des20039:1065-75.


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Endothelial Function in the Normal Vasculature (1 of 2)Figure 17aLarge conductance vessels (left), for example, epicardial coronary rteries, and resistance arterioles (right), are shown. In normal conductancearteries, platelets and monocytes circulate freely, and oxidation of LDL is prevented by a preponderance of NO formation. At the level of thesmall arterioles, reduced vascular tone is maintained by constant release of NO. Endothelin-1 normally induces no vasoconstriction or onlyminimal vasoconstriction through stimulation of type A endothelin receptors (ETA) located on smooth-muscle cells, and contributes to basal NOrelease by stimulating type B endothelin receptors (ETB) on endothelial cells.



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Endothelial Function in the Hypertensive Vasculature (2 of 2)Figure 17bIn the hypertensive microvasculature, decreased activity of NO and enhanced ETA-mediated vasoconstrictor activity of endothelin-1 result inincreased vascular tone and medial hypertrophy, with a consequent increase in systemic vascular resistance. At the level of conductancearteries, a similar imbalance in the activity of endothelial factors leads to a pro-atherosclerotic milieu that is conducive to the oxidation of LDL, theadhesion and migration of monocytes, and the formation of foam cells. These activities ultimately lead to the development of atheroscleroticplaques, the rupture of which, in conjunction with enhanced platelet aggregation and impaired fibrinolysis, results in acute intravascularthrombosis, thus explaining the increased risk for CV events in patients with hypertension. These mechanisms may be operative in patients withhigh normal BP and may contribute to their increased CV risk.



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Target Organs(1 of 2)

High BP has significance only insofar as it causes damage to target organs. The common theme in many of theseeffects is inward eutrophic remodeling of small resistance arteries, increased large artery stiffness, and acceleratedatherogenesis. 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 laterwill hypertrophy. The etiology of this hypertension-induced cardiac damage is complex, and includes pressure overload,circulating and local factors such as angiotensin II, catecholamines, and ET1, which promote vascular and myocytegrowth, increased connective tissue deposition, and collagen cross-linking.

Increased LV stiffness and hypertrophy have several consequences: limitation of the rate at which the LV can fill duringdiastole causes left atrial (LA) enlargement and thickening, with the development of a fourth heart sound or gallop andthe 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 effectsof hypertension on the heart. New-onset atrial fibrillation is more likely to develop in hypertensive patients with increasedLA size, and antihypertensive therapy is protective against this arrhythmia. Increased LV stiffness may produce thesymptoms and signs of diastolic heart failure. LV hypertrophy (LVH) also imposes an increase in myocardial oxygendemand, which in the presence of occlusive coronary artery disease (itself accelerated by hypertension) and impairedcoronary flow reserve, makes the individual more susceptible to myocardial ischemia, infarction, or heart failure. ECGevidence of LVH, strain pattern and prolonged QRS duration are all markers of cardiac target-organ 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 Theechocardiographic diagnosis of LV diastolic dysfunction due to decreased LV compliance is more complex, and isdiscussed in the section on LV failure with preserved systolic function.

The prevalence of LVH in hypertensive individuals is 25-35%. LVH is associated with a graded increase in the risk ofCVD, proportional to the degree of hypertrophy and over and above the risk of the hypertension per se. Patients withhypertension and LVH are at increased risk of acute coronary syndrome due to the increased metabolic demand of thehypertrophied myocardium, the increased output impedance of the elevated aortic BP, the impairment of myocardialperfusion 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 ischemicheart disease. Many studies have shown significant regression of LVH when BP is reduced it is not clear whether this issimply a function of the degree of BP lowering or whether some antihypertensive drugs are better than others at dosesthat are equipotent for BP reduction. ACE inhibitors, ARBs, CCBs, and diuretics all regress LVH, whereas beta-blockersare 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. Thismay be due to lipohyalinosis or fibrinoid necrosis with associated focal damage to small resistance vessels, which mayocclude, causing lacunar infarcts, or rupture, causing hemorrhagic strokes. Hypertension may exacerbateatherosclerosis of larger vessels, which if occluded, will cause ischemic stroke, or if ruptured, hemorrhagic stroke. Othermechanisms of stroke include embolization of thrombus from hypertension-related atheroma in the carotid arteries orascending aorta, or from hypertension-related heart disease, such as atrial fibrillation, MI, ventricular dyskinesia or

aneurysm, and rarely, paradoxical emboli through a patent foramen ovale.


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Most strokes have a central core of severe blood flow reduction with permanent infarction and a surrounding penumbra ofischemic, but salvageable tissue. The purpose of prompt therapy with anticoagulants, fibrinolytics, and neuroprotectivetherapies is to improve flow to the ischemic penumbra. The management of hypertension in the patient with acute strokeis controversial. Cerebrovascular autoregulation is impaired or abolished in the ischemic penumbra because of localhypoxia and acidosis, resulting in a passive pressure-flow 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 Post-Stroke),22

has shown improved stroke outcomes (lower mortality and less post-stroke dependency) if the BP is lowered to a SBP of145-155 mm Hg acutely. In the longer-term, there is ample evidence from many clinical trials that BP lowering isimportant 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 onthe 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 andindapamide 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 benefitof telmisartan in the secondary prevention of stroke. This may be explained on the basis that, compared tothe 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 inhypertensive patients who have had a stroke remains strong.


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Target Organs(2 of 2)

Acute Hypertensive Encephalopat hy

Acute hypertensive encephalopathy is a medical emergency characterized by a very high BP (hypertensive crisis), severeheadache, 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 post-capillaryvenules exceeds the upper limit of cerebrovascular autoregulation, causing pressure-related dilatation with disruption of

the blood-brain barrier and focal cerebral edema.

Factors which may facilitate the "breakthrough" of autoregulation include activation of potassium channels and ofparasympathetic nerves to cerebral vessels. Hypertensive encephalopathy is a hypertensive emergency: Patients shouldbe 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'sdisease (AD). VD and AD have different pathogeneses VD produces small infarcts, arteriosclerosis, particularly medialnecrosis of small penetrating arterioles (Binswanger's disease or subcortical arteriosclerotic encephalopathy), andsubcortical demyelination. The hallmark lesion of AD is the deposition of extracellular amyloid plaques and intracellularneurofibrillary tangles. VD and AD are often not easy to differentiate clinically or by current imaging techniques, and areoften 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 long-standing injury to the kidney,

confirmed by kidney biopsy or a glomerular filtration rate (GFR) of 300 mg/day). Diabetes and hypertension account for the bulk of patients with end-stagerenal failure.

The key components of hypertension in patients with kidney disease include: 1) inappropriately elevated sympatheticnervous activity, 2) activation of the RAAS, and 3) impaired sodium and water excretion by the kidney. Both sympatheticoveractivity and angiotensin II selectively constrict the efferent arterioles of the kidney, increasing glomerular filtrationpressure and therefore filtration fraction. As a consequence, the colloid osmotic pressure of the fluid leaving theglomerular capillary to enter the peritubular network of capillaries is increased, resulting in greater sodium reabsorptionthrough 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 -receptors, resulting in anincrease in angiotensin II.

Another stimulus to renin release is the low sodium concentration in the distal nephron, a consequence of the greatersodium reabsorption in the proximal renal tubule. Other mechanisms include a direct effect of angiotensin II to enhancethe sodium/hydrogen antiporter, of the proximal tubule cells to increase sodium reabsorption, and the angiotensin IImediated release of the mineralocorticoid hormone, aldosterone. Angiotensin II also causes morphologic changes in thekidney, mesangial cell proliferation, and the activation and release of pro-inflammatory cytokines in the renalparenchyma.

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


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artery stenosis should be suspected and the RAAS blocker should be withheld until the underlying condition can bediagnosed and corrected.

Similarly, a rise in serum potassium should be expected with ACEI or ARB therapy this should be a concern only if theserum potassium rises 0.5 mEq/L or more from a baseline level of >5.0 mEq/L. Otherwise the rise in serum potassiumcan be managed by educating the patient to reduce the intake of potassium.


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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


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References

1. World Health Organization. The World Health Report, 2008. Primary Health Care. Geneva, Switzerland: WorldHealth Organization. Available at: www.who.int/whr/2008/whr08_en.pdf. Accessed 12/19/2011.

2. Hsia J, Margolis KL, Eaton CB, et al. for the Women's Health Initiative Investigators. Prehypertension andcardiovascular disease risk in the Women's Health Initiative. Circulation 2007115:855-60.

3. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report on the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA 2003289:2560-72.

4. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey Data. Hyattsville,MD: US Department of Health and Human Services 2010. Available at: http://www.cdc.gov/nchs/nhanes.htm.

Accessed 12/19/2011.5. Roger VL, Go AS, Lloyd-Jones DM, et al., on behalf of the American Heart Association Statistics Committee and

Stroke Statistics Subcommittee. Heart disease and stroke statistics--2011 update: a report from the AmericanHeart Association. Circulation 2011123:e18-.

6. Ong KL, Cheung BM, Man YB, Lau CP, Lam KS. Prevalence, awareness, treatment, and control of hypertensionamong United States adults, 1999-2004. Hypertension 200749:69-75.

7. 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 meta-analysis of individual data for one millionadults in 61 prospective studies. Lancet 2002360:1903-13.

8. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease.N Engl J Med 2001345:1291-7.

9. Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann Intern Med 2003139:761-76.

10. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of sevencommon diseases and 3,000 shared controls. Nature 2007447:661-78.11. Adrogu HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med

2007356:1966-78.12. Rosendorff C. The renin-angiotensin system and vascular hypertrophy. J Am Coll Cardiol 199628:803-12.13. Pitt B, Zannad WF, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with

severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999341:709-17.14. Pitt B, Remme W, Zannad WF, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular

dysfunction after myocardial infarction. N Engl J Med 2003348:1309-21.15. Rosendorff C. Endothelin, vascular hypertrophy, and hypertension. Cardiovasc Drugs Ther 199710:795-802.16. Bakris GL, Lindholm LH, Black HR, et al. Divergent results using clinic and ambulatory blood pressures: report of

a darusentan-resistant hypertension trial. Hypertension 201056:824-30.17. Yambe M, Tomiyama H, Yamada J, et al. Arterial stiffness and progression to hypertension in Japanese male

subjects with high normal blood pressure. J Hypertens 200724:87-93.

18. Dhingra R, Pencina MJ, Wang TJ, et al. Electrocardiographic QRS duration and the risk of congestive heart failure:the Framingham Heart study. Hypertension 200647:861-7.

19. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the AmericanSociety of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification WritingGroup, developed in conjunction with the European Association of Echocardiography. J Am Soc Echocardiogr200518:1440-63.

20. Ingelsson E, Bjorklund-Bodegard K, Lind L, Arnlov J, Sundstrom J. Diurnal blood pressure pattern and risk ofcongestive heart failure. JAMA 2006295:2859-66.

21. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke:a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical CardiologyCouncil, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Diseaseand Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke 200738:1655-711.

22. Potter J, Robinson TG, Ford GA, et al. Controlling hypertension and hypotension immediately post-stroke

(CHHIPS): a randomized, placebo-controlled, double-blind pilot trial. Lancet Neurol 20098:48-56.23. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimenamong 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001358:1033-41.

24. Yusuf S, Diener HC, Sacco RL, et al., on behalf of the PRoFESS Study Group. Telmisartan to prevent recurrentstroke and cardiovascular events. N Engl J Med 2008359:1225-37.

25. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P, on behalf of the Irbesartan inPatients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development ofdiabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001345:870-8.

26. Brenner BM, Cooper ME, de Zeeuw D, et al., on behalf of the RENAAL Study Investigators. Effects of losartan onrenal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001345:861-9.

27. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartanin patients with nephropathy due to type 2 diabetes. N Engl J Med 2001345:851-60.


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5.2: Diagnosis and Management of Hypertension


Learner Objectives

Upon completion of this module, the reader will be able to implement current guidelines for the diagnosis and treatment ofhypertensive patients, including multiple risk factor modification.


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Diagnosis of Hypertension

Hypertension should be diagnosed and treated in the context of reducing overallcardiovascular (CV) risk and preventing morbidity and mortality from CV disease(CVD). In most hypertensive patients, there are multiple risk factors foratherosclerotic disease. Therefore, comprehensive assessment and treatment of allrisk 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 initialassessment (Figure 1), and addressed by the treatment plan. In addition, the initialevaluation should include an accurate measurement of blood pressure (BP),screening for secondary causes of hypertension, and assessment of target-organdamage.

Figure 1


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Cardiovascular Assessment in the Hypertensive PatientFigure 1Reproduced with permission from Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the UnitedStates, 1988-2000. JAMA 2003290:199-206. Copyrighted 2003, American Medical Association. All Rights reserved.


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Blood Pressure Measurement

In-Office Blood Pressure Measurement

Except in cases of extreme BP elevation with systolic BP (SBP) >210 mm Hg, and/ordiastolic BP (DBP) >120 mm Hg (hypertensive urgency), or elevated BP withevidence of ongoing target-organ damage (hypertensive emergency), hypertensionshould not be diagnosed on the basis of measurements made on a singleoccasion. Hypertension is diagnosed when at least two separate readings obtained

at least 1-2 weeks apart average 140/90 mm Hg.1 Procedures to ensure accuratemeasurement of BP in the office setting are outlined in Figure 2.

Patients should abstain from tobacco use and caffeine ingestion for at least 30minutes before the BP measurement is taken. The arm should be exposed and freeof constricting clothing. Patients should be asked to sit quietly for 5 minutes beforethe BP is measured. Use of an appropriately sized cuff, in which the bladderencircles at least 80% of the arm, is essential because a cuff that is too large or toosmall will result in falsely low or falsely high readings, respectively. A common erroris to use a regular cuff on a larger arm this will overestimate the true BP. During BPmeasurement, the arm should be supported with the cuff at approximately heartlevel.

Determining BP accurately can be difficult in elderly patients because of stiffening ofarterial walls. The loss of arterial wall compliance can result in falsely elevated BPmeasurements when a standard sphygmomanometer is used.Pseudohypertension, a falsely elevated BP obtained by indirect cuff measurementsecondary to loss of arterial compliance or even calcification, should be suspectedin 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 theBP cuff above the level of the SBP if the pulseless radial or brachial artery remainspalpable, stiffening of the artery may falsely elevate the BP measurement. Directintra-arterial BP determinations may be necessary to accurately diagnosehypertension in this setting.

It is now known that some classes of BP-lowering drugs, such as beta-blockers,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 Thenoninvasive measurement of central aortic BP involves the translation of the brachialor radial pulse waveforms to a central aortic waveform using an experimentallyderived transfer function. This requires special equipment, as it is not likely to beadopted for general use soon.

Out-of-Office Blood Pressure Measurement

Home BP measurement or automated ambulatory BP monitoring often helps toverify the diagnosis and assess the severity of hypertension. BP values obtainedoutside the clinic setting are generally lower and correlate better with target-organdamage 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 accurateand calibrated BP monitors and careful repeated instruction in good BPmeasurement technique. Normal mean 24-hour ambulatory BP is


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response that may be amplified through patient-physician interactions.

White-coat hypertension is associated with other coronary risk factors, and isgenerally thought to be associated with increased CVD risk, but not to the levelobserved in fixed hypertension. In the absence of reliable prognostic data andwithout prospective randomized outcome trials of antihypertensive drug treatment inwhite-coat hypertension, at a minimum, lifestyle modification should be employedfor BP control, and concomitant CVD risk factors should be treated aggressively.Some hypertension authorities advocate antihypertensive drug therapy for thesepatients.

In some patients, office BP may be significantly lower than ambulatory BP ("maskedhypertension" or "reverse white-coat hypertension"). This may lead to a falsely lowestimate of daily BP and possible undertreatment of some patients. Patients withmasked 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 forand guide a possible evaluation of secondary causes of hypertension, 2) todetermine the presence and severity of target organ damage, and 3) to assessoverall CV risk and identify all modifiable CV risk factors (Figure 3). Patients shouldalso be questioned about the duration and severity of their hypertension, priorworkup 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 theabsence of a positive family history of hypertension, and an abrupt worsening in theseverity of hypertension in an older patient. Patients with resistant hypertension thatremains uncontrolled in the presence of an aggressive multidrug regimen shouldalso be worked up for secondary hypertension.

Target-organ damage must be documented by history and physical examination. Ahistory of coronary heart disease (CHD), cerebrovascular disease, peripheralvascular disease, or chronic kidney disease (CKD) suggests long-standing, poorlycontrolled hypertension. In addition, prior diagnosis and treatment of other CV riskfactors (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 asweight gain, sedentary lifestyle, high dietary salt ingestion, and excessive alcoholconsumption should be reviewed.

Physical Examination

The physical examination should accurately determine the BP, identify signs ofsecondary causes of hypertension, and document the presence and degree oftarget-organ damage. The BP determination should be the average of a minimum oftwo BP readings obtained 2-3 minutes apart. Initially, the BP should be measured inboth arms. Although there are often small variations between arms, large

differences suggest subclavian artery obstruction. In general, the BP measurementshould be obtained from the arm that yields the higher readings. Standing BP levelsshould be checked during the initial evaluation and after drug titrations to excludesignificant orthostasis.

Laboratory Evaluation

Laboratory evaluation should document target-organ damage (Figure 5). Blood ureanitrogen (BUN) and serum creatinine levels should be obtained to quantify renalfunction. Serum creatinine can be supplemented as an index of renal function withthe calculation of estimated glomerular filtration rate (eGFR), which is derived from

an equation that includes terms for gender, race, and age.5 Urine should beanalyzed for microalbuminuria, one of the earliest signs of endothelial dysfunctionand generalized vascular disease.


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CKD is both a cause and a complication of hypertension, and is defined as either: 1)

reduced excretory function with an eGFR 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 reducedeGFR. Albumin excretion can be most conveniently assessed by measuring thealbumin:creatinine ratio on a spot urine sample: A ratio of 30-300 mg albumin/gcreatinine signifies microalbuminuria >300 mg albumin/g creatinine signifies CKD.

A recent trend is to abandon the term microalbuminuria and to regard all levels ofalbumin excretion above 30 mg/g creatinine as signifying CKD. Serum potassium

should be measured to rule out hypokalemia suggestive of hyperaldosteronism, orthe 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. Afasting lipid profile should be obtained to diagnose dyslipidemia, which is alsocommon in hypertensive patients. An electrocardiogram (ECG) should be obtainedto look for evidence of ischemic heart disease, left ventricular (LV) hypertrophy, orboth.


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Blood Pressure MeasurementFigure 2


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Evidence of Secondary Hypertension (1 of 4)Figure 4a


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Causes of Secondary Hypertension (2 of 4)Figure 4bReproduced with permission from Oparil S, Calhoun D (2000). High blood pressure. Scientific American Medicine, vol. 1, part 3, pp. 1 16. NewYork: Scientific American.


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Causes of Secondary Hypertension (3 of 4)Figure 4cReproduced with permission from Oparil S, Calhoun D (2000). High blood pressure. Scientific American Medicine, vol. 1, part 3, pp. 1 16.NewYork: Scientific American.


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Causes of Secondary Hypertension (4 of 4)Figure 4dReproduced with permission from Oparil S, Calhoun D (2000). High blood pressure. Scientific American Medicine, vol. 1, part 3, pp. 1 16. NewYork: Scientific American.


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Baseline Laboratory TestsFigure 5


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Benefits of Pharmacologic Treatment

Reducing BP by pharmacologic means reduces CV morbidity and mortality. Inclinical trials, antihypertensive therapy has been associated with reductions instroke incidence of 35-40%, in myocardial infarction (MI) of 20-25%, and in thedevelopment of congestive heart failure (CHF) of >50%.

Meta-analyses of randomized controlled trials of antihypertensive therapy haveshown outcome benefits with the major classes of antihypertensive drugs, including

angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, andcalcium channel blockers.6, 7 The evidence for beta-blockers and thiazide-typediuretics for CV protection in uncomplicated hypertension is controversial, and willbe described in the module on Pharmacologic Treatment of Hypertension in thischapter.

Antihypertensive drug treatment also slows progression to more severehypertension, development of LV hypertrophy, progression of renal disease andCHF, and reduces all-cause mortality. Clinical trials in elderly patients, particularlythose with ISH, have shown even greater benefit than in younger persons.

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 othermodifiable CV risk factors should be addressed. Based on evidence from multipleclinical trials, the seventh report of the Joint National Committee for the Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),1

recommends that the threshold for the pharmacologic treatment of hypertensionshould be a BP of 140/90 mm Hg, except in the presence of diabetes or CKD whenpatients should be started on appropriate drug therapy with a goal BP of


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pharmacologic therapy should be administered. Home BP measurement or 24-hourambulatory BP monitoring (ABPM) is useful to avoid overtreatment of these patients.

Antihypertensive treatment is indicated in isolated systolic hypertension becauseSBP is a better predictor of events (CHD, CVD, CHF, stroke, end-stage renaldisease, and all-cause mortality) than is DBP, especially among older persons.Elevated pulse pressure, an indicator of reduced compliance in large vessels, is abetter marker of increased CV risk than is SBP or DBP alone, particularly in elderlyindividuals. Pharmacologic therapy in patients with ISH is well tolerated and effectivein both lowering BP and reducing CV morbidity and mortality, particularly throughreductions in stroke. The goal of treatment in patients with ISH is to lower SBP to


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Classification and Management of Blood Pressure for Adults Ages 18 Years or OlderFigure 6Reproduced 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 2003289:2560-72. Copyrighted 2003,



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Algorithm for Treatment of HypertensionFigure 7Reproduced 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 2003289:2560-72. Copyrighted 2003,



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Calculation of a 10-Year Risk for Coronary Heart Disease Using the Framingham Point Score (1 of 2) - MenFigure 8aReproduced from the National Heart, Lung, and Blood Institute as part of the National Institutes of Health and the US Department of Health andHuman Services. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm. Accessed 11/30/2011.


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Calculation of a 10-Year Risk for Coronary Heart Disease Using the Framingham Point Score (2 of 2) - WomenFigure 8bReproduced from the National Heart, Lung, and Blood Institute as part of the National Institutes of Health and the US Department of Health andHuman Services. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm. Accessed 11/30/2011.


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Data From the Framingham Heart Study ExperienceFigure 9

Much of the young and middle-aged population has a low to intermediate risk for hard coronary heart disease (CHD) events (myocardialinfarction or CHD death). Even up to age 80 years, more than three-quarters of women experience a 10-year 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 70-79 yearage 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 #1identification of coronary heart disease risk: is there a detection gap? J Am Coll Cardiol200341:1863-74.


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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 andmortality, it has been shown in randomized controlled trials to lower BP in bothhypertensive and high-risk prehypertensive persons, and can prevent hypertensionin the latter group. In addition, lifestyle modification can potentially reduce thenumber and dosage of antihypertensive medications needed to control a patient'shigh BP.

Advice on l ifestyle modification should be tailored to each patient's needs. Forexample, emphasis should be placed on weight loss and increased physical activityfor obese patients. All hypertensive patients should be advised to adopt the followinglifestyle modifications: 1) eat a well-balanced diet rich in fruits, vegetables, and low-fat dairy products 2) lose weight if not at ideal body weight 3) pursue regularphysical exercise 4) decrease alcohol consumption to less than 2-3 standarddrinks a day for those who drink 5) reduce dietary sodium and 6) stop smoking.

Diet

The DASH Collaborative Research Group has provided strong evidence that totaldiet 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 low-fat dairy products and low in saturated and total fat, lowered BP by 3.5/2.1mm Hg in normotensive individuals, and by 11.4/5.5 mm Hg in hypertensives, eventhough sodium intake and weight were held constant.

Importantly, the DASH eating plan was particularly effective in reducing BP in theblack study participants (Figures 11a, b). The BP reduction in hypertensive blackswas 13.6/6.1 mm Hg, an effect comparable to that achieved with many singleantihypertensive drugs. The DASH diet can be approximated by taking four servingsof fruit, four servings of vegetables, and three servings of low-fat dairy products perday (Figure 12).

Weight Loss

Weight loss is potentially the most effective lifestyle modification for those with highBP. The BP-lowering effect of weight loss is independent of sodium restriction, andis seen in both obese and nonobese hypertensive individuals. Clinical trial evidencesuggests that weight loss interventions produce BP benefits that persist even aftercessation of active therapy. In addition, weight loss decreases insulin resistance,the incidence and severity of diabetes, serum cholesterol, and the prevalence of LVhypertrophy. 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, emphasisshould be placed on prevention of weight gain, particularly in younger individualswith prehypertension and in families with a high prevalence of hypertension. Whenprescribing 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. Exercisewith a goal of achieving 40-60% of maximum O2consumption (30-45 minutes of

brisk walking for most days of the week is recommended) has been shown todecrease SBP by 4-9 mm Hg in both normotensives and hypertensives. In addition,regular physical activity promotes a sense of well-being and decreases CV risk,morbidity, and mortality. Exercise also reduces overall mortality and has beneficialeffects on serum lipid profiles.

Prescriptions for exercise should, as other lifestyle modifications, be tailored to eachindividual patient's condition and preference. Persons with advanced or unstable

CVD may require a medical evaluation before initiation of exercise and/or a

Figure 10

Figure 11a

Figure 11b

Figure 12


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Effect of DASH Diet on Blood Pressure by Race and Hypertension Status (2 of 2) Diastolic Blood PressureFigure 11bReproduced with permission from Svetkey LP, Simons-Morton D, Vollmer WM, et al. Effects of dietary patterns on blood pressure: subgroupanalysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med 1999159:285-93. Copyrighted 1999, American Medical Association. All Rights reserved.


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DASH DietFigure 12Tips 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 low-fat, low-energy foods such as sugar-free gelatin for desserts or snacks.


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Key Points

There are distinct advantages and disadvantages of measuring BP at home versus the clinic or office.White-coat hypertension is not benign, and should probably be treated with aggressive lifestyle modification, andpossibly with pharmacologic therapy.In all patients, a careful history and physical examination should be directed to the following objectives: 1) toidentify secondary causes of hypertension, 2) to establish the presence and severity of hypertensive target-organdamage, 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:creatinineratio in a spot urine sample.The threshold for pharmacologic treatment is 140/90 mm Hg, except in patients with diabetes, CKD, CAD, CADequivalents (cerebrovascular disease, carotid artery disease, aortic aneurysm, peripheral vascular disease) andthose 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 ofnormal body weight increased physical activity dietary modification to include more fruits, vegetables, and low fatdairy products moderation of alcohol intake and sodium reduction in salt-sensitive individuals, can lower BP inboth 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 animportant adjunct to pharmacologic therapy in patients with hypertension.


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References

. o an an , a r s , ac , et a . event report o t e o nt at ona omm ttee on revent on,Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 200342:1206-52.

2. Williams B, Lacy PS, Thom SM, et al., on behalf of the CAF Investigators Anglo-Scandinavian Cardiac OutcomesTrial Investigators CAF 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 FunctionEvaluation (CAFE) study. Circulation 2006113:1213-25.

3. Kikuya M, Hansen TW, Thijs L, et al. Diagnostic thresholds for ambulatory blood pressure monitoring based on10-year cardiovascular risk. Circulation 2007115:2145-52.

4. Hara A, Ohkubo T, Kikuya M, et al. Detection of carotid atherosclerosis in individuals with masked hypertensionand white-coat hypertension by self-measured blood pressure at home: the Ohasama study. J Hypertens200725:321-7.

5. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension andantihypertensive agents in chronic kidney disease. Am J Kidney Dis 200443(5 Suppl 1):S1-290.

6. Turnbull F, on behalf of the Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews ofrandomised trials. Blood Pressure Lowering Treatment Trialists Collaboration. Lancet 2003362:1527-35.

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 blood-pressure-lowering drugs: results of prospectivelydesigned overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration. Lancet2000356:1955-64.

8. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management ofischemic heart disease: a scientific statement from the American Heart Association Council for High BloodPressure Research and the Councils on Clinical Cardiology and Epidemiology and. Circulation 2007115:2761-88.

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 meta-analysis of individual data for one millionadults in 61 prospective studies. Lancet 2002360:1903-13.

10. ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med2010362:1575-85.

11. Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer PJ, Sacks FM. Dietary approaches to prevention andtreatment of hypertension: a scientific statement from the American Heart Association. Hypertension 200647:296-308.

12. Cook NR, Cutler JA, Obarzanek E, et al. Long term effects of dietary sodium reduction on cardiovascular diseaseoutcomes: observational follow-up of trials of hypertensive prevention (TOHP). BMJ 2007334:885-8.

13. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: TheTask Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of theEuropean Society of Cardiology (ESC). J Hypertens 200725:1105-87.


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5.3: Pharmacologic Treatment of Hypertension


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.


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Pharmacologic Treatment

General Considerations

Abundant clinical trial data indicate that lowering blood pressure (BP) withantihypertensive drugs effectively reduces the risk of a variety of cardiovasculardisease (CVD) outcomes, including CV death, as well as total mortality. Outcomebenefits have been seen with treatment based on diuretics, beta-blockers,angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers

(ARBs), and calcium channel blockers (CCBs).1,2

Most hypertensive patients require more than one drug, so the emphasis should beon the choice of compatible combinations and correct doses, rather than individualdrug choices. It should be noted, also, that the eighth report of the Joint NationalCommittee on Prevention, Detection, Evaluation, and Treatment of High BloodPressure (JNC 8) is in preparation at the time of this writing, and therecommendations 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 BPlowering, or whether some classes of antihypertensive drugs have additionalvasoprotective properties which make them more appropriate than others. Someauthorities have claimed that, for outcomes other than HF, differences in achievedsystolic BP (SBP) lowering are linearly related to the extent of risk reduction ( Figure1), and, therefore, BP reduction is everything. On the other hand, trials such as LIFE(Losartan Intervention For Endpoint reduction in hypertension),3ACCOMPLISH(Avoiding Cardiovascular Events through Combination Therapy in Patients Living

with Systolic Hypertension),4 andASCOT-BPLA (Anglo-Scandinavian Cardiac

Outcomes Trial-Blood Pressure Lowering Arm)5 have demonstrated majortreatment advantages of one treatment over another without associated differencesin BP reduction or in attained BP. It is clear that, for hypertensive patients overall, BPreduction is the first priority, but also that providers should be more discriminating intheir choice of antihypertensive drug, to take advantage of drug properties that areadditional to BP lowering alone.

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, high-risk comorbid conditions for which clinicaltrials have demonstrated benefit of specific classes of antihypertensive drugs

(Figures 2, 3).6 For hypertensive persons with compelling indications, drugselections are dictated by the comorbid condition as well as the BP. In the absenceof compelling indications, JNC 7 recommends that most patients be treated with athiazide-type diuretic, either alone or in combination with other classes of drugs(ACEIs, ARBs, CCBs, or beta-blockers) that have been shown to be beneficial inrandomized controlled outcome trials. The latest European guidelines have alsotaken the view that these five classes of drugs are suitable for the initiation andmaintenance of antihypertensive treatment, alone and in combination, except thatbeta-blockers, especially in combination with thiazide diuretics, should not be used

in patients with the metabolic syndrome or at high risk of incident diabetes.7

Angiotensin-Converting Enzyme Inhibitors and Angiot

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5 Hypertension