Hypertension

Mohammed A. Rafey
CHAPTER SECTION LINKS

Definition and etiology

Prevalence and risk factors

Pathophysiology and natural history

Diagnosis

Treatment

Conclusions

References

Definition and Etiology

Normal or optimal blood pressure (BP) is defined as the level above which minimal vascular damage occurs. There is
a continuous, consistent, and independent relationship between elevated BP and risk of cardiovascular events. This
was clearly demonstrated in a meta-analysis that included 1,000,000 individuals with no history of vascular disease.
Among this group, during 12.7 million person-years at risk, there were about 56000 deaths categorized as vascular in
origin (12000 stroke, 34000 ischemic heart disease, and 10000 other vascular) and 66000 other deaths at ages 4089 years.1 Results from this study demonstrated that a BP level lower than 115/75 mmHg appears to better define
optimal BP.1 According to the Joint National Committee 7 (JNC 7), hypertension is defined as physician office systolic
BP level of 140mmHg and diastolic BP of 90mmHg. The JNC 7 defines normal BP as a systolic BP <120mmHg
and diastolic BP <80mmHg. The gray area between systolic BP of 120-139 mmHg and diastolic BP of 80-89 mmHg is
defined as prehypertension.2
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Prevalence and Risk Factors

One in 3 Americans over the age of 18 years suffers from hypertension. The prevalence is higher among older
individuals, women and non-Hispanic blacks. Despite the increase in prevalence, recent data from the National

Health and Nutrition Examination Survey (NHANES) demonstrate an improvement in blood pressure control (50%)
among Americans with hypertension.3 However, the blood pressure control rate remains suboptimal in people who
have serious comorbid conditions such as chronic kidney disease. In a survey of patients with chronic kidney
disease, BP control was found to be just 13.2%.4 On a global level, hypertension is a greater problem, with 13.5% of
all deaths attributed to BP-related diseases. Individuals in lower economic strata are disproportionately afflicted with
hypertension.5
The prevalence of hypertension increases progressively with age. Results from the Framingham study demonstrate
that among middle-aged and elderly persons, the residual lifetime risk of developing hypertension is 90%.6 In the
majority of patients (95%), hypertension is primary or idiopathic; there is no identifiable risk factor. The remainder of
these patients have hypertension caused by renovascular disease, primary aldosteronism, etc.
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Pathophysiology and Natural History

The role of altered salt excretion by the kidney as a central mechanism in the development of hypertension was
proposed by Arthur C. Guyton.7 According to Dr. Guyton's hypothesis, there is impaired excretion of sodium ions by
tubular epithelial cells in the kidney. To maintain salt and water homoeostasis, the body adopts a pressure-natriuresis
approach that ultimately leads to an elevation in BP. Animal studies and studies evaluating Mendelian forms of
syndromes that manifest as hypertension and hypotension, such as Bartter's syndrome and Liddle's syndrome, have
provided insight into the pathophysiology of hypertension.8 These data confirm that the basic problem in conditions
leading to alteration in BP lies in the genetic alteration of sodium transport in renal epithelial cells. Several factors
including aging, sympathetic overactivity, toxins, and a low nephron number have been proposed as factors that
could ultimately damage the renal tubules and alter epithelial cells, resulting in defective sodium excretion.
In addition, several new conditions that can cause hypertension have been identified. The metabolic syndrome, with
insulin resistance and elevation in insulin levels, leads to increased sympathetic activity and hypertension. In patients
with obstructive sleep apnea, activation of the sympathetic and renin angiotensin systems has been defined as a
possible mechanism for elevation in BP.
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Diagnosis
A detailed history and physical examination is essential for identifying risk factors and stratifying patients to target
those who need more aggressive therapy to achieve goal BP. The history should include details of dietary salt intake
and should explore lifestyle patterns and social and psychosocial stressors that could potentially affect BP levels.
Ophthalmologic assessment and funduscopic examination are simple techniques to identify the severity of disease
and target organ damage by grading retinal changes.

Office Blood Pressure Measurement

Careful measurement of BP should be an integral part of any physical examination in a physician's office. Because
inaccuracies in blood pressure measurement can occur frequently in clinical practice, the following guidelines should
be followed when measuring a patient's BP.9 The patient should be seated comfortably with the back supported and
the upper arm bared without constrictive clothing. The legs should not be crossed. The arm should be supported at
the level of the heart, and the bladder of the BP cuff should encircle at least 80% of the arm circumference. The blood
pressure measuring device should be deflated at the rate of 2 to 3 mm/sec, and the first and last audible sounds
should be taken as the systolic and diastolic pressure respectively. Neither the patient nor the observer should talk
during the measurement.

Ambulatory Blood Pressure Monitoring

In addition to office BP measurements, 24-hour ambulatory BP monitoring and home BP monitoring are now
acceptable methods for evaluating BP more comprehensively on an individual basis. A mean (average) 24 hour BP of
130/80 mmHg is regarded as elevated blood pressure.9
The recently released National Institute of Health and Clinical Excellence (NICE) guidelines published in the United
Kingdom recommend that a diagnosis of primary hypertension should be confirmed with 24-hour ambulatory blood
pressure monitoring or home blood pressure monitoring rather than by relying solely on office blood pressure
measurement. Twenty-four-hour ambulatory BP monitoring is indicated to rule out white-coat hypertension, to
uncover apparent drug resistance (office resistance), to better define resistant hypertension, to identify hypotensive
symptoms while the patient is being treated with anti-hypertensive medications, to monitor episodic hypertension, and
to identify autonomic dysfunction states. Twenty-four-hour ambulatory BP monitoring also helps identify abnormal
patterns in blood pressure that could remain undetected if a patient is evaluated based on physician office blood
pressure measurements alone.

Patterns of Blood Pressure

Based on 24-hour ambulatory BP monitoring and office BP readings, 4 patterns of BP have been described (Figure
1).

Figure 1: Click to Enlarge

In sustained hypertension, BP measurements taken in the office and at home are elevated. Studies done in patients
with sustained hypertension for more than 40 years have consistently demonstrated that this condition is closely
related to target organ damage and worse cardiac and renal outcomes.
Masked hypertension is defined as normal office BP and elevated home BP.10Its prevalence ranges from 8% in the
general population to as much as 20% in hypertensive patients receiving treatment. Although there are no outcome
trials available in patients with masked hypertension, the fact that elevated ambulatory BP is closely related to
cardiovascular events implies that its risk profile is similar to that of sustained hypertension. In fact, patients with
masked hypertension might have a worse outcome because they are not easily identified and do not receive
adequate therapy.
Patients with white coat hypertension have an elevated office BP and normal home BP measurements. The
prevalence of white coat hypertension has been reported to be 12% to 18% in the general population. Initially, this
was thought to be a benign condition, because prospective trials evaluating white coat hypertension have shown less
target-organ damage (increased left ventricular mass, carotid media intimal thickness) than that with sustained
hypertension. Clinical studies evaluating cardiovascular outcomes have consistently demonstrated a lower morbidity
with white coat hypertension, supporting a more benign course. Based on these studies, it has been hypothesized
that white coat hypertension represents an intermediate risk state between normotension and sustained
hypertension. One study that followed patients with white coat hypertension demonstrated a significantly elevated risk
of stroke in these patients after 6 years of follow-up, emphasizing the importance of long-term follow-up for these
individuals.11
Normally, there is a diurnal variation in BP, with a 10% to 20% decrease in systolic BP during sleep, which is
described as the normal dipping pattern. Abnormalities in the normal nocturnal dipping pattern of BP have been
associated with worse cardiovascular outcomes, even in subjects who are normotensive.12 A 24-hour ambulatory BP
measurement remains the only technique to assess the dipping status of patients. Nocturnal hypertension defines a
pattern of BP where BP measured during sleep is higher than that measured when the patient is awake. In the
African American Study of Kidney Disease and Hypertension (AASK), an abnormal dipping pattern was detected in
80% of patients and nocturnal hypertension was found in 40%.13 All of these patients with an abnormal dipping
pattern and nocturnal hypertension had hypertension that was apparently well controlled based on office BP
readings.

Home Blood Pressure Monitoring

Several prospective trials have demonstrated that home BP is a better predictor of cardiovascular morbidity and
mortality than are office BP measurements. Based on these data, the first home BP monitoring guidelines endorsed
by national societies, including the American Heart Association (AHA) and American Society of Hypertension (ASH),
among others, have been published.14

These home BP measurement guidelines recommend that a validated device be used to measure BP at home. Blood
pressure measurements using such validated devices should be taken before an office visit, with at least 2 morning
and 2 evening readings everyday for 1 week (but discarding the readings of the first day), which gives a total of 12 BP
readings over a week, based on which clinical decisions can be made. Hypertension is defined as a mean home
blood pressure of 135/85 mmHg. Home blood pressure monitoring provides an inexpensive alternative to 24-hour
ambulatory BP monitoring which is not yet widely available. One of the main drawbacks in home blood pressure
measurement when compared to 24-hour ambulatory BP monitoring, is that sleep time blood pressures cannot be
recorded and therefore those patients with abnormal dipping pattern in blood pressure and nocturnal hypertension
will be missed.

Central Blood Pressure Measurement

Measures of arterial stiffness such as central (aortic) blood pressure and pulse wave velocity (PWV) can now be
measured non-invasively in an outpatient setting. Preliminary data from clinical studies indicate that these measures
of arterial stiffness may provide better prognostic indices and therapeutic targets in hypertensive
patients.15,16Interventional trials that can test the potential value of treating to a predefined central blood pressure goal
for a given brachial blood pressure will clarify the utility of these measures in the future clinical management of
hypertension. Guidelines of the European Society of Hypertension have incorporated measurement of PWV for risk
stratification of patients with hypertension.

Laboratory Tests
Baseline blood tests are recommended by JNC 7 to identify those individuals at risk for hypertensive events (Table 1).
In addition, laboratory tests can provide clues to the etiology in those with resistant or secondary hypertension (Table
2).

Table 1. Baseline blood tests recommended by JNC 7

Routine tests
Electrocardiogram
Urinalysis
Blood glucose, and hematocrit
Serum potassium, creatinine, or the corresponding estimated glomerular filtration rate, and calcium
Lipid profile, after 9- to 12-hour fast, that includes high-density and low-density lipoprotein cholesterol, and
triglycerides
Optional test

Measurement of urinary albumin excretion or albumin/creatinine ratio

More extensive testing for identifiable causes is not generally indicated unless blood pressure control is not achieved.

Table 2. Laboratory tests and their clues to etiology in patients with resistant or secondary
hypertension
Laboratory Test

Possible Clinical Implication

Change in Management

Urinalysis

Renal disease

Lower blood pressure goal

Serum potassium

Primary aldosteronism, Cushing

syndrome

Further evaluation for secondary hypertension

Further evaluation and more aggressive

Serum creatinine

Renal disease and renovascular disease

Hematocrit

Polycythemia

Further evaluation

Electrocardiogram

Left ventricular hypertrophy

More aggressive therapy

Elevated risk for cardiovascular events

Aggressive lifestyle modifications

Fasting lipid
profile

therapy

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Summary

Proper technique of BP measurement should be an integral part of the evaluation and management of
hypertension.

Home blood pressure recording is now recommended as an inexpensive and accurate method of measuring
blood pressure

Patterns of BP based on ambulatory BP monitoring play an important role in altering therapy and outcomes.

Laboratory examination helps in stratifying patients who will need more extensive evaluation and aggressive
therapy.

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Treatment

Figure 2: Click to Enlarge

Current JNC 7 guidelines are still largely based on threshold levels of BP. In addition, JNC 7 guidelines do recognize
and incorporate the importance of increased cardiovascular risk across a broad spectrum of BP values, as well as a
high lifetime risk of developing hypertension (Figure 2). The new JNC 8 guidelines are under preparation and are
expected to be released soon. The European Society of Hypertension (ESH) and European Society of Cardiology
(ESC) 2009 guidelines have embraced the concept of global cardiovascular risk in recommending that patients be
classified not only in relation to grades of hypertension but also in terms of total cardiovascular risk, which represents
cumulative risk from the coexistence of multiple factors and target organ damage.17 These guidelines stress that the
threshold for hypertension and subsequent drug therapy should remain flexible and should be a function of each
patient's individual and total cardiovascular risk.
It is clearly recognized that an increasing BP level is associated with a greater risk of heart attack, stroke, and kidney
disease. In fact, for persons aged 40 to 70 years, each increment of 20 mmHg in systolic BP or 10 mmHg increase in
diastolic BP doubles the risk of cardiovascular disease across the entire range of BP, from 115/75 to 185/115 mmHg.
In an effort to highlight this relationship between elevated BP and cardiovascular disease, a revised classification of
hypertension has been provided by JNC 7 (Table 3). Blood pressures below 120/80 mmHg are now considered
normal, whereas the previous categories of normal and high-normal BP have been combined into the new
classification of pre-hypertension (systolic BP 120-139 mmHg, and diastolic BP 80-89 mmHg).

Table 3: Classification of Blood Pressure (BP)

Classification

Systolic BP (mmHg)

Diastolic BP (mmHg)

Normal

<120

And <80

Prehypertension

120-139

Or 80-89

Stage 1 hypertension

140-159

Or 90-99

Stage 2 hypertension

160

Or 100

BP, blood pressure.

Data from National Heart, Lung, and Blood Institute: www.nhlbi.nih.gov/guidelines/hypertension/ (accessed April 25, 2013).

Based on JNC 7, patients with sustained hypertension are further divided into stage 1 hypertension (systolic BP 140159 or diastolic BP 90-99 mmHg), stage 2 hypertension (systolic BP 160 or diastolic BP 100 mmHg), and those
with compelling indications that include diabetes, cardiovascular disease, and renal disease. The JNC 7
recommended a blood pressure goal of <140/90 mmHg for patients with hypertension and more intense lowering (a
BP target of <130/80 mmHg) in hypertensive patients with diabetes or kidney disease. In recent years however, large
clinical trials performed in patients with kidney disease and diabetes have failed to demonstrate clear benefit with
intense blood pressure control.
Data from clinical trials published after the release of JNC 7 have provided new information that will likely be
addressed in JNC 8. The Hypertension in the Very Elderly Trial (HYVET) trial is the first study that clearly
demonstrated the benefits of anti-hypertensive therapy in older patients with hypertension.18 In this study, lowering BP
in patients with hypertension (mean age of 84 years) lowered the risk of both stroke and all-cause mortality. In the
AASK, there was no benefit associated with intense blood pressure reduction in hypertensive patients with kidney
disease.19 Similar results were seen in hypertensive patients with diabetes who were treated to lower-thanconventional blood pressure goals, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial.20

Lifestyle Modification
Educating patients regarding the importance of non-pharmacologic interventions for effective BP control is an
important component of reducing cardiovascular risk in the general population. This is particularly true for the prehypertensive and hypertensive patient. However, aggressive efforts are needed to ensure optimal adherence to these
recommendations.
Lifestyle modifications include limiting alcohol intake, increasing physical activity, and reducing sodium intake to <6 g
of sodium chloride daily. Results from the long-term follow-up of the Trials of Hypertension Prevention (TOHP) study
demonstrated that patients who were randomly assigned to a low-salt diet (sodium <1800 mg/24 hr) had a 25% risk
reduction in cardiovascular events.21
Weight reduction of as little as 10 to 12 pounds in an obese hypertensive patient can have a considerable effect on
elevated BP. Appropriate nutritional counseling can encourage a diet with reduced total fat and cholesterol intake, in
addition to providing an adequate daily intake of potassium, calcium, and magnesium. The Dietary Approaches to
Stop Hypertension (DASH) trial has provided substantial data that a diet rich in fruits, nuts, vegetables, and low-fat
dairy products and with an emphasis on fish and chicken rather than red meat lowered BP even without weight
reduction and was particularly effective in those who also restricted sodium chloride intake.22 Dietary
recommendations must be made on an individualized basis and should be well supported with continued educational
and counseling efforts. Cigarette smoking is a recognized accelerator of cardiovascular disease. Smoking cessation

should therefore be strongly encouraged for all patients, and education, counseling, and medication should be
provided as needed.
Table 4 lists lifestyle modifications for which evidence-based data are available to support BP reductions. The effects
of implementing these modifications are both dose dependent and time dependent and could be greater for some
patients. Also, a combination of 2 or more lifestyle modifications can help patients achieve even better results.
Lifestyle modifications not only reduce BP but also enhance the efficacy of antihypertensive drugs and decrease
cardiovascular risk.

Table 4: Lifestyle modifications to manage hypertension. *2

Modification

Weight reduction

Recommendation

Reduction Range

Maintain normal body weight (body mass index, 18.424.9

5-20 mmHg;

kg/m2)

10-kg weight loss

Adopt DASH eating

Consume diet rich in fruits, vegetables, low-fat dairy

plan

products, with reduced content of saturated and total fats

Dietary sodium

Reduce dietary sodium intake to no more than 100

reduction

mmol/day (2.4g sodium or 6g sodium chloride)

Physical activity

Approximate SBP

Engage in regular aerobic physical activity (e.g., brisk

walking) at least 30 min/day, most days of the week

8-14 mmHg

2-8 mmHg

4-9 mmHg

Most men: limit consumption to no more than two

Moderation of alcohol

drinks/day

consumption

Most women and those who weigh less than normal: no

2-4 mmHg

more than one drink/day

DASH, Dietary Approaches to Stop Hypertension; SBP, systolic blood pressure
*
For overall cardiovascular risk reduction, stop smoking.

The effects of implementing these modifications are dose- and time-dependent and could be more effective for some patients.

1 oz or 30 mL ethanol: 12 oz beer, 5 oz wine, 1.5 oz of 80-proof whiskey.

Medical Treatment
Prehypertension
An estimated 70 million Americans have prehypertension. The Framingham study demonstrates that if
prehypertension is left untreated, these patients go on to develop hypertension. Current recommendations center on
nonpharmacologic interventions, which include lifestyle modifications such as weight reduction, increased physical
activity, and reduced dietary salt intake. Antihypertensive therapy is not indicated in those with prehypertension at this
time.

The Trial of Preventing Hypertension (TROPHY) was conducted to explore whether temporary treatment of
prehypertension patients with an antihypertensive agent would reduce the future risk of developing
hypertension.23Patients were randomly assigned in a double-blind manner to treatment with candesartan (16 mg
daily; n = 391) or matching placebo (n = 381) for a 2-year period, after which all patients were treated with placebo for
an additional 2 years. At the 4-year follow-up, hypertension was noted to have developed less frequently in the
individuals initially assigned to take candesartan (53.2% vs 63.0%, relative risk [RR], 0.84; P <0.007). The overall
relative risk of hypertension in candesartan group was decreased (RR, 0.58; P = 0.001).

Stage 1 and Stage 2 Hypertetension

Based on Antihypertensive and Lipid Lowering to Reduce Heart Attack Trial (ALLHAT) data, JNC 7 recommends
diuretics as first-line therapy for the management of stage 1 hypertension and a combination of 2 drugs as an initial
therapy in those with stage 2 hypertension, 1 of which should be a diuretic.24
The ALLHAT trial was designed to compare antihypertensive therapy using an ACE inhibitor, a dihydropyridine
calcium antagonist, and an alpha-adrenergic blocker with treatment with an oral diuretic, chlorthalidone, as the
standard of therapy. The alpha-adrenergic blocker arm of this study was discontinued early in the trial because it was
observed that patients receiving an alpha-adrenergic blocker as monotherapy demonstrated twice the risk of
congestive heart failure when compared with those treated with an oral diuretic. The diuretic, calcium antagonist, and
angiotensin-converting enzyme (ACE) inhibitor groups were continued to an average follow-up of 4.9 years, at which
time no differences were noted among groups with regard to the primary outcome (fatal coronary disease or nonfatal
myocardial infarction) or all-cause mortality. However, compared with the diuretic (chlorthalidone) group, the calcium
antagonist (amlodipine) group had a significantly higher cumulative incidence of heart failure, and the ACE inhibitor
(lisinopril) group had significantly higher incidences of heart failure, stroke, and angina pectoris.
Trial-design issues subsequently generated significant debate regarding the ALLHAT results, particularly the
magnitude of the differences noted. Nevertheless, it was concluded from this trial that diuretic therapy is as effective
as a calcium channel blocker or an ACE inhibitor from the standpoint of the primary outcome of the trial, and diuretic
therapy is superior for select subgroup analyses. A critical look at the trial design suggests a more prudent conclusion
that diuretics should be part of all antihypertensive regimens unless they are clearly contraindicated. Further, there
was concern that diuretics might worsen glucose tolerance and insulin resistance. Recent data demonstrate that the
higher incidence of diabetes mellitus related to thiazides does not appear to be responsible for the increase in risk for
coronary heart disease.25
In addition to thiazide diuretics, JNC 7 guidelines also recommend ACE inhibitors, angiotensin receptor blockers
(ARBs), beta blockers, and calcium channel blockers as first-line therapy for hypertension. Based on evidence of
improved outcomes, JNC 7 has recommended several medications for compelling indications (Tables 5 and 6).
These include beta blockers and aldosterone antagonists in patients with cardiac disease, ACE inhibitors and ARBs
in patients with chronic kidney disease, and diuretics and calcium channel blockers in patients with isolated systolic
hypertension. A combination of ACE inhibitors and diuretics instead of ACE inhibitors alone is recommended for

preventing recurrence of stroke based on findings of Perindopril Protection Against Recurrent Stroke Study
(PROGRESS), which showed a 42% stroke reduction in those treated with this combination of therapy.26

Table 5. Classification and management of blood pressure for adults. 2

Initial Drug Therapy

SBP,*
BP Classification mm
Hg

Normal

Prehypertension

<120

DBP,*

Lifestyle

With Compelling

Without Compelling

mm Hg

Modifications

Indications

Indications

No antihypertensive

Drug(s) for compelling

drug indicated

indications

And
<80

120-

Or80-

139

89

Encourage

Yes

Thiazide-type diuretics
Stage 1

140-

Or90-

Hypertension

159

99

for most. May consider

Yes

ACEI, ARB, BB, CCB,

or combination

Drug(s) for the compelling

indications. Other
antihypertensive drugs
(diuretics, ACEI, ARB, BB,
CCB) as needed

Two-drug combination
Stage 2
Hypertension

for most (usually

160

Or100

Yes

thiazide-type diuretic
and ACEI or ARB or BB
or CCB)

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta blocker; CCB, calcium channel blocker;
DBP, diastolic blood pressure, SBP, systolic blood pressure.
*Treatment determined by highest blood pressure category.
Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.
Treat patients with chronic kidney disease or diabetes to blood pressure goal <130/80 mmHg.

Table 6: Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes
Recommended Drugs

Compelling

Diureti

ACE

AR

Clinical Trial Basis

CC

Aldo

Indication*

ANT
ACC/AHA heart failure guideline, MERIT-HF,

Heart failure

COPERNICUS, CIBIS, SOLVD, AIRE,

TRACE, ValHEFT, RALES

Postmyocardial

infarction
High coronary
disease risk
Diabetes
Chronic kidney
disease
Recurrent stroke
prevention

ACC/AHA post-MI guideline, BHAT, SAVE,

Capricorn, EPHESUS

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE

NKF-ADA guideline, UKPDS, ALLHat

NKF guideline, captopril trial, RENAAL, IDNT,
REIN, AASK

PROGRESS

ACEI, angiotensin-converting enzyme inhibitor; Aldo ANT, aldosterone antagonist; ARB, angiotensin receptor blocker; BB, beta
blocker; CCB, calcium channel blocker.
*Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the
compelling indication is managed in parallel with the BP.
Conditions for which clinical trials have demonstrated benefit of specific classes of antihypertensive drugs.

Since the release of JNC 7, new information has emerged in the area of anti-hypertensive therapy. Clinical trials like
ASCOT and several meta-analyses have demonstrated that a beta-blocker may not be an appropriate first line
medication. Based on results of these studies, beta blockers are now generally indicated as first-line antihypertensive medications only in those patients who have compelling cardiac indications.27
In the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension
(ACCOMPLISH) trial, which included hypertensive adults at high risk for cardiovascular events, patients were
randomly assigned to receive the ACE inhibitor benazepril plus either the calcium channel blocker amlodipine or the
diuretic hydrochlorothiazide.28 There was significant reduction in morbidity and mortality in patients in the benazepril
plus calcium channel blocker group compared to conventional diuretic based therapy.
In the ONTARGET study, treatment of hypertension in patients who were at high risk for cardiovascular disease with
a combination of ACE inhibitor and ARB was associated with additional adverse events without additional benefit.29
Data from large intervention trials in hypertension clearly demonstrate that patients enrolled in these trials required an
average of more than 2 medications for blood pressure control.19,24 It is also true that about two-thirds of patients with
hypertension required more than 1 anti-hypertensive medication for BP control. Fixed-dose combinations of 2-3

classes of antihypertensive medications are now approved for management of hypertension. These combinations
offer superior efficacy as each agent in the combination blocks the counter regulatory system activity triggered by the
other. In addition, single fixed-dose combination improves adherence to medications and BP control.

Summary

Classification of hypertension is based on BP levels as well as comorbidities such as heart disease,

diabetes, and renal disease.

Lifestyle intervention should be recommended for patients with prehypertension and all stages of
hypertension.

Compelling indications mandate therapy with specific medications.

Secondary Hypertension
Approximately 5% of patients with hypertension have a secondary etiology that leads to an elevation in blood
pressure. In some conditions, hypertension is potentially curable when the underlying cause is treated.

Chronic kidney disease (CKD): CKD is the most common cause of secondary hypertension. Impaired renal
function can worsen blood pressure control by reducing sodium and water excretion, and leading to volume
overload and hypertension. In the Modification of Diet in Renal Disease (MDRD) study, the prevalence of
hypertension increased linearly from 65% to 95% as the glomerular filtration rate declined progressively
toward end-stage renal disease.30 Both hypertension and CKD are independently associated with increased
cardiovascular mortality and the effect is amplified in CKD patients with hypertension.

Renovascular disease: New onset of uncontrolled hypertension or acute worsening of previously wellcontrolled hypertension in an older individual could likely be due to renal artery stenosis as a result of
atherosclerotic renal artery disease. In younger women, fibromuscular dysplasia of renal arteries could lead
to uncontrolled hypertension. Significant renal artery stenosis leads to hypoperfusion of the kidney that
results in activation of the renin-angiotensin-aldosterone system leading to retention of sodium and water
and worsening blood pressure control. Patients may also present with acute worsening in renal function,
asymmetric kidney size, or flash pulmonary edema; a systolic diastolic bruit may be heard over the
epigastrium.

Mineralocorticoid-induced hypertension: A history of spontaneous hypokalemia (serum potassium of <3

mEq/L), inappropriate kaliuresis (urine potassium of >30 mEq/24 hour), plasma rennin activity <1

ng/mL/hour and plasma aldosterone >22 ng/dL increases the likelihood of primary aldosteronism in a
hypertensive patient. These patients may also complain of muscle cramping and weakness if they develop
severe hypokalemia. In Cushing syndrome, prolonged exposure to endogenous or exogenous cortisol leads
to elevated blood pressure. In addition, these patients may also present with moon facies, prominent
supraclavicular fat pad, buffalo hump, truncal obesity, and purple striae.

Pheochromocytoma: These are chromaffin cell tumors that arise in the adrenal medulla or sympathetic
ganglia and cause excess production and secretion of catecholamines. Patients may present clinically with
wide fluctuations in blood pressure, sustained hypertension, or with abrupt paroxysms of hypertension.
Elevations in blood pressure may be associated with palpitations, headache, pallor, tremor and diaphoresis.

Coarctation of aorta: These patients present with radiofemoral pulse delay and a relatively weaker pulse in
the legs compared to arms. A bruit may be heard on auscultation of the back.

Diagnostic tests and management of these conditions are provided in Table 7.

Table 7: Workup and management of secondary hypertension

Cause of Secondary
Hypertension

Diagnostic Tests

Management

Balloon angioplasty in patients with

Renovascular

Renal duplex ultrasonography, CT or MR

disease

angiography, renal angiogram.

FMD; medical management with ACE

inhibitor or ARB in combination with a
diuretic for patients with atherosclerotic
renal artery disease.
In a patient with adrenal hyperplasia or
bilateral functional adrenal adenoma,

Primary
aldosteronism

Plasma aldosterone renin ratio, salt loading

medical therapy with aldosterone

test for confirmation, CT scan of adrenal

antagonist.

and adrenal vein sampling for localization.

In a patient with unilateral functional

adenoma, adrenalectomy of the
affected adrenal gland.

Cushing syndrome

Dexamethasone suppression test, salivary

Treat primary cause for excess cortisol

cortisol levels, CT adrenal gland.

levels.

Plasma metanephrines, 24-hour urinary

Pheochromocytoma

metanephrines and catecholamines, CT,

Adrenalectomy of the affected adrenal

MRI, metaiodobenzylguanidine scan if CT or

gland.

MRI are not conclusive.

Coarctation of aorta

Echocardiogram, MR angiography,
aortogram.

Angioplasty or surgical correction.

Balloon angioplasty in patient with

Renovascular

Renal duplex ultrasonography, CT or MR

disease

angiography, renal angiogram.

FMD; medical management with ACE

inhibitor or ARB in combination with a
diuretic for patient with atherosclerotic
renal artery disease.

ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker (antagonist); CT, computed tomography; FMD,
fibromuscular dysplasia; MR, magnetic resonance; MRI, magnetic resonance imaging.

Summary

A careful history and physical examination of patients with hypertension provides important clues that help in
the diagnosis of secondary hypertension.

Some forms of secondary hypertension are potentially curable when the underlying pathology is treated.

Resistant Hypertension
Resistant hypertension (RH) is defined as blood pressure that remains above goal in spite of the concurrent use of 3
antihypertensive agents of different classes. Ideally, 1 of the 3 agents should be a diuretic and all agents should be
prescribed at optimal dose amounts.31
Recent American Heart Association (AHA) guidelines also include patients who are well controlled but require 4 or
more medications as having resistant hypertension. Recent data suggest that the incidence rate of resistant
hypertension is 2% in patients who were newly diagnosed with hypertension and receiving therapy. Results from
NHANES survey reveal that prevalence of resistant hypertension in US adults is nearly 9%. Patients with resistant
hypertension are at a significantly higher risk for cardiovascular events compared to those with non-resistant
hypertension.
Resistant hypertension can be thus broadly divided into pseudo-resistant hypertension and true resistant
hypertension(Table 8).32 Among patients with pseudo-resistant hypertension, sub-optimal anti-hypertensive therapy

has been identified as an important cause leading to uncontrolled hypertension. In the ALLHAT study more than 25%
of patients remained on sub-optimal therapy during the course of the study, although their blood pressures were
elevated and anti-hypertensive therapy was provided free of cost as part of the study. In patients who have
uncontrolled hypertension despite being on adequate anti-hypertensive therapy, it is important to confirm the
diagnosis with home BP monitoring or 24-hour ambulatory BP measurement. In a Spanish cohort of patients who
were defined as having resistant hypertension based on the American Heart Association (AHA) criteria and who
underwent 24-hour ambulatory BP measurement, 37.5% patients were found to have white coat hypertension.

Table 8. Causes of Resistant Hypertension

Pseudo-resistant hypertension:
Incorrect technique in measuring blood pressure
Pseudohypertension
Lack of adherence to lifestyle interventions
Foods and over-the-counter medications
Sub-optimal therapy
Lack of patient adherence to antihypertensive therapy
White coat hypertension
True resistant hypertension:
Sleep apnea
Paroxysmal hypertension
Hypertension related to secondary etiology
Pseudo-hypertension can lead to a false positive diagnosis of resistant hypertension. In this condition, the measured
cuff pressure is inappropriately higher than true intra-arterial blood pressure due to excessive arteriosclerosis and
arterial stiffness which is common in the elderly. The thickened and calcified arteries that result from arteriosclerosis
are not compressed adequately during inflation of the blood pressure cuff. There is currently no reliable clinical
method to diagnose or detect this condition.
Obstructive sleep apnea (OSA) is increasingly being recognized as an important cause for the development of
resistant hypertension. Several studies have reported a strong correlation between obstructive sleep apnea and
hypertension.33Several mechanisms are hypothesized to explain this association, including chronic night time

hypoxemia, altered chemoreceptor stimulation, and activation of the sympathetic and renin-angiotensin systems.
Frequent night-time hypoxia and hypercapnia also appear to stimulate aldosterone production independent of plasma
renin levels.
Management of resistant hypertension includes a detailed history, accurate BP measurement, recommending lower
dietary salt intake, and other lifestyle interventions. Food and medications that interfere with hypertension therapy or
cause elevation of blood pressure should be discontinued. Antihypertensive therapy should be optimized. The choice
and dose of diuretic should be individualized to each patient. There is some evidence from clinical trials suggesting
that the addition of an aldosterone antagonist to an existing anti-hypertensive regimen even in those patients with
normal or low aldosterone levels improves blood pressure levels. In patients with OSA and resistant hypertension,
treatment with aldosterone antagonists and non-invasive positive pressure ventilatory support (NIPPV) may improve
blood pressure control. If secondary hypertension is suspected it should be thoroughly investigated, as in some
instances, such as pheochromocytoma or adrenal adenoma, this may be of curable etiology.
Two new techniques to treat resistant hypertension that are undergoing clinical trials involve baroreceptor activation
therapy and renal artery denervation in order to lower blood pressure:

Baroreceptor activation therapy is performed using a Rheos baroreflex hypertension therapy system which
is surgically implanted in the subclavicular region. The electrodes connected to this device are attached to
the carotid body on each side of the neck. Activation of baroreceptors leads to significant lowering of blood
pressure. A phase III trial evaluating this device has yielded mixed results. Although there was sustained
long-term reduction in blood pressure, 2 end points (acute systolic BP response and procedural safety) did
not meet pre-specified expectations.34

The Symplicity renal denervation system uses a catheter to perform radiofrequency ablation when applied to
the lumen of renal arteries through a femoral access. In the Symplicity HTN-1 study, 153 patients with
resistant hypertension (baseline BP of 176/98 + 17/15 mmHg) underwent catheter-based renal sympathetic
denervation. Patients experienced a sustained BP reduction averaging 32/14 mmHg at 24 months; 92% had
an office blood pressure reduction of >10mmHg and 97% of patients were free of procedure-related
complications.35

These interventions are not yet FDA approved but hold promise to lower blood pressure in patients with resistant
hypertension.

Hypertensive Emergencies
Approximately 1% of Americans with hypertension are estimated to be affected by hypertensive crises. Hypertensive
crisis broadly covers both hypertensive urgency and emergency. JNC 7 defines hypertensive emergency as severe

elevation in BP (>180/120 mmHg) complicated by evidence of impending or progressive target organ dysfunction and
damage.2 When severe elevation in BP occurs without acute target organ dysfunction or damage, it is defined as
hypertensive urgency.
Hypertensive emergencies are more common in patients with essential hypertension (20%-30% in Caucasians and
80% in African Americans). Factors such as renal failure, heart failure, cerebrovascular accidents, and nonadherence
to antihypertensive therapy are associated with hypertensive crisis. Illicit drug use is an important cause for
hypertensive crisis. The pathophysiology of hypertensive crisis remains unclear. It has been proposed that an acute
increase in humoral factors leads to systemic vasoconstriction and increased vascular resistance causing elevation in
blood pressure. Very high BP in turn causes shear stress and endothelial injury thereby further aggravating blood
pressure levels and hypertensive crisis.36
Patients with hypertensive emergencies may present with hypertensive encephalopathy, intracerebral hemorrhage,
acute myocardial infarction, acute left ventricular failure with pulmonary edema, unstable angina pectoris, dissecting
aortic aneurysm, or eclampsia. When evaluating patients with severe hypertension, it is important to distinguish
hypertensive urgency from hypertensive emergency as the treatment plan is based on the diagnosis. Patients with
hypertensive emergency require immediate BP lowering (by 25%) within minutes to an hour and then gradually to
160/110 mmHg over next 2 to 6 hours in order to prevent or limit target organ damage. Rapid lowering of BP to near
normal levels is avoided as it could lead to renal, cerebral and coronary ischemia. These patients require monitoring
in intensive care units and parenteral anti-hypertensive medications (Table 9). In contrast, for patients with
hypertensive urgency, blood pressure can be lowered gradually over 24-48 hours.

Table 9. Intravenous Agents for Hypertensive Emergencies

Agent

Onset

Duration

Advantages

Disadvantages

Nitroprusside

Immediate

1-2 minutes

Potent, titratable

Cyanide, isocyanide

Nitroglycerine

2-5 minutes

3-5 minutes

Coronary perfusion

Tolerance, variable efficacy

Fenoldopam

<5 minutes

5-10 minutes

Renal perfusion

Increased intraocular pressure

Hydralazine

10-20 minutes

3-8 hours

Eclampsia

Tachycardia, headache

Nicardipine

5-15 minutes

1-4 hours

CNS protection

Avoid in CHF and cardiac ischemia

Enalaprilat

15-30 minutes

6 hours

CHF, acute LV failure

Avoid in MI

CNS, central nervous system; CHF, congestive heart failure; LV, left ventricular; MI, myocardial infarction.

Summary

Underlying history of hypertension is an important factor in patients who develop hypertensive crisis.

Triaging patients with hypertensive emergencies early and initiating parenteral antihypertensive therapy
helps to limit target organ damage.

Overly rapid lowering of BP to normal levels in patients with hypertensive emergencies should be avoided as
it can cause renal, cerebral, and coronary ischemia.

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Conclusions
Hypertension is an important modifiable risk factor. Although a majority of patients with hypertension remain
asymptomatic, a careful early evaluation identifies those with or at risk for target organ damage with left ventricular
hypertrophy and microalbuminuria, both of which portend serious future cardiovascular and renal events. Early
identification of these patients and achieving BP goals could reverse early end-organ damage and improve outcomes
in these patients. Analysis of the data from Framingham Heart study demonstrates that a 2-mmHg reduction in blood
pressure would result in 14% reduction in the risk of stroke and transient ischemic attacks, and a 6% reduction in risk
of coronary heart disease. The effective management of hypertension is therefore an important primary health care
objective in managing cardiovascular and renal disease.
It must be emphasized that accurate measurement of blood pressure is of fundamental importance in management of
hypertension. It is also important to identify the modifiable risk factors that can help improve blood pressure control
and reduce cardiovascular and renal damage. Certain classes of medications appear to have a more beneficial effect
than others in managing high-risk patients with hypertension leading to the recommendation of compelling
indications. Thus anti-hypertensive therapy should be tailored and personalized based on an individual's health
profile. For instance, in patients with hypertension associated with unusual features such as early onset of severe
hypertension or clinical features such as palpitations and diaphoresis, further evaluation for secondary hypertension
is recommended as these conditions are potentially curable. On the other hand, patients with severely elevated
hypertension and with evidence of target organ dysfunction or damage need to be triaged early and started on
parenteral antihypertensive therapy to lower cardiovascular and renal morbidity and mortality.
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