Mohamed A. Rafey, Martin J. Schreiber, Jr., and Joseph V. Nally, Jr.
PATHOGENESIS OF HYPERTENSION
A number of pathophysiologic factors have been implicated in the development of essential hypertension, making selective mechanistically based antihypertensive therapy in any one patient difficult.1 In a broad sense, increased sympathetic nervous system activity, autonomic imbalance (increased sympathetic tone, abnormally reduced parasympathetic tone), vascular remodeling, arterial stiffness, and endothelial dysfunction contribute to both the development and maintenance of essential hypertension. Increased sympathetic activity may stem from alterations in baroflex and chemoreflex pathways, both peripherally and centrally. The renin–angiotensin system plays a major role in vascular remodeling (alterations in structure, mechanical properties, and function of small arteries) and critical target organ damage (TOD) (myocardial fibrosis, renal injury). In addition, arterial stiffness—a primary contributor to increased vascular resistance, especially with advancing age—results from continued collagen deposition, smooth muscle hypertrophy, and changes in the elastin media fibers. Although intact vascular endothelium is critical to maintaining vascular tone (relaxation and contraction), we now know that multiple insults (decreased nitric oxide synthesis, increased endothelin, estrogen deficiency, high dietary salt intake, diabetes mellitus, tobacco use, and increased homocysteine) can damage vascular endothelium and contribute to important clinical findings. These vascular factors or conditions disrupt normal endothelial function, initiating the cascade of cardiovascular events that results in atherosclerosis, thrombosis, and heart failure.
Renal microvascular disease remains a viable theory as being responsible for the development of hypertension.2 Renal vasoconstriction resulting from the renin–angiotensin–aldosterone system (RAAS) activation, increased sodium reabsorption, and primary microvascular injury may all lead to renal ischemia (particularly in the outer medullary section). Local production of angiotensin-II plus reactive oxygen species at sites of renal injury potentially result in structural alterations and hemodynamic events that cause hypertension.3
Hyperuricemia in humans is associated with renal vasoconstriction, activation of the RAAS, cardiovascular disease (CVD) risk, and hypertension. Theoretically, uric acid stimulates renal afferent arteriopathy and tubular interstitial disease, resulting in hypertension. Renal lesions and hypertension could be prevented or reversed in a rodent model by decreasing uric acid levels coupled with use of angiotensin-converting enzyme (ACE) inhibition, but not hydrochlorothiazide (HCTZ).4 Continued studies leveraging these observations in humans warrant further investigation. Moving forward, medication selection may be directed as much to specific detrimental microvascular effects as to the actual lowering of blood pressure (BP) to target levels.
GENETICS OF HYPERTENSION
Hypertension results from a complex interaction of genetic, environmental, and demographic factors. In patients with essential hypertension, heritability (h2) has been estimated to range from 30% to 50% indicating that a large proportion of variation in BP can be attributed to additive genetic effects. Variation in BP appears to be the result of contribution by several different genes (it is polygenic).5 In addition, there are reported rare cases of simple Mendelian forms of high BP in which a single gene defect may be largely responsible for the hypertensive phenotype.
Improved techniques of genetic analysis (i.e., genetic-wide linkage analysis) have aided in the search for genes that contribute to the development of primary hypertension. Genetic causes of hypertension, though uncommon in the general population, may be more frequent in selective hypertensive populations, particularly patients with resistant hypertension. Genome scans have identified regions of specific human chromosomes that influence BP, which are called the BP quantitative trait loci (QTL) (i.e., chromosome 6.2). Lack of standardization in BP measurement, dichotomization of BP levels for diagnosis of hypertension, and inappropriate selection of cases and controls in clinical studies may result in substantial variation in the hypertension phenotype, which may have contributed to the slow progress in identification of genetic variants associated with BP. Consequently, genetic profiling is not currently beneficial in the diagnostic evaluation of hypertension.
From the clinical perspective, a family with a history of hypertension can be a surrogate marker for undefined, genetically linked risk factors shared by the family. Risk factors such as obesity, dyslipidemia, and insulin resistance are predictive of future hypertension. Having a single first-degree relative with hypertension is only a weak predictor of hypertension, whereas a finding of two or more relatives with hypertension at an early age (before age 55 years) identifies a smaller subset of families who are at much higher risk for the future development of hypertension.6
Wilk et al.7 reported findings to support a link between the quantitative trait age at hypertensive diagnosis and the qualitatively defined early-onset trait in African Americans. Several genes with specific salt interactions have been identified, for example, ones for glucocorticoid remedial hypertension and apparent mineralocorticoid excess.8 In addition, the α-adducin gene is associated with an increased risk of renal tubular absorption of sodium, and angiotensinogen gene polymorphism (A-to-G substitution and methionine-to-threonine amino acid substitution) has been linked to an increase in plasma levels of angiotensinogen.9
Patients with specific gene patterns may respond preferentially to one class of drugs more than another. Patients with the α-adducin gene respond best to thiazide diuretics, those with (Met235 thr) angiotensinogen to ACE inhibitor and calcium channel blocker (CCB), and those with specific G-protein genes impart response to beta-blockers (BBs) and diuretics10
A number of syndromes represent genetic mutations of hypertension single-gene forms including glucocorticoid remedial hypertension (chimeric gene formation; autosomal dominant), 11-β-hydroxylase (mutation in gene encoding), 17-α-hydroxylase deficiency, Liddle syndrome (mutation in the sodium channel gene), hypertension exacerbated by pregnancy, syndrome of apparent mineralocorticoid excess, and pseudohypoaldosteronism.11 Also, human atrial natriuretic peptide (hANP) is an attractive gene for linking specific population groups to an associated increased risk for hypertension. More recently, polymorphisms of the angiotensinogen gene have been detected in hypertensive patients and in children of hypertensive parents.
The continued advances in molecular biology and newer technologies make likely the possibility of gene expression profiling being applied to hypertensive research, diagnosis, and treatment selection in the future.12
SIGNIFICANCE OF SYSTOLIC, DIASTOLIC, AND PULSE PRESSURE
A shift in diagnostic emphasis from diastolic BP to systolic BP has occurred beginning in the 1990s.13–15 A reanalysis of the Framingham Heart Study with longer follow-up data and more extensive cardiovascular data tracking showed that at all levels of systolic pressure (even within a normal range), the height of the systolic BP accurately predicted coronary heart disease (CHD).16 In addition, these data also suggest that the pulse pressure (systolic BP–diastolic BP) is a major independent predictor of CHD. A wide pulse pressure is a marker for large artery stiffness and for vascular aging (arteriosclerosis). Elevated coronary arterial calcification scores are associated with arterial stiffness and increased pulse pressure.17 Age is a determinant of the importance of pulse pressure in hypertension. A growing body of evidence supports pulse pressure readings as an important predictor in patients >65 years of age.18,19 Furthermore, pulse pressure may be a strong predictor of CV risk in the presence of compromised ventricular function with normal or low systolic BP.20
Therefore, systolic BP, diastolic BP, and pulse pressure are important in staging hypertension at different ages. Earlier generations of physicians favored the importance of diastolic BP over systolic BP, in part because hypertension was apparently a young person’s disease. With the aging of the population, hypertension has become a disease of older patients specifically reflected by isolated systolic hypertension (ISH). As arteries stiffen and pulse wave amplification decreases with aging, a general shift in elevation occurs from diastolic BP to systolic BP, and eventually in some, to pulse pressure as predictors of CV risk.21
There are patients in whom pulse pressure does not represent arterial stiffness (discrepancy between central and brachial pulse pressure, mild arterial stiffness, increased cardiac output, variable heart rate, and vasodilation). Moreover, pulse pressure cannot replace systolic BP as a single measure of CHD risk. Systolic BP and diastolic BP together are frequently superior to systolic BP alone in predicting CV risk. From a practical standpoint, physicians should first measure systolic BP (especially in healthy middle-aged and elderly cohorts) and then adjust risk upward for pulse pressure if there is a discordantly low diastolic BP (postmyocardial infarction, heart failure, end-stage renal disease [ESRD], etc.). Only when there is a discordantly low diastolic BP does pulse pressure add to systolic BP in predicting CV risk.
EVALUATION OF HYPERTENSION
A complete history, physical examination, basic serum chemistries, urinalysis, and electrocardiogram (ECG) are recommended for the initial evaluation of a hypertensive patient. Urinalysis is especially important because of the impact that renal disease has on both treatment selection and target goals for BP lowering.
The patient’s history should include a detailed family history, notation of early cerebrovascular hemorrhagic stroke (if <60 years old), nonprescription medications (nonsteroidal anti-inflammatory drugs, diet pills, decongestants, appetite suppressants, herbal therapy), birth control pills, alcohol/street drugs, and sleep history. The physician should always be alert to history or physical exam findings that suggest a secondary cause for the hypertension.
The physical examination should include two or more BP measurements separated by 2 minutes, with the patient either supine or seated, and after standing for at least 2 minutes, in accordance with recommended techniques. BP should be verified in the contralateral arms; if values are different, the higher value should be used. Measurements of height, weight, and waist circumference should be obtained. Special attention should be directed to the funduscopic examination; the presence or absence of carotid bruits or distended neck veins, thyroid enlargements; and examination of the heart, lungs, abdomen, and extremities. Particular attention should be directed to peripheral pulses, presence of abdominal bruits, and presence or absence of edema. A neurologic assessment should also be performed.
The presence of significant arteriosclerosis or arterio-venous (AV) nicking on funduscopic examination indicates in most cases that the BP has been elevated for >6 months. Arteriolar changes are the most common manifestation of hypertensive retinopathy. The mean ratio of arteriole-to-venular diameter in nonhypertensive patients is 0.84. This ratio progressively decreases with increased mean arterial BP. AV nicking can be detected where branch retinal arteries cross over veins. The thickened arteriole wall compresses the thin-walled vein, causing a tapering or “nicked” appearance.
A basic laboratory evaluation should include a urinalysis, microalbuminuria measurement, complete blood count, blood chemistry (potassium, sodium, creatinine, fasting glucose, uric acid), a full fasting lipid profile, and an ECG. An elevated uric acid value may predict the development of hypertension, is frequently present in patients with hypertension, and the degree of elevation also correlates with the degree of BP elevation. Uric acid may also have a pathogenic role in progressive renal disease.
Ambulatory blood pressure monitoring (ABPM), an echocardiogram, and assessment of plasma renin activity (PRA) are not indicated for routine evaluation of most hypertensive patients at the first visit. Recent European guidelines for hypertension have emphasized the importance of estimating the degree of underlying arterial disease by measuring arterial brachi index (ABI) and pulse wave velocity (PWV) when available, to better stratify patients at risk for cardiovascular complications and to tailor aggressive antihypertensive therapy for these individuals.
ABPM is currently considered the gold standard for measuring BP accurately. An average 24 hour BP of ≥130/80 mm Hg is considered diagnostic of hypertension. Based on 24 hour ABPM results and office BP readings, several patterns of BP have been identified which that may have a bearing on managing patients with hypertension (see Fig. 52.1.). Individuals with white coat hypertension have persistently elevated office BP (≥140/90 mm Hg) and normal 24-hours ABPM (<130/80 mm Hg). Data are not yet clear on the clinical significance of white coat hypertension and its impact on TOD and cardiovascular outcomes. In current clinical practice, identifying patients with white coat hypertension helps in reducing overtreatment of these individuals with antihypertensive medications and avoiding iatrogenic complications including hypotension. Masked hypertension is defined as persistently normal or controlled office BP measurements with elevated outside office BPs. The prevalence of masked hypertension ranges from 8% to 16% based on the population sampled. Preliminary studies indicate that the burden of TOD in these individuals may be similar to that of patients with essential hypertension. Nocturnal hypertension (average night-time BP of >120/70 mm Hg) is a subgroup of masked hypertension and was recently demonstrated to be high in prevalence among African Americans with hypertension and chronic kidney disease (CKD). There are no expert guidelines available yet regarding the management of masked hypertension.
FIGURE 52.1 Patterns of blood pressure which may have a bearing on managing patients with hypertension.
Higher ambulatory systolic or diastolic BP predicts CV events even after adjustment for classic risk factors.22 Data from clinical trials that treated patients based on office BP readings demonstrate that individuals who had better average 24-hour BP control during the study had improved cardiovascular outcomes.
A major drawback in the routine use of 24-hour ABPM is that it is expensive and not reimbursed by health insurance plans. Home blood pressure monitoring (HBPM), if performed correctly, is a much cheaper alternative and provides similar accuracy to 24-hour ABPM in managing patients with hypertension. Guidelines on HBPM were recently released by the American Heart Association and American Society of hypertension and have recommended a cutoff of 135/85 mm Hg to define hypertension. A major drawback of HBPM when compared to 24-hour ABPM is the lack of evaluation of BP during sleep.
RESISTANT HYPERTENSION
Resistant hypertension is defined as the persistence of BP >140/90 mm Hg while being treated with a rational triple-drug therapy, optimally including a diuretic. In addition, patients with hypertension who require four or more antihypertensive medications to control BP are also termed to have refractory hypertension. Resistant hypertension falls into two broad categories: apparent resistance and true resistance (Table 52.1).23
TABLE
52.1 Causes of Refractory Hypertension
aObesity, insulin resistance, ethanol excess, sleep apnea.
bDrug–drug interactions and specific drugs that may produce refractory hypertension include: nonsteroidal antiinflammatory drugs (NSAIDs), sympathomimetic drugs (decongestants, appetite suppressants), corticosteroids, chlorpromazine, over-the-counter dietary substances (i.e., ephedra, rehung, bitter orange), tricyclic antidepressants, cocaine, amphetamines, cyclosporine, tacrolimus, erythropoietin, anabolic steroids, monamine oxidase inhibitors, oral contraceptives, licorice, and some chewing tobaccos.
The exact prevalence of resistant hypertension is unknown. Clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. Review of clinical records of patients seen in an outpatient setting demonstrates resistant hypertension to be present in approximately 10% of patients in a primary care setting and in more than 30% of patients in subspecialty clinics. Patient noncompliance and suboptimal therapeutic regimens are the major causes for apparent resistant hypertension (Fig. 52.2).24 More intensive therapy with emphasis on targeted volume control using diuretic therapy can achieve goal BP levels in a significant percentage of patients with apparent resistant hypertension.25
FIGURE 52.2 Of 436 patients treated at a hypertension clinic, 92 (21%) had refractory hypertension. In 83 patients, a cause was identified, the most frequent being suboptimal therapy. BP was brought under control or improved in 58 patients. (Data from Yakovlevitch M, Black HR. Resistant hypertension in a tertiary care clinic. Arch Intern Med. 1991;151:1786–1792.)
Awareness of the association among sleep-disordered breathing, sleep apnea, and hypertension has increased over the past few years.26 Both hypoxia and CO2 retention excite central and peripheral chemoreceptors activating the renin–angiotensin system, which can lead to vasoconstriction and increased BP. Typically, the onset of sleep is associated with a significant decrease in BP of 10% to 20% in normotensive individuals. Patients with disrupted sleep patterns do not experience a nocturnal dip in BP. When treated with cPAP, the nocturnal dip in BP is restored (Fig. 52.3).27
FIGURE 52.3 Randomized trial comparing treated (therapeutic vs. subtherapeutic CPAP (1 cm H2O over a 1-month period) and untreated men with sleep apnea. Bars are standard errors for every 30-minute period, synchronized to wake and sleep times. (Reprinted from the Lancet, 359, Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial, 204–210, © 2002, with permission from Elsevier.)
Novel therapies are being developed to improve BP control in patients with resistant hypertension. Some recent reports indicate a high prevalence of primary aldosteronism in patients with resistant hypertension and others have demonstrated that mineralocorticoid receptor (MR) antagonists provide significant antihypertensive benefit when added to existing multidrug regimens. Catheter-based renal denervation for treatment-resistant hypertension appears to be another novel approach. Results of a recent multicentre, prospective, randomized trial demonstrate that a significantly higher percentage of patients with drug-resistant hypertension who underwent renal denervation had improved BP control when compared to those receiving usual medical therapy.
CLINICAL APPROACHES TO HYPERTENSION
Contrary to results from National Health and Nutrition Examination Survey (NHANES) surveys in the past, which demonstrated an increasing prevalence of hypertension in the United States, results of the latest NHANES show that the prevalence of hypertension has remained at 29% over the past decade. Results from this survey also demonstrated that BP control (achieving a target BP of <140/90 mm Hg) has improved from 27.3% in 1988 to 1994 period to 50.1% in 2007 to 2008. Hypertension prevalence is highest among non-Hispanic blacks and women, and increases with age and elevated body mass index (BMI). Interestingly, hypertension control is lower in younger individuals (18 to 39 years) as compared to older individuals.28
Several landmark clinical trials have assessed the impact of different therapeutic agents on outcome in the presence of hypertension. These studies highlight the importance of treatment selection in the individual hypertension patient.29 These trial findings, coupled with the recommendations of the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII),30,31 underscore the importance of recognizing up-to-date BP classification, selecting the appropriate agents for the clinical setting and achieving effective target BP lowering.
The current classification of BP for adults 18 years of age or older in JNC VII defines a prehypertension category that precedes stages I and II.32 When considering the number of patients with a BP of 120 to 139/80 to 89 mm Hg, prehypertension represents a major public health problem. Vigorous attempts at lifestyle modifications should be undertaken for individuals categorized as prehypertensive. Patients with systolic BPs between 120 and 140 mm Hg are not entirely free from a potential CV event; these prehypertensive individuals have a higher risk for developing hypertension than those with systolic BPs < 120 mm Hg. Figure 52.4 shows the importance of matching the initial drug selection with the stage of hypertension and the presence or absence of compelling indications (heart failure, diabetes mellitus type 1 or 2, proteinuria, renal disease, isolated hypertension, myocardial infarction, etc.). In the JNC VII, there was emphasis on attention to antihypertensive drug selection as well as intense BP control (defined as target BP <130/80 mm Hg) in the presence of compelling indications including diabetes mellitus, CKD with proteinuria, and congestive heart failure (CHF). However, recent results from two large prospective clinical trials, Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial and African-American Study of Kidney Disease and Hypertension (AASK), have brought into question the premise that intense BP lowering in these high-risk goups is beneficial. In the ACCORD trial, lowering of systolic BP to a goal of 120 mm Hg (intense BP-lowering group) in patients with diabetes was not associated with a reduction in cardiovascular outcomes when compared with the standard therapy group (systolic blood pressure [SBP] goal of 140 mm Hg). However, the risk of stroke was reduced in the intense BP-lowering group. The overall analysis of the follow up study of AASK participants (African American patients with CKD and hypertension) who were randonmized to intense and usual/standard BP-lowering goals did not show any benefit with intense BP lowering in these patients. However, for individuals with an elevated urine protein-to-creatinine ratio (>0.22), more intensive therapy, with a BP goal/target of approximately 130/80 mm Hg, appeared to reduce the likelihood of death or progression to ESRD.
FIGURE 52.4 Algorithm for treatment of hypertension, based on randomized controlled trials. SBP, systolic blood pressure; DPB, diastolic blood pressure; ACE, angiotensin-converting enzyme; ARB, angiotensin-II receptor blocker; CCB, calcium channel blocker; HYTN, hypertension. (Adapted from Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet. 2002;359:204–210; 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 Report. JAMA. 2003;289:2560–2571.)
Findings from recent clinical trials (Table 52.2) point out specific caveats for therapeutic selection in high-risk patients for CVD,33 for those with diabetic renal disease,34,35 and in high-risk ethnic groups (e.g., African Americans).36 For patients with essential hypertension who are at high risk for CVD, the use of diuretic therapy resulted in outcomes at least equivalent to the use of ACE inhibitors or CCBs in the ALLHAT study.37 Dihydropyridine calcium blockers should not be used as monotherapy in patients with proteinuric renal disease, whether associated with diabetes mellitus or hypertension. The role of BBs, especially those without vasodilating properties such as atenolol, in the management of hypertension in the absence of compelling cardiac indications is still under debate and will need further clarification. Recent clinical trials with metoprolol and newer vasodilating BBs (carvedilol and bucindolol) have shown benefit in CHF patients when added to standard therapy including ACE inhibitors.38,39 For patients with type 1 diabetes, ACE inhibitor therapy is the cornerstone of treatment. ACE inhibitors and angiotensin-II receptor blockers (ARBs) have demonstrated favorable results in both diabetic and nondiabetic renal disease. The greatest benefit for slowing progression of type 2 diabetes with renal disease can be seen with ARBs, based on findings from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy Trial (IDNT) studies.40,41 Aliskiren belongs to a new class of antihypertensive medication that act by direct renin inhibition (DRI). In clinical trials, BP reduction by aliskiren was equivalent to ARBs including valsartan, irbesartan, and losartan. Several trials have examined the effect of aliskiren in combination with other antihypertensive drugs. Aliskiren when used in combination with atenolol showed a significantly greater reduction in diastolic BP (14.1 mm Hg) when compared with aliskiren monotherapy (11.3 mm Hg) but not with atenolol alone (13.7 mm Hg).12 The additive effects of a high-dose combination of aliskiren and valsartan demonstrated that the combination reduced BP by a mean of 17.2/12.2 mm Hg, a greater reduction than was observed with either component (aliskiren, 13.0/9.0 mm Hg; valsartan, 12.8/9.7 mm Hg; p < 0.0001). The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study evaluated the additive effect of aliskiren in patients with hypertension and type 2 diabetes with nephropathy who were on an ARB (losartan). The study arm that received a combination of aliskiren and losartan had a significant reduction in albuminuria, a surrogate end point for renoprotection. Direct renin inhibitors offer an additional choice in the current armamentarium of antihypertensive medications, to treat those with hypertension and provide renoprotection in those with diabetic nephropathy. Data on the effects of DRI on cardiovascular and renal end points are lacking and need to be studied further before they can be considered a first-line agent in treating patients with compelling indications.
TABLE
52.2 Summary of Cardiovascular and Kidney Outcome Trials (2001–2010)
y, year(s); CHF, congestive heart failure; ACE, angiotensin-converting enzyme; CCB, calcium channel blocker; SCr, serum creatinine; ESRD, end-stage renal disease; DHP CCB, dihydropyridine calcium channel blocker; BP, blood pressure. Trial names: ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IDNT, Irbesartan Diabetic Nephropathy Trial; AASK, African American Study of Kidney Disease and Hypertension; HYVET, Hypertension in the Very Elderly Trial; ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial.
Because patients with CKD (serum creatinine ≥1.4 mg/dL or estimated glomerular filtration rate [eGFR] <60 mL/min) are more likely to die from CVD than from ESRD, hypertension should be aggressively controlled.42 Despite this, awareness of kidney disease is low, especially with respect to other chronic diseases. Decreased CKD awareness is most prevalent in first-degree Spanish speakers, male gender, non-Hispanic blacks, and in patients with hypertension.43 The risk for CV and renal disease events starts at systolic BP levels as low as 115 mm Hg.44 ACE inhibitors or ARBs should be used in CKD patients whenever possible. An increase in baseline serum creatinine up to 35% on these agents is acceptable unless clinically resistant hyperkalemia develops. Hypertensive patients with eGFR <30 mL/min/1.73 m2will require increasing doses of loop diuretic in combination with other agents to optimize volume, a critical determinant of elevated BP.
The development of microalbuminuria is associated with abnormal vascular reactivity, salt sensitivity, increased presence of TOD, and loss of nocturnal dipping in BP.45 An elevated urine albumin-to-creatinine ratio heralds the need for aggressive BP control.
Effective BP control can be achieved in the majority of patients with hypertension, but more than two (2.7 to 3.8) medications may be needed to reach target BP levels.46 When BP is >20/10 mm Hg above target, consideration should be given to initiating therapy with two drugs. Extensive clinical experience with available antihypertensive agents suggests that any single drug preparation will control only 30% to 65% of patients treated, whereas the addition of a second or third drug to the regimen can improve control rates into the range of 90% to 95%. Patients should return for follow-up monthly until the BP goal is achieved. Serum potassium and creatinine should be monitored at least twice per year.47
Among older persons, systolic BP is a better predictor of events (CHD, CVD, heart failure, stroke, ESRD, and all-cause mortality) than diastolic BP. The initial treatment goal in older patients should be the same as in younger individuals, namely, to achieve a BP below 140/90 mm Hg. However, the concept of a J curve for mortality with exaggerated BP lowering may be of greatest importance in the elderly. Findings from both the Systolic Hypertension in the Elderly Program (SHEP) trial48 and the Rotterdam Study49 suggest that there may be an increased CV risk in the lowest strata of BP and that reducing systolic BP to <130 mm Hg or diastolic BP to <65 mm Hg may not represent optimal strategy in the elderly.
Electrocardiographic or echocardiographic evidence of left ventricular hypertrophy (LVH) is associated with increased risk of coronary disease, ventricular dysrhythmias, and sudden death50,51 and requires optimal target BP. Most of the antihypertensive drugs used for initial hypertension therapy induce regression of LVH. In the losartan intervention for endpoint reduction trial, ARBs were superior to BB therapy in reducing CV endpoints in hypertensive patients with electrocardiogram evidence of LVH.
Because the risk of heart disease and stroke increases with age among women, increasing attention has been focused on the nearly 30 million American women over age 50 years. In women 50 to 64 years of age, 47% have high BP—this figure increases to 58% in women 65 to 74 years of age, and to 75% for those 75 years and older. African American women have a death rate from hypertension that is approximately 4.5 times higher than the rate for white women, which makes hypertension the probable cause of up to 20% of all deaths in hypertensive African American women. There is no evidence that women respond any differently than men to the risk-reduction effect of antihypertensive drugs,52 and the JNC VII guidelines should be applied equally to women.
SECONDARY HYPERTENSION
For hypertensive patients who are resistant to treatment with two or more agents, a number of clinical clues can suggest the possible presence of secondary hypertension. Table 52.3 divides the causes of secondary hypertension into four broad categories. Secondary hypertensive disorders can be effectively treated or cured, leading to partial or complete normalization of resistant hypertension in most patients.
TABLE
52.3 Clues to Secondary Hypertension
Primary Aldosteronism
Primary aldosteronism is the most common cause of hypertension due to an endocrinopathy. The most common cause of primary aldosteronism is an aldosterone-producing adenoma (70% to 80%). However, glucocorticoid-remediable aldosteronism (GRA), adrenal hyperplasia, and adrenal carcinoma are other considerations. Although the clinical manifestations of primary aldosteronism are not distinctive, the best clues to the presence of primary aldosteronism include hypertension with spontaneous hypokalemia (<3.5 mEq/L), hypertension with provoked hypokalemia (<3.0 mEq/L during diuretic therapy), and hypertension with difficulty in maintaining normokalemia despite potassium supplementation.
Primary aldosteronism should be considered in any patient with both refractory hypertension and hypokalemia with inappropriate kaliuresis (urine potassium >30 mEq/L per 24 hours). One should be especially suspicious of primary aldosteronism if potassium is <3.5 mEq/L despite potassium supplementation, ACE inhibitor or ARB therapy, and/or a potassium-sparing diuretic. In addition, patients may develop muscle spasms, periodic paralysis, or metabolic alkalosis. The clinician needs to remember that not all patients with primary aldosteronism have hypokalemia; 7% to 38% of patients with primary aldosteronism may have normal serum potassium.53 Even 10% to 12% patients with positive tumors may not have hypokalemia during short-term salt loading. Individuals with hypertension and renal potassium wasting can be differentiated into high-renin and low-renin states (Table 52.4). Usually, the plasma renin concentration is <1 ng/mL/h in mineralocorticoid excess, and fails to rise above 2 ng/mL/h after salt depletion and upright posture.
TABLE
52.4 Biochemical Classification of Patients with Hypertension, Hypokalemia, and Renal Potassium Wasting
aAldosterone-secreting adrenal adenoma.
bChildren, early-onset severe hypertension, history of early hemorrhagic stroke, adrenocorticotropic hormone (ACTH) and renin–angiotensin system is suppressed. Suppression of ACTH with glucocorticoids decreases aldosterone and cures the hypertension. Diagnose by high 18-hydroxycortisol/18-oxycortisol.
cHypertension, decreased potassium, alkalosis, decreased aldosterone, and sodium channel mutation.
The best screening test for primary aldosteronism is the ratio between plasma aldosterone (PA) and PRA.54 Patients with hypokalemia and resistant hypertension should undergo measurement of both PRA and aldosterone concentration. Both specific medications55 and variability of PA levels may affect the accuracy of the ratio. All diuretics should be discontinued 1 to 2 weeks prior to laboratory workup of hypokalemia. If the patient has uncontrolled hypertension, a CCB or a nonatenolol BB may be used. Although doxazosin and irbesartan have the least impact on the ratio, atenolol may lead to an increased rate of false-positive aldosterone/renin ratios. Spironolactone and ACE inhibitors also affect this ratio adversely. Physicians may be confused by values measured as PRA versus the new assay of direct renin measurement. The direct renin measurement divided by 8 is roughly equivalent to the PRA. An elevated PA/PRA ratio alone does not establish a diagnosis of primary aldosteronism. The diagnostic suspicion should be confirmed by demonstrating inappropriate aldosterone secretion.
Table 52.5 lists the laboratory evaluation for patients with hypertension, hypokalemia, and kaliuresis. A high renin value does not exclude primary aldosteronism. The most important test in diagnosing primary aldosteronism is a nonsuppressed 24-hour urinary aldosterone excretion rate during a salt load. A rate >14 µg/24 hours following 3 days of salt loading (24 mL/kg of physiologic saline over 4 hours for 3 days, or a home oral salt load) distinguishes most cases of primary aldosteronism from essential hypertension. Those specific situations that warrant salt loading (>250 mEq/d) include individuals with hypertension and normal PA, with a PRA ≤ 1.0, those with high PA and normal–high PRA, and those with spontaneous hypokalemia who have normal PA and normal PRA. Individuals who warrant salt loading can be placed on a high-salt diet (1 level teaspoon of salt each day for 5 days). The urinary aldosterone excretion rate should be determined on days 4 and 5, along with urinary creatinine, potassium, and sodium measurements. If the sodium concentration is <250 mEq in 24 hours, mild increases in urinary aldosterone excretion rate may represent inadequate suppression.
TABLE
52.5 Hypertension; Hypokalemia (ks < 3.5 mEq/L) with kaliuresis (ukv >30 mEq/24 h)
ks, serum potassium concentration; ukv, urinary potassium per 24 h; PRA, plasma renin activity; Na, sodium; K, potassium; Cr, creatinine; UNaV, urinary sodium per volume of urine.
Combining urinary aldosterone levels with urinary free cortisol results can distinguish nonaldosterone mineralocorticoid excess from aldosterone mineralocorticoid excess (Table 52.6). Patients with Liddle syndrome usually present with hypertension, hypokalemia, and metabolic alkalosis at an early age. Liddle syndrome is an autosomal dominant disorder associated with low/normal urinary excretion of aldosterone, increased kaliuresis occurring with increased collecting tubular sodium reabsorption via amiloride-sensitive channels, and normal urinary free cortisol measurements. The increased sodium reabsorption in collecting tubules results in increased potassium secretion and hypokalemia. Amiloride has been used to close the sodium channels and correct the defect clinically. Liddle syndrome can be differentiated from congenital adrenal hyperplasia and 11-β-hydroxysteroid dehydrogenase deficiency (11-β-OHSD) by analyzing urinary aldosterone and urinary free cortisol values in addition to the clinical presentation.
TABLE
52.6 Combining Urinary Aldosterone Levels with Urinary Free Cortisol Results Can Distinguish Nonaldosterone Mineralocorticoid Excess from Aldosterone Mineralocorticoid Excess
OHSD, hydroxysteroid dehydrogenate deficiency; GRA, glucocorticoid remediable aldosteronism.
The MRs in the distal nephron have equal affinity for both aldosterone and cortisol but are normally protected from cortisol by the presence of 11-β-dehydrogenase, which inactivates the conversion of cortisol to cortisone. The 11 to 18 hemiacetal structure of aldosterone protects it from the action of 11-β-dehydrogenase so that aldosterone gains specific access to the receptors. When this mechanism (normal 11-β-hydrogenase and aldosterone) is defective, either because of congenital 11-β-OHSD or because of enzyme inhibition (licorice or carbenoxalone), the intrarenal levels of cortisol increase and inappropriately activate the MRs, resulting in antinatiuresis and kaliuresis associated with hypertension and hypokalemia. Plasma cortisol concentrations in 11-β-OHSD are usually not elevated. The laboratory abnormalities and symptoms are reversed by spironolactone or dexamethasone but are exacerbated by physiologic doses of cortisone.
Licorice-induced hypermineralocorticoidism has both low PA and low PRA levels. The glycyrrhetinic acid inhibits the enzyme 11-β-dehydroxyase steroid dehydrogenase, allowing cortisol to act as the major endogenous mineralocorticoid avidly binding to the MRs and inducing inappropriate kaliuresis. It is interesting to note that essential hypertension patients are more sensitive to the inhibition of 11-β-hydroxysteroid dehydrogenase by licorice than normotensive subjects, and this inhibition causes more clinical symptoms in women than in men.56 Glycyrrhetinic acid-containing compounds include antipeptic ulcer medication, carbenoxalone sodium, antituberculosis medication, p-aminosalicylic acid, the French alcoholic beverage Boisson de coco, chewing tobacco,57 and some Asian herbal preparations. Diagnosis depends on the elicitation of a thorough history and laboratory evidence of hypokalemia. In general, regular daily intake of 100 mg of glycyrrhizic acid produces adverse effects in sensitive individuals, whereas consumption of 400 mg/d produces adverse effects in most subjects.58
GRA is an inherited autosomal dominant disorder that mimics primary aldostoneronism. Aldosterone-like GRA should be suspected in any patient with a primary aldosterone-like presentation who presents with a positive family history and primary aldosteronism, early age (under 21 years) of hypertension onset, or severe hypertension with early death of affected members from a cerebrovascular accident. GRA is usually associated with bilateral adrenal hyperplasia. Patients with GRA have adrenocorticotropic hormone (ACTH)-sensitive aldosterone production occurring in the zona fasciculata rather than in the zona glomerulosa, which is the normal site of production. The isoenzyme in the zona glomerulosa catalyzes conversion of deoxycorticosterrone to corticosterone and of 18-hydroxycorticosterone to aldosterone. The hybrid gene in GRA results from a genetic mutation. This defect allows for an ectopic expression of aldosterone synthesis activity in the ACTH-regulated zona fasciculata. The plasma potassium concentration is normal in more than one-half of patients with GRA, in contrast to the pattern seen most commonly with primary aldosteronism. Genetic testing using molecular biologic techniques can detect a chimeric gene responsible for GRA. Standard laboratory testing includes a dexamethasone suppression test and measures of 18-hydroxycortisol and 18-oxycortisol. Both 18-hydroxycortisol and 18-oxycortisol are usually increased. Administration of dexamethasone in doses of 2 mg in 24 hours (0.5 mg every 6 hours) usually results in remission of hypertension and hypokalemia within 7 to 10 days. The suppression of ACTH with exogenous glucocorticoid should correct the metabolic defect and control hypertension in GRA. The use of spironolactone and/or amiloride may be supplemental treatment in addition to exogenous glucocorticoid therapy.
An adrenal computed tomography (CT) scan is helpful in differentiating among adrenal adenoma, adrenal hyperplasia, and adrenal carcinoma. The overall sensitivity of localizing aldosterone-producing tumors by high-resolution CT scanning exceeds 90%. Adrenal carcinomas are typically large (>5 cm) in comparison to a hypodense unilateral macroadenoma (>1 cm). Normally, abnormalities in both glands represent adrenal hyperplasia. Hounsfield units >10 usually indicate adrenal carcinoma, whereas Hounsfield units <10 most likely suggest an adrenal adenoma. The difference in density results from a vascular tumor versus a lipid-rich adenoma.
Adrenal vein sampling after administration of ACTH may be useful when no adrenal abnormality exists on CT scan or magnetic resonance imaging (MRI) or when there is an asymmetric abnormality in both glands. The sampling of the adrenal vein is technically difficult and should be restricted to experienced centers. It is important to assess both aldosterone and cortisol values at the time of sampling from the right and left adrenal glands and high and low inferior vena cava. To be certain the samples are from the adrenal veins, cortisol should also be measured in the same samples. Serum cortisol concentrations should be roughly the same in both adrenal veins and approximately 10-fold higher than in the peripheral vein. The aldosterone concentrations should be two times higher from the adrenal vein versus periphery. An aldosterone ratio >10:1 in the presence of a symmetric ACTH-induced cortisol response is diagnostic of an aldosterone-producing adenoma.
Medical therapy with eplerenone (selective aldosterone-receptor antagonist) or spironolactone can be used in patients with bilateral adrenal adenomas, adenomas that cannot be excised surgically (poor surgical risk), in individuals with adrenal hyperplasia, and in those with significant responses to aldosterone-receptor antagonists who do not desire surgery. Surgical removal of an aldosterone-producing adenoma renders normotension and restoration of normal potassium homeostasis in most patients. Adrenal adenomas may be removed laparoscopically. Patients may require drug treatment for 3 to 6 months prior to surgery. Selective hypoaldosteronism usually occurs after aldosterone-producing adenoma removal.
Cushing Syndrome
Clinical clues for Cushing syndrome include a history of recent change in facial appearance and considerable weight gain, together with complaints of weakness, muscle wasting, peripheral bruising, impotence, and, in women, amenorrhea and hirsutism.59 Typical physical features include truncal obesity, moon face, plethora, and purplish skin stria.
Screening and laboratory studies may indicate glucose intolerance or frank diabetes mellitus, and occasionally neutrophilia with relative lymphocytopenia. Pathologic fractures of a rib are common. A dexamethasone suppression test may be helpful. For diagnosis and localization, a 24-hour urinary free cortisol test, CT, and radioimmunoassay of plasma adrenocorticotropic hormone may be helpful.
The standard of care for most cases of Cushing syndrome is surgical resection of a pituitary gland or an ectopic source of adrenocorticotropic hormone or removal of a cortisol-producing adrenal cortical tumor. Transsphenoidal pituitary adenomectomy or radiation therapy to the pituitary bed may be considered in selected cases.
Pheochromocytoma
Pheochromocytoma can present in many ways, reflecting variation in the hormone it releases, the pattern of release, and differences in each individual’s catecholamine sensitivities. Eighty percent of patients with pheochromocytoma present with headache, 57% with sweating, 48% with paroxysmal hypertension, 39% with persistent hypertension, 64% with palpitations; 13% of patients may be normotensive, and 8% may be completely asymptomatic. In approximately 10% of patients, tumors are discovered incidentally during CT/MRI of the abdomen for unrelated symptoms. Those individuals who warrant a workup for pheochromocytoma include patients with (a) episodic symptoms of headache, tachycardia,diaphoresis; (b) family history of pheochromocytoma or multiple endocrine neoplasia (MEN) syndrome; (c) unexplained paroxysms of tachy/brady dysrhythmias; and/or (d) hypertension during intubation, induction of anesthesia, prolonged or unexplained hypotension after surgery, or adverse CV responses to ingestion or inhalation of certain drugs including anesthetic agents, glucagon, ACTH, thyrotropin-releasing hormone, antidopaminergic agents, miloxane, phenothiazine, guanethidine, and tricyclic antibiotics.
Currently available tests can establish the diagnosis of pheochromocytoma in >90% of cases. Figure 52.5 illustrates the approach to using plasma catecholamines and urinary metanephrines in the evaluation of patients suspected of having pheochromocytoma.60 Fractionated plasma free metanephrines are the best test for familial (hereditary) pheochromocytoma, whereas 24-hour urinary metanephrines and catecholamines provide adequate sensitivity with low false-positive rates for sporadic pheochromocytoma. The combination of resting plasma catecholamines (NE plus E) at least 2,000 pg/mL and urinary metanephrines (normetanephrines plus metanephrines) at least 1.8 mg in 24 hours has a diagnostic accuracy of approximately 98% in both sporadic and hereditary pheochromocytoma. A number of medications interfere with the biochemical diagnosis of pheochromocytoma. Methylglucamine results in a decrease in metanephrines, whereas sotalol increases metanephrine concentration. ARBs, ACE inhibitors, and bromocriptine decrease catecholamine values, whereas α1-blockers, BBs, and labetalol increase catecholamine values. Methyldopa and monamine oxidase inhibitors decrease vanillylmandelic acid (VMA) values, whereas nalidixic acid and anileridine increase VMA values. Phenothiazine, methyldopa, and tricyclic antibiotics have varying effects on these tests. A urinary metabolite of buspirone, an anxiolytic drug, is artificially measured as metanephrines, resulting in a marked increase in the measured metanephrine excretion. When blood specimens are drawn under standardized conditions, a total plasma catecholamine level ≥2,000 pg/mL is diagnostic of pheochromocytoma, whereas a value of <500 pg/mL excludes pheochromocytoma.
FIGURE 52.5 Pheochromocytoma suspected. (Adapted from Bravo EL. Pheochromocytoma. Cardiol Rev. 2002;10:44–50.)
For localization, CT scanning and MRI are equally sensitive (98% vs. 100%), whereas131 I-metaiodobenzyl-guanadine iothalamate (MIBG) has excellent specificity (100%) but low sensitivity (78%). Pheochromocytomas are typically hyperdense compared to the liver on T2-weighted images, whereas benign tumors are isodense. If no tumor is detected (by either CT or MRI) in a highly suspicious setting, then MIBG scintigraphy should be used.
A provocative test is employed when the clinical findings are highly suggestive of pheochromocytoma but the BP is normal or slightly increased and plasma catecholamines are between 500 and 1,000 pg/mL. The glucagon test has a high specificity (100%) but low sensitivity (81%). Drugs that inhibit central sympathetic outflow (e.g., clonidine, bromocryptine, haloperidol, methyldopa) may decrease plasma catecholamines in normal and hypertensive subjects but have little effect on the excessive catecholamine secretion by pheochromocytoma. A clonidine suppression test is used for a patient whose plasma catecholamine level is between 1,000 and 2,000 pg/mL, with or without hypertension. A normal clonidine suppression test requires at least a 50% fall of plasma catecholamines from baseline to <500 pg/mL.
Such clinical situations as acute clonidine withdrawal, acute alcohol withdrawal, monotherapy with a pure arterial vasodilator (hydralazine or minoxidil), cocaine abuse, severe CHF, acute myocardial ischemia/infarction, and acute cerebrovascular accident can increase both plasma catecholamines and urine catecholamine metabolites.
Pheochromocytomas may develop in about 50% of patients with MEN type 2a and type 2b, in 25% of patients with von Hippel–Lindau (VHL) type 2, and in 5% with Von Recklinghausen disease (neurofibromatosis). However, in patients with Von Recklinghausen disease and hypertension, a pheochromocytoma has been identified in more than one-third of patients.
CCBs (nifedipine, verapamil, or diltiazem) are used with or without selective α1-receptor blockers (prazosin, terazosin, doxazosin) in the preoperative management of pheochromocytoma patients. The CCBs relax arterial smooth muscle and decrease peripheral vascular resistance by inhibiting norepinenephrine-mediated release of intracellular calcium and/or calcium transmembrane influx. These agents do not usually produce the overshoot hypotension seen with nonselective α-adrenergic blockade. Selective α1-blockers do not enhance norepinenephrine release and usually are not associated with reflex tachycardia. Therefore, CCBs or selective α1-receptor blockers are effective and safe, without the adverse effects associated with the relatively nonspecific complete and prolonged α1-blockade with phenoxybenzamine.61Phenoxybenzamine, traditionally used to counteract the sudden release of massive quantities of catecholamines during surgical intervention, is associated with dramatic hypertension with tumor manipulation and therefore is used less today than previously.
Current medications and surgical techniques have significantly decreased the risk of surgical intervention in pheochromocytoma. Laparoscopic surgery can be used successfully for tumor removal in the majority of cases. Patients undergoing laparoscopy have less severe intraoperative hypotension, minimal blood loss, shorter duration of hospitalization, and earlier resumption of normal activities.
Several prognostic factors have been suggested for characterizing patients with malignant pheochromocytoma. These characteristics include large tumor size, local tumor extension at the time of surgery, and a DNA ploidy pattern with diploid DNA being benign and DNA anuloploidy/tetraploidy having a more progressive nature.62
Renal Parenchymal Disease
CKD defined by either a reduction in glomerular filtration rate (GFR) <60 mL/min/1.73 m2 (corresponding male creatinine >1.5 mg/dL or female >1.3 mg/dL) or the presence of albuminuria >300 mg/d or 200 mg of albumin per gram of creatinine has been associated with an increased risk for hypertension.
The HOPE study data demonstrated a continuous relationship between serum creatinine levels and CV outcomes in hypertensive and normotensive patients. An additive risk exists with increased serum creatinine and microalbuminuria.63
Hypertension is one of the main contributing factors to progressive renal injury, and lowering BP to <130/80 mm Hg is recommended. Patients with renal parenchymal disease usually present with renal insufficiency, proteinuria, or hematuria.64,65 Renal parenchymal disease is a common secondary cause of hypertension, although not often reversible. The clinical clues are easily detected with a carefully performed urinalysis and screening tests of renal function (serum creatinine and eGFR). Verifying proteinuria with sulfosalicylic acid is important because it detects protein light chains present in dysproteinemic states. Urinary protein should be quantitated with a urine protein-to-creatinine ratio to establish the level of the proteinuria. Additional screening studies may include renal ultrasonography. For diagnosis, assessment of the iothalamate GFR and renal biopsy may be helpful.
Baseline systolic BP is a stronger predictor than diastolic BP of renal outcome in patients with type 2 diabetes mellitus and diabetic nephropathy. Patients with the highest baseline pulse pressure have the highest risk for nephropathy progression and experience the greatest risk reduction with systolic BP lowered to <140 mm Hg.40 The underlying etiology of the renal disease (focal segmental glomerulosclerosis, chronic interstitial nephritis, amyloidosis, etc.), determines the immediate and long-term management of renal parenchymal disease. Aggressive treatment and control of BP can slow the progression of renal function loss, especially with ACE inhibitors or ARBs as specific additions to the regimen.66 With advanced renal failure (GFR < 30 mL/min/1.73 m2, corresponding to a serum creatinine of 2.5 to 3.0 mg/dL), the use of loop diuretics is usually warranted to optimize fluid volume, which is critical for BP control. There is a significant opportunity to improve the treatment of hypertension in proteinuric CKD by the increased use of ACE inhibitors and ARBs.67 In diabetics, tight control of blood sugar can also slow the loss of renal function. For patients who do progress to ESRD, renal replacement therapies, including hemodialysis or peritoneal dialysis, are available, together with renal transplantation for selected patients.
Renovascular Disease
Renal artery stenosis that results in renovascular hypertension occurs in 1% to 5% of all patients with hypertension.68 The most common causes of renovascular disease are either fibromuscular dysplasia (FMD) or atherosclerosis.
Atherosclerotic renal artery disease (RAD) accounts for 90% of all renovascular lesions, usually occurring at the ostium or within the proximal 2 cm of the renal artery.69 Patients with atherosclerotic renal artery stenosis may present with hypertension, renal failure secondary to ischemia, and/or recurrent episodes of CHF, and “flash pulmonary edema.”
FMD is found predominantly in young women.70 Radiographically it is characterized by a “string of beads” appearance, with the beading extending beyond the normal caliber of the artery, located in the middle to distal portion of the artery. Less common forms of fibrous renal artery stenosis include perimedial fibroplasia, medial hyperplasia, intimal fibroplasia, and adventitial hyperplasia.
Clinical clues for renovascular hypertension include abrupt onset of hypertension, age <30 years or >55 years, accelerated/malignant hypertension (grade 3 or 4 retinopathy), hypertension refractory to a triple-drug regimen, hypertension and diffuse vascular disease (carotid, coronary, peripheral vascular), systolic/diastolic epigastric bruit, hypertension and unexplained renal insufficiency, renal insufficiency induced by ACE inhibitor therapy, severe hypertension, and recurrent “flash pulmonary edema.”64,71,72,
A number of specialized diagnostic tests have been used to screen patients suspected of having renovascular disease. Duplex Doppler ultrasonography, spiral CT angiography, and magnetic resonance angiography (MRA) are replacing traditional screening tests (i.e., intravenous pyelogram [IVP], PRA, captopril renogram). Renal arteriography remains the “gold standard” for diagnosing renal artery stenosis. Renovascular disease can be effectively diagnosed with an acceptable specificity and sensitivity utilizing most forms of newer diagnosis tests (Table 52.7).
TABLE
52.7 Specificity and Sensitivity of Screening Tests for Renovascular Hypertension
IVP, intravenous pyelogram; PRA, plasma renin activity; MRA, magnetic resonance angiography.
Uncontrolled BP and progressive compromise in renal function are the primary indicators for intervention. For younger patients with FMD (medial fibroplasia, intimal fibroplasia, periarterial hyperplasia), percutaneous transluminal renal angioplasty (PTRA) is the mainstay of therapy, with surgical revascularization considered a secondary indication. Successful angioplasty results in reduction of both the disease and hypertension.70
The primary goal of therapy for patients with hemodynamically significant RAD is control of hypertension and preservation of kidney function. The four current therapeutic options available to treat patients with RAD include (a) medical management, (b) surgical revascularization, (c) PTRA, and (d) stents. The risks versus benefits of medical and interventional therapies, PTRA, and renal stents in treating patients with RAD have been under debate for a long time now. In the past, three randomized controlled trials (RCTs) of medical versus PTRA (no stents) demonstrated a slight benefit in BP control with less medication (2.5 vs. 3.0), but kidney function was unaffected in patients randomized to PTRA. Another RCT of medical versus surgical revascularization did not demonstrate any difference in composite “stop points,” including uncontrolled hypertension, 50% decrease in GFR, CV event, or mortality. The “Stent Placement and Blood Pressure and Lipid-Lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery” (STAR) trial that randomized patients with RAD either to percutaneous revascularization or medical treatment demonstrated that at 2 years, 16% of the revascularized and 22% of the medical group reached the primary end point of 20% or more reduction in creatinine clearance, the difference not achieving statistical significance. Another large study, Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial randomized patients with significant atherosclerotic RAD to renal revascularization coupled with medical therapy versus medical therapy alone. In this study, renal revascularization provided no benefit in renal function, BP or cardiovascular events, and mortality, when compared to patients who were managed conservatively. Nonetheless, selected patients may derive benefit in BP control and/or kidney function following interventions.
Hypertension in Women
In the United States, CVD has accounted for more deaths in women than in men every year since 1984.73 Hypertension is a strong determinant of CVD in women, although CVD is delayed approximately 10 years compared to men.74 Although essential hypertension accounts for the majority of women with hypertension, the primary causes of hypertension that occur only in women are eclampsia in pregnancy and hypertension associated with oral contraceptives.
A point that is frequently forgotten in hypertension diagnosis and treatment is that women have lower brachial systolic BP, diastolic BP, and mean BP than men. Also, they exhibit lower brachial pulse pressure below age 40 years and a higher pulse pressure over age 55 years.75
Gueyffier et al. compared the effects of antihypertensive drug treatment in 20,802 women and 19,975 men from a meta-analysis of seven previous therapeutic trials.52 The odds ratios for benefit in any category of CV event did not differ between men and women. Because many women with hypertension require more than one medication for optimal BP control, a number of reports have examined the relationship between baseline use of ACE inhibitors, BBs, CCB, diuretics, or a combination of these and the incidence of CHD, stroke, and CVD mortality. The Women’s Health Initiative Observational Study (WHI-OS)76 examined differences in CV mortality among postmenopausal women with hypertension but no history of CVD who were treated with different classes of anti-hypertensive agents, single agent or combination therapy. Among women with hypertension but no history of CVD, a two-drug class regimen of CCB plus diuretics was associated with a higher risk of CVD mortality versus BB with diuretics. Risks were similar for ACE inhibitors plus diuretics and BBs plus diuretics. Monotherapy with diuretics was equal or superior to other monotherapy in preventing CVD complications of high BP. Further work examining the importance of antihypertensive drug treatment is essential to clarifying the link between treatment strategies and risk in the postmenopausal woman.
Hypertension disorders occur in 6% to 8% of all pregnancies, are the second leading cause of maternal death, and contribute to significant neonatal morbidity and mortality.77 The U.S. National High Blood Pressure Education Program (NHBPEP) recommends the use of four categories in defining pregnancy-related hypertension: “chronic hypertension, preeclampsia/eclampsia, preeclampsia superimposed upon hypertension, and gestational (transient/chronic) hypertension.” Chronic hypertension (>140/90 mm Hg) is defined as hypertension that was either present before conception or detected before the 20th week of gestation and did not resolve in the early postpartum period. Diagnosis of preeclampsia after the 20th week of gestation denotes the presence of hypertension.
Medication selection in pregnancy is critical to avoiding embryotoxic complications. Methyldopa, hydralazine, and labetalol have been used most often in controlling BP in pregnancy. ACE inhibitors are contraindicated in pregnancy. Angiotensin-II antagonists are believed to raise similar concerns. Beta-adrenergic blocking agents, especially atenolol, may be associated with retardation of fetal growth. CCB may adversely affect uterine placental blood flow. Diuretics have been used for treating hypertension prepregnancy or before midpregnancy. Thiazide diuretics are preferable to loop diuretics. Short-term studies have not found adverse effects from either methyldopa or hydralazine administered during lactation.
Oral contraceptives induce hypertension in approximately 5% of women using high-dose pills containing at least 50 μg of estrogen and 1 to 4 mg of progestin.78 Systolic BP and diastolic BP are significantly higher in patients who use oral contraceptives for more than 8 years.79 BP should return to pretreatment levels within 3 months of discontinuation of oral contraceptives if the hypertension is attributable to the oral contraceptive. All levels of progestational potency and low levels of estrogen potency have been associated with a significantly increased risk of hypertension.
Thyroid and Parathyroid Disorders
Thyroid dysfunction together with renovascular hypertension represent the most common forms of reversible secondary hypertension observed in hypertensive individuals >60 years of age.80,81 Thyrotoxic patients have hyperdynamic hypertension and high cardiac output seen predominantly as an elevated systolic BP, whereas elevation in diastolic BP is uncommon. Overall, the prevalence of hypertension in hyperthyroidism varies from 20% to 26%. On the other hand, hypothyroid patients have a high prevalence of elevated diastolic BP, and this can be a valuable clue in the elderly, in whom primary diastolic hypertension is rare. Hypertension in hypothyroid disease is associated with decreased cardiac index, low stroke volume, and increased systemic vascular resistance. Beta-adrenergic receptors are reported to be decreased, while α-adrenergic responses are increased.
Most patients with primary hyperparathyroidism are asymptomatic; clinical diagnosis should be strongly suspected in the presence of hypercalcemia. The side effects of hypercalcemia, such as polyuria, polydipsia, renal calculi, peptic ulcer disease, and hypertension, may offer diagnostic clues. MEN syndromes are the exception to the above, and the finding of a thyroid nodule, thyroid mass, or cervical lymphadenopathy should suggest the possibility of a medullary thyroid carcinoma.
Additional screening studies may include assessment of thyroid-stimulating hormone level, serum thyroid hormone level, and serum calcitonin level for thyroid disease. For hyperparathyroidism, serum calcium, serum phosphorus, and serum parathyroid hormone level should be assessed.
For diagnosis, decreased thyroid-stimulating hormone and increased free thyroxine index should be assessed in the hyperthyroid patient; increased thyroid-stimulating hormone, decreased free thyroxine index, presence of medullary thyroid carcinoma, and increased calcitonin in the hypothyroid patient; and hypercalcemia, hypophosphatemia, and increased parathyroid hormone level in the hyperparathyroid patient.
Coarctation of the Aorta
Although coarctation of the aorta may cause left ventricular failure in early life, adults with coarctation are often asymptomatic.82,83 As a result, the medical history may be of little help in suggesting the presence of coarctation unless the diagnosis is suspected in association with other congenital malformations, such as bicuspid aortic valve, patent ductus arteriosus or ventricular septal defect, and mitral valve abnormalities. The most common location for a coarctation is distal to the left subclavian artery, but it may occasionally involve the origin of the left subclavian artery and may be missed if BPs are not checked in both upper extremities and at least one lower extremity. Absent or reduced pulses in the legs, together with hypertension in the upper extremities and low BP in the lower extremities, are obviously valuable clues to diagnosis. Systolic BPs are elevated disproportionately to the diastolic BP, resulting in wide pulse pressure and bounding pulses proximal to the coarctation. A thrill may be observed in the suprasternal notch, together with palpable pulsations or auscultated bruits over the intercostal arteries.
Additional screening studies may include an abnormal chest x-ray with a “three sign” (proximal aorta, coarctated segment with poststenotic dilation, and indentation of the aortic knob). For diagnosis and localization, two-dimensional echocardiography, aortography, and MRI may be helpful. Management should consist of surgical repair or angioplasty.
HYPERTENSIVE EMERGENCIES AND URGENCIES
A number of different terms including “accelerated hypertension,” “hypertensive crisis,” “malignant hypertension,” “hypertension emergencies,” and “hypertensive urgencies” generally denote severe hypertension. Conditions associated with systolic BP >200 mm Hg and diastolic BP >110 mm Hg are associated with TOD (papilledema, CHF, central nervous system dysfunction, etc.). These emergencies require immediate BP reduction, not necessarily to normal, to prevent or limit ongoing TOD.
The primary pathophysiologic abnormalities in patients presenting with hypertensive urgencies stem from defective autoregulation mechanisms of certain vascular beds that lead to arteritis and ischemia. Whereas normal arteries maintain blood flow over a broad range of mean arterial pressures from 60 to 150 mm Hg, excessive abrupt increases in BP above this autoregulation range result in TOD, especially within the brain and kidney. In these settings, the disruption of the blood–brain barrier, diffuse cerebral edema, and subsequent fibrinoid necrosis of medium arteries, small arteries, and arterioles can occur. The abruptness of the BP increase may be more critical than the actual level of BP rise. Because the risk–benefit ratio of immediate therapy for some forms of hypertensive emergencies has not been clearly established, an individual approach should be invoked to guide therapy (clinical setting, absolute level of BP increase, potential for worsening target organ perfusion). The target BP is usually lower for encephalopathy than for an acute stroke in evolution. Hypertensive emergencies are those occasional situations that require immediate BP reduction (not necessarily to normal) to prevent or limit TOD. Examples include hypertensive encephalopathy, intracranial hemorrhage, acute pulmonary edema, or a dissecting aortic aneurysm.84 Hypertensive urgencies are those situations in which reduction of BP over several hours to 24 hours is desirable. Examples include patients with upper levels of stage II hypertension and those with progressive target organ complications but not acute deterioration in target organ disease. Elevated BP alone, in the absence of symptoms or new or progressive TOD, rarely requires emergency therapy. A number of effective agents are available for the management of hypertensive emergencies and urgencies (Table 52.8).
TABLE
52.8 Drugs for the Management of Hypertensive Emergencies and Urgencies
aRequires special delivery system.
From Vidt DG. Treatment of hypertensive urgencies and emergencies. In: Izzo JL Jr, Black HR, eds. Hypertension Primer: The Essentials of High Blood Pressure, Third Edition. Dallas: Council on High Blood Pressure Research, American Heart Association; 2003.
Hypertensive emergencies during pregnancy warrant careful drug selection and hemodynamic monitoring to avoid any increase in fetal risk. Hydralazine, methyldopa, and magnesium sulfate are traditional therapeutic agents in pregnancy; however, labetalol has been used more recently. Bolus injections may achieve therapeutic BP-lowering goals sooner than continuous infusion. Consideration of timely delivery of the infant will often help with BP control.
Most hypertensive urgencies represent patients who are noncompliant with therapy or who are inadequately treated patients with essential hypertension. In most cases, immediate resumption of medication with appropriate outpatient follow-up represents appropriate therapy.
The use of fast-acting nifedipine in hypertensive urgencies has been discouraged by the U.S. Food and Drug Administration. A number of reported serious adverse effects and the inability to control the rate or degree of decline in BP make this agent unacceptable.85,86 The routine use of sublingual or oral nifedipine in patients with chronic hypertension, when BPs increase beyond a predetermined level, is also considered unacceptable.
For patients who present with a hypertensive emergency, parenteral therapy may be initiated in the Emergency Department under supervision. Most patients with true hypertensive emergencies should be admitted to an intensive care unit (ICU) for continuous monitoring. The initial goal for BP reduction is not to immediately reduce the BP to normal, but rather to achieve a controlled, progressive decrease in BP to a safer level and to minimize the risk of hypoperfusion in the cerebral, coronary, and renal vascular circulation.
CONCLUSION
Hypertension is a major public health problem worldwide, affecting over 50 million individuals in the United States alone. Hypertension may result from a number of different pathophysiologic factors that lead to both microvascular and, in time, macrovascular damage. Discovering genetic, environmental, and demographic factors that truly affect both the development and the maintenance of BP should offer hope for future medication development. The classification of patients into a prehypertensive BP category has reemphasized the need for earlier recognition of patients who may have or develop BP elevations that warrant intervention. A significant percentage of hypertensive patients warrant two or three medications to achieve a 90% control rate. Physicians should not sacrifice BP control in their desire to limit the number of medications used in treating hypertension. In the case of resistant hypertension, a series of clinical clues suggests the presence of secondary hypertension, and in specific situations, a comprehensive workup is necessary. Since the early 1980s, coronary vascular disease has accounted for more deaths among women than among men, so renewed emphasis on the importance of diagnosing and effectively treating hypertension in the female population is paramount. Although the availability of medications and increased public awareness of hypertension have decreased the total number of hypertensive emergencies, the importance of appropriate medication selection and achieving BP-lowering rates is critical to the success of avoiding end-organ damage in this setting. Even though hypertension requires simple diagnostic maneuvers and basic clinical skills, it remains a significant medical problem, with the potential for limiting long-term patient survival.
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QUESTIONS AND ANSWERS
Questions
1. A 55-year-old white man is referred for evaluation of hypertension (blood pressure [BP] 185/95 mm Hg), discovered during a BP screening at his workplace. The patient states that he is well and has not seen a physician in many years. He describes himself as “a fitness freak,” as he is an active jogger, abstains from alcohol, and limits his salt and fat intake. He denies any knowledge of hypertension, cardiovascular disease (CVD), renal disease, or diabetes mellitus. He takes no medications regularly. Family history is significant in that his father was known to be hypertensive and died of a stroke. His older brother is being treated for hypertension.
On examination, the patient appears well, with a BP of 178/96 mm Hg while seated and standing. Body weight is 71 kg (157 pounds), and height is 178 cm (70 in). Optic fundus examination is significant for grade II hypertensive retinopathy. The remainder of the examination is normal.
Complete blood count, electrolyte panel, blood urea nitrogen level, creatinine concentration, thyroid-stimulating hormone level, and results of urinalysis are normal. Electrocardiography demonstrates normal sinus rhythm with left ventricular hypertrophy (LVH).
To reduce the patient’s cardiovascular morbidity and mortality, which therapy would you prescribe?
a. Hydralazine
b. Atenolol
c. Losartan
d. Doxazosin
2. A 51-year-old white man transfers to your practice after a change of insurance status. His medical history is positive for primary hypertension without target organ damage (TOD). He has no history of renal or prostatic disease. Laboratory values obtained from his former primary care physician show normal results for blood urea nitrogen, serum creatinine, electrolytes, urinalysis, prostate-specific antigen, and electrocardiography. He takes the α-blocker doxazosin, 2 mg at bedtime.
On examination, BP is 152/93 mm Hg seated and standing. Body weight is 84 kg (185 pounds). The remainder of the examination is normal.
What is the appropriate course of action regarding the patient’s antihypertensive therapy?
a. Advise a low-sodium diet.
b. Discontinue doxazosin therapy and consider an alternative agent.
c. Advise high dietary intake of calcium and potassium.
d. Increase the doxazosin to 4 mg a day.
3. Which of the following statements about microalbuminuria is true?
a. To be of clinical value, microalbuminuria must be measured in a timed 12- to 24-hour sample.
b. Microalbuminuria is a cardiovascular risk factor that is independent of traditional Framingham risk factors.
c. Microalbuminuria is present when the “spot” urine albumin-to-creatinine ratio is >500 mg/g.
d. Microalbuminuria is a predictor of cardiovascular risk only in patients with diabetes.
4. A 37-year-old woman calls Monday morning seeking help with “the worst headache ever” Friday night and Saturday. The headache was associated with severe lethargy and intermittent confusion. She recovered and has felt well for the past 24 hours. She states that she does not have fever or neurologic or cardiovascular symptoms. Her medical history is significant for hypertension, and recurrent urinary tract infections related to her known autosomal dominant polycystic kidney disease. She is concerned because her father died of a stroke during dialysis. Her serum creatinine concentration is 2.6 mg/dL. BP at home currently is 146/92 mm Hg.
What do you recommend for this patient?
a. Arrange urgent magnetic resonance angiography (MRA) of her head.
b. Order computed tomography (CT) of her head without contrast.
c. Arrange a consultation with the neurology/headache clinic.
d. Make an office appointment for her to see you
5. 5. A 52-year-old rodeo rider is referred by his primary care physician for hypertension and hypokalemia over the past 6 months. BP and routine chemistries were normal last year at the time of a company physical. He has no history of CVD, stroke, or renal disease. Family history is negative for hypertension. He uses alcohol socially and does not smoke, but chews tobacco. He takes no medications regularly.
On examination, the patient weights 77 kg (168 pounds). BP is 184/102 mm Hg seated and standing. Except for trace pedal edema, the remainder of examination is normal.
The primary care physician provides the following laboratory values:
Blood urea nitrogen: 21 mg/dL
Serum creatinine: 0.9 mg/dL
Serum sodium: 141 mEq/L
Serum potassium: 3.1 mEq/DL
Serum chloride: 100 mEq/L
Serum bicarbonate: 28 mEq/L
A 24-hour urine test during salt loading reveals the following values:
Creatinine: 1.1 g
Sodium: 252 mEq
Potassium: 128 mEq
The daily aldosterone excretion rate is 6 mg (normal, 5 to 10 mg), plasma renin activity (PRA) is 1 µg/L/h, and plasma aldosterone (PA) level is 9 ng/dL.
Which diagnostic test would you order next?
a. Adrenocorticotropin hormone stimulation test
b. MRA with gadolinium
c. Serum cortisol and urinary free cortisol measurement
d. CT of the adrenal glands
Answers
1. Answer C: The educational objective of this question is to recognize the superiority of therapy with an angiotensin-receptor blocker (ARB) over a traditional beta-blocker (BB) for cardiovascular morbidity and mortality in treating patients with primary hypertension and electrocardiographic evidence of LVH.
Most previous antihypertensive trials that demonstrated reductions in cardiovascular morbidity and mortality were based on a “stepped care” approach using diuretics and BBs. The recent Losartan Intervention for Endpoint Reduction in Hypertension Study compared the angiotensinreceptor blocker losartan with the BB atenolol in patients with primary hypertension who had evidence of LVH. Despite similar reductions in BP between the groups, losartan recipients had fewer primary cardiovascular events (death, myocardial infarction, or cerebrovascular accident), experienced a lower rate of new-onset diabetes mellitus, and tolerated the medication with fewer side effects.88
2. Answer B: The objective of this question is to recognize that withdrawal of monotherapy with an α-blocker is recommended to treat hypertension. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial documented an increased risk of cardiovascular events (especially congestive heart failure [CHF]) with use of α-blockers. This adverse finding was published before completion of the full trial. The authors recommended that clinicians discontinue use of α-blocker monotherapy for hypertension and consider alternative therapy. Use of α-blocker therapy in combination with other antihypertensive agents and as therapy for symptomatic benign prostatic hyperplasia was not precluded.89
3. Answer B: The educational objective is to identify microalbuminuria as a cardiovascular risk factor and appreciate its measurement in clinical practice.
Further analysis of data from the Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that microalbuminuria was an independent predictor of cardiovascular events in both diabetic and nondiabetic persons at risk for such events.
Clinical measurement of microalbuminuria is an important tool for assessment of chronic kidney disease (CKD) and estimation of cardiovascular risk. Recent guidelines from the National Kidney Foundation suggest that timed urine collections are not required and that a “spot” urine sample to calculate the albumin-to-creatinine ratio is preferred. The albumin-to-creatinine ratio varies by gender because of differences in muscle mass. The established criteria for albumin-to-creatinine ratios for normal, microalbuminuria, and overt clinical proteinuria are as follows: in men, a normal albumin-to-creatinine ratio is <17 mg/g, whereas in women, <25 mg/g is normal. In microalbuminuria, the ratio is 17 to 250 mg/g in men and 25 to 355 mg/g in women; in clinical proteinuria, the ratio is >250 mg/g in men, whereas in women, it is >255 mg/g (90,91).
4. Answer A: The educational objective is to recognize the presentation and diagnosis of berry aneurysm in a patient with autosomal dominant polycystic kidney disease.The patient’s neurologic symptoms 48 hours earlier probably represent a “sentinel bleed” from a berry aneurysm. The likelihood of central nervous system bleeding after such an event is high and warrants urgent evaluation. MRA with gadolinium provides acceptable imaging of the carotids, circle of Willis, and central nervous system vasculature to identify or exclude berry aneurysm, which might require intervention. Overall, aneurysm is found in approximately 10% of all patients with autosomal dominant polycystic kidney disease and in about 24% of patients with polycystic kidney disease who have a positive family history of aneurysm. Routine screening with MRA is often recommended for patients with this family history and autosomal dominant polycystic kidney disease. All patients with autosomal dominant polycystic kidney disease who have central nervous system symptoms should undergo MRA evaluation to exclude a life-threatening condition.92-94
5. Answer C: The educational objective of this question is to recognize corticoid excess in a patient with hypertension and hypokalemia.
This patient presents with hypertension, metabolic alkalosis with hypokalemia, and a low normal plasma and urinary aldosterone suggestive of corticoid excess due to tobacco chewing. Chewing tobacco is adulterated with licorice-containing glycyrrhizic acid. Licorice and its derivatives cause hypertension by inhibiting inactivation of cortisol by 11-β-dehydrogenase. This results in increased activation of corticosteroid receptors by cortisol, an effect that is most obvious for renal mineralocorticoid receptors (MRs), resulting in sodium retention and kaliuresis. Modest increases in the serum cortisol level and urinary level of free cortisol are diagnostic of the licorice-containing products. The biochemical data do not support the diagnosis of primary hyperaldosteronism. The low PRA and clinical presentation do not suggest renal artery stenosis.95