Role of Diuretics

Early literature on diuretics did not show as great a reduction in cardiovascular events as had been predicted by epidemiologic data. Many believed that such a discrepancy was explained by the shorter duration of clinical trials compared with epidemiologic studies. Others postulated that the increased risk of cardiovascular effects was attributed to the many potential adverse, metabolic effects of diuretics, which include electrolyte abnormalities, hyperlipidemia, hyperglycemia, and impaired insulin sensitivity.

Diuretics can alter the lipid profile by increasing both serum low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) cholesterol, without having a significant effect on high-density lipoprotein (HDL) cholesterol or the apoproteins. The mechanism of diuretic-induced dyslipidemia is unclear, and whether this occurs for all patients taking diuretics requires further investigation. Diuretics may also impair insulin sensitivity in both diabetic and nondiabetic patients, which alone or together with resulting compensatory hyperinsulinemia can promote dyslipidemia and atherogenesis. There may be an increased risk of new-onset diabetes or metabolic syndrome with the use of thiazides, especially at higher doses.

More recent clinical trials question the role that diuretics have in reducing insulin sensitivity. Systolic Hypertension in the Elderly Program (SHEP) and Hypertension in the Very Elderly Trial (HYVET), in which diuretics were used as initial therapy or in combination with other agents, showed a significant reduction in cardiovascular events with no significant change in lipid profiles and a minimal increase in blood glucose levels. A mean follow-up of 14.3 years of patients from the SHEP trial showed that diabetes that developed during the trial among subjects receiving placebo was associated with worsened cardiovascular outcomes. However, diabetes that developed among subjects during diuretic therapy did not significantly affect cardiovascular mortality.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) randomized more than 33,000 high-risk hypertensive patients to a regimen of chlorthalidone, amlodipine, or lisinopril as first-line therapy. More than half of the patients enrolled had evidence of atherosclerotic heart disease, with one quarter having a history of myocardial infarction or stroke. No difference in cardiovascular outcomes or mortality was noted among the different agents. Although cholesterol levels and the prevalence of new-onset diabetes (11.6% versus 9.8% and 8.1%) were higher in the diuretic group up to a mean 4.9-year follow-up, these metabolic differences did not translate into increased cardiovascular events or mortality. Whether the follow-up period for ALLHAT was adequate to reveal the impact of dyslipidemia and new-onset diabetes on outcomes remains unclear.

The SHEP, HYVET, and ALLHAT trials were performed in older populations with an average age of 67 to 84 years. Data from these trials may not be applicable to younger patients with hypertension, particularly in association with comorbid conditions such as obesity, dyslipidemia, and abnormal glucose tolerance. In contrast to ALLHAT, the Second Australian National Blood Pressure (ANBP2) trial showed a significant improvement in cardiovascular outcomes in elderly hypertensive patients who were started with an angiotensin-converting enzyme (ACE) inhibitor compared with a thiazide diuretic. There were several differences between these trials, including differences in the antihypertensive agents used (enalapril instead of lisinopril and hydrochlorothiazide instead of chlorthalidone) and the population of patients studied (lower baseline risk factors). Nonetheless, thiazide diuretics appear highly effective in lowering blood pressure and reducing cardiovascular events ( Table 11-2 ).

Renal Effects

Aside from altered lipid profiles and glycemic control, the SHEP and International Nifedipine GITS (INSIGHT) studies showed a greater decline in renal function with diuretic therapy, assessed by a rise in serum creatinine. The proposed mechanisms of renal injury by diuretics are varied and include volume depletion leading to renal ischemia and stimulation of the RAAS, arteriolar vasoconstriction from endothelial dysfunction and increased oxidative stress, metabolic abnormalities leading to renal hypertrophy and fibrosis, and direct toxic effects on the distal tubular cells ( Table 11-3 ).

Summary

Diuretics are an acceptable therapy for uncomplicated hypertension. The substitution of hydrochlorothiazide with chlorthalidone in clinical practice may be indicated because of its better tolerability (longer half-life). In younger hypertensive patients and in patients with comorbid conditions, especially diabetes or when the pathophysiology of hypertension may be driven by activation of the RAAS or sympathetic activation, agents other than diuretics or diuretic combinations may be preferred (see Table 11-1 ).

Role of Nitrates

Rapid anginal improvement and the resolution of electrocardiographic signs of ischemia have promoted the use of nitrates for the treatment of angina. Trials comparing long-acting nitrates with both calcium channel blockers and beta blockers have shown no significant difference in antianginal efficacy. In the treatment of heart failure, the use of nitrates reduces secondary pulmonary hypertension and improves heart failure symptoms. There are few prognostic data on nitrate therapy in heart failure. The effect of vasodilator therapy on mortality in a chronic congestive heart failure (CHF) trial (V-HeFT I) showed that when oral nitrates are used with an arterial vasodilator, hydralazine, there is a 34% reduction in overall mortality compared with alpha blockade or placebo. The V-HeFT II trial compared the same combination of nitrate and hydralazine with enalapril in patients with symptomatic CHF. Enalapril showed a further 28% reduction in mortality over combination therapy.

For post–myocardial infarction patients in the fibrinolytic era, trials have failed to show a significant benefit of short-term, early nitrate therapy. In the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico trial (GISSI-3), administration of transdermal nitroglycerin for 6 weeks after acute myocardial infarction demonstrated a nonstatistically significant 6% risk reduction in overall mortality. In the Fourth International Study of Infarct Survival (ISIS-4) trial, administration of oral mononitrate for 1 month after acute myocardial infarction also did not demonstrate an impact on postinfarction mortality or combined endpoint of death and heart failure or extensive ventricular dysfunction. The duration of nitrate therapy and follow-up of these trials were relatively short, and the open-label use of nitrates was high in the placebo arms.

With contemporary percutaneous revascularization, one early trial evaluated the long-term nitrate treatment of post–myocardial infarction patients and suggested an increase in cardiac events. Nitrate rebound during nitrate-free intervals and tolerance have been suggested as mechanisms to blunt hemodynamic effects and to increase cardiovascular events. There is also the suggestion of reflex neurohormonal activation with an increase in plasma renin activity and circulating angiotensin II (A II) levels during nitrate therapy, which attenuates the vasodilator effect of nitroglycerin during prolonged treatment. Both the rebound phenomenon and tolerance may be suppressed by the use of ACE inhibitor or angiotensin receptor blocker (ARB) therapy. More recent retrospective studies using optimal medical therapy have not identified an increase in adverse events, but a more neutral effect, further questioning the utility of nitrates in secondary prevention (see Table 11-2 ).

Summary

Nitrates are effective antianginal agents used for the symptomatic therapy of all entities of myocardial ischemia. Nitrate therapy can be effective in patients with coronary vasospasm or heart failure caused by myocardial infarction. Their role in the treatment of hypertension is limited. In post–myocardial infarction patients without evidence of myocardial ischemia or heart failure, the role of nitrate therapy in secondary prevention is not well established (see Table 11-2 ).

Role of Calcium Channel Blockers

Renal Effects

CCBs have pleiotropic effects that might contribute to renal protection against hypertension-induced damage. These effects include a reduction in mesangial inflammation and proliferation and the promotion of nephrotoxic free radical removal. At the renovascular level, CCBs preferentially dilate the glomerular afferent arteriole, with only modest action on the efferent arteriole. This preferential effect, potentially noted more predominantly with dihydropyridine CCBs, may cause glomerular hypertension, increasing capillary intraglomerular pressure that could be associated with progression of renal disease.

Given their diversity of renal effects and the potential class differences between CCBs on intraglomerular pressures, trials evaluating the effects of CCBs on nephropathy are equally divergent. The African American Study of Kidney Disease and Hypertension (AASK) showed a lesser degree of renal function preservation in African Americans with hypertensive nephrosclerosis treated with amlodipine than with the ACE inhibitor ramipril. Furthermore, in this population of patients, amlodipine showed a significant increase in proteinuria compared with both metoprolol and ramipril. The ALLHAT study, on the other hand, showed that amlodipine maintained glomerular filtration rate (GFR) better than therapy with a diuretic or ACE inhibitor. Overall, the use of CCBs in renal disease is safe without any evidence of further deterioration of renal function. CCBs may be better than diuretics and beta blockers, but they are not as effective as RAAS inhibitors in reducing proteinuria and preventing the progression of renal disease (see Table 11-2 ).

Summary

In patients with chronic stable angina, CCBs may be considered for adjunctive treatment but not as monotherapy unless beta blockers and RAAS inhibitors are not tolerated. Early administration of nifedipine in acute myocardial infarction, unless it is specifically indicated in vasospastic angina, is contraindicated. The nondihydropyridines, possibly because of their heart rate–lowering properties, are the only CCBs to show benefit in the post–myocardial infarction population. They also increase the risk for subsequent CHF in post–myocardial infarction patients with reduced ejection fractions and should probably be reserved for patients without heart failure who cannot tolerate a beta blocker or in whom a beta blocker is contraindicated. Amlodipine and felodipine, given their neutral effect on cardiac morbidity and mortality and ease of tolerance, may be considered in the management of hypertension or coronary artery disease (CAD) in patients with heart failure (see Table 11-1 ).

Role of Beta Blockers

For decades, beta blockers have been widely used in the treatment of uncomplicated hypertension. However, no trial has shown that lowering of blood pressure with a beta blocker reduces the risk of cardiovascular events in patients with hypertension compared with placebo. More recently, beta blocker treatment has been associated with a substantially higher (16%) risk of stroke than treatment with other antihypertensive agents. A proposed mechanism may be differences in the hemodynamic effects of beta blockade.

Treatment with a beta blocker results in reduced brachial blood pressure but does not lower central aortic blood pressure as much as treatment with an ACE inhibitor, diuretic, or CCB does. Central aortic blood pressure may be more predictive of cardiovascular events than traditional brachial blood pressure measurements. The outcome of both the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA) and the Losartan Intervention For Endpoint reduction in hypertension study (LIFE) showed a stroke reduction of approximately 25% when treatment with either a CCB or an ARB, respectively, was given instead of a beta blocker.

Renal Effects

Beta ₁ receptors alter the release of renin, and beta ₂ and alpha ₁ receptors alter sympathetic activity responsible for renovascular tone, important in the genesis of hypertension and progression of kidney disease. Although beta blockers improve cardiac mortality, they have not shown the same benefit on renal outcomes compared with other agents that lower blood pressure and albuminuria. Studies in both diabetic and nondiabetic nephropathy do not show a significant reduction in microalbuminuria with beta blockade compared with ACE inhibition.

In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial, 1235 hypertensive, diabetic patients were enrolled to evaluate the effects of metoprolol versus carvedilol on glycemic control, with a secondary endpoint of change in microalbuminuria. There was a 16.2% reduction in microalbuminuria for patients randomized to carvedilol compared with metoprolol despite similar blood pressure control during 3 years. Among patients with normal albuminuria at baseline, fewer in the carvedilol group (6.6%) than in the metoprolol group (11.1%) progressed to microalbuminuria. GEMINI suggests that beta blockers with alpha ₁ receptor activity may reduce the compensatory stimulation of the sympathetic system and RAAS caused by beta blockade and may further reduce the progression of albuminuria, providing cardiorenal protection (see Table 11-2 ).

Summary

Beta blockers have an established benefit for the treatment of patients after myocardial infarction or with heart failure and play an important role in secondary prevention. The role of beta blockade in the treatment of uncomplicated hypertension remains unclear, given the paucity of data and the possible mild increased risk of stroke. Delay of the initiation of beta blocker therapy until after stabilization of the patient from an acute myocardial infarction may avoid the excess risk of shock and early mortality while preserving much of its described benefits. Controversy remains as to the duration of beta blocker therapy in post–myocardial infarction patients, but if the medication remains well tolerated, discontinuation should be discouraged (see Table 11-4 ).

Intracellular Renin-Angiotensin-Aldosterone System

Despite the multiorgan involvement, specifically in the kidney, vasculature, and heart, for the full physiologic axis of the RAAS, local tissue or intracellular RAAS has been identified and is believed to play a significant role in cardiovascular pathophysiology. The intracellular RAAS is defined by a functionally active complete RAAS within a cell, including components that participate in A II production and its receptors and effector proteins. In the heart, angiotensinogen is internalized and basal expression of RAAS components is very low. Intracellular RAAS is activated in response to pathologic conditions such as pressure or volume overload, myocardial infarction, and diabetes.

Potential mechanisms of action include direct intracellular A II effects on the heart, which are non–AT ₁ receptor mediated, and intracellular A II regulation of the AT ₁ receptor, providing an improved response to extracellular A II. These mechanisms have been suggested to have a role in left ventricular hypertrophy, activation of metalloproteinases with facilitation of plaque rupture, and pathogenesis of vascular disease. Intracellular A II actions are not blocked by ACE inhibitors or ARBs because of their inability to enter the cell and to block these pathways. More complete RAAS inhibition may be provided by direct renin inhibitors that can block both extracellular and intracellular pathways.

Alternative Pathways of Angiotensin II Production

In addition to intracellular RAAS, alternative pathways of A II production independent of ACE, termed ACE escape, have been established. These include chymase and ACE-2–dependent pathways. Chymase is a protease stored within the secretory granules of mast cells; it is present within the blood vessels, the heart, and other tissues but does not circulate within the blood. In blood vessels, chymase is localized to mast cells in the adventitia, whereas ACE is localized in the vascular endothelium. In normal vasculature, circulating A I does not readily penetrate into the interstitial space, and hence A I is converted to A II in an ACE-dependent fashion. In the setting of vascular injury or inflammation, mast cells are activated, allowing a chymase-dependent conversion of A I to A II.

Although chymase may have only a limited physiologic role in the generation of A II, residual A II formation may be observed in the presence of ACE inhibitor due to this chymase-dependent pathway. Other effects of chymase, outside of the A II–mediated effects, include promotion of atherosclerosis through the prevention of cholesterol removal by HDL, intimal hyperplasia of injured arteries, potential erosion and rupture of coronary atheroma leading to an acute coronary syndrome, and stimulation of transforming growth factor-β (TGF-β) leading to cardiac fibrosis.

Angiotensin-converting enzyme 2 (ACE-2) is a peptidase present throughout the cardiovascular system, including in macrophages, vascular endothelium, smooth muscle cells, and potentially cardiac myocytes. It has been shown to convert A I and A II to Ang-(1-9) and Ang-(1-7), respectively. The full physiologic importance of this pathway has yet to be determined. However, ACE-2 may have a counterregulatory role with ACE in fine-tuning the RAAS system through increased production of Ang-(1-7), balancing A II vasopressor effects.

Kallikrein-Kinin System

The main effector protein of the kallikrein-kinin system is bradykinin, produced by the proteolytic cleavage of a high-molecular-weight kininogen by kallikrein. Bradykinin has a variety of biologic effects, some cardioprotective. These effects are mediated through BK ₁ and BK ₂ receptors located on endothelial cells. The BK ₁ receptor is rarely expressed in normal tissue but is upregulated in pathologic states associated with inflammation and tissue injury. It causes stimulation of smooth muscle cells, cell proliferation, and collagen synthesis. The BK ₂ receptor, on the other hand, leads to increased stimulation of nitric oxide and prostacyclin, exerting vasodilator, anti-ischemic, and antiproliferative effects. Kinins are released in the setting of ischemia, myocardial infarction, and heart failure, and the ability of ACE inhibitor to prevent the breakdown of kinins represents a potential mechanism contributing to the drug’s cardioprotective effects.

Prorenin and Prorenin Receptor

Renin is synthesized as a prohormone, prorenin, and stored in granules within the renal juxtaglomerular cells. Prorenin is activated by removal of its N terminus that covers the active site and blocks access to angiotensinogen. The recent discovery of the prorenin receptor has expanded the physiologic role of this once believed inactive prohormone. The prorenin receptor binds to both renin and prorenin and has been localized to the vascular smooth muscle, the heart, and the distal and collecting tubules of the kidney.

When renin binds to the receptor, its activity is amplified fivefold, accelerating the production of A I and in turn A II. Prorenin, when it is bound to the receptor, can undergo nonproteolytic activation by unfolding of the peptide, exposing its active site. This allows prorenin to assume full activity and to contribute to the production of A I. Independent of A II, both renin and prorenin exert physiologic effects through the prorenin receptor. The activated receptor stimulates the production of TGF-β and heat shock proteins, increasing levels of PAI-1 and collagen involved in organ fibrosis and actin filament dynamics involved in contractility, hypertrophy, and apoptosis.

Plasma Renin Activity

Renin is the primary effector hormone of the RAAS, the first and rate-limiting step in A II synthesis. Plasma renin concentration is a measure of the amount of renin in the circulation, and plasma renin activity is a measure of its catalytic activity. Plasma renin activity correlates with the rate at which A I is generated and is a marker of the activation of the RAAS.

Early data have identified that elevated plasma renin activity has a direct relationship with adverse cardiovascular outcomes, including CHF and death, particularly in patients with CAD. More recently, several studies by the Intermountain Heart Collaborative Study Investigators have demonstrated a correlation of plasma renin activity to both worsened ischemia and heart failure outcomes at 3 years in patients with mild and moderate coronary atherosclerosis. The use of ACE inhibitors or ARBs can increase plasma renin activity by inhibiting the feedback loop that governs activity of the RAAS. The role and importance of prorenin, plasma renin concentration, and plasma renin activity have raised interest in the use of direct renin inhibitors (see Table 11-3 ).

Association Between Renal Insufficiency and Cardiovascular Disease

Many studies have demonstrated that the relationship between renal dysfunction and increased cardiovascular morbidity and mortality extends across the spectrum of renal dysfunction to include even the mildest degree of renal impairment. This relationship is also maintained across varying degrees of baseline cardiovascular health. In the general population and in patients with hypertension, stable CAD, post–myocardial infarction, or heart failure, there is an independent and strong correlation between worsening renal function and an increase in cardiovascular events. Baseline GFR has even been suggested to be a stronger predictor of mortality than either left ventricular ejection fraction or New York Heart Association class.

The increased cardiovascular risk for individuals with renal insufficiency is explained in part by the increased prevalence and severity of diabetes and hypertension ( Fig. 11-3 ). However, other mechanisms have been proposed to contribute to the increased risk of cardiovascular events in renal insufficiency. These mechanisms include an increase in endothelial dysfunction, an increase in oxidant stress and inflammation, progressive dyslipidemia, and stimulation of the RAAS that accompanies this disorder.

Interaction of cardiovascular and renovascular disease. DM, diabetes mellitus; HTN, hypertension.

In renal disease, the initial insult to the kidney results in a decline in the GFR, noted by an increase in serum creatinine concentration. When nephrons are damaged, the remaining nephrons undergo hypertrophy with alterations in arteriolar tone. This in turn increases hydraulic pressure within the glomerular capillaries. The filtration capacity of the remaining nephrons increases, minimizing the functional consequences of nephron loss. The high glomerular capillary pressure enlarges the glomerular membrane pores through a process partially attributed to angiotensin (A II), which subsequently increases the number of proteins, both albumin and nonselective proteins, filtered. It is these proteins that become reabsorbed by the proximal tubular cells and may stimulate a vasoactive and inflammatory framework leading to a systemic vascular disease that can affect the kidneys as well as other arterial systems in the body, including the heart. Endothelial dysfunction, which is associated with alterations in vasomotor tone, inflammation, and oxidative stress, plays a key role in remodeling of the vasculature and increases the risk for atherosclerosis.

Described mediators of inflammation and coagulation known to be increased during renal insufficiency include C-reactive protein, fibrinogen, homocysteine, interleukin-6, factor VII/VIII, von Willebrand factor, D-dimer, and plasmin-antiplasmin complex. These mediators, derived in part from increased A II and the modifications of lipids, directly affect endothelial function and vascular remodeling through enhanced oxidative stress. Increased oxidative stress produces reactive oxygen species mainly through the activation of nicotinamide adenine dinucleotide (NADPH) oxidase and the uncoupling of endothelial synthase. The production of reactive oxygen species directly reduces nitric oxide activity, promoting endothelial dysfunction and atherosclerosis.

Dyslipidemia associated with renal insufficiency further contributes to the production of reactive oxygen species and inflammation. Notable alterations in lipid synthesis include elevated levels of lipoprotein(a) and triglycerides, decreased levels of apo A and HDL, and the decreased ability to reduce oxidized, small dense LDL. These defects are the result of a combination of overproduction and clearance defects in apo B–containing lipoproteins. The dyslipidemia of renal disease is complex, with an atherogenic profile similar to that of metabolic syndrome. In general, the severity of dyslipidemia correlates with the severity of proteinuria.

It has been demonstrated that the severity of atherosclerosis is highly correlated with severity of glomerulosclerosis and of renal arteriolosclerosis. Renal insufficiency may be a marker for generalized atherosclerotic burden. However, the presence of these altered pathways has been noted in people with renal insufficiency but with no evidence of clinical or subclinical cardiovascular disease. The prevalence of endothelial dysfunction, low-grade inflammation, dyslipidemia, and RAAS stimulation associated with renal disease may explain the acceleration of atherosclerosis. In combination with hypertension and associated left ventricular hypertrophy, this may lead to a reduction in coronary reserve, explaining the prevalence of coronary ischemia and cardiovascular events in people with renal insufficiency.

Association Between Proteinuria and Cardiovascular Disease

Whereas an elevated serum creatinine concentration reflects a decline in the GFR, an increased rate of albumin or protein excretion reflects a derangement in the glomerular filtration barrier. The presence of abnormal quantities of albumin in the urine often precedes renal functional deterioration. Microalbuminuria, an albumin-to-creatinine ratio (ACR) of 30 to 300 mg/g, correlates with nephrosclerosis; macroalbuminuria (ACR > 300 mg/g) generally indicates established renal parenchymal damage.

Proteinuria (or albuminuria) has been shown to be an independent marker of cardiovascular risk. The link between albuminuria and adverse cardiovascular events was first recognized with macroalbuminuria, later with microalbuminuria, and currently with any evidence of albuminuria. It has been suggested that proteinuria is a continuous cardiovascular risk factor, whereas microalbuminuria is a designated threshold for renal functional deterioration in individuals with and without diabetes.

Proteinuria, despite its association with renal injury, may also reflect a systemic increase in endothelial permeability or dysfunction. The vascular endothelium has an important role in regulating the transport of proteins across vessel walls. Endothelial dysfunction, as a result of shear stress, may allow the deposition of lipoproteins in the subendothelial space, promoting atherogenesis. Further injury to the endothelium results in increased cell and platelet adhesiveness, greater permeability to inflammatory cells, and altered production of vasoactive mediators, specifically nitric oxide. This suggests that proteinuria may be a marker of generalized damage to the peripheral vasculature, paralleling the degree of cardiac organ damage.

The Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial were the first trials to help establish proteinuria as a cardiovascular risk factor. IDNT enrolled subjects with type 2 diabetes, hypertension, and macroalbuminuria. A total of 1715 subjects were randomized to irbesartan, amlodipine, or placebo and were observed for a mean period of 2.6 years. The primary outcome was a composite of serum creatinine doubling, end-stage renal disease (ESRD), or death. Although irbesartan proved to have a significant benefit compared with other therapies, no difference was detected on a secondary outcome of cardiovascular events. Further analysis of baseline albuminuria and cardiovascular composite endpoint showed that the proportion of patients who experienced cardiovascular events progressively increased with increasing quartiles of albuminuria, a 1.3-fold increased risk for each natural log unit increase in ACR.

RENAAL enrolled the same population of subjects as IDNT did, with a total of 1513 subjects randomized to either losartan or placebo. Baseline albuminuria was again shown to be a predictor of composite cardiovascular endpoint as well as heart failure alone. In addition, the change in urinary albumin from baseline to 6 months was the only correlate of adverse cardiovascular outcomes; a 50% reduction in baseline albuminuria translated into an 18% reduction in cardiovascular events and a 27% reduction in the risk of heart failure.

Other trials, such as the Heart Outcomes Prevention Evaluation (HOPE) and the Losartan Intervention For Endpoint reduction in hypertension (LIFE), reconfirmed the association between varying degrees of proteinuria and cardiovascular risk, independent of blood pressure. Reductions in proteinuria over time translate into improved outcomes, and it appears that proteinuria may even be more predictive than the other traditional cardiovascular risk factors. Proteinuria can be used as a potential target or indicator of therapeutic response with antihypertensive therapy.