New Directions in Hypertension Management

Recent findings about hypertension, such as the importance of left ventricular hypertrophy, endothelial dysfunction, and microalbuminuria in cardiovascular risk stratification of patients with high or borderline blood pressure, provide a stronger foundation for therapeutic decisions.

By Louis Kuritzky, MD

Dr. Kuritzy is clinical assistant professor in the department of community health and family medicine at the University of Florida in Gainesville.

Despite the availability of multiple therapeutic options for managing hypertension, the most recent report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) states that only about 29% of Americans have their blood pressure controlled to meet the committee's goal of maintaining levels below 140/90. Of equal concern is the fact that trends in awareness, treatment, and control of blood pressure do not appear to be heading in a favorable direction (see table below). Since heart disease and stroke remain the number 1 and number 3 killers in the United States, respectively, renewed vigor in addressing hypertension and its sequelae is in order.

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Four Supranormal Levels of Blood Pressure

According to JNC-VI, optimal blood pressure for adults is 120/80, with 130/85 as the upper limit of normal. The four supranormal levels of blood pressure are high-normal, stage 1, stage 2, and stage 3 (see table below).

However, it is not only blood pressure level that must be considered when making therapeutic choices, but also the presence of concomitant disease, target organ damage, and additional risk factors. Among the well established risk factors for cardiovascular disease, left ventricular hypertrophy (LVH) appears to be the most dangerous in combination with hypertension. Other modifiable risk factors such as smoking, dyslipidemia, diabetes, and homocysteine levels exaggerate the risk of cardiovascular disease. Similarly, the presence of target organ damage, including clinical cardiovascular disease (for example, stroke or myocardial infarction [MI]), heart failure, peripheral arterial disease, and nephropathy adds to or even compounds the risk in hypertensive persons. It is recommended that persons with risk factors and/or target organ damage initiate pharmacotherapy at a lower category of hypertension than those without risk factors or such damage (see table below).

For otherwise uncomplicated hypertension, initial JNC-VI recommended treatment includes thiazide diuretics and beta blockers, based on accumulated data from individual randomized prospective trials and metaanalyses reported through 1997, which indicate significant reductions in stroke and cardiac endpoints in patients who receive such antihypertensive therapy. For instance, according to a meta-analysis of five randomized trials in the elderly, clinicians may anticipate as much as a 34% reduction in stroke and a 19% reduction in coronary heart disease by lowering blood pressure with diuretics and beta blockers. Subsequent to JNC-VI, trial data suggest that newer agents such as ACE inhibitors and long-acting calcium channel blockers are as efficacious as beta blockers and diuretics for reduction in cardiovascular endpoints. In addition, as anticipated, ACE inhibitors were found to be superior to other classes of agents for reducing the incidence of congestive heart failure. Another large trial (n = 10,881) comparing diltiazem with diuretics and beta blockers for endpoints of stroke, MI, and other cardiovascular death also showed equal efficacy for all treatment groups.

Hypertension is often complicated by disorders such as previous MI, heart failure, and diabetes with proteinuria. In the JNC-VI report, these concomitant diseases were singled out as compelling indications for the use of agents other than beta blockers and diuretics as initial therapy (see table below). This list of diseases will undoubtedly expand as additional randomized trials add to the evidence for specific interventions in various populations.

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Advances in Treatment

New directions in hypertension treatment include the recognition that lower blood pressure goals are appropriate in certain risk groups (such as patients with renal disease and diabetes), that metabolic abnormalities and target organ damage should be prevented, and that treating patients at risk for vascular complications may significantly reduce cardiovascular disease endpoints. The HOPE trial, for example, prospectively evaluated the impact of renin-angiotensin-aldosterone modulation by the ACE inhibitor ramipril in patients considered to be at high risk for a vascular event. The population studied included persons with previous MI, stroke, or peripheral vascular disease, and diabetic patients older than 55 with any cardiovascular risk factor (such as hypertension, smoking, hyperlipidemia, or microalbuminuria).

This study convincingly demonstrated that the use of ramipril resulted in statistically significant reductions in MI, stroke, cardiovascular death, and death from any cause. Reassuringly, further analysis showed that these benefits were seen in various subgroups, irrespective of the presence or absence of hypertension, preexisting cardiovascular disease, diabetes, age over 65, history of coronary artery disease, previous MI, peripheral vascular disease, or microalbuminuria.

Endothelial health may be a crucial element in achieving favorable effects with treatments aimed at improving cardiovascular outcomes. The endothelium lines the myocardium and every vascular channel in the body. Interest in the role of the endothelium in vascular disease was heightened by the serendipitous discovery that coronary arteries, when exposed to acetylcholine, will not dilate if the endothelium is removed. Unsure about the exact nature of the endothelial substance that was necessary for adequate arterial dilation in response to acetylcholine, researchers initially named it endothelial-derived relaxing factor. This substance was subsequently determined to be nitric oxide, a gas-phase mediator with a half-life of only six seconds, which accounts for the difficulty investigators encountered in identifying it.

Whenever the endothelium is diseased or damaged, vasodilative responsiveness is reduced. In fact, it is replaced by hyperresponsiveness to contractile stimuli. This phenomenon can be observed during cardiac catheterization when atherosclerotic coronary arteries may actually contract in response to exercise stress. Indeed, it has been suggested that nitric oxide is the principal determinant of blood pressure.

Various stressors can impair the functional integrity of the endothelium (see table below), resulting in endothelial dysfunction and greater susceptibility to arterial contraction, which may in turn enhance the likelihood that a susceptible plaque will rupture, attract a thrombus, and produce an MI. Diabetic patients are at particularly high risk for endothelial dysfunction. This is at least partially explained by their frequent hypertension, dyslipidemia, and glucose elevations, all of which have been shown to impair endothelial activity.

In the past, coronary heart disease was thought of as essentially a disorder of "clogged pipes." However, the fact that more than half of all MIs occur in persons with less than 50% stenosis in the involved coronary artery has prompted recognition that susceptible plaques and arterial hypercontractility are the culpable underlying pathologies. Rather than simply being a tissue layer separating blood from the vascular wall, the endothelium is actually a regulatory organ, involved in processes that crucially affect hemostasis, vascular contractility, cellular proliferation, and inflammation.

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Importance of Circadian Rhythm

Myocardial infarctions occur with disproportionate frequency early in the morning, around the time of awakening. Because of the body's circadian rhythm, catecholamine levels and coagulation system activity‹risk factors that can cause coronary constriction and thrombosis‹are at their peak at this time of the day. It has been postulated that in normal, healthy, young individuals, endothelial activity counterbalances these risk factors. In persons with atherosclerosis or other forms of endothelial dysfunction, however, the inability of the endothelium to modulate the risk may lead to myocardial ischemia.

Fortunately, endothelial dysfunction does appear to be amenable to interventions that have a favorable impact on cardiovascular outcomes. The statins, for example, which lower cholesterol levels, have been associated with reductions in both primary and secondary prevention of stroke and MI. Although some reports on statin trials have focused on the degree of regression of arterial stenosis, the very small absolute change in arterial lumen size (generally in the range of 2% to 3%) is unlikely to reverse a critical reduction in flow.

On the other hand, studies of statin therapy demonstrate clearly that reduced cholesterol levels are associated with improved endothelial function, particularly arterial responsiveness to vasodilative stimuli. These improvements in endothelial responsiveness occur within as brief a time period as 8 to 12 weeks after reductions in cholesterol levels. It has also been suggested that adding antioxidant therapy to lipid lowering may further enhance arterial responsiveness; unfortunately, the only randomized prospective trials that have examined the effects of antioxidant therapy on cardiovascular outcomes have found no evidence of favorable impact.

Microalbuminuria and proteinuria are both predictors of eventual noxious endpoints. The earliest stage of albumin hyperexcretion, microalbuminuria is defined as the loss of 30 to 300 mg albumin daily. The presence of microalbuminuria correlates with vascular disease in other tissue compartments, including coronary artery disease. Hence, persons with microalbuminuria are at increased risk for other vascular endpoints.

Normal urine protein excretion should not exceed 30 mg/day. Excess protein excretion begets further excesses because these highly charged molecules, when passing through glomerular membranes, cause further damage to glomerular integrity. The modest levels of protein excretion seen in microalbuminuria are not detected on routine office dipstick testing, which only detects protein at a threshold of 500 mg/day or higher. There is a specialized dipstick test (trade name, Micral) that specifically tests for microalbuminuria levels of protein excretion.

When treated early, microalbuminuria can be arrested or even reversed. On the other hand, by the time proteinuria is present, treatment typically retards progression to overt nephropathy but does not prevent its eventual onset.

The progression of microalbuminuria can be modified whether or not the patient has hypertension. In the largest trial of diabetic proteinuria using ACE inhibitors, captopril treatment was associated with a 50% decline in death, dialysis, and transplantation, irrespective of the therapy's effect on blood pressure. A metaanalysis of multiple trials of pharmacotherapy for proteinuria indicated that ACE inhibitors are the most effective class of agents when compared with beta blockers, calcium channel blockers, and diuretics. The benefits of ACE inhibitors in treating proteinuria appear to be a class effect; there is no suggestion that one ACE inhibitor is more effective than another. Several independent recent trials indicate that angiotensin receptor blockers produce similar favorable outcomes in patients with proteinuria.

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Left Ventricular Hypertrophy

In keeping with the new paradigms for hypertension management, LVH as a manifestation of target organ damage must be addressed. The Framingham study has demonstrated that of all modifiable risk factors, LVH is the strongest predictor of an adverse outcome, even more so than smoking, hypertension, or diabetes mellitus. Surprisingly, there is scant literature focusing on LVH as a primary endpoint for managing hypertension. However, meta-analyses have indicated that ACE inhibitors are the most effective class of agents for reversing LVH, followed by beta blockers, calcium channel blockers, and diuretics.

Clinicians are often surprised to learn that in some studies of unselected ambulatory hypertensive patients, LVH is found in as many as one third of these subjects. Since LVH is so prevalent and so potent a predictor of adverse outcomes, it has been suggested that prevention or reversal of LVH is an appropriate goal.

The precise mechanism by which LVH increases the risk for adverse outcomes is not completely understood. It has been theorized, however, that a thickened and enlarged ventricular muscle, without concomitant enhanced circulation, can induce myocardial ischemia and arrhythmia. In contrast, athletes who develop exercise-induced LVH have an increased circulation that can adequately supply their enlarged heart muscle, which is healthy and well conditioned. In hypertension-induced LVH, the ventricle is stiff, collagen-laden muscle, which requires more energy to contract and relax.

Left ventricular hypertrophy appears to be induced by either pressure overload or excess neurohumoral activation, including the release of angiotensin II, norepinephrine, and aldosterone. Regression of LVH may be effected over the short term most efficiently by agents that specifically block one or more of these neurohumors. Long-term studies suggest that all agents that reduce blood pressure may effect LVH regression.

A final evolving area in hypertension management is a greater appreciation for the prevalence of aldosteronism in hypertensive patients. Most clinicians believe that aldosteronism is a rare disease. However, recent reports indicate that as many as 9% to 14% of hypertensive patients may harbor aldosteronism. This condition may be screened for by obtaining a aldosterone:renin ratio. A positive aldosterone:renin is a ratio of more than 20. Since aldosteronism may be cured by surgical resection and also responds well to inexpensive pharmacotherapy with spironolactone, clinicians may be encouraged to screen more frequently for the disorder.

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Pertinent Pathophysiologies

Knowledge of pertinent pathophysiologies in hypertensive patients has turned our focus to the role of the endothelium, microalbuminuria, and LVH in this condition. Recent clinical trials indicate favorable outcomes for cardiovascular endpoints with new as well as older agents. Hyperaldosteronism merits consideration for screening because it is not as rare as previously thought. Overall, clinicians today have a diversity of tools at hand for better management of hypertension.

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