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Hypertension control: multifactorial contributions
AJH
1999;12:164S–169S
Hypertension Control: Multifactorial Contributions Joel M. Neutel and David H.G. Smith
Treatment of hypertension reduces the risk of several associated deleterious conditions, although it does not lower risk for all cardiovascular diseases. A new theory suggests that high blood pressure is but one piece in the puzzle of a complex syndrome of inherited risk factors called the hypertension syndrome. Several new findings have emerged theorizing that patients may have coronary artery disease before the actual onset of elevated blood pressure. Epidemiologic studies have found that normotensive patients with a family history of hypertension often have a disease process and prognosis similar to that of hypertensives. It seems that some patients may “inherit” abnormalities that make them prone to the development of hypertension, as well as a complex series of cardiovascular disease risk factors. These include elevated lipids, increased
A
lthough epidemiologic studies have revealed that treating hypertension significantly reduces the incidence of stroke, a comparable reduction in the incidence of coronary artery disease has been more difficult to document.1,2 Several reasons contribute to these disturbing findings. Perhaps most important to bear in mind is that hypertension is not simply a disease of numbers, but rather a complex inherited syndrome of cardiovascular risk factors. Moreover, there is increasing evidence suggesting that high blood pressure may
From the Orange County Heart Institute and Research Center, Orange, California. Address correspondence and reprint requests to Joel M. Neutel, MD, Orange County Heart Institute and Research Center, 505 S. Main Street, Suite 1025, Orange, CA 92868.
© 1999 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
left ventricular hypertrophy, arterial stiffening, insulin resistance, renal function abnormalities, and neuroendocrine changes. It is conceivable that the hypertension syndrome may be reversible if the disease process is diagnosed early, which appears to be well before the actual onset of high blood pressure. High blood pressure may be a risk marker for irreversible vascular disease and early detection of the many components of hypertension syndrome may delay or prevent cardiovascular disease from developing in high-risk patients. Am J Hypertens 1999;12:164S–169S © 1999 American Journal of Hypertension, Ltd.
KEY WORDS:
Hypertension syndrome, cardiovascular risk, angiotensin receptor blockers, normotensive, heart disease.
be a late manifestation of this complex disease syndrome and that coronary artery disease may develop in hypertensive patients long before the onset of elevated blood pressure. The purpose of this paper is to demonstrate that hypertension is just one part of a much broader socalled “hypertension syndrome” and that in many patients, changes in blood pressure only manifest late in the course of this disease process. LIPIDS Epidemiologic studies have clearly demonstrated that hypertensive patients have significantly higher plasma lipids at every age group than their normotensive counterparts.3 It has been shown that approximately 80% of hypertensive patients have lipid abnormalities, of whom approximately half require drug 0895-7061/99/$20.00 PII S0895-7061(99)00221-6
AJH–DECEMBER 1999 –VOL. 12, NO. 12, PART 2
treatment.4 This incidence of hypercholesterolemia among hypertensive patients is simply too common to be coincidence, and suggests that hypertensive patients also inherit abnormalities of lipid metabolism. To assess when in the course of this disease syndrome hypertensive patients develop abnormalities of cholesterol, we performed a study in a population of normotensive subjects who were prone to the development of high blood pressure by virtue of a strong family history of hypertension. As a control group, we used a group of patients similar in age, gender, body mass index, and blood pressure, with a negative family history for hypertension. Cholesterol levels in subjects with a family history of hypertension were significantly higher than in those without a family history of hypertension, despite normal blood pressure.5 High-density lipoprotein levels were similar in both groups. These findings would suggest that the lipid abnormalities in patients prone to developing hypertension precede blood pressure abnormalities. Furthermore, the long-term effects of lipids on endothelial structure and function may result in decreases in arterial compliance that may eventually contribute to the increase of blood pressure that these patients frequently develop. Although both lipid abnormalities and elevated blood pressure are inherited abnormalities that clinically manifest independent of one another, both factors may contribute to the increased risk of coronary artery disease. Furthermore, it appears that in many instances, lipid abnormalities precede changes in blood pressure. LEFT VENTRICULAR HYPERTROPHY Left ventricular hypertrophy (LVH) is commonly associated with hypertension and is frequently regarded as a so-called “normal” response of the left ventricle to elevated blood pressure. However, data from the Framingham study have clearly demonstrated that LVH is a powerful predictor of cardiovascular disease.6,7 Hypertensive patients with LVH have a fivefold increase in the risk of sudden death and a threefold increase in the risk of coronary artery disease, compared with hypertensive patients with similar blood pressure without LVH. It was originally thought that LVH occurs in hypertensive patients only as a consequence of elevated pressure in the cardiovascular system. However, studies have demonstrated that normotensive young adults with a family history of hypertension have a significantly increased left ventricular mass index when compared with normotensive young adults without a family history of hypertension.8 These findings suggest that LVH may precede the onset of high blood pressure and most likely occurs as
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a consequence of inherited abnormalities of growthstimulating neurohormones. VENTRICULAR COMPLIANCE Diastolic dysfunction (reduced ventricular compliance) is commonly associated with hypertension and may be an important factor in the development of congestive heart failure in hypertensive subjects.9 As is the case with LVH, it is believed that diastolic dysfunction is a structural change that occurs in the left ventricle in response to increased blood pressure. However, studies using Doppler measuring techniques have shown significant reductions in ventricular compliance in normotensive subjects with a family history of hypertension when compared with similar normotensive subjects without a family history of hypertension.9 These findings demonstrate there were significant changes in ventricular wall structure before the onset of hypertension that may be a result of abnormal levels of neurohormonal growth factors occurring early in the course of this disease process. ARTERIAL COMPLIANCE Changes in arterial stiffness in hypertensive patients also often occur before the onset of hypertension. Studies assessing both arterial structure and function have shown reduced arterial compliance in normotensive subjects with a family history of hypertension, compared with those who did not have a family history of hypertension.10,11 These arterial changes in normotensive subjects with a family history of hypertension are probably a result of the increased activity of several growth factors. Changes in arterial compliance are undoubtedly important in the pathogenesis of hypertension, as it has been well documented that stiff, noncompliant vessels result in increased pressure in the cardiovascular system due to the inability of vessels to expand (stretch) during systole. Moreover, the structural changes in the arterial system provide the environment required for the development of atherosclerotic disease. These earlier arterial changes may have some important diagnostic implications in that they may provide an important early marker (that precedes the development of hypertension) in patients with the hypertension syndrome. The development of noninvasive tools for measuring arterial compliance may enable physicians to isolate these patients earlier in the course of the disease process. SYNDROME X Insulin resistance has been shown to occur in approximately 50% of hypertensive patients.4 These patients are resistant to their own insulin, and thus to normalize their plasma glucose levels require almost twice as much insulin as normotensive subjects.12 Increased
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insulin levels are frequently associated with increased triglycerides, increased total cholesterol, decreased high-density lipoprotein cholesterol, increased blood pressure, and centripetal obesity (apple-shaped obesity). This group of associated cardiovascular risk factors is often referred to as syndrome X.13 Insulin is a powerful growth factor, and independent of blood pressure, causes smooth muscle hypertrophy. It is also a very powerful atherogenic agent and is likely to play a role in the early stages of atherosclerosis. Insulin resistance has also been shown to develop before the onset of high blood pressure. Normotensive subjects with a family history of hypertension were shown to be less sensitive to insulin and consequently had higher plasma insulin levels than subjects with no family history of hypertension.5 Mediated by its effects on vascular structure and function, insulin probably plays an important role in both the pathogenesis of hypertension and atherosclerotic disease in patients with hypertension syndrome.13,14 RENAL FUNCTION Normotensive subjects with a family history of hypertension are more likely to develop microalbuminuria than those without a family history of high blood pressure.5 Elevated blood pressure has been implicated as the cause for renal dysfunction in hypertensive patients. Although it is clear that high blood pressure accelerates these renal changes, it appears that some of the changes (probably in the efferent arterioles) occur years before the onset of hypertension. There may be a shift in cause and effect whereby patients may have undiagnosed renal dysfunction that contributes to the development of elevated blood pressure. The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors on renal function in normotensive patients are further evidence that many of these renal changes are independent of blood pressure. NEUROENDOCRINE CHANGES The sympathetic nervous system and the renin-angiotensin system (RAS) are believed to be pivotal in the pathogenesis of hypertension. Interruptions of these systems effectively reduce blood pressure. However, recent studies have demonstrated that plasma norepinephrine levels and plasma renin activity are significantly elevated in normotensive patients with a family history of hypertension, compared with normotensive subjects without a family history of hypertension.5 It is interesting that patients with elevated vasoactive neurohormones are often normotensive. These findings suggest that the hypertensive effects of these hormones are not entirely due to their vasoconstrictor properties but may influence structure and function of cardiovascular smooth muscle.
AJH–DECEMBER 1999 –VOL. 12, NO. 12, PART 2
NORMOTENSIVE SUBJECTS WITH THE HYPERTENSION SYNDROME VERSUS HYPERTENSIVE SUBJECTS Convincing evidence suggests that many of the components of the hypertension syndrome precede the onset of high blood pressure. Furthermore, normotensive subjects who are prone to develop hypertension (by virtue of a strong positive family history of hypertension) have significantly more cardiovascular risk factors than normotensive subjects with no family history of hypertension. How do normotensive subjects with a family history of hypertension (who are very seldom treated) compare to true hypertensive subjects (who are usually treated) in terms of cardiovascular risk factors? We demonstrated that when comparing normotensive patients, with and without a family history of hypertension, with hypertensive patients (matched for age and body mass index), with and without a family history of hypertension, there were no differences in plasma levels of insulin, norepinephrine, renin activity, or cholesterol between currently hypertensive subjects, regardless of a family history of hypertension.5 There were also no differences in insulin sensitivity, microalbuminuria, or systolic blood pressure (SBP) responses to exercise. All three groups, however, were significantly worse off in each of the stated parameters than the control group (normotensive subjects with no family history of hypertension) (Figure 1). Thus, in terms of cardiovascular risk, normotensive subjects with a family history of hypertension have a cardiovascular risk factor profile similar to the hypertensive subjects. The only difference between the groups is that the normotensive subjects have not yet developed high blood pressure, which seems to be a late manifestation of this disease process. As blood pressure measurement is used to diagnose patients with the hypertension syndrome to protect them from developing heart disease, it is possible that we are treating these patients too late in the disease process. If we were to diagnose and treat these patients before they developed hypertension, we would have the potential to prevent the onset of hypertension and perhaps prevent the development of heart disease. It is conceivable that the hypertension syndrome may be reversible before the onset of high blood pressure, and that the development of high blood pressure is a marker of irreversible vascular disease after which we can only control the disease. This is evidenced by the fact that early in the disease process, aerobic exercise may reverse many of the cardiovascular risk factors associated with hypertension and may prolong or prevent the onset of high blood pressure. This is not the case in overt hypertension. In addition, studies have found that patients with controlled hypertension
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FIGURE 1. Comparison of normotensive patients with (solid bars) and without (open bars) a family history of hypertension, to hypertensive patients (matched for age and body mass index) with (solid bars) and without (open bars) a family history of hypertension. There were no significant differences between currently hypertensive subjects, regardless of a family history of the disease. Plasma insulin concentrations, insulin-glucose ratio, norepinephrine concentrations, plasma renin activity, total cholesterol levels (not shown), creatinine clearance (not shown), and albumin excretion rate (not shown) were all significantly higher in patients with a family history of hypertension, whether or not they were currently hypertensive. NT, normotensive; HT, hypertensive. *P ⬍ .03, †P ⬍ .01, ‡P ⬍ .02, **P ⬍ .05, ††P ⬍ .07.5
are more likely than normotensive subjects with a family history of hypertension to develop cardiovascular disease, suggesting that there is more to hypertension than high blood pressure.15 FROM HYPERTENSION TO HEART DISEASE What is the relationship between cardiovascular risk factors associated with hypertension and the development of heart disease? Using newly developed techniques for measuring arterial compliance, it has been shown that when comparing hypertensive and normotensive subjects, the hypertensive group exhibits significantly decreased proximal and distal arterial system compliance.16 This stiffness is usually a result of proliferation and hypertrophy of vascular smooth muscle as well as the deposit of collagen and other connective tissue elements in the media of the blood vessels. These changes also seem to be associated with disruption of the protective endothelial surface of the blood vessels.17 It is also becoming evident that atherosclerotic plaques are much less likely to develop in normal vessels than in abnormal vessels and that the vascular changes seen in hypertensive patients provide the environment required for the early development of atheromatosis lesions. In a study using intraarterial measurements of arterial compliance, we have demonstrated that the changes in stiffness of both the
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FIGURE 2. Factors that lead to endothelial dysfunction. Hypertension and atherosclerosis may occur simultaneously, with hypertension leading to the possible potentiation of atherosclerosis and to the same factors that predispose for endothelial dysfunction.
proximal and distal vessels typically seen in hypertensive patients precede the onset of overt high blood pressure. The majority of the changes in the vessels occur during the period between normotension and the onset of borderline hypertension.18 Once hypertension develops, there are only minimal changes in the compliance of the proximal vessels and no changes in the compliance of the distal vessels.18 These data suggest that maximal changes to arterial structure and function in hypertensive patients actually occur before the onset of high blood pressure and that factors other than hypertension are causing the vascular changes. In normotensive subjects with abnormal arterial compliance, there is a significant inverse correlation with plasma levels of norepinephrine, cholesterol, insulin, and plasma renin activity.19 This would suggest that these neurohormones, which are powerful growth factors, play an important role in the structural and functional changes in the arteries before the onset of hypertension. Furthermore, it is believed that stiff vessels actually cause blood pressure to increase. It is thus possible that patients with the hypertension syndrome inherit abnormalities of neurohormonal function. Through their growth effects, these hormones will, over time, alter vascular compliance by causing smooth muscle cell hypertrophy and connective tissue deposit. This process has a dual effect: it creates the environment for atheromatosis plaque development and the possible development of cardiovascular disease, and it increases arterial stiffness, which results in increased blood pressure. It seems that the development of elevated blood pressure and atheromatosis disease may occur simultaneously (Figure 2). It is also possible that cardiovascular disease, and a cardiovascular event, can develop before the onset of hypertension. Furthermore, hypertension may potentiate arterial changes resulting in reduced compliance, and provide an environment for
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atheromatosis development. It is important to reduce blood pressure even in patients with advanced disease, although the maximal benefits may be derived from treatment with drugs that reduce blood pressure and beneficially affect vascular structure and function. THERAPEUTIC IMPLICATIONS It has been demonstrated that blood pressure reduction in hypertensive patients is associated with target organ protection and a decrease in cardiovascular morbidity. However, simply treating the blood pressure in hypertensive patients is not sufficient. The entire syndrome needs to be considered and an attempt should be made to address all its components. Selection of drugs for hypertensive patients should include agents that reduce blood pressure as well as have beneficial or neutral effects on other parameters of the hypertension syndrome. Drugs that block the RAS have been shown to provide benefits beyond blood pressure control due to their inhibition of angiotensin II. For this reason, angiotensin receptor blockers (ARB) and ACE inhibitors are important in hypertension management, as they are safe, efficacious, well tolerated, and are “syndrome-friendly” agents. With respect to the ARB, these agents may offer special advantages. Controlling and maintaining blood pressure to less than 140/90 mm Hg, as recommended by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI),20 continues to be problematic, with only 27% of hypertensive patients attaining blood pressure control. Poor compliance with therapy may be one explanation for the poor hypertension control rates. In this regard, the ARB may hold an advantage in that these agents are associated with tolerability that is similar to placebo and is not affected by increases in dose.21–26 Even when compared with ACE inhibitors, arguably the most well tolerated of the other classes of antihypertensive agents, the ARB have been demonstrated to hold an advantage with respect to tolerability.27 Further, it has now been well documented that these agents provide levels of blood pressure control that are similar to those attained with other classes of antihypertensive agents.21–26 These observations may be of particular interest with respect to combination therapy. Results of the Hypertension Optimal Treatment (HOT) study have demonstrated that although it is possible for clinicians to control blood pressure in a majority of patients, combination therapy is often required.28 In HOT, combination therapy was required in 63% of patients controlled to 90 mm Hg or less. Fixed-dose combinations of ARB and diuretics are now available. As with other ARB/diuretic combinations, the combination of irbe-
sartan and hydrochlorothiazide has been demonstrated to improve long-term blood pressure response rates, compared with either agent as monotherapy. Results of an extended study of 1098 subjects demonstrated that as many as 85% of subjects attained blood pressure normalization (seated diastolic blood pressure [SeDBP] ⬍ 90 mm Hg) at 1 year.29 Importantly, there is no statistical change in the rates of adverse events with the addition of the diuretic to the ARB irbesartan. CONCLUSIONS Studies have demonstrated that the incidence of coronary artery disease in well-controlled hypertensive patients is approximately 30% higher than in normotensive subjects.29 This underscores the fact that hypertension is not simply a disease of numbers but rather a complex inherited syndrome of cardiovascular risk factors, all of which appear to have genetic links. It is clear that, in many patients with this syndrome, high blood pressure is a late manifestation of the disease process. Moreover, it is conceivable that patients with this syndrome may develop a myocardial infarction before the development of high blood pressure and, due to ventricular dysfunction, may never develop blood pressure abnormalities. The realization that hypertension is a disease syndrome has many important diagnostic and therapeutic implications in the management of hypertension. REFERENCES 1.
Samuelsson OG, Wilhelmsen LW, Svardsudd KF, Pennert KM, Wedel H, Berglund GL: Mortality and morbidity in relation to systolic blood pressure in two populations with different management of hypertension: the study of men born in 1913 and the multifactorial primary prevention trial. J Hypertens 1987;5: 57– 66.
2.
Grimm RH Jr, Flack JM, Byington R, Bond G, Brugger S: A comparison of antihypertensive drug effects on the progression of extracranial carotid atherosclerosis. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). Drugs 1990;40:38 – 43.
3.
Laurenzi M, Mancini M, Menotti A, Stamler J, Stamler R, Trevisan M, Zanchetti A: Multiple risk factors in hypertension: results from the Gubbio study. J Hypertens 1990;8(suppl):S7–S12.
4.
Kaplan NM: Treatment of hypertension: drug therapy, in Clinical Hypertension, 6th Edition. Williams & Wilkins, Baltimore, 1994, chapter 7.
5.
Neutel JM, Smith DHG, Graettinger WF, Winer RL, Weber MA: Heredity and hypertension: impact on metabolic characteristics. Am Heart J 1992;124:435– 440.
6.
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP: Prognostic implications of echocardiographically determined left ventricular mass in Framingham Heart Study. N Engl J Med 1990;332:1561–1566.
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7.
Cassale PN, Milner A, Devereux RB: Value of echocardiographic left ventricular mass in predicting cardiovascular morbidity events in hypertensive men. Circulation 1985;72:130 –135.
19.
Neutel JM, Smith DHG, Graettinger WF, Weber MA: Dependency of arterial compliance on circulating neuroendocrine and metabolic factors. Am J Cardiol 1992; 69:1340 –1344.
8.
Celentano A, Galderisis M, Garafalo M: Blood pressure and cardiac morphology in young children of hypertensive subjects. J Hypertens 1988;6(suppl 4):S107– S109.
20.
The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report. Arch Intern Med 1997;157:2413– 2446.
9.
Graettinger WF, Neutel JM, Smith DHG, Weber MA: Left ventricular diastolic filling alterations in normotensive young adults with a family history of systemic hypertension. Am J Cardiol 1991;68:51–56.
21.
Goa KL, Wagstaff AJ: Losartan potassium. A review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996;51:820 – 845.
10.
Taddei S, Virdis A, Mattei P, Arzilli F, Salvetti A: Endothelium-dependent forearm vasodilation is reduced in normotensive subjects with family history of hypertension. J Cardiovasc Pharmacol 1992;20(suppl 12):S193–S195.
22.
Markham A, Goa KL: Valsartan. A review of its pharmacology and therapeutic use in essential hypertension. Drugs 1997;54:299 –311.
23.
McClellan KJ, Goa KL: Candesartan cilexetil. A review of its use in essential hypertension. Drugs 1998;56:847– 869.
24.
Mimran A, Ruilope L, Kerwin L, Nys M, Owens D, Kassler-Taub K, Osbakken M: A randomised, doubleblind comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of mild-to-moderate hypertension. J Hum Hypertens 1998;12:203–208.
25.
Pohl M, Cooper M, Ulrey J, Pauls J, Rohde R: Safety and efficacy of irbesartan in hypertensive patients with type 2 diabetes and proteinuria. Am J Hypertens 1997;10: 105A.
26.
Stumpe KO, Haworth D, Hoglund C, Kerwin L, Martin A, Simon T, Masson C, Kassler-Taub K, Osbakken M: Comparison of the angiotensin II receptor antagonist irbesartan with atenolol for the treatment of hypertension. Blood Press 1998;7:31–37.
27.
Pylypchuk GB. ACE inhibitor—versus angiotensin II blocker—induced cough and angioedema. Ann Pharmacother 1998;32:1060 –1066.
28.
Hansson L, Zanchetti A, Julius S, Caruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351: 1755–1762.
29.
Raskin P, Saini R, Kassler-Taub K, Mulhall L, Freitag S: Irbesartan and low-dose hydrochlorothiazide combination as long-term therapy for mild to moderate hypertension. J Hypertens 1998;16(suppl 2):S239.
11.
Safar ME, Laurent S, Pannier BM, London GM: Structural and functional modification of peripheral large arteries in hypertensive patients. J Clin Hypertens 1987; 3:360 –367.
12.
Swislocki ALM, Hoffman BB, Reaven GM: Insulin resistance, glucose intolerance, and hyperinsulinemia in patients with hypertension. Am J Hypertens 1989;2: 419 – 423.
13.
Zavaroni I, Bonora E, Pagliara M: Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 1989;320:702–706.
14.
Reaven GM, Hoffman BB: A role for insulin in the aetiology and course of hypertension. Lancet 1987;ii: 435– 437.
15.
Havlik H, La Croix A, Kleinman J, Ingram D, Harris T, Cornoni-Huntley J: Antihypertensive drug therapy and survival by treatment status in a national survey. Hypertension 1989;13(suppl 1):1-28 –1-32.
16.
Mc Veigh YE, Burns DE, Finkelstein SM, McDonald KM, Cohn JN: Reduced valsartan compliance as a marker for essential hypertension. Am J Hypertens 1991;4:245–251.
17.
Clozel JP, Kuhn H, Hefti F: Decreases of vascular hypertrophy in four different types of arteries in spontaneously hypertensive rats. Am J Med 1989;87(suppl 6B):92.
18.
Weber MA, Smith DHG, Neutel JM, Graettinger WF: Arterial properties of early hypertension. J Hum Hypertens 1991;5:1–7.
1999;12:164S–169S
Hypertension Control: Multifactorial Contributions Joel M. Neutel and David H.G. Smith
Treatment of hypertension reduces the risk of several associated deleterious conditions, although it does not lower risk for all cardiovascular diseases. A new theory suggests that high blood pressure is but one piece in the puzzle of a complex syndrome of inherited risk factors called the hypertension syndrome. Several new findings have emerged theorizing that patients may have coronary artery disease before the actual onset of elevated blood pressure. Epidemiologic studies have found that normotensive patients with a family history of hypertension often have a disease process and prognosis similar to that of hypertensives. It seems that some patients may “inherit” abnormalities that make them prone to the development of hypertension, as well as a complex series of cardiovascular disease risk factors. These include elevated lipids, increased
A
lthough epidemiologic studies have revealed that treating hypertension significantly reduces the incidence of stroke, a comparable reduction in the incidence of coronary artery disease has been more difficult to document.1,2 Several reasons contribute to these disturbing findings. Perhaps most important to bear in mind is that hypertension is not simply a disease of numbers, but rather a complex inherited syndrome of cardiovascular risk factors. Moreover, there is increasing evidence suggesting that high blood pressure may
From the Orange County Heart Institute and Research Center, Orange, California. Address correspondence and reprint requests to Joel M. Neutel, MD, Orange County Heart Institute and Research Center, 505 S. Main Street, Suite 1025, Orange, CA 92868.
© 1999 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
left ventricular hypertrophy, arterial stiffening, insulin resistance, renal function abnormalities, and neuroendocrine changes. It is conceivable that the hypertension syndrome may be reversible if the disease process is diagnosed early, which appears to be well before the actual onset of high blood pressure. High blood pressure may be a risk marker for irreversible vascular disease and early detection of the many components of hypertension syndrome may delay or prevent cardiovascular disease from developing in high-risk patients. Am J Hypertens 1999;12:164S–169S © 1999 American Journal of Hypertension, Ltd.
KEY WORDS:
Hypertension syndrome, cardiovascular risk, angiotensin receptor blockers, normotensive, heart disease.
be a late manifestation of this complex disease syndrome and that coronary artery disease may develop in hypertensive patients long before the onset of elevated blood pressure. The purpose of this paper is to demonstrate that hypertension is just one part of a much broader socalled “hypertension syndrome” and that in many patients, changes in blood pressure only manifest late in the course of this disease process. LIPIDS Epidemiologic studies have clearly demonstrated that hypertensive patients have significantly higher plasma lipids at every age group than their normotensive counterparts.3 It has been shown that approximately 80% of hypertensive patients have lipid abnormalities, of whom approximately half require drug 0895-7061/99/$20.00 PII S0895-7061(99)00221-6
AJH–DECEMBER 1999 –VOL. 12, NO. 12, PART 2
treatment.4 This incidence of hypercholesterolemia among hypertensive patients is simply too common to be coincidence, and suggests that hypertensive patients also inherit abnormalities of lipid metabolism. To assess when in the course of this disease syndrome hypertensive patients develop abnormalities of cholesterol, we performed a study in a population of normotensive subjects who were prone to the development of high blood pressure by virtue of a strong family history of hypertension. As a control group, we used a group of patients similar in age, gender, body mass index, and blood pressure, with a negative family history for hypertension. Cholesterol levels in subjects with a family history of hypertension were significantly higher than in those without a family history of hypertension, despite normal blood pressure.5 High-density lipoprotein levels were similar in both groups. These findings would suggest that the lipid abnormalities in patients prone to developing hypertension precede blood pressure abnormalities. Furthermore, the long-term effects of lipids on endothelial structure and function may result in decreases in arterial compliance that may eventually contribute to the increase of blood pressure that these patients frequently develop. Although both lipid abnormalities and elevated blood pressure are inherited abnormalities that clinically manifest independent of one another, both factors may contribute to the increased risk of coronary artery disease. Furthermore, it appears that in many instances, lipid abnormalities precede changes in blood pressure. LEFT VENTRICULAR HYPERTROPHY Left ventricular hypertrophy (LVH) is commonly associated with hypertension and is frequently regarded as a so-called “normal” response of the left ventricle to elevated blood pressure. However, data from the Framingham study have clearly demonstrated that LVH is a powerful predictor of cardiovascular disease.6,7 Hypertensive patients with LVH have a fivefold increase in the risk of sudden death and a threefold increase in the risk of coronary artery disease, compared with hypertensive patients with similar blood pressure without LVH. It was originally thought that LVH occurs in hypertensive patients only as a consequence of elevated pressure in the cardiovascular system. However, studies have demonstrated that normotensive young adults with a family history of hypertension have a significantly increased left ventricular mass index when compared with normotensive young adults without a family history of hypertension.8 These findings suggest that LVH may precede the onset of high blood pressure and most likely occurs as
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a consequence of inherited abnormalities of growthstimulating neurohormones. VENTRICULAR COMPLIANCE Diastolic dysfunction (reduced ventricular compliance) is commonly associated with hypertension and may be an important factor in the development of congestive heart failure in hypertensive subjects.9 As is the case with LVH, it is believed that diastolic dysfunction is a structural change that occurs in the left ventricle in response to increased blood pressure. However, studies using Doppler measuring techniques have shown significant reductions in ventricular compliance in normotensive subjects with a family history of hypertension when compared with similar normotensive subjects without a family history of hypertension.9 These findings demonstrate there were significant changes in ventricular wall structure before the onset of hypertension that may be a result of abnormal levels of neurohormonal growth factors occurring early in the course of this disease process. ARTERIAL COMPLIANCE Changes in arterial stiffness in hypertensive patients also often occur before the onset of hypertension. Studies assessing both arterial structure and function have shown reduced arterial compliance in normotensive subjects with a family history of hypertension, compared with those who did not have a family history of hypertension.10,11 These arterial changes in normotensive subjects with a family history of hypertension are probably a result of the increased activity of several growth factors. Changes in arterial compliance are undoubtedly important in the pathogenesis of hypertension, as it has been well documented that stiff, noncompliant vessels result in increased pressure in the cardiovascular system due to the inability of vessels to expand (stretch) during systole. Moreover, the structural changes in the arterial system provide the environment required for the development of atherosclerotic disease. These earlier arterial changes may have some important diagnostic implications in that they may provide an important early marker (that precedes the development of hypertension) in patients with the hypertension syndrome. The development of noninvasive tools for measuring arterial compliance may enable physicians to isolate these patients earlier in the course of the disease process. SYNDROME X Insulin resistance has been shown to occur in approximately 50% of hypertensive patients.4 These patients are resistant to their own insulin, and thus to normalize their plasma glucose levels require almost twice as much insulin as normotensive subjects.12 Increased
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insulin levels are frequently associated with increased triglycerides, increased total cholesterol, decreased high-density lipoprotein cholesterol, increased blood pressure, and centripetal obesity (apple-shaped obesity). This group of associated cardiovascular risk factors is often referred to as syndrome X.13 Insulin is a powerful growth factor, and independent of blood pressure, causes smooth muscle hypertrophy. It is also a very powerful atherogenic agent and is likely to play a role in the early stages of atherosclerosis. Insulin resistance has also been shown to develop before the onset of high blood pressure. Normotensive subjects with a family history of hypertension were shown to be less sensitive to insulin and consequently had higher plasma insulin levels than subjects with no family history of hypertension.5 Mediated by its effects on vascular structure and function, insulin probably plays an important role in both the pathogenesis of hypertension and atherosclerotic disease in patients with hypertension syndrome.13,14 RENAL FUNCTION Normotensive subjects with a family history of hypertension are more likely to develop microalbuminuria than those without a family history of high blood pressure.5 Elevated blood pressure has been implicated as the cause for renal dysfunction in hypertensive patients. Although it is clear that high blood pressure accelerates these renal changes, it appears that some of the changes (probably in the efferent arterioles) occur years before the onset of hypertension. There may be a shift in cause and effect whereby patients may have undiagnosed renal dysfunction that contributes to the development of elevated blood pressure. The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors on renal function in normotensive patients are further evidence that many of these renal changes are independent of blood pressure. NEUROENDOCRINE CHANGES The sympathetic nervous system and the renin-angiotensin system (RAS) are believed to be pivotal in the pathogenesis of hypertension. Interruptions of these systems effectively reduce blood pressure. However, recent studies have demonstrated that plasma norepinephrine levels and plasma renin activity are significantly elevated in normotensive patients with a family history of hypertension, compared with normotensive subjects without a family history of hypertension.5 It is interesting that patients with elevated vasoactive neurohormones are often normotensive. These findings suggest that the hypertensive effects of these hormones are not entirely due to their vasoconstrictor properties but may influence structure and function of cardiovascular smooth muscle.
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NORMOTENSIVE SUBJECTS WITH THE HYPERTENSION SYNDROME VERSUS HYPERTENSIVE SUBJECTS Convincing evidence suggests that many of the components of the hypertension syndrome precede the onset of high blood pressure. Furthermore, normotensive subjects who are prone to develop hypertension (by virtue of a strong positive family history of hypertension) have significantly more cardiovascular risk factors than normotensive subjects with no family history of hypertension. How do normotensive subjects with a family history of hypertension (who are very seldom treated) compare to true hypertensive subjects (who are usually treated) in terms of cardiovascular risk factors? We demonstrated that when comparing normotensive patients, with and without a family history of hypertension, with hypertensive patients (matched for age and body mass index), with and without a family history of hypertension, there were no differences in plasma levels of insulin, norepinephrine, renin activity, or cholesterol between currently hypertensive subjects, regardless of a family history of hypertension.5 There were also no differences in insulin sensitivity, microalbuminuria, or systolic blood pressure (SBP) responses to exercise. All three groups, however, were significantly worse off in each of the stated parameters than the control group (normotensive subjects with no family history of hypertension) (Figure 1). Thus, in terms of cardiovascular risk, normotensive subjects with a family history of hypertension have a cardiovascular risk factor profile similar to the hypertensive subjects. The only difference between the groups is that the normotensive subjects have not yet developed high blood pressure, which seems to be a late manifestation of this disease process. As blood pressure measurement is used to diagnose patients with the hypertension syndrome to protect them from developing heart disease, it is possible that we are treating these patients too late in the disease process. If we were to diagnose and treat these patients before they developed hypertension, we would have the potential to prevent the onset of hypertension and perhaps prevent the development of heart disease. It is conceivable that the hypertension syndrome may be reversible before the onset of high blood pressure, and that the development of high blood pressure is a marker of irreversible vascular disease after which we can only control the disease. This is evidenced by the fact that early in the disease process, aerobic exercise may reverse many of the cardiovascular risk factors associated with hypertension and may prolong or prevent the onset of high blood pressure. This is not the case in overt hypertension. In addition, studies have found that patients with controlled hypertension
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FIGURE 1. Comparison of normotensive patients with (solid bars) and without (open bars) a family history of hypertension, to hypertensive patients (matched for age and body mass index) with (solid bars) and without (open bars) a family history of hypertension. There were no significant differences between currently hypertensive subjects, regardless of a family history of the disease. Plasma insulin concentrations, insulin-glucose ratio, norepinephrine concentrations, plasma renin activity, total cholesterol levels (not shown), creatinine clearance (not shown), and albumin excretion rate (not shown) were all significantly higher in patients with a family history of hypertension, whether or not they were currently hypertensive. NT, normotensive; HT, hypertensive. *P ⬍ .03, †P ⬍ .01, ‡P ⬍ .02, **P ⬍ .05, ††P ⬍ .07.5
are more likely than normotensive subjects with a family history of hypertension to develop cardiovascular disease, suggesting that there is more to hypertension than high blood pressure.15 FROM HYPERTENSION TO HEART DISEASE What is the relationship between cardiovascular risk factors associated with hypertension and the development of heart disease? Using newly developed techniques for measuring arterial compliance, it has been shown that when comparing hypertensive and normotensive subjects, the hypertensive group exhibits significantly decreased proximal and distal arterial system compliance.16 This stiffness is usually a result of proliferation and hypertrophy of vascular smooth muscle as well as the deposit of collagen and other connective tissue elements in the media of the blood vessels. These changes also seem to be associated with disruption of the protective endothelial surface of the blood vessels.17 It is also becoming evident that atherosclerotic plaques are much less likely to develop in normal vessels than in abnormal vessels and that the vascular changes seen in hypertensive patients provide the environment required for the early development of atheromatosis lesions. In a study using intraarterial measurements of arterial compliance, we have demonstrated that the changes in stiffness of both the
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FIGURE 2. Factors that lead to endothelial dysfunction. Hypertension and atherosclerosis may occur simultaneously, with hypertension leading to the possible potentiation of atherosclerosis and to the same factors that predispose for endothelial dysfunction.
proximal and distal vessels typically seen in hypertensive patients precede the onset of overt high blood pressure. The majority of the changes in the vessels occur during the period between normotension and the onset of borderline hypertension.18 Once hypertension develops, there are only minimal changes in the compliance of the proximal vessels and no changes in the compliance of the distal vessels.18 These data suggest that maximal changes to arterial structure and function in hypertensive patients actually occur before the onset of high blood pressure and that factors other than hypertension are causing the vascular changes. In normotensive subjects with abnormal arterial compliance, there is a significant inverse correlation with plasma levels of norepinephrine, cholesterol, insulin, and plasma renin activity.19 This would suggest that these neurohormones, which are powerful growth factors, play an important role in the structural and functional changes in the arteries before the onset of hypertension. Furthermore, it is believed that stiff vessels actually cause blood pressure to increase. It is thus possible that patients with the hypertension syndrome inherit abnormalities of neurohormonal function. Through their growth effects, these hormones will, over time, alter vascular compliance by causing smooth muscle cell hypertrophy and connective tissue deposit. This process has a dual effect: it creates the environment for atheromatosis plaque development and the possible development of cardiovascular disease, and it increases arterial stiffness, which results in increased blood pressure. It seems that the development of elevated blood pressure and atheromatosis disease may occur simultaneously (Figure 2). It is also possible that cardiovascular disease, and a cardiovascular event, can develop before the onset of hypertension. Furthermore, hypertension may potentiate arterial changes resulting in reduced compliance, and provide an environment for
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atheromatosis development. It is important to reduce blood pressure even in patients with advanced disease, although the maximal benefits may be derived from treatment with drugs that reduce blood pressure and beneficially affect vascular structure and function. THERAPEUTIC IMPLICATIONS It has been demonstrated that blood pressure reduction in hypertensive patients is associated with target organ protection and a decrease in cardiovascular morbidity. However, simply treating the blood pressure in hypertensive patients is not sufficient. The entire syndrome needs to be considered and an attempt should be made to address all its components. Selection of drugs for hypertensive patients should include agents that reduce blood pressure as well as have beneficial or neutral effects on other parameters of the hypertension syndrome. Drugs that block the RAS have been shown to provide benefits beyond blood pressure control due to their inhibition of angiotensin II. For this reason, angiotensin receptor blockers (ARB) and ACE inhibitors are important in hypertension management, as they are safe, efficacious, well tolerated, and are “syndrome-friendly” agents. With respect to the ARB, these agents may offer special advantages. Controlling and maintaining blood pressure to less than 140/90 mm Hg, as recommended by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI),20 continues to be problematic, with only 27% of hypertensive patients attaining blood pressure control. Poor compliance with therapy may be one explanation for the poor hypertension control rates. In this regard, the ARB may hold an advantage in that these agents are associated with tolerability that is similar to placebo and is not affected by increases in dose.21–26 Even when compared with ACE inhibitors, arguably the most well tolerated of the other classes of antihypertensive agents, the ARB have been demonstrated to hold an advantage with respect to tolerability.27 Further, it has now been well documented that these agents provide levels of blood pressure control that are similar to those attained with other classes of antihypertensive agents.21–26 These observations may be of particular interest with respect to combination therapy. Results of the Hypertension Optimal Treatment (HOT) study have demonstrated that although it is possible for clinicians to control blood pressure in a majority of patients, combination therapy is often required.28 In HOT, combination therapy was required in 63% of patients controlled to 90 mm Hg or less. Fixed-dose combinations of ARB and diuretics are now available. As with other ARB/diuretic combinations, the combination of irbe-
sartan and hydrochlorothiazide has been demonstrated to improve long-term blood pressure response rates, compared with either agent as monotherapy. Results of an extended study of 1098 subjects demonstrated that as many as 85% of subjects attained blood pressure normalization (seated diastolic blood pressure [SeDBP] ⬍ 90 mm Hg) at 1 year.29 Importantly, there is no statistical change in the rates of adverse events with the addition of the diuretic to the ARB irbesartan. CONCLUSIONS Studies have demonstrated that the incidence of coronary artery disease in well-controlled hypertensive patients is approximately 30% higher than in normotensive subjects.29 This underscores the fact that hypertension is not simply a disease of numbers but rather a complex inherited syndrome of cardiovascular risk factors, all of which appear to have genetic links. It is clear that, in many patients with this syndrome, high blood pressure is a late manifestation of the disease process. Moreover, it is conceivable that patients with this syndrome may develop a myocardial infarction before the development of high blood pressure and, due to ventricular dysfunction, may never develop blood pressure abnormalities. The realization that hypertension is a disease syndrome has many important diagnostic and therapeutic implications in the management of hypertension. REFERENCES 1.
Samuelsson OG, Wilhelmsen LW, Svardsudd KF, Pennert KM, Wedel H, Berglund GL: Mortality and morbidity in relation to systolic blood pressure in two populations with different management of hypertension: the study of men born in 1913 and the multifactorial primary prevention trial. J Hypertens 1987;5: 57– 66.
2.
Grimm RH Jr, Flack JM, Byington R, Bond G, Brugger S: A comparison of antihypertensive drug effects on the progression of extracranial carotid atherosclerosis. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). Drugs 1990;40:38 – 43.
3.
Laurenzi M, Mancini M, Menotti A, Stamler J, Stamler R, Trevisan M, Zanchetti A: Multiple risk factors in hypertension: results from the Gubbio study. J Hypertens 1990;8(suppl):S7–S12.
4.
Kaplan NM: Treatment of hypertension: drug therapy, in Clinical Hypertension, 6th Edition. Williams & Wilkins, Baltimore, 1994, chapter 7.
5.
Neutel JM, Smith DHG, Graettinger WF, Winer RL, Weber MA: Heredity and hypertension: impact on metabolic characteristics. Am Heart J 1992;124:435– 440.
6.
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP: Prognostic implications of echocardiographically determined left ventricular mass in Framingham Heart Study. N Engl J Med 1990;332:1561–1566.
AJH–DECEMBER 1999 –VOL. 12, NO. 12, PART 2
THE HYPERTENSION SYNDROME
169S
7.
Cassale PN, Milner A, Devereux RB: Value of echocardiographic left ventricular mass in predicting cardiovascular morbidity events in hypertensive men. Circulation 1985;72:130 –135.
19.
Neutel JM, Smith DHG, Graettinger WF, Weber MA: Dependency of arterial compliance on circulating neuroendocrine and metabolic factors. Am J Cardiol 1992; 69:1340 –1344.
8.
Celentano A, Galderisis M, Garafalo M: Blood pressure and cardiac morphology in young children of hypertensive subjects. J Hypertens 1988;6(suppl 4):S107– S109.
20.
The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report. Arch Intern Med 1997;157:2413– 2446.
9.
Graettinger WF, Neutel JM, Smith DHG, Weber MA: Left ventricular diastolic filling alterations in normotensive young adults with a family history of systemic hypertension. Am J Cardiol 1991;68:51–56.
21.
Goa KL, Wagstaff AJ: Losartan potassium. A review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996;51:820 – 845.
10.
Taddei S, Virdis A, Mattei P, Arzilli F, Salvetti A: Endothelium-dependent forearm vasodilation is reduced in normotensive subjects with family history of hypertension. J Cardiovasc Pharmacol 1992;20(suppl 12):S193–S195.
22.
Markham A, Goa KL: Valsartan. A review of its pharmacology and therapeutic use in essential hypertension. Drugs 1997;54:299 –311.
23.
McClellan KJ, Goa KL: Candesartan cilexetil. A review of its use in essential hypertension. Drugs 1998;56:847– 869.
24.
Mimran A, Ruilope L, Kerwin L, Nys M, Owens D, Kassler-Taub K, Osbakken M: A randomised, doubleblind comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of mild-to-moderate hypertension. J Hum Hypertens 1998;12:203–208.
25.
Pohl M, Cooper M, Ulrey J, Pauls J, Rohde R: Safety and efficacy of irbesartan in hypertensive patients with type 2 diabetes and proteinuria. Am J Hypertens 1997;10: 105A.
26.
Stumpe KO, Haworth D, Hoglund C, Kerwin L, Martin A, Simon T, Masson C, Kassler-Taub K, Osbakken M: Comparison of the angiotensin II receptor antagonist irbesartan with atenolol for the treatment of hypertension. Blood Press 1998;7:31–37.
27.
Pylypchuk GB. ACE inhibitor—versus angiotensin II blocker—induced cough and angioedema. Ann Pharmacother 1998;32:1060 –1066.
28.
Hansson L, Zanchetti A, Julius S, Caruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351: 1755–1762.
29.
Raskin P, Saini R, Kassler-Taub K, Mulhall L, Freitag S: Irbesartan and low-dose hydrochlorothiazide combination as long-term therapy for mild to moderate hypertension. J Hypertens 1998;16(suppl 2):S239.
11.
Safar ME, Laurent S, Pannier BM, London GM: Structural and functional modification of peripheral large arteries in hypertensive patients. J Clin Hypertens 1987; 3:360 –367.
12.
Swislocki ALM, Hoffman BB, Reaven GM: Insulin resistance, glucose intolerance, and hyperinsulinemia in patients with hypertension. Am J Hypertens 1989;2: 419 – 423.
13.
Zavaroni I, Bonora E, Pagliara M: Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 1989;320:702–706.
14.
Reaven GM, Hoffman BB: A role for insulin in the aetiology and course of hypertension. Lancet 1987;ii: 435– 437.
15.
Havlik H, La Croix A, Kleinman J, Ingram D, Harris T, Cornoni-Huntley J: Antihypertensive drug therapy and survival by treatment status in a national survey. Hypertension 1989;13(suppl 1):1-28 –1-32.
16.
Mc Veigh YE, Burns DE, Finkelstein SM, McDonald KM, Cohn JN: Reduced valsartan compliance as a marker for essential hypertension. Am J Hypertens 1991;4:245–251.
17.
Clozel JP, Kuhn H, Hefti F: Decreases of vascular hypertrophy in four different types of arteries in spontaneously hypertensive rats. Am J Med 1989;87(suppl 6B):92.
18.
Weber MA, Smith DHG, Neutel JM, Graettinger WF: Arterial properties of early hypertension. J Hum Hypertens 1991;5:1–7.