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Hypertension: Where have we gone wrong and how can we fix it?
AJH
1998;11:150S–157S
Hypertension: Where Have We Gone Wrong and How Can We Fix It? Joel M. Neutel and David H.G. Smith
Hypertension is defined as a disease of elevated systolic and diastolic blood pressure and consequently the goals of treating hypertension have been simply to normalize the blood pressure. However, effective blood pressure control has not resulted in the expected decreases in coronary artery disease. These findings have forced researchers to reexamine the importance of blood pressure in causing coronary artery disease, and to pose the question “Is there more to hypertension than high blood pressure?” Although there are probably several reasons for the poor reduction in the incidence of coronary artery disease in hypertensive patients, one of the most compelling appears to be the realization that hypertension is not simply a disease of numbers, but is a complex inherited syndrome of cardiovascular risk factors, all of which contribute to heart disease in these patients. Included in the hypertension syndrome are abnormalities of lipid profile, insulin resistance, changes in renal
H
ypertension as a disease process was born out of epidemiologic studies, which showed that people with increased blood pressure had an increased risk of developing heart attacks and strokes. As a result, hypertension was defined simply as a disease of increased systolic and diastolic blood pressure, and the goal in
From the Orange County Heart Institute and Research Center, Orange, California and the University of California Irvine, Irvine, California. Address correspondence and reprint requests to Joel M. Neutel, MD, Director, Orange County Heart Institute and Research Center, 505 S. Main Street, Suite 1025, Orange, CA 92868.
© 1998 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
function, endocrine changes, obesity, abnormalities of coagulation factors, left ventricular hypertrophy and diastolic dysfunction, and abnormalities of vascular structure and compliance. In many patients, high blood pressure is a late manifestation of this disease process and is preceded by some or all of the associated cardiovascular risk factors. Perhaps where we have gone wrong in the management of hypertension is in the belief that this is simply a disease of numbers. To improve our management, we need to find methods to diagnose these patients early in the course of this disease process, and to treat it as a syndrome rather than as a number. Am J Hypertens 1998; 11:150S–157S © 1998 American Journal of Hypertension, Ltd.
KEY WORDS:
Hypertension, treatment, family history, multifactorial risk.
treating hypertension was to normalize elevated blood pressures. It was believed that if normal blood pressure were achieved in hypertensive patients, there would be significant reductions in the incidence of the associated cardiovascular events. Studies performed to assess cardiovascular events in hypertensive patients have repeatedly demonstrated that reducing blood pressure has resulted in very impressive reductions in cerebrovascular disease, but the reductions in coronary artery disease have been far lower than what had been statistically predicted from the reductions in blood pressure. Thus, although we can normalize blood pressure in hypertensive patients, this only results in a 14% reduction in 0895-7061/98/$19.00 PII S0895-7061(98)00192-7
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TABLE 1. COMPONENTS OF HYPERTENSION High blood pressure, including variability of blood pressure and its circadian effects Lipid abnormalities: increased prevalence and heightened coronary risk associated with hypertension Underlying insulin resistance Early changes in renal function Changes in left ventricular structure and function Reduced proximal and distal arterial compliance Prothrombotic tendencies
the number of myocardial infarcts in these patients.1–3 The only plausible explanation for these findings is the presence of additional cardiovascular risk factors, which contribute to the development of coronary artery disease, in these patients. The objective of this manuscript is to show data that suggest that hypertension is an inherited syndrome of cardiovascular risk factors, all of which clinically manifest at different times and all of which contribute to the development of heart disease in these patients (Table 1). Furthermore, there is growing evidence that high blood pressure may be a late manifestation of this disease process. The realization that hypertension is a syndrome may have some important implications for the effective management of this disease process. HYPERLIPIDEMIA It has been well demonstrated that hypertension is commonly associated with hyperlipidemia. Indeed, a linear relationship exists between blood pressure levels and total cholesterol concentrations among young and middle-aged hypertensive individuals.4 Both hypertension and hyperlipidemia are known to be important cardiovascular risk factors. However, when these two risk factors occur together, there is a markedly exaggerated risk of coronary events.5 The explanation for this phenomenon is unclear, but data from animal models of genetic hypertension indicate that vascular smooth muscle cells in these animals bind with greater affinity to low-density lipoprotein than do the smooth muscle cells from normotensive controls.6 The high incidence of hyperlipidemia in hypertensive patients has prompted the belief that high blood pressure may play some role in the genesis of lipid abnormalities in hypertensive patients. However, in a study comparing age-matched, gender-matched, body mass index-matched normotensive subjects with and without a family history of hypertension, the hypertensive-prone patients (patients with a family history) had significantly higher total cholesterol levels than those subjects without a family history of hypertension.7 This would suggest that the lipid abnormalities precede the abnormalities of blood pressure in hyper-
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tensive patients. Thus, it appears that in this patient group, both high blood pressure and hyperlipidemia are inherited, clinically manifest at different times independent of one another, and that both contribute to the development of coronary artery disease in these patients. These data may have important therapeutic implications, as studies using coronary events as the endpoint of treatment of hypertensive patients have shown that simply treating the hypertension alone, or the hypercholesterolemia alone, produce only modest results; only when both problems are treated at the same time is there a marked reduction in coronary disease.8 GLUCOSE AND INSULIN METABOLISM There is good evidence that insulin resistance and hyperinsulinemia are important cardiovascular risk factors. Early evidence linking type II diabetes and atherosclerosis came from the International Atherosclerosis Project.9 Later, in prospective population studies, elevated insulin levels were implicated in the development of coronary artery disease.10,11 The pathophysiology of the relationship between insulin and coronary artery disease is not completely understood, but it has been shown that hyperinsulinemia is associated with increased triglyceridemia and total cholesterol levels and decreased high-density lipoprotein levels.10 Insulin also appears to enhance the participation of atherogenic lipid particles in the formation of vascular plaques by facilitating their transport into the media of the vessel wall.12 Moreover, insulin may directly stimulate vascular smooth muscle proliferation as well as promote the action of other growth factors of vascular tissue.13 Both type I and type II diabetes often coexist with hypertension. There is growing evidence that many hypertensive patients can be characterized as having borderline glucose intolerance and insulin resistance. These patients usually have normal fasting blood glucose concentrations and are not regarded as having clinical diabetes. A large-scale population survey has indicated that approximately 50% of hypertensive patients have glucose intolerance, as measured by plasma glucose levels measured 2 h after glucose load14; this prevalence was far higher than in normotensive controls. The explanation for this finding appears to be resistance to the action of insulin. In a study of well-matched groups of normal volunteers and hypertensive patients given a standard oral glucose tolerance test, there was a tendency for maximum plasma glucose concentrations to be slightly higher in the hypertensive group than in the normal subjects. More impressively, this study showed that the plasma insulin concentrations were significantly higher in the hypertensive patients than in their normotensive
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FIGURE 1. Plasma glucose (left) and insulin (right) concentrations before and during a 75-g oral glucose tolerance test in four groups of subjects. Values are mean 1 SEM.
counterparts during most of the study15 (Figure 1). It appears that insulin resistance and increased insulin levels precede the increases in blood pressure in hypertensive patients. In a study comparing matched normotensive adults with and without a family history of hypertension, insulin levels were significantly higher in patients with a family history of hypertension than in those without.7 Furthermore, the insulin/ glucose ratio, which gives a crude indication of insulin sensitivity, demonstrated that patients with a family history of hypertension were less sensitive to their insulin than patients without a family history.7 Similar findings were reported in a study of young black men. Fasting plasma insulin concentrations were significantly higher in patients with borderline hypertension than in normal controls, and the young hypertensives exhibited a diminished capacity to clear glucose from their plasma.16 This suggests that insulin resistance is also part of the hypertension syndrome. In addition, insulin resistance appears to be genetically inherited and seems to precede high blood pressure in the course of the disease process. Furthermore, insulin may play an important role in the pathogenesis of high blood pressure, both directly by mediating increased sodium retention17,18 and sympathetic drive, and indirectly by its effects on vascular smooth muscle, resulting in decreased arterial compliance and an associated increase in blood pressure.19 LEFT VENTRICULAR HYPERTROPHY AND DIASTOLIC DYSFUNCTION Left ventricular hypertrophy (LVH) is an extremely common finding in hypertensive patients. Echocardiographic data have shown an overall LVH prevalence of 20% in patients with mild hypertension and up to
50% in patients with more severe hypertension.20,21 Left ventricular hypertrophy has been identified as the most powerful risk factor for future cardiovascular events, including myocardial infarction, congestive heart failure, and sudden death.22 The risk of these cardiovascular events increases six- to eightfold in patients with LVH when compared with hypertensive patients without LVH who have similar blood pressures.22,23 Sustained high blood pressure has for many years been implicated as the primary etiology of LVH, although the actual correlation between left ventricular mass and arterial pressure is surprisingly poor.24 However, there is now good evidence that LVH may develop early in the course of hypertension and may actually precede the onset of high blood pressure. In a study of young individuals (aged , 30 years) with mild hypertension, it was found that approximately half of these patients has septal and posterior wall thickness greater than the highest values found in an aged-matched control group.25 Interestingly, subsequent blood pressure measurements indicated that many of these young hypertensive patients had normal or borderline blood pressure values. However, the echocardiographic wall thickness in this subgroup was increased and was not different from that of those patients who were truly hypertensive. In a separate study, which compared the echocardiographic findings in normotensive children of normotensive parents with those of aged-matched, gender-matched normotensive children of hypertensive parents, the offspring from hypertensive families had significantly greater left ventricular wall thickness and muscle than those from normotensive families.26 These findings suggest that although high blood pressure may facilitate the progression of LVH in
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patients with underlying abnormalities in the myocardial smooth muscle, in some patients there are other factors that play a role in the development of the LVH, which may develop several years before the onset of high blood pressure. The changes in left ventricular mass are frequently associated with changes in ventricular function. These functional changes are frequently referred to as diastolic dysfunction and occur usually as a consequence of decreased left ventricular compliance. Transmitral flow characteristics, measured by Doppler echocardiography, have been used as an index of left ventricular filling during diastole. An increased ratio of late filling (atrial component) to early filling (early peak flow velocity) reflects individual compliance of the left ventricular wall. Indices of diastolic function have been shown to correlate significantly with left ventricular muscle mass in hypertensive patients, suggesting that there are functional consequences associated with early hypertrophy.27 Because LVH frequently precedes the onset of high blood pressure it is not surprising that diastolic function can also occur before the onset of increased blood pressure. In a group of normotensive male college students matched for age and left ventricular muscle mass, subjects with a family history of hypertension had delayed diastolic filling compared with those who did not have a family history of hypertension.28 Thus, changes in ventricular structure and function also constitute part of the hypertension syndrome. These changes may occur before the onset of high blood pressure and appear to be genetically determined in these patients; it may predispose them to the development of heart disease early in the course of their disease process. ARTERIAL COMPLIANCE Hypertension is characterized by structural changes in the arterial circulation. Hypertrophy and hyperplasia of the arterial walls, linked to increased laying down of connective tissues, are common findings in hypertensive patients.29 These changes result in stiffening of the arterial walls and decreased compliance of the arteries. Comparisons of normotensive and hypertensive patients have established that cardiovascular compliance is not necessarily linked to increases in blood pressure. On the contrary, there is growing evidence that abnormalities in arterial compliance precede the abnormalities in blood pressure and may not worsen with increasing blood pressure.30 In a study comparing normotensive children with a family history of hypertension with matched normotensive children without a family history of hypertension, the offspring of hypertensive parents had de-
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FIGURE 2. Measurements of distal and proximal compliance in normal volunteers (DBP , 90 mm Hg), and in patients with borderline (DBP 90 to 99 mm Hg) or established (DBP . 100 mm Hg) hypertension. Values are mean 1 SEM.
creased forearm blood flow in response to acetylcholine stimulation, indicating abnormalities of vascular function early in the course of the disease process.31 In a separate study using pulse contour analysis to calculate proximal (large vessel) and distal or reflective (small vessel) compliance, it was demonstrated that the major changes in compliance, both proximal and distal, coincide with the time period that blood pressure increases from normal to borderline elevated. There are no further changes in the distal compliance as blood pressure increases from borderline levels to overt hypertension, with only small changes in proximal compliance32 (Figure 2). There are thus compelling data to suggest that the changes in vascular structure and function precede the changes in blood pressure. Furthermore, as decreased arterial compliance results in increasing blood pressure, these early changes in compliance may play an important role in the pathogenesis of high blood pressure.33 Recent observations have suggested that neuroendocrine and hormonal factors may be responsible for these early changes in arterial compliance. In patients with reduced arterial compliance, the changes in compliance have been shown to correlate with increased plasma concentrations of insulin, triglycerides, total cholesterol, norepinephrine, and plasma renin activity
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FIGURE 3. A) Plasma immunoreactive insulin levels in patients with normal (. 1.65 mL/mm Hg) and reduced (, 1.65 mL/mm Hg) proximal arterial compliance and in patients with normal (. 0.035 mL/mm Hg) arterial compliance. Values are mean 1 SEM. B) Plasma concentrations of triglycerides, total cholesterol, and high-density lipoprotein cholesterol in patients with normal (. 1.65 mL/mm Hg) and reduced (, 1.65 mL/mm Hg) proximal arterial compliance. Plotted values are mean 1 SEM.
(Figure 3).34 These factors, by hypertrophy of vascular wall smooth muscle and by deposition of lipid and collagen in the media of the vessel wall, may clearly have an impact on vascular structure and function, independent of blood pressure. In addition to causing increases in blood pressure, the vessel wall changes may be the starting point of early atheromatous plaque formation. It may thus be argued that decreases in arterial compliance, independent of blood pressure, may be an early and important cardiovascular risk factor in hypertensive patients. First, changes in wall structure create the environment for lipid deposit and early plaque formation, which may be important in the development of cardiovascular disease. Second, arterial compliance is a powerful predictor of endothelial reliance of von Willebrand Factor (VWF) and tissue plasminogen activator.35 Elevated levels of VWF have been described in patients with prothrombotic tendencies, including those with acute myocardial infarction.35 Third, decreased compliance is associated with increased blood pressure. Thus, the changes that occur in the vessel walls (similar to those that occur in the ventricle), are also an early and inherited part of the hypertension syndrome, frequently preceding the changes in blood pressure, and may also play a pivotal role in the pathogenesis of high blood pressure and cardiovascular disease in these patients.
OBESITY Obesity is a more common finding in hypertensive patients than in matched normotensive patients, and it is estimated that approximately 40% of the hypertensive patients in the United States are obese. In the majority of patients, the obesity precedes the onset of hypertension and may contribute to the development of high blood pressure in these patients. Obesity is associated with metabolic complications considered to be risk factors for cardiovascular disease, including insulin resistance, hyperinsulinemia, glucose intolerance, high blood pressure, and changes in the concentration of plasma lipids and lipoproteins.26,36 –38 Only recently has truncal obesity, characterized by a large waist-to-hip ratio (apple-shaped obesity), been recognized to predict the risk of coronary artery disease.39 Based on the efficacy of weight loss and exercise in reducing blood pressure,40 it has been speculated that insulin provides the link between obesity and increased sympathetic nervous system activity. RENAL CHANGES For many years, it was believed that renal changes in hypertensive patients occurred as a consequence of high blood pressure. However, with recent interest in mild forms of hypertension, early changes in renal function have been observed. Studies have demonstrated that there are differences in renal functional
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FIGURE 4. Plasma immunoreactive insulin levels (A), insulin/glucose ratios (B), plasma norepinephrine levels (C), and plasma renin activity (D) in normotensive (NT) and hypertensive (HT) subjects with and without a family history of hypertension. Differences shown are between the control group (NT with no family history of hypertension) and each of the other three groups. Values are mean 1 SEM. Black bar, no family history; white bar, family history.
reserve in children of normotensive parents compared with children of hypertensive parents.40 Thus, despite apparently normal renal function, the children of hypertensive parents appeared to be less able than the children of normotensive parents to increase their creatinine clearance in response to protein loading and were also more likely to exhibit microalbuminurea.41 These data were confirmed in a later study that demonstrated increased microalbuminurea in normotensive adults with a family history of hypertension than matched normotensive adults without a family history of hypertension.7 These data suggest that renal changes in hypertensive patients may also occur early in the course of the disease and may contribute to the development of high blood pressure. Furthermore, it appears that other factors, distinct from blood pressure, play a role in the pathogenesis of renal changes in hypertensive patients. ENDOCRINE CHANGES The sympathetic nervous system and the renin angiotensin system are thought to be pivotal in causing high
blood pressure. However, studies have shown that plasma norepinephrine levels and plasma renin activity were significant elevated in the normotensive offspring of hypertensive parents.7 It is interesting that these increases in neuroendocrine levels occur before the development of high blood pressure and that in hypertension-prone patients with significantly elevated norepinephrine and angiotensin II, levels can be normotensive. These findings suggest that the hypertensive effect of these hormonal systems are not entirely due to their vasoconstrictor properties but may also be due to their influence on the structure and compliance of cardiovascular smooth muscle. SUMMARY As has been shown, there is compelling evidence that many of the cardiovascular risk factors that are associated with hypertension, and which play a major role in the development of cardiovascular disease, occur long before these patients develop high blood pressure. It is thus possible that these patients have myocardial infarctions before the onset of high blood pres-
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sure and may then never develop high blood due to their damaged myocardium. In a study comparing cardiovascular risk factors in normotensive subjects with a family history of hypertension with those of hypertensive patients—with and without a family history of hypertension—there were no differences among the groups. All three groups, however, had significantly more cardiovascular risk factors than normotensive subjects without a family history of hypertension. Thus, in terms of cardiovascular risk these “normotensive hypertensive” (hypertensive-prone) patients were at equal risk of developing cardiovascular disease as were the hypertensive subjects, the only difference being that they had not, as yet, developed the high blood pressure (Figure 4). Thus, it would appear that a major problem in the management of hypertension is that the tool we use to isolate these patients, high blood pressure, is a late manifestation of a much broader inherited syndrome of cardiovascular risk factors, and that much of the damage that occurs in these patients is present prior to the onset of high blood pressure. It is possible, although not proven, that the development of high blood pressure may represent a late and irreversible stage of cardiovascular damage in these patients and that earlier intervention may be necessary to reverse the disease process. The existence of the hypertension syndrome has some important diagnostic and therapeutic implications, which may be necessary to consider to decrease coronary artery disease in hypertensive patients. First, we need a tool that will enable us to diagnose this syndrome early on in the disease process and, second, we need to treat hypertension in such a way that all the associated risk factors are included in our treatment plan. The reduction of strokes and overall mortality in treated hypertensive patients warrants our continued enthusiasm for treating high blood pressure, and improved performance in reducing other cardiovascular risk factors would add to the benefits of antihypertensive therapy. Perhaps treating this disease as a syndrome rather than a number will result in a reduction in the incidence of coronary heart disease, similar to that demonstrated for strokes. REFERENCES 1.
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Samuelsson OG, Wilhelmsen LW, Svardsudd KF, et al: 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. Grimm RH Jr, Flack JM, Byington R, et al: 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.
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Robertson WB, Strong JP: Atherosclerosis in persons with hypertension and diabetes mellitus. Lab Invest 1968;18:538 –551.
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Stout RW: Insulin and atheroma. 20-yr perspective. Diabetes Care 1990;13:631– 654.
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Stout RW: Overview of the association between insulin and atherosclerosis. Metab Clin Exp 1985;34(suppl 1): 7–12.
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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.
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Banskota NK, Taub R, Zellner K, et al: Characterization of induction of protooncogene C-myc and cellular growth in human vascular smooth cells by insulin and IGF-I. Diabetes 1989;38:123–129.
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Modan M, Halkin H, Almog S, et al: Hyperinsulinemia a link between hypertension, obesity and glucose intolerance. J Clin Invest 1985;75:809 – 817.
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Swislocki ALM, Hoffman BB, Reaven GM: Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am J Hypertens 1989;2: 419 – 423.
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Falkner B, Hulman S, Tannebaum J, Kushner H: Insulin resistance and blood pressure in young black men. Hypertension 1990;16:706 –711.
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Williams RR, Hunt SC, Hassted SJ, et al: Multigenic human hypertension: evidence for subtypes and hope for haplotypes. J Hypertens 1990;8(suppl):S39 – 46.
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Gupta AK, Clark RV, Kirchner KA: Effects of insulin and renal sodium excretion. Hypertension 1992; 19(suppl 1):8 –18.
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Neutel JM, Smith DHG, Graettinger WF, Weber MA: Dependency of arterial compliance on circulating neu-
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roendocrine and metabolic factors in normal subjects. Am J Cardiol 1992;69:1340 –1344. 20.
Devereux RB, Alonso E, Lutas EM: Sensitivity of echocardiography for detection of left ventricular hypertrophy, in Ter Keurs H, Schipperheyn JJ (eds): Cardiac Left Ventricular Hypertrophy. Martinus Nijhoff, The Hague, 1983; pp. 16 –20.
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Savage DD, Drayer J, Henry WL: Echocardiographic assessment of cardiac anatomy and function in hypertensive subjects. Circulation 1979;59:623– 627.
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Kannel WB: Prevalence and natural history heart of electrocardiographic left ventricular hypertrophy. Am J Med 1983;75(suppl 3a):4 –10.
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Levy D, Garrison RJ, Savage DD, et al: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561–1566.
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Drayer JI, Gardin J, Brewer D: Disparate relationships between blood pressure and left ventricular mass in patients with and without left ventricular hypertrophy. Hypertension 1987;14(suppl II):II-61–II-67.
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Drayer JIM, Weber MA, Laragh JH: Echocardiography in the evaluation of patients with mild or borderline hypertension, in Weber MA (ed): Treatment Strategies in Hypertension. Symposia Specialists, Miami, 1981, pp 21–32.
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Taddel S, Viridis A, Mattei P, et al: Endothelin-dependent forearm vasodilation is reduced in normotensive subjects with family history of hypertension. J Cardiovasc Pharmacol 1992:20(suppl 12):S193–S195.
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McVeigh GE, Burns DE, Carlyle PF, et al: Vascular compliance in essential hypertension. Circulation 1989; 80:11594 –11599.
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Neutel JM, Smith DHG, Graettinger WF, Weber MA: Dependency of arterial compliance on circulating neuroendocrine and metabolic factors in normal subjects. Am J Cardiol 1992;69:1340 –1344.
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1998;11:150S–157S
Hypertension: Where Have We Gone Wrong and How Can We Fix It? Joel M. Neutel and David H.G. Smith
Hypertension is defined as a disease of elevated systolic and diastolic blood pressure and consequently the goals of treating hypertension have been simply to normalize the blood pressure. However, effective blood pressure control has not resulted in the expected decreases in coronary artery disease. These findings have forced researchers to reexamine the importance of blood pressure in causing coronary artery disease, and to pose the question “Is there more to hypertension than high blood pressure?” Although there are probably several reasons for the poor reduction in the incidence of coronary artery disease in hypertensive patients, one of the most compelling appears to be the realization that hypertension is not simply a disease of numbers, but is a complex inherited syndrome of cardiovascular risk factors, all of which contribute to heart disease in these patients. Included in the hypertension syndrome are abnormalities of lipid profile, insulin resistance, changes in renal
H
ypertension as a disease process was born out of epidemiologic studies, which showed that people with increased blood pressure had an increased risk of developing heart attacks and strokes. As a result, hypertension was defined simply as a disease of increased systolic and diastolic blood pressure, and the goal in
From the Orange County Heart Institute and Research Center, Orange, California and the University of California Irvine, Irvine, California. Address correspondence and reprint requests to Joel M. Neutel, MD, Director, Orange County Heart Institute and Research Center, 505 S. Main Street, Suite 1025, Orange, CA 92868.
© 1998 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
function, endocrine changes, obesity, abnormalities of coagulation factors, left ventricular hypertrophy and diastolic dysfunction, and abnormalities of vascular structure and compliance. In many patients, high blood pressure is a late manifestation of this disease process and is preceded by some or all of the associated cardiovascular risk factors. Perhaps where we have gone wrong in the management of hypertension is in the belief that this is simply a disease of numbers. To improve our management, we need to find methods to diagnose these patients early in the course of this disease process, and to treat it as a syndrome rather than as a number. Am J Hypertens 1998; 11:150S–157S © 1998 American Journal of Hypertension, Ltd.
KEY WORDS:
Hypertension, treatment, family history, multifactorial risk.
treating hypertension was to normalize elevated blood pressures. It was believed that if normal blood pressure were achieved in hypertensive patients, there would be significant reductions in the incidence of the associated cardiovascular events. Studies performed to assess cardiovascular events in hypertensive patients have repeatedly demonstrated that reducing blood pressure has resulted in very impressive reductions in cerebrovascular disease, but the reductions in coronary artery disease have been far lower than what had been statistically predicted from the reductions in blood pressure. Thus, although we can normalize blood pressure in hypertensive patients, this only results in a 14% reduction in 0895-7061/98/$19.00 PII S0895-7061(98)00192-7
AJH–OCTOBER 1998 –VOL. 11, NO. 10, PART 2
TABLE 1. COMPONENTS OF HYPERTENSION High blood pressure, including variability of blood pressure and its circadian effects Lipid abnormalities: increased prevalence and heightened coronary risk associated with hypertension Underlying insulin resistance Early changes in renal function Changes in left ventricular structure and function Reduced proximal and distal arterial compliance Prothrombotic tendencies
the number of myocardial infarcts in these patients.1–3 The only plausible explanation for these findings is the presence of additional cardiovascular risk factors, which contribute to the development of coronary artery disease, in these patients. The objective of this manuscript is to show data that suggest that hypertension is an inherited syndrome of cardiovascular risk factors, all of which clinically manifest at different times and all of which contribute to the development of heart disease in these patients (Table 1). Furthermore, there is growing evidence that high blood pressure may be a late manifestation of this disease process. The realization that hypertension is a syndrome may have some important implications for the effective management of this disease process. HYPERLIPIDEMIA It has been well demonstrated that hypertension is commonly associated with hyperlipidemia. Indeed, a linear relationship exists between blood pressure levels and total cholesterol concentrations among young and middle-aged hypertensive individuals.4 Both hypertension and hyperlipidemia are known to be important cardiovascular risk factors. However, when these two risk factors occur together, there is a markedly exaggerated risk of coronary events.5 The explanation for this phenomenon is unclear, but data from animal models of genetic hypertension indicate that vascular smooth muscle cells in these animals bind with greater affinity to low-density lipoprotein than do the smooth muscle cells from normotensive controls.6 The high incidence of hyperlipidemia in hypertensive patients has prompted the belief that high blood pressure may play some role in the genesis of lipid abnormalities in hypertensive patients. However, in a study comparing age-matched, gender-matched, body mass index-matched normotensive subjects with and without a family history of hypertension, the hypertensive-prone patients (patients with a family history) had significantly higher total cholesterol levels than those subjects without a family history of hypertension.7 This would suggest that the lipid abnormalities precede the abnormalities of blood pressure in hyper-
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tensive patients. Thus, it appears that in this patient group, both high blood pressure and hyperlipidemia are inherited, clinically manifest at different times independent of one another, and that both contribute to the development of coronary artery disease in these patients. These data may have important therapeutic implications, as studies using coronary events as the endpoint of treatment of hypertensive patients have shown that simply treating the hypertension alone, or the hypercholesterolemia alone, produce only modest results; only when both problems are treated at the same time is there a marked reduction in coronary disease.8 GLUCOSE AND INSULIN METABOLISM There is good evidence that insulin resistance and hyperinsulinemia are important cardiovascular risk factors. Early evidence linking type II diabetes and atherosclerosis came from the International Atherosclerosis Project.9 Later, in prospective population studies, elevated insulin levels were implicated in the development of coronary artery disease.10,11 The pathophysiology of the relationship between insulin and coronary artery disease is not completely understood, but it has been shown that hyperinsulinemia is associated with increased triglyceridemia and total cholesterol levels and decreased high-density lipoprotein levels.10 Insulin also appears to enhance the participation of atherogenic lipid particles in the formation of vascular plaques by facilitating their transport into the media of the vessel wall.12 Moreover, insulin may directly stimulate vascular smooth muscle proliferation as well as promote the action of other growth factors of vascular tissue.13 Both type I and type II diabetes often coexist with hypertension. There is growing evidence that many hypertensive patients can be characterized as having borderline glucose intolerance and insulin resistance. These patients usually have normal fasting blood glucose concentrations and are not regarded as having clinical diabetes. A large-scale population survey has indicated that approximately 50% of hypertensive patients have glucose intolerance, as measured by plasma glucose levels measured 2 h after glucose load14; this prevalence was far higher than in normotensive controls. The explanation for this finding appears to be resistance to the action of insulin. In a study of well-matched groups of normal volunteers and hypertensive patients given a standard oral glucose tolerance test, there was a tendency for maximum plasma glucose concentrations to be slightly higher in the hypertensive group than in the normal subjects. More impressively, this study showed that the plasma insulin concentrations were significantly higher in the hypertensive patients than in their normotensive
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FIGURE 1. Plasma glucose (left) and insulin (right) concentrations before and during a 75-g oral glucose tolerance test in four groups of subjects. Values are mean 1 SEM.
counterparts during most of the study15 (Figure 1). It appears that insulin resistance and increased insulin levels precede the increases in blood pressure in hypertensive patients. In a study comparing matched normotensive adults with and without a family history of hypertension, insulin levels were significantly higher in patients with a family history of hypertension than in those without.7 Furthermore, the insulin/ glucose ratio, which gives a crude indication of insulin sensitivity, demonstrated that patients with a family history of hypertension were less sensitive to their insulin than patients without a family history.7 Similar findings were reported in a study of young black men. Fasting plasma insulin concentrations were significantly higher in patients with borderline hypertension than in normal controls, and the young hypertensives exhibited a diminished capacity to clear glucose from their plasma.16 This suggests that insulin resistance is also part of the hypertension syndrome. In addition, insulin resistance appears to be genetically inherited and seems to precede high blood pressure in the course of the disease process. Furthermore, insulin may play an important role in the pathogenesis of high blood pressure, both directly by mediating increased sodium retention17,18 and sympathetic drive, and indirectly by its effects on vascular smooth muscle, resulting in decreased arterial compliance and an associated increase in blood pressure.19 LEFT VENTRICULAR HYPERTROPHY AND DIASTOLIC DYSFUNCTION Left ventricular hypertrophy (LVH) is an extremely common finding in hypertensive patients. Echocardiographic data have shown an overall LVH prevalence of 20% in patients with mild hypertension and up to
50% in patients with more severe hypertension.20,21 Left ventricular hypertrophy has been identified as the most powerful risk factor for future cardiovascular events, including myocardial infarction, congestive heart failure, and sudden death.22 The risk of these cardiovascular events increases six- to eightfold in patients with LVH when compared with hypertensive patients without LVH who have similar blood pressures.22,23 Sustained high blood pressure has for many years been implicated as the primary etiology of LVH, although the actual correlation between left ventricular mass and arterial pressure is surprisingly poor.24 However, there is now good evidence that LVH may develop early in the course of hypertension and may actually precede the onset of high blood pressure. In a study of young individuals (aged , 30 years) with mild hypertension, it was found that approximately half of these patients has septal and posterior wall thickness greater than the highest values found in an aged-matched control group.25 Interestingly, subsequent blood pressure measurements indicated that many of these young hypertensive patients had normal or borderline blood pressure values. However, the echocardiographic wall thickness in this subgroup was increased and was not different from that of those patients who were truly hypertensive. In a separate study, which compared the echocardiographic findings in normotensive children of normotensive parents with those of aged-matched, gender-matched normotensive children of hypertensive parents, the offspring from hypertensive families had significantly greater left ventricular wall thickness and muscle than those from normotensive families.26 These findings suggest that although high blood pressure may facilitate the progression of LVH in
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patients with underlying abnormalities in the myocardial smooth muscle, in some patients there are other factors that play a role in the development of the LVH, which may develop several years before the onset of high blood pressure. The changes in left ventricular mass are frequently associated with changes in ventricular function. These functional changes are frequently referred to as diastolic dysfunction and occur usually as a consequence of decreased left ventricular compliance. Transmitral flow characteristics, measured by Doppler echocardiography, have been used as an index of left ventricular filling during diastole. An increased ratio of late filling (atrial component) to early filling (early peak flow velocity) reflects individual compliance of the left ventricular wall. Indices of diastolic function have been shown to correlate significantly with left ventricular muscle mass in hypertensive patients, suggesting that there are functional consequences associated with early hypertrophy.27 Because LVH frequently precedes the onset of high blood pressure it is not surprising that diastolic function can also occur before the onset of increased blood pressure. In a group of normotensive male college students matched for age and left ventricular muscle mass, subjects with a family history of hypertension had delayed diastolic filling compared with those who did not have a family history of hypertension.28 Thus, changes in ventricular structure and function also constitute part of the hypertension syndrome. These changes may occur before the onset of high blood pressure and appear to be genetically determined in these patients; it may predispose them to the development of heart disease early in the course of their disease process. ARTERIAL COMPLIANCE Hypertension is characterized by structural changes in the arterial circulation. Hypertrophy and hyperplasia of the arterial walls, linked to increased laying down of connective tissues, are common findings in hypertensive patients.29 These changes result in stiffening of the arterial walls and decreased compliance of the arteries. Comparisons of normotensive and hypertensive patients have established that cardiovascular compliance is not necessarily linked to increases in blood pressure. On the contrary, there is growing evidence that abnormalities in arterial compliance precede the abnormalities in blood pressure and may not worsen with increasing blood pressure.30 In a study comparing normotensive children with a family history of hypertension with matched normotensive children without a family history of hypertension, the offspring of hypertensive parents had de-
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FIGURE 2. Measurements of distal and proximal compliance in normal volunteers (DBP , 90 mm Hg), and in patients with borderline (DBP 90 to 99 mm Hg) or established (DBP . 100 mm Hg) hypertension. Values are mean 1 SEM.
creased forearm blood flow in response to acetylcholine stimulation, indicating abnormalities of vascular function early in the course of the disease process.31 In a separate study using pulse contour analysis to calculate proximal (large vessel) and distal or reflective (small vessel) compliance, it was demonstrated that the major changes in compliance, both proximal and distal, coincide with the time period that blood pressure increases from normal to borderline elevated. There are no further changes in the distal compliance as blood pressure increases from borderline levels to overt hypertension, with only small changes in proximal compliance32 (Figure 2). There are thus compelling data to suggest that the changes in vascular structure and function precede the changes in blood pressure. Furthermore, as decreased arterial compliance results in increasing blood pressure, these early changes in compliance may play an important role in the pathogenesis of high blood pressure.33 Recent observations have suggested that neuroendocrine and hormonal factors may be responsible for these early changes in arterial compliance. In patients with reduced arterial compliance, the changes in compliance have been shown to correlate with increased plasma concentrations of insulin, triglycerides, total cholesterol, norepinephrine, and plasma renin activity
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FIGURE 3. A) Plasma immunoreactive insulin levels in patients with normal (. 1.65 mL/mm Hg) and reduced (, 1.65 mL/mm Hg) proximal arterial compliance and in patients with normal (. 0.035 mL/mm Hg) arterial compliance. Values are mean 1 SEM. B) Plasma concentrations of triglycerides, total cholesterol, and high-density lipoprotein cholesterol in patients with normal (. 1.65 mL/mm Hg) and reduced (, 1.65 mL/mm Hg) proximal arterial compliance. Plotted values are mean 1 SEM.
(Figure 3).34 These factors, by hypertrophy of vascular wall smooth muscle and by deposition of lipid and collagen in the media of the vessel wall, may clearly have an impact on vascular structure and function, independent of blood pressure. In addition to causing increases in blood pressure, the vessel wall changes may be the starting point of early atheromatous plaque formation. It may thus be argued that decreases in arterial compliance, independent of blood pressure, may be an early and important cardiovascular risk factor in hypertensive patients. First, changes in wall structure create the environment for lipid deposit and early plaque formation, which may be important in the development of cardiovascular disease. Second, arterial compliance is a powerful predictor of endothelial reliance of von Willebrand Factor (VWF) and tissue plasminogen activator.35 Elevated levels of VWF have been described in patients with prothrombotic tendencies, including those with acute myocardial infarction.35 Third, decreased compliance is associated with increased blood pressure. Thus, the changes that occur in the vessel walls (similar to those that occur in the ventricle), are also an early and inherited part of the hypertension syndrome, frequently preceding the changes in blood pressure, and may also play a pivotal role in the pathogenesis of high blood pressure and cardiovascular disease in these patients.
OBESITY Obesity is a more common finding in hypertensive patients than in matched normotensive patients, and it is estimated that approximately 40% of the hypertensive patients in the United States are obese. In the majority of patients, the obesity precedes the onset of hypertension and may contribute to the development of high blood pressure in these patients. Obesity is associated with metabolic complications considered to be risk factors for cardiovascular disease, including insulin resistance, hyperinsulinemia, glucose intolerance, high blood pressure, and changes in the concentration of plasma lipids and lipoproteins.26,36 –38 Only recently has truncal obesity, characterized by a large waist-to-hip ratio (apple-shaped obesity), been recognized to predict the risk of coronary artery disease.39 Based on the efficacy of weight loss and exercise in reducing blood pressure,40 it has been speculated that insulin provides the link between obesity and increased sympathetic nervous system activity. RENAL CHANGES For many years, it was believed that renal changes in hypertensive patients occurred as a consequence of high blood pressure. However, with recent interest in mild forms of hypertension, early changes in renal function have been observed. Studies have demonstrated that there are differences in renal functional
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FIGURE 4. Plasma immunoreactive insulin levels (A), insulin/glucose ratios (B), plasma norepinephrine levels (C), and plasma renin activity (D) in normotensive (NT) and hypertensive (HT) subjects with and without a family history of hypertension. Differences shown are between the control group (NT with no family history of hypertension) and each of the other three groups. Values are mean 1 SEM. Black bar, no family history; white bar, family history.
reserve in children of normotensive parents compared with children of hypertensive parents.40 Thus, despite apparently normal renal function, the children of hypertensive parents appeared to be less able than the children of normotensive parents to increase their creatinine clearance in response to protein loading and were also more likely to exhibit microalbuminurea.41 These data were confirmed in a later study that demonstrated increased microalbuminurea in normotensive adults with a family history of hypertension than matched normotensive adults without a family history of hypertension.7 These data suggest that renal changes in hypertensive patients may also occur early in the course of the disease and may contribute to the development of high blood pressure. Furthermore, it appears that other factors, distinct from blood pressure, play a role in the pathogenesis of renal changes in hypertensive patients. ENDOCRINE CHANGES The sympathetic nervous system and the renin angiotensin system are thought to be pivotal in causing high
blood pressure. However, studies have shown that plasma norepinephrine levels and plasma renin activity were significant elevated in the normotensive offspring of hypertensive parents.7 It is interesting that these increases in neuroendocrine levels occur before the development of high blood pressure and that in hypertension-prone patients with significantly elevated norepinephrine and angiotensin II, levels can be normotensive. These findings suggest that the hypertensive effect of these hormonal systems are not entirely due to their vasoconstrictor properties but may also be due to their influence on the structure and compliance of cardiovascular smooth muscle. SUMMARY As has been shown, there is compelling evidence that many of the cardiovascular risk factors that are associated with hypertension, and which play a major role in the development of cardiovascular disease, occur long before these patients develop high blood pressure. It is thus possible that these patients have myocardial infarctions before the onset of high blood pres-
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sure and may then never develop high blood due to their damaged myocardium. In a study comparing cardiovascular risk factors in normotensive subjects with a family history of hypertension with those of hypertensive patients—with and without a family history of hypertension—there were no differences among the groups. All three groups, however, had significantly more cardiovascular risk factors than normotensive subjects without a family history of hypertension. Thus, in terms of cardiovascular risk these “normotensive hypertensive” (hypertensive-prone) patients were at equal risk of developing cardiovascular disease as were the hypertensive subjects, the only difference being that they had not, as yet, developed the high blood pressure (Figure 4). Thus, it would appear that a major problem in the management of hypertension is that the tool we use to isolate these patients, high blood pressure, is a late manifestation of a much broader inherited syndrome of cardiovascular risk factors, and that much of the damage that occurs in these patients is present prior to the onset of high blood pressure. It is possible, although not proven, that the development of high blood pressure may represent a late and irreversible stage of cardiovascular damage in these patients and that earlier intervention may be necessary to reverse the disease process. The existence of the hypertension syndrome has some important diagnostic and therapeutic implications, which may be necessary to consider to decrease coronary artery disease in hypertensive patients. First, we need a tool that will enable us to diagnose this syndrome early on in the disease process and, second, we need to treat hypertension in such a way that all the associated risk factors are included in our treatment plan. The reduction of strokes and overall mortality in treated hypertensive patients warrants our continued enthusiasm for treating high blood pressure, and improved performance in reducing other cardiovascular risk factors would add to the benefits of antihypertensive therapy. Perhaps treating this disease as a syndrome rather than a number will result in a reduction in the incidence of coronary heart disease, similar to that demonstrated for strokes. REFERENCES 1.
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