Insulin Resistance/Compensatory Hyperinsulinemia, Essential Hypertension, and Cardiovascular Disease
Gerald M. Reaven
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305
Address all correspondence and requests for reprints to: Gerald Reaven, M.D., Falk Cardiovascular Research Center, Stanford Medical Center, 300 Pasteur Drive, Stanford, California 94305. E-mail: greaven{at}cvmed.stanford.edu.
 |
Introduction
|
---|
In 1966, Welborn et al. (1) studied 19 nondiabetic patients with essential hypertension and demonstrated that these individuals had significantly higher plasma insulin concentrations compared with a normotensive control group. Although these observations suggested that the prevalence of resistance to insulin-mediated glucose disposal would be increased in patients with essential hypertension, it wasnt until approximately 20 yr later that several research groups demonstrated that this was the case (2, 3, 4, 5, 6, 7). Although the relationship between insulin resistance, hyperinsulinemia, and essential hypertension has been extensively studied in the past 15 yr, questions continue to be raised as to the nature of the link between these variables. Indeed, there is not even consensus as to whether or not there is a physiological relationship between insulin resistance/compensatory hyperinsulinemia and blood pressure regulation.
Another issue, and perhaps of greater clinical relevance, is whether the insulin resistance/compensatory hyperinsulinemia that is frequently present in patients with essential hypertension plays any role in the increased prevalence of cardiovascular disease (CVD) that is the major cause of morbidity and mortality in this clinical syndrome.
The goals of this review are to address both of these issues. To begin with, the evidence in support of a role for insulin resistance and compensatory hyperinsulinemia in the pathogenesis of essential hypertension will be summarized. In addition, an argument will be made that insulin resistance and its manifestations play major roles in the development of CVD in patients with essential hypertension. In both instances, only experimental evidence obtained in human beings will be considered. Finally, although it remains an issue of major scientific importance, a discussion of the possible mechanistic links between insulin resistance and hyperinsulinemia will not be addressed.
 |
The role of insulin resistance and compensatory hyperinsulinemia in the pathogenesis of essential hypertension?
|
---|
Although there is substantial evidence that patients with essential hypertension are insulin resistant/hyperinsulinemic compared with normotensive individuals (2, 3, 4, 5, 6, 7), some population-based studies have not been able to discern a significant relationship between insulin resistance and hyperinsulinemia (8, 9, 10). In an effort to resolve these apparently discordant results, the European Group for the Study of Insulin Resistance examined the relationship between a specific measure of insulin-mediated glucose disposal, fasting insulin concentration, and blood pressure in 333 normotensive individuals, studied in 20 different clinical research centers (11). The results indicated that blood pressure was directly related to both insulin resistance and insulin concentration. Furthermore, these relationships were independent of differences in age, gender, and degree of obesity.
The size of the European study, in addition to its use of a direct measure of insulin action, as contrasted to surrogate estimates, provides strong evidence that there is a relationship between insulin resistance, hyperinsulinemia, and blood pressure. However, it does not establish the causal nature of the observed link. For example, it could be argued that hypertension per se will lead to insulin resistance/hyperinsulinemia, rather than vice versa. However, there is considerable evidence that this is unlikely. At the simplest level, the prevalence of insulin resistance is not increased in patients with secondary forms of hypertension (12, 13). In addition, insulin resistance/hyperinsulinemia exist in normotensive, first-degree relatives of patients with essential hypertension (14, 15, 16, 17, 18). Furthermore, results of several prospective studies in which hyperinsulinemia has been used as a surrogate marker of insulin resistance support the view that insulin resistance/compensatory hyperinsulinemia are causally linked to the development of essential hypertension (19, 20, 21, 22, 23). The study that seems most relevant to this review was performed by Skarfors et al. (19), who evaluated risk factors for the development of hypertension in 2130 men observed over a 10-yr period. Not surprisingly, they found that baseline blood pressure was the strongest predictor of the development of hypertension. In addition, baseline characteristics of normotensive men who became hypertensive were compared with individuals who remained normotensive. The analysis showed that individuals who subsequently developed hypertension were more obese, had higher plasma insulin (fasting and after iv glucose) and triglyceride (TG) concentrations. When baseline blood pressure was excluded from multivariate analysis, independent predictors of the progression to hypertension were obesity (as estimated by body mass index), fasting and postglucose challenge plasma insulin concentrations, and a family history of hypertension.
A somewhat similar prospective study was performed by Lissner et al. (20), who evaluated risk factors for the development of hypertension in 278 women followed over a 12-yr period. In addition, they examined the relationship between blood pressure and risk factors in 219 women not receiving antihypertensive medication. Hypertension developed in approximately one third of the population in the 12-yr period. In multiple logistic regression analysis, fasting plasma insulin concentration was found to be a predictor of the transition from normal to high blood pressure, independent of adjustments for initial body mass index, waist/hip ratio, and weight gain. The finding that the upper quartile in terms of fasting plasma insulin concentration was greater than 3-fold more likely to develop hypertension than those in the lowest quartile further emphasized the power of hyperinsulinemia as a predictor of the development of essential hypertension. Essentially similar conclusions were observed when changes in blood pressure over the 12-yr period were considered as a continuous variable.
The ability of insulin to predict changes in blood pressure over time has also been shown in Finnish children and adolescents (21). The ages of the study population ranged from 318 yr at baseline, and they were followed for 16 yr. The results of this study indicated that fasting insulin concentrations "seem to regulate actual blood pressure within the normal range and to predict future blood pressure." It was also pointed out that these conclusions applied to boys and girls and were independent of differences in age and weight.
Essentially similar conclusions were reached from a somewhat more complicated study of 1865 children and adolescents, followed over a 6-yr period (22). In general, the results of this study demonstrated that the higher the fasting insulin concentration at baseline, the greater the increase in blood pressure over the 6-yr period of observation. Perhaps of greater interest was the finding that "high insulin levels seems to precede the development of a potentially atherogenic risk factor profile including low high-density lipoprotein cholesterol (HDL-C), high TG, and high systolic blood pressure."
Despite the evidence summarized above as to the role played by insulin resistance/compensatory hyperinsulinemia in the pathogenesis of hypertension, interpretations of the results of statistical analyses of population-based studies continue to question the existence of this relationship. More specifically, when the statistical technique of factor analysis is used to evaluate the relationship between insulin resistance and conditions thought to be related to it, blood pressure appears to be a factor separate from the other cluster of abnormalities that associate with insulin resistance and/or hyperinsulinemia (24). Although these findings are usually interpreted to signify the lack of an independent relationship between insulin resistance/hyperinsulinemia, the etiological and clinical heterogeneity of patients with essential hypertension provides a most obvious reason why this conclusion is suspect. Resistance to insulin-mediated glucose disposal and compensatory hyperinsulinemia are continuous variables (25), not dichotomous ones, and there is no simple way to classify a person as being insulin resistant or insulin sensitive. We have tried to estimate the number of patients with essential hypertension who are insulin resistant by measuring blood pressure and the plasma insulin response 120 min after a 75-g oral glucose challenge in an unselected population of 732 factory workers (26). As a result of this survey, 41 individuals were identified as having essential hypertension. Figure 1
illustrates the distribution of the plasma insulin responses to the glucose challenge of the 41 hypertensive individuals and those of 41 participants in the same survey with normal blood pressure. The two groups were matched for gender, degree of obesity, ethnic background, type of employment in the factory, and level of physical activity. Only 10% of the normotensive subjects had plasma insulin concentrations 120 min after the oral glucose challenge greater than 80 mU/liter, compared with 45% of the patients with essential hypertension. On the basis of these and other findings (7), approximately 50% of patients with essential hypertension can be considered to be insulin resistant and hyperinsulinemic.

View larger version (24K):
[in this window]
[in a new window]
|
Figure 1. Frequency distribution of the plasma insulin response 2 h after a 75-g oral glucose challenge in normotensive and hypertensive factory workers. [Reproduced with permission from I. Zavaroni et al.: J Intern Med 231:235240, 1992 (26 )].
|
|
The observation that only approximately 50% of patients with high blood pressure are insulin resistant/hyperinsulinemic helps explain why controversy continues as to whether or not insulin resistance contributes to the development of essential hypertension. At the simplest level, it should not be surprising that population-based studies, in which surrogate markers of insulin resistance are applied to primarily normotensive individuals, would have difficulty in discerning a relationship between insulin resistance and blood pressure. When the fact that at least half the patients with essential hypertension are not insulin resistant is added to these confounding variables, it is not difficult to understand why studies based on the use of factor analysis find that blood pressure does not segregate with whatever surrogate measures of insulin resistance are being used. However, these findings do not speak to the 50% of patients with essential hypertension that are insulin resistant/hyperinsulinemic, and in these individuals it is very likely that the abnormality in insulin-mediated glucose disposal and the consequences of this defect play an important role in the genesis of the increase in blood pressure, as well as the clinical outcome of patients with essential hypertension. It must be remembered that the results of population-based studies that conclude that insulin resistance is not related to the development of essential hypertension do not negate the observations that: 1) the prevalence of insulin resistance/hyperinsulinemia is increased in patients with essential hypertension; 2) these changes can be seen in normotensive, first-degree relatives of patients with essential hypertension; and 3) insulin resistance/hyperinsulinemia have been shown in prospective studies to be independent predictors of the development of essential hypertension. The fact that insulin resistance/hyperinsulinemia do not contribute to the etiology of essential hypertension in some individuals should not obscure the conclusion based on extensive data that it does in others. Furthermore, and perhaps of greater relevance, as will be discussed in the next section, it is the subset of patients that are both hypertensive and insulin resistant that are by far at the greatest CVD risk.
 |
Insulin resistance/compensatory hyperinsulinemia and CVD
|
---|
The advent of more effective antihypertensive drugs has greatly decreased morbidity and mortality in patients with high blood pressure. However, the clinical benefit of lowering blood pressure has been much more dramatic in decreasing risk of stroke compared with CVD (27). Because CVD is the major cause of morbidity and mortality in patients with hypertension, this apparent paradox has received a great deal of attention. Not surprisingly, many different explanations have been proposed to account for this finding. For example, it has been argued that stroke is more directly related to blood pressure than is heart attack, and that the apparent difference in outcome is a function of the relatively short duration of the intervention trials. Another suggestion has been that thiazide diuretics and/or ß-receptor antagonists, the drugs used in the controlled clinical trials, are associated with adverse changes in carbohydrate and lipid metabolism that tended to mitigate their beneficial effect on blood pressure. Although this may be true to some extent, there is a much simpler explanation for the observation that the beneficial effect of lowering blood pressure on CVD risk was less than might have been anticipated. As emphasized above (26), no more than half of the patients with essential hypertension are insulin resistant/hyperinsulinemic, and exhibit the cluster of CVD risk factors common to individuals with the insulin resistance syndrome (IRS). Thus, the subset of patients with essential hypertension that are also insulin resistant are likely to have some degree of glucose intolerance, as well as the atherogenic lipoprotein phenotype characteristic of individuals with the IRS: high TG and low HDL-C concentrations, smaller and denser LDL particles, and an exaggerated degree of postprandial lipemia (28). Furthermore, there is evidence that it is these patients in whom essential hypertension is present as a component of the IRS that are at the greatest CVD risk (29, 30, 31). For example, Fig. 2
compares the plasma glucose and insulin concentrations in response to a 75-g oral glucose challenge in untreated patients with essential hypertension, without clinical evidence of CVD, who have ischemic heart disease by Minnesota Code criteria, with those of healthy volunteers, as well as a matched group of equally hypertensive individuals with normal electrocardiograms (29). It is apparent that the patients with essential hypertension with electrocardiographic evidence of CVD were somewhat glucose intolerant and hyperinsulinemic compared with either the normotensive control group or those with normal electrocardiograms. Not surprisingly, measurement of insulin-mediated glucose disposal demonstrates that the patents with essential hypertension and ischemic electrocardiographic changes were also insulin resistant. In addition, the patients with high blood pressure and abnormal electrocardiograms were also significantly more dyslipidemic (higher plasma TG and lower HDL-C concentrations) compared with normotensive individuals or hypertensive patients with normal electrocardiograms. The existence of these CVD risk factors in the hypertensive patients with abnormal electrocardiograms was seen in the absence of pharmacological treatment of their high blood pressure. Furthermore, the magnitude of the abnormalities in insulin, glucose, and lipid metabolism when present in patients with high blood pressure is much greater than the untoward effect of any antihypertensive treatment (32). Finally, lowering blood pressure with antihypertensive treatment does not return these metabolic abnormalities to normal (5, 6).

View larger version (22K):
[in this window]
[in a new window]
|
Figure 2. Plasma glucose and insulin responses to a 75-g oral glucose challenge in normal volunteers, patients with essential hypertension with normal electrocardiograms, and patients with essential hypertension and electrocardiographic evidence of ischemic heart disease. [Reproduced with permission from W.W.-H. Sheuh et al.: Am J Hypertens 5:444448, 1992 (29 )].
|
|
The importance of the link between the dyslipidemia present in insulin resistant/hyperinsulinemic patients with essential hypertension and CVD has received considerable additional support from two recent reports from the Copenhagen Male Study. In the first publication, Jeppesen et al. (30) evaluated the hypothesis that blood pressure would be less predictive of CVD in individuals with the characteristic dyslipidemia of the IRSa high TG and a low HDL-C concentrationthan in those without these changes in lipid metabolism. Their results were consistent with the proposed hypothesis in that the development of CVD in individuals with a high TG and low HDL-C concentration was independent of differences in baseline systolic or diastolic blood pressure. In contrast, the higher either systolic (P < 0.001) or diastolic (P < 0.03) blood pressure was at the beginning of the study, the greater the incidence of CVD in those without the dyslipidemia of the IRS.
In a second study (31), the 2906 participants enrolled in the Copenhagen Male Study were divided into three groups on the basis of their fasting plasma TG and HDL-C concentrations. Individuals, whose plasma TG and HDL-C concentrations were in the upper third or lower third, respectively, of the whole population, were assigned to the high TG-low HDL-C group. At the other extreme, a low TG-high HDL-C group was composed of those individuals whose plasma TG and HDL-C concentrations were in the lower third and upper third, respectively, of the study population for these two lipid measurements. The intermediate group consisted of those participants whose lipid values did not qualify them for either of the two extreme groups. The investigators then defined the interaction between TG-HDL-C group and four conventional CVD risk factors: smoking, sedentary lifestyle, hypercholesterolemia, and essential hypertension. Irrespective of which of the four conventional CVD risk factors were considered, there was an approximate 23 times higher risk of CVD in those in the high TG-low HDL-C group. It was also demonstrated that the incidence of CVD in the face of any of the four conventional CVD risk factors was less than 5% during the 8-yr period of observation, as long as the individual with one of the conventional risk factors was also in the lowest TG-highest HDL-C group.
It should be emphasized that Jeppesen et al. (30, 31) used a high plasma TG and low HDL-C concentration as a marker of the IRS, without necessarily suggesting that these specific changes in lipoprotein metabolism were the total explanation of why CVD risk was increased in this subset of the population with essential hypertension. There is no reason to suspect that the hyperinsulinemia, glucose intolerance, dyslipidemia, and prothrombotic state associated with the IRS will not contribute to the increased CVD risk in those patients with essential hypertension that are also insulin resistant (33). In addition, changes in endothelial function that might contribute to increased CVD risk also vary as a function of differences in insulin-mediated glucose disposal in patients with essential hypertension. For example, the first step in the process of atherogenesis is the binding of circulating mononuclear cells to the endothelium (34), and the data in the right panel of Fig. 3
indicate that the binding of mononuclear cells isolated from patients with hypertension is directly related to their degree of insulin resistance as quantified by the steady state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide, insulin, and glucose (35). Indeed, it can be seen by comparing the two panels of Fig. 3
that the relationship between SSPG concentration and binding of isolated mononuclear cells to endothelium was similar in normotensive and hypertensive volunteers in that the more insulin resistant an individual (the higher the SSPG concentration), the greater the adherence of their isolated mononuclear cells to endothelium.

View larger version (19K):
[in this window]
[in a new window]
|
Figure 3. Relationship between the SSPG concentration and the adherence of mononuclear cells isolated from the plasma of normal volunteers and patients with essential hypertension to cultured endothelial cells. The SSPG concentration is the average of four measurements of plasma glucose concentration obtained during the last 30 min of a 180-min infusion of somatostatin, glucose, and insulin; the higher the SSPG concentration, the more insulin resistant the individual.
|
|
Essentially identical findings were observed when the relationship between plasma asymmetric dimethylarginine (ADMA) concentration and insulin-mediated glucose disposal was evaluated (36). Plasma concentrations of ADMA, an endogenous inhibitor of nitric oxide synthase, have been shown to be predictive of CVD in several clinical syndromes (37), and Fig. 4
depicts the relationship between SSPG concentration (the specific measurement of insulin resistance) and plasma ADMA concentrations in normal volunteers (left panel) and patients with essential hypertension (right panel). It is apparent that plasma ADMA and SSPG concentrations varied widely in both experimental groups, but it is also obvious that the elevations in plasma ADMA concentrations are associated with higher SSPG concentrations (greater degrees of insulin resistance). Thus, plasma ADMA concentrations are increased to a similar degree in insulin-resistant individuals, whether they are normotensive or hypertensive.

View larger version (22K):
[in this window]
[in a new window]
|
Figure 4. Relationship between the SSPG concentration and plasma concentration of ADMA concentrations in normotensive and hypertensive individuals. The SSPG concentration is obtained as described in Fig. 3 .
|
|
 |
Conclusion
|
---|
There is a large body of experimental evidence that insulin resistance and compensatory hyperinsulinemia are increased in prevalence in patients with essential hypertension, and similar changes can be seen in first-degree relatives of patients with essential hypertension. In addition, insulin resistance and/or compensatory hyperinsulinemia have also been shown in several large, prospective, population-based studies to predict the development of essential hypertension. However, not all patients with essential hypertension are insulin resistant/hyperinsulinemic, and it is obvious that the increase in blood pressure in these individuals is unrelated to any change in insulin action. It is this heterogeneity in the multiple factors that increases the likelihood of a person developing hypertension that almost certainly accounts for the continuing argument as to whether or not insulin resistance/hyperinsulinemia play a role in the etiology of essential hypertension. On the other hand, the fact that insulin resistance does not provide a unitarian hypothesis to account for the etiology of essential hypertension should not obscure the large amount of evidence of the importance of insulin resistance, and its metabolic consequences, in both the pathogenesis and clinical course of perhaps as many as half of the patients with essential hypertension.
 |
Footnotes
|
---|
Abbreviations: ADMA, Asymmetric dimethylarginine; CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; IRS, insulin resistance syndrome; SSPG, steady state plasma glucose; TG, triglyceride.
Received January 17, 2003.
Accepted March 3, 2003.
 |
References
|
---|
- Welborn TA, Breckenridge A, Rubinstein AH, Dollery CT, Fraser TR 1966 Serum-insulin in essential hypertension and in peripheral vascular disease. Lancet 1:11361137[Medline]
- Lucas CP, Estigarribia JA, Darga LL, Reaven GM 1985 Insulin and blood pressure in obesity. Hypertension 7:702706[Abstract]
- Modan M, Halkin H, Almog S, Lusky A, Eshkil A, Shefi M, Shitrit A, Fuchs A 1985 Hyperinsulinemia: a link between hypertension, obesity and glucose intolerance. J Clin Invest 75:809817[Medline]
- Ferrannini E, Buzzigoli G, Bonadona R 1987 Insulin resistance in essential hypertension. N Engl J Med 317:350357[Abstract]
- Shen D-C, Shieh S-M, Fuh M, Wu D-A, Chen Y-DI, Reaven GM 1988 Resistance to insulin-stimulated glucose uptake in patients with hypertension. J Clin Endocrinol Metab 66:580583[Abstract]
- Swislocki ALM, Hoffman BB, Reaven GM 1989 Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am J Hypertens 2:419423[Medline]
- Pollare T, Lithell H, Berne C 1990 Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism 39:167174[Medline]
- Mbanya J-C, Wilkinson R, Thomas T, Alberti K, Taylor R 1988 Hypertension and hyperinsulinemia: a relation in diabetes but not in essential hypertension. Lancet I:733734
- Collins VR, Dowse GK, Finch CF, Zimmet PZ 1990 An inconsistent relationship between insulin and blood pressure in three Pacific Island populations. J Clin Epidemiol 43:13691378[Medline]
- Saad MF, Lillioja S, Nyomba BL, Castillo C, Ferraro R, DeGregorio M, Ravussin E, Knowler WC, Bennett PH, Havard VV, Bogardus C 1991 Racial differences in the relation between blood pressure and insulin resistance. N Engl J Med 324:733739[Abstract]
- Ferrannini E, Natali A, Capaldo B, Lehtovirta M, Jacob S, Yki-Järvinen H, for the European Group for the Study of Insulin Resistance (EGIR) 1992 Insulin resistance, hyperinsulinemia, and blood pressure. Role of age and obesity. Hypertension 30:11441149
- Marigliano A, Tedde R, Sechi LA, Para A, Pisanu G, Pacifico A 1990 Insulinemia and blood pressure: relationships in patients with primary and secondary hypertension, and with or without glucose metabolism impairment. Am J Hypertens 3:521526[Medline]
- Shamiss A, Carroll J, Rosenthall T 1992 Insulin resistance in secondary hypertension. Am J Hypertens 5:2628[Medline]
- Ferrari P, Weidmann P, Shaw S, Giachino D, Riesen W, Allemann Y, Heynen G 1991 Altered insulin sensitivity, hyperinsulinemia and dyslipidemia in individuals with a hypertensive parent. Am J Med 91:589596[Medline]
- Facchini F, Chen Y-DI, Clinkingbeard C, Jeppesen J, Reaven GM 1992 Insulin resistance, hyperinsulinemia, and dyslipidemia in nonobese individuals with a family history of hypertension. Am J Hypertens 5:694699[Medline]
- Allemann Y, Horber FF, Colombo M, Ferrari P, Shaw S, Jaeger P, Weidman P 1993 Insulin sensitivity and body fat distribution in normotensive offspring of hypertensive parents. Lancet 341:327331[Medline]
- Ohno Y, Suzuki H, Yamakawa H, Nakamura M, Otsuka K, Saruta T 1993 Impaired insulin sensitivity in young, lean normotensive offspring of essential hypertensive: possible role of disturbed calcium metabolism. J Hypertens 11:421426[Medline]
- Beatty OL, Harper R, Sheridan B, Atkinson AB, Bell PM 1993 Insulin resistance in offspring of hypertensive parents. BMJ 307:9296[Medline]
- Skarfors ET, Lithell HO, Selinus I 1991 Risk factors for the development of hypertension: a 10-year longitudinal study in middle-aged men. J Hypertens 9:217223[Medline]
- Lissner L, Bengtsson C, Lapidus L, Kristjansson K, Wedel H 1992 Fasting insulin in relation to subsequent blood pressure changes and hypertension in women. Hypertension 20:797801[Abstract]
- Taittonen L, Uhari M, Nuutinen M, Turtinen J, Pokka T, Akerblom HK 1996 Insulin and blood pressure among healthy children. Am J Hypertens 9:193199[CrossRef]
- Raitakari OT, Porkka KVK, Rönnemaa T, Knip M, Uhari M, Akerblom HK, Viikari JSA 1995 The role of insulin in clustering of serum lipids and blood pressure in children and adolescents. Diabetologia 38:10421050[CrossRef][Medline]
- Zavaroni I, Bonini L, Gasparini P, Barilli AL, Zuccarelli A, DallAglio E, Delsignore R., Reaven GM 1994 Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: The Barilla factory revisited. Metabolism 48:989994
- Meigs JB 2000 Invited commentary: insulin resistance syndrome? Syndrome X? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 152:908911[Abstract/Free Full Text]
- Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM 2000 Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy, nondiabetic volunteers. Diabetes Care 23:171175[Abstract]
- Zavaroni I, Mazza S, DallAglio E, Gasparini P, Passeri M, Reaven GM 1992 Prevalence of hyperinsulinaemia in patients with high blood pressure. J Intern Med 231:235240[Medline]
- Collins R, Peto R, MacMahon S, Herber P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH 1990 Blood pressure, stroke and coronary heart disease. Pt. 2. Short-term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet 335:827838[Medline]
- Reaven GM 1991 Relationship between insulin resistance and hypertension. Diabetes Care 14:3338[Medline]
- Sheuh WH-H, Jeng C-Y, Shieh S-M, Fuh MM, Shen DD, Chen Y-DI, Reaven GM 1992 Insulin resistance and abnormal electrocardiograms in patients with high blood pressure. Am J Hypertens 5:444448[Medline]
- Jeppesen J, Hein HO, Suadicani P, Gynelberg F 2000 High triglycerides and low HDL cholesterol and blood pressure and risk of ischemic heart disease. Hypertension 36:226239[Abstract/Free Full Text]
- Jeppesen J, Hein HO, Suadicani P, Gynterberg F 2001 Low triglycerides-high high-density lipoprotein cholesterol and risk of ischemic heart disease. Arch Int Med 361366
- Reaven GM 1993 Treatment of hypertension; focus on prevention of coronary heart disease. J Clin Endocrinol Metab 76:537540[Medline]
- Reaven GM 2002 Insulin resistance, compensatory hyperinsulinemia, and coronary heart disease: syndrome X. In: Sobell BE, Schneider DJ, eds. Medical management of diabetes and heart disease. New York: Mercel Dekker, Inc.; 117136
- Ross R 1986 The pathogenesis of atherosclerosis. N Engl J Med 314:488500[Medline]
- Chen N-G, Abbasi F, Lamendola C, McLaughlin T, Cooke JP, Tsao PS, Reaven GM 1999 Mononuclear cell adherence to cultured endothelium is enhanced by hypertension and insulin resistance in healthy nondiabetic volunteers. Circulation 100:940943[Abstract/Free Full Text]
- Stuhlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP, Reaven GM, Tsao PS 2002 Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287:14201426[Abstract/Free Full Text]
- Vallance P 2001 Importance of asymmetrical dimethylarginine in cardiovascular risk. Lancet 358:20962097[CrossRef][Medline]