Essential hypertension, metabolic disorders, and insulin resistance

Essential hypertension, insulin resistance

metabolic

disorders,

and

Essential hypertension is frequently associated with several metabolic abnormalities, of which obesity, glucose intolerance, and dyslipidemia are the most common. This report discusses the epidemiologic evidence for the coexistence of these risk factors and questions why hyperinsulinemia and essential hypertension cosegregate. The euglycemic insulin clamp and the insulin suppression test are documented with respect to the physiologic functions of insulin, and the mechanisms of insulin resistance in essential hypertension are dlscussed. Evidence to suggest that insulin resistance is a marker for an “atherogenic syndrome” is reviewed. It is concluded that all the hemodynamic and metabolic disorders of essential hypertension and insulin resistance are closely related. The clinical approach to the patient with any of the abnormalities in question should take into consideration the whole cluster, with therapy aimed at ameliorating the entire hemodynamic-metabolic profile. (AM HEART J 1991;121:1274-82.)

Eleuterio

Ferrannini,

MD, and Andrea Natali,

MD Piss, Italy

Many physicians are so convinced of the importance of lowering blood pressure in their hypertensive patients that hypertension, at least in the Western world, appears to be a slightly overtreated condition. As recently reviewed,l this attention toward blood pressure is probably fueled by the results of some important prospective studies, which have emphasized the role of high blood pressure as one of the major risk factors for atherosclerotic vascular disease. These data predicted that significant benefits, in terms of survival and morbidity, would follow the lowering of blood pressure in the hypertensive patient. When this hypothesis was directly tested by long-term controlled clinical trials, the actual benefits of several antihypertensive regimens appeared to be limited to subgroups of hypertensive patients, or to be confined to cerebrovascular but not to cardiovascular events. The partial failure of antihypertensive management in general has been attributed to the metabolic adverse side effects of many drugs, particularly thiazide diuretics and P-blockers. This explanation is certainly based on good evidence, but probably focuses on only one aspect of a longer story. Essential hypertension per se is frequently associated with From the Metabolism Unit the University of Pisa.

of the C.N.R.

Institute

Reprint requests: Eleuterio Ferrannini, MD, Physiology, Via Savi 8, 56100 Pisa, Italy. 4/O/26959

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Physiology of Clinical

at

several metabolic abnormalities, among which obesity, glucose intolerance, and dyslipidemia are the most common. The nature and origin of these irregularities in glucose and lipid metabolism are still uncertain, but their impact on the risk of ischemic cardiovascular disease is extensively documented.2* 3 This report attempts to discuss the metabolic changes of essential hypertension, in particular with relation to the role of insulin resistance. EPIDEMIOLOGY

As a group, hypertensive individuals appear to be remarkably different from their normotensive counterparts in more than just high blood pressure. In fact, they are more obese and less tolerant to glucose, have a higher prevalence of diabetes and cardiac hypertrophy, with higher circulating levels of cholesterol, triglycerides, uric acid, insulin, and plasminogen activator inhibitor (PAI-1). Each of these nine abnormalities has been shown to be an independent risk factor for atherosclerotic vascular disease.3-10 Therefore essential hypertension seems to be a multifaceted syndrome, and any therapeutic intervention selectively directed at a single aspect of the disease, even if successful, does not necessarily improve (and may even worsen) the overall risk for atherosclerotic vascular disease. A formal analysis of this clustering of hemodynamic and metabolic disorders can now be attempted by utilizing the database of a cross-sectional, population-based survey on risk factors for atherosclerotic

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I. Physiologic and metabolic parameters of normal subjects and “pure” hypertensive patients

No. Age (yr) Male/female

MA/NHW Body mass index (kg/m2) Fasting plasma glucose (mmol/L) 2 Hr plasma glucose (mmol/L) Fasting plasma insulin (pmol/L) 2 Hr plasma insulin (pmol/L) Serum triglycerides (mmol/L) Serum total cholesterol (mmol/L) Serum HDL cholesterol (mmol/L) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)

MAINHW, Ratio of Mexican *p 5 0.05 for the comparison

Normal subjects

“Pure” hypertensive patients

1049 39.6 k 0.3 0.73 1.34 22.8 2 0.1 4.56 +- 0.02 5.02 k 0.04 59 t 1 368 k 9 1.11 ?z 0.02 4.78 r 0.01 1.33 2 0.01 113 + 0.4 69 k 0.3

44 50.0 + 2.0 0.91 1.09 21.6 f 0.8 4.79 f 0.09 5.41 + 0.23 76 k 11 460 +- 52 1.45 f 0.08 4.90 + 0.14 1.34 + 0.08 133 i 3 81 k 2

% Difference

+3* -4 +35* +36* +26* -3 -1 +13* +15*

Americans to non-Hispanic whites; HDL, high-density lipoprotein. between the two groups after adjusting for age, sex, and body mass index.

vascular disease conducted on 2930 individuals living in the Southwestern United States (the San Antonio Heart Study).l’ Of the 287 hypertensive subjects in the sample (an overall crude prevalence rate of 9.8%), about three quarters were obese, approximately half had type II diabetes (non-insulin-dependent diabetes mellitus [NIDDM]) or impaired glucose tolerance (according to the WHO criteria), while hypertriglyceridemia (serum triglycerides >250 mg/ dl [2.82 mmol/L]) or hypercholesterolemia (serum total cholesterol >250 mg/dl [6.48 mmol/L]) were present in 21% and 18 % , respectively, of the hypertensive population. In seven hypertensive patients, all of the above conditions (NIDDM or impaired glucose tolerance, obesity, hypertriglyceridemia, and hypercholesterolemia) were present at the same time (“complicated” hypertension), whereas only 44 hypertensive subjects were free of all five metabolic abnormalities (“isolated” hypertension). Obesity was the only associated metabolic abnormality in just one third of all the obese hypertensive patients. Likewise, patients in whom NIDDM, impaired glucose tolerance, hypertriglyceridemia, or hypercholesterolemia was the only associated problem constituted only a small percentage of all the hypertensive subjects, with prevalence rates always lower than those expected on the basis of chance association. This apparent protection among hypertensive individuals from having only one metabolic problem really arose from the high frequency (56% of all cases) of multiple (two or more) associated metabolic defects. When we analyzed the metabolic profile of the small (n = 44) subgroup of hypertensive patients in whom high blood pressure was the only problem

(“isolated” hypertension), we were surprised to find that these patients still had an altered metabolic profile in comparison with the “normal” control group (consisting of 1049 nonobese, normolipidemic, normotolerant, normotensive individuals). In addition to raised diastolic blood pressure (DBP), the patients had plasma glucose, insulin, and triglyceride concentrations above the respective mean values of the controls, and a lower high-density lipoprotein (HDL):total cholesterol ratio. Since gender, age, and race are related to the prevalence of hypertension in this biethnic population, l2 the comparison between the isolated hypertensive group and the controls was carried out after adjusting for age, gender, body mass index, and ethnicity (by multivariate analysis). The results show that “pure” hypertension is associated with a significant (p < 0.05), if small, elevation in fasting plasma glucose levels, raised fasting and postglucose plasma insulin concentrations, higher triglyceride levels, and lower HDL:total cholesterol ratios (p < 0.02 or less, Table I). Thus even “pure” hypertension presents slight glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and a relatively low HDL cholesterol level. Clustering of metabolic abnormalities would thus appear to be inherent in essential hypertension. However, metabolic and blood pressure variables show some degree of mutual interrelation even in normal individuals. With regard to this, two independent reports are of particular interest. First, among normotensive nondiabetic employees of an Italian factory, metabolic parameters such as plasma insulin, triglycerides, and HDL cholesterol have been reported to covary with blood pressure levels.13 Sec-

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Fig. 1. Mean value of an insulin resistance (IR) score (calculated as the sum of the standardized values of all 13 measured variables in each individual case) in the control population (n = 1049), and in the six patient groups (obese, diabetic [NIDDM], glucose intolerant [ZGT], hypertensive [HBP], hypertriglyceridemic [High TG], and hypercholesterolemic [High Ch]). For each patient group, the mean value for all the cases with the disease as well as the cases with the “pure” or isolated form of the same disease are given.

ond, in a large biracial community of children, fasting plasma insulin and glucose levels were found to be positively related to measures of obesity, blood pressure, triglycerides, and cholesterol levels.14In the San Antonio Heart Study database, many statistically significant correlations existed among the biochemical, physiologic, and hemodynamic variables in the healthy control group. In particular, DBP was found to be directly related to both fasting and postglucose plasma insulin levels, even after adjusting for confounding factors such as age, body mass index, waist:hip ratio, gender, ethnicity, and concurrent plasma glucose concentrations.15 To investigate further the hypothesis that metabolic and physiologic parameters and arterial blood pressure values show consensual changes over a continuum of values (both within and beyond the normal range), an integrated index of the physical (age, gender, body mass index, and waist:hip ratio), metabolic (glucose, insulin, triglyceride, cholesterol and HDL cholesterol levels), and hemodynamic (DBP and systolic blood pressure [SBP]) characteristics (measured in the San Antonio Heart Study population sample) was derived by adding up, for each subject, the individual standardized values of these 13 variables. This index ranks individuals according to their physical-metabolic-hemodynamic status. The results, calculated for the control group and the subgroups of hypertensive patients, show that there is an almost linear increase in this score as hypertension

appears in isolation (0.31 + 0.71 [SEMI arbitrary units versus -5.24 & 0.14 of the control group), or associated with one or more of the other metabolic disorders (mean score value = 5.88 -t 0.32), or complicated by all the metabolic irregularities considered here (mean value = 9.62 ? 3.70). Of further interest is to compare the mean value of this score among the other five conditions most often found in association with hypertension (obesity, NIDDM, impaired glucose tolerance, hypertriglyceridemia, and hypercholesterolemia), both in their respective “pure” forms and in general. As shown in Fig. 1, in each “isolated” condition the mean score is much higher than in the controls, with a progression such that hypercholesterolemia, obesity, hypertension, and impaired glucose tolerance rank about the same, while hypertriglyceridemia and NIDDM reach still higher values. In comparison, when considering all casesof each member condition of the sextet, the scores are rather more uniformly increased. The suggestion from these data is that the differences in this integrated “disease” index between the various isolated forms are largely lost in the mixed conditions, precisely on account of the multiple overlap of each disorder with several of the others. It is intriguing to speculate that such a simple index might be a predictor of the cumulative risk

of incurring

atherosclerotic

vascular

disease.

In summary, analysis of these data indicates that hypertension is seldom an isolated condition, that it is often (>80% of the time) associated with multiple

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q

Normotensives(17= 5 I )

l

Hypertensives()I= 143)

resistance

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.

L f/,,-.

I., 1.50

100

-?ik---

230

Supinesystolic blood pressure(mm Hg) Fig. 2. Inverse relationship between insulin-mediated whole-body glucoseuptake (MAO.,& during a euglycemic insulin clamp (ordinate) and systolic blood pressure(abscissa) in normotensive and hypertensive subjects.(Reproduced with permissionfrom Pollare T, Lithe11H, Berne C. Insulin resistanceis a characteristic feature of primary hypertension independent of obesity. Metabolism 1990;39:167-74.)

metabolic irregularities, and that hyperinsulinemia is an inherent feature of hypertension. There is also evidence that age, gender, amount and distribution of

body fat, glucose tolerance, insulin sensitivity, blood pressure, and lipid metabolism constitute a network of interrelated functions. Finally, some degree of deviation in physiologic and biochemical variables is already present in “pure” hypertension, and as expected, is worsened by the coexistence of other clinically manifest disorders of weight maintenance,

carbohydrate tolerance, and lipid metabolism. Similar conclusions are suggested by other epidemiologic surveys.‘“-la EXPERIMENTAL

EVIDENCE

OF

INSULIN

RESISTANCE

The next step is to understand why all these conditions tend to cosegregate or less ambitiously, whether a common factor or set of factors can be identified. The most consistent finding in the epidemiologic data previously reviewed is the presence of

either fasting or postglucose hyperinsulinemia in essential hypertension. This characteristic is not unique to hypertension, but is also found in obesity, glucose intolerance, and milder forms of diabetes and hyper-

triglyceridemia. Hyperinsulinemia typically evolves as a compensatory response to a reduced action of the hormone on target tissues (i.e., partial insulin insensitivity or insulin resistance). The very first evidence of insulin

resistance in essential hypertension and in peripheral vascular disease dates back to 1966, a few years after the development of a radioimmunologic method for insulin assay. Welborn et al.lg compared the peripheral plasma insulin levels of 19 patients with essential hypertension and seven patients with peripheral vascular disease (all with normal glucose tolerance) with those of 45 healthy individuals. At each sampling time after an oral glucose load, hypertensive patients showed higher insulin values than did controls. In the patients with peripheral vascular disease, insulin values were similar to those of the hypertensive subjects, but the statistical comparison with the controls fell short of significance because of the small number of subjects in this group. These data were confirmed several years later by independent observations,20, 21 and extended to insulin measurements obtained hourly for 24 hours.2” The insulin sensitivity of patients with essential hypertension has been investigated with the use of more direct and precise techniques: the euglycemic insulin clamp23 and the insulin suppression test.2“ Moderate insulin resistance has been uniformly reported to be present in untreated hypertensive individuals as a group,25, 26 while treated hypertensive patients showed comparable or higher degrees of insulin resistance when compared with untreated hy-

pertensive subjects in cross-sectional studies.“7l “8 Obesity or diabetes (which are known conditions of

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Ii. Characteristics of the insulin resistanceof obesity, non-insulin-dependent diabetes mellitus (NIDDM), essentialhypertension, and aging Table

Insulin-sensitive

pathway

Obesity

NIDDM

Essential hypertension

Aging

Whole-body glucose uptake Suppression of glucose output Glucose oxidation Nonoxidative glucose disposal Lipid oxidation Suppression of lipolysis Promotion of potassium uptake Suppression of proteolysis -, Reduced;

+, increased;

&, unchanged;

?, unknown.

insulin resistance), if coexistent

with hypertension, mark a further impairment in the ability of insulin to stimulate whole body glucose utilization.26* 2g An inverse relationship has been noted between insulinmediated glucose disposal and the height of SBP (Fig. 2).26 Promotion of whole-body glucose disposal is only one of the physiologic functions of insulin; the hormone also has rather potent effects in enhancing cellular potassium uptake and renal sodium reabsorption, and in suppressing lipolysis, hepatic glucose production, ketogenesis, and proteolysis. Other known insulin-resistant states (such as aging, NIDDM, and obesity [Table II]) are characterized by various degrees and combinations of specific defects in insulin action. These actions of insulin other than stimulation of overall glucose metabolism have been investigated in essential hypertension. Thus the ability of the hormone to suppress endogenous (hepatic) glucose production, lipolysis, and protein breakdown (as reflected by the hypoaminoacidemic effect of the hormone), and to promote potassium uptake appears to be unimpaired in patients with untreated, uncomplicated essential hypertension, at least at the plasma insulin concentrations (60 to 70 &J/ml) tested in these studies.25 Likewise, the antinatriuretic action of insulin (as reflected by the reduction in urinary sodium output during euglycemic hyperinsulinemia)30 has been found to be essentially preserved in obese, insulin-resistant normotensive individuals.31 The insulin resistance of essential hypertension therefore appears to be primary (i.e., independent of associated diseases such as obesity or diabetes) and selective in so far as it involves mostly glucose metabolism. Insulin-stimulated whole body glucose disposal (i.e., that which is usually referred to as insulin sensitivity) is the cumulative response of target tissues to the hormone. Among these tissues, skeletal muscle plays a quantitatively dominant role. It has been

suggested therefore that skeletal muscle insulin resistance is responsible, at least in part, for the insulin resistance of essential hypertension. In recent studies using the perfused forearm technique,32 considerable insulin resistance has been found in the deep tissues of the forearm in a group of patients with essential hypertension; the degree of this defect was somewhat proportional to the height of intra-arterial blood pressure levels. With the use of the euglycemic clamp technique, insulin resistance has also been detected in selected groups of patients with simple (“pure”) obesity,3” NIDDM,34 glucose intolerance,35 and hypertriglyceridemia.36 Moreover, there is evidence, both in normal and in NIDDM subjects, that insulin sensitivity is inversely related to the serum levels of HDL cholesterol.37 To our knowledge, direct measurements of insulin sensitivity in patients with pure hypertension and cardiac hypertrophy, in subjects with isolated hypercholesterolemia or hyperuricemia, or in states of isolated deficits of fibrinolysis, have not been carried out. It is relevant in this respect that insulin promotes PAIactivity38 and cellular hypertrophy. 3g Thus the whole syndrome, which is broader than that which Reaven40 has termed syndrome X, is still incompletely characterized in terms of the independent contribution of individual member diseases to the overall insulin resistance. MECHANISMS OF INSULIN HYPERTENSION

RESISTANCE

IN ESSENTIAL

Before discussing the various possible mechanisms, mention should be made of whether the skeletal muscle insulin resistance of essential hypertension is a tissue or a cellular phenomenon. A difference between hypertensive and normotensive individuals in the structural array of metabolically active units or the perfusion/metabolism relation in the same tissue volume can theoretically result in relative insulin insensitivity in vivo. For example, in skeletal muscle

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insulin resistance could result from different proportions of muscle fibers with high (type I and type IIA) or low (type IIB) insulin sensitivity,41 rather than from a different sensitivity of the same muscle fiber type. Alternatively, in the hypertensive individual a greater fraction of total limb blood flow could be directed to insulin-resistant fibers, thereby blunting the cumulative response of any given volume of muscle tissue to insulin exposure. If some muscle sections were relatively hyperperfused, and others consequently hypoperfused (the total blood flow being the same), the effect of any given level of insulin stimulation would be unchanged in the former but reduced in the latter, and the overall result would be a deficient insulin action at the organ level. In other words, if rarefaction of the capillary tree in some parts of the tissue mass was to shunt blood flow into the neighboring muscle elements in which the capillary network is intact, flow would be accelerated through already perfused (and fully metabolically active) sections. Thus in the hypertensive individual there might be structural abnormalities, either inherited or acquired, with the potential to affect the efficiency of insulin and substrate delivery to target tissues. Furthermore, if there is a limitation on the ability of a given vascular district to expand by recruiting underperfused branches of the capillary tree, again the supply of hormonal stimuli and substrates would be restrained. In other words, if the vasculature of the hypertensive subject has a blunted response to vasodilating influences, insulin resistance in the tissue would be an epiphenomenon of a generalized inability to match perfusion to metabolism under conditions of changing energy requirements. Thus functional abnormalities of the resistance vessels, alone or in combination with structural changes of the microcirculation, can conceivably translate into a metabolic equivalent as insulin resistance. At present, the support for these conjectures is rather limited. In brief: (1) Glucose uptake during euglycemic hyperinsulinemia is inversely related to the percentage of type IIB fibers and directly related to capillary density in the vastus Zateralis of human quadriceps muscles.42 (2) Untreated hypertensive patients have been reported to have fewer type I fibers in quadriceps muscle than normotensive individuals.43 (3) Capillary rarefaction is an established structural abnormality of hypertension44 and is probably accompanied by a heterogeneous blood flow distribution.4” (4) Obese, insulin-resistant individuals show a reduced vasodilation in the leg in response to systemic insulinization.46 As far as cellular mechanisms are concerned, a primary defect in transmembrane glucose transport

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would not seemto be a very likely mechanism. In fact, in the event of reduced inward glucose flux, both glucose oxidation and glycogen synthesis would be affected to the same extent, whereas only the latter is found to be decreased in hypertension. Number and affinity of insulin receptors on plasma cell membranes have not been investigated, nor has the ability of insulin to activate receptor-associated tyrosine kinase. The concentrations and/or activity of ratelimiting enzymes such as glycogen synthase (for glycogen synthesis), phosphofructokinase (for anaerobic glycolysis), and pyruvate dehydrogenase (for pyruvate oxidation) are classic potential sites of altered intracellular glucose disposition. Measurement of enzyme activity or levels of intermediate products in the pathway can be done using tissue biopsy specimens. Circulating inhibitors, or insufficient generation of potentiating mediators, could be responsible for the insulin insensitivity. For example, in young borderline hypertensive individuals4’ and in several secondary forms of hypertension (i.e., stress, overfeeding, high salt intake, alcohol consumption, cigarette smoking4*), the sympathetic outflow is increased and local catecholamine concentrations are higher than normal. These abnormalities could at least contribute to the reduced insulin sensitivity.4g The bradykinin system could also play a role as a local mediator of hemodynamic and metabolic effects. The intra-arterial infusion of bradykinin mimics the metabolic effects of insulin in the forearm tissues of normal individuals, and a reduced muscular production of bradykinin in response to exercise has been observed in diabetic patients and in the majority of hypertensive subjects.50 SIGNIFICANCE HYPERTENSION

OF

INSULIN

RESISTANCE

IN

An obvious issue of broader interest is whether insulin resistance is a marker or a mechanism for the “atherogenic syndrome.” Bearing in mind that these two possibilities are not mutually exclusive, the current balance of evidence appears to be evenly distributed between them. That hyperinsulinemia/insulin resistance is a marker of disease is suggested by the following facts: (1) Diabetes, hypertension, and dyslipidemia each have a solid genetic background, although the precise model of genetic transmission is unknown for all. Even obesity, apparently the more “acquired” of the diseasesin the syndrome, seemsto develop from a strong genetic predisposition.51 (2) In ethnic groups with a high incidence of diabetes (i.e., Mexican-Americans or Pima Indians), fasting hyperinsulinemia is associated with a higher overall prevalence of diabetes, and is a strong predictor of subsequent diabetes development, independent of age or

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Fig. 3. A possible explanation ic) for diabetic individuals.

for consensual

changes in different

obesity. 52 (3) Insuli n sensitivity is, at least in part, under genetic control; its intrafamilial variance is significantly lower than its interfamilial variance.5z (4) Nondiabetic individuals with a positive family history of diabetes show higher fasting plasma insulin levels54 and a higher incidence of hypertension and dyslipidemia.55 (5) In at least one form of familial dyslipidemic hypertension in which hypertension and dyslipidemia are coinherited, the elevated plasma insulin levels that are found are not explained by obesity.56 On the whole, these findings suggest that different genes may code for the different diseases, and that these genes are distributed in close and interrelated loci together with the genes of insulin resistance (linkage disequilibrium). The hypothesis of hyperinsulinemia/insulin resistance as a mechanism in the pathogenesis of one or more member conditions of the syndrome is supported by the following observations: (1) Insulin resistance per se worsens glucose tolerance; moreover, by imposing a chronic secretory stress on the endocrine pancreas, hyperinsulinemia may uncover or amplify a preexistent defect of the fl-cel1.j’ (2) Hyperinsulinemia stimulates the hepatic production of very-low-density lipoproteins.40 (3) Hyperinsulinemia is still present in postobese subjects (previously obese subjects who have regained a normal body weight); in these subjects, the hyperinsulinemia may have preceded and favored the development of obesity.58 (4) Hyperinsulinemia could induce elevation of blood pressure levels via a variety of different mechanisms including sodium-water retention, sympathetic nerve stimulation, changes in transmembrane ion traffic, and direct stimulation of smooth muscle cell growth. 5g(5) In animal models, insulin is atherogenic.60

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April 1991 Heart Journal

threshold

(metabolic

and hemodynam-

In conclusion, two points are the keys for interpretation of these varied and complex interactions: (1) Any one member of a constellation of hemodynamic and metabolic disorders bears at least a trace of the others and (2) in the normal state, such physiologic functions as regulation of blood pressure, glucose tolerance, body weight, insulin sensitivity, and lipid metabolism are linked with one another. A schematic representation of these statements is depicted in Fig. 3, in which the physiologic functions are shown as groups of knots or areas of a network. Whatever the nature of the connecting arms in the network, it is obvious that distorting one region will induce some distortion in neighboring areas, the more so if the areas are closer to each other and the links tighter. In the example in Fig. 3, if the genetics of an individual include the gene(s) for diabetes mellitus, then development of the disease, by straining the “glucose tolerance” areas of the network, will drag several other regions outside the normal range. Subclinical changes in the parameters of lipid metabolism or body fat mass or blood pressure homeostasis will therefore also be present. In subgroups of diabetic patients (or at different stages of diabetes), the diagnostic threshold for some other disease will be crossed, and the diabetes will become a clinical syndrome complicated by other disorders. This simplistic description does not take into consideration whether the putative “drag effect” takes on the form of a mechanism at the physiologic level or a linkage at the genetic level, nor does it feature a definite primacy of insulin resistance among the possible means of connecting the various functions. There is just not enough information to support specific roles. However, the scheme does have two plausible corollaries. One is that multiple abnormalities of hemodynamics

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and metabolism can be present at the preclinical stage of any of the member diseases, thereby only predicting or actually predisposing to disease development. The other is that as the genes pull their strings, the very existence of linked functions may feed back on the genes, hasten their expression, and contribute to the surfacing of the constellation. Clearly, much more investigation is needed to assessthe value of these hypotheses. A better understanding of the interaction between environmental factors and genetic pressure in the natural history of the atherosclerotic disease, and the selection of highrisk patients, may be of great help in terms of primary prevention. Moreover, the clinical approach to the patient with any of the abnormalities in question should take into account the whole cluster, and therapy should aim at ameliorating the entire hemodynamic-metabolic profile. We thank Steven M. Haffner and Michael P. Stern of the Division of Clinical Epidemiology at the University of Texas Health Science Center in San Antonio, Texas, for their extraordinary generosity in making the San Antonio Heart Study database available to us, and for their invaluable assistance in the analysis of epidemiologic data.

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