The Metabolic Syndrome and Its Relationship to Hypertensive Target Organ Damage

Abstract

High blood pressure is often associated with various metabolic abnormalities, including abdominal obesity, dyslipidemia, elevated plasma glucose, and insulin resistance, which are the main features of the metabolic syndrome. The metabolic syndrome is extremely common worldwide. This high prevalence is of considerable concern because several studies suggest that the metabolic syndrome carries an increased risk for cardiovascular events. Several lines of evidence seem to indicate that the metabolic syndrome is associated with an increased prevalence of preclinical cardiovascular and renal changes, such as left ventricular hypertrophy, microalbuminuria, impaired aortic elasticity, and early carotid atherosclerosis, most of which are recognized as significant independent predictors of adverse cardiovascular outcomes. It is conceivable that these data may partly explain the high rates of cardiovascular morbidity and mortality that are observed in patients with the metabolic syndrome.

It has long been recognized that high blood pressure (BP) tends to cluster with various metabolic abnormalities, including elevated triglycerides, reduced high‐density lipoprotein (HDL) cholesterol, glucose intolerance, insulin resistance, abdominal obesity, and hyperuricemia, which are the main features of the metabolic syndrome.

As early as 1923, Kylin ¹ recognized that hypertension, hyperuricemia, and hyperglycemia tended to occur together and, in 1967, Avogaro and colleagues ² described a new syndrome (plurimetabolic syndrome) characterized by an association of hyperlipidemia, obesity, and diabetes. Interestingly, the Italian authors also pointed out the frequent presence of hypertension in association with these abnormalities, as well as a high risk of coronary artery disease in individuals with this syndrome.

This early conceptualization of the metabolic syndrome has evolved considerably since that time. In 1988, at the Banting lecture of the American Diabetes Association annual meeting, Reaven ³ introduced the concept that an impaired in vivo insulin action was a central component of a cluster of metabolic abnormalities that did not necessarily include classic risk factors, such as raised low‐density lipoprotein cholesterol, but rather included elevated triglyceride concentrations, low HDL cholesterol, fasting hyperinsulinemia, and elevated BP. Obesity was not included as a feature of his “insulin resistance syndrome,” because Reaven argued that he could find insulin‐resistant subjects among nonobese individuals. Reaven referred to this agglomeration of metabolic complications as syndrome X.

Subsequently, Kaplan ⁴ defined the presence of a “deadly quartet” as the concurrent association of upper body obesity, glucose intolerance, hypertriglyceridemia, and hypertension.

More recently, the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EMIR), the American Association of Clinical Endocrinologists (AACE), the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) ⁵ , ⁶ and, last, the International Diabetes Federation (IDF) ⁷ endorsed the concept of the metabolic syndrome and proposed working definitions for the condition (Table).

Table I.

Comparison of Definitions of the Metabolic Syndrome

Criteria	WHO 1999	EGIR 1999	ATP III 2001	AACE 2003	IDF 2005
A) Glucose intolerance	Type 2 diabetes or IFG or IGT	Fasting glucose: 110–125 mg/dL	Fasting glucose: ≥110 mg/d*	IFG or IGT	Fasting glucose: ≥100 mg/dL or type 2 diabetes
B) Insulin resistance	Hyperinsulinemic, euglycemic clamp: glucose uptake in lowest 25%	Hyperinsulinemic: top 25% of fasting insulin values from nondiabetic population
C) High blood pressure	>140/90 mm Hg	≥140/90 mm Hg and/or medication	≥130/85 mm Hg or medication	≥130/85 mm Hg	≥130/85 mm Hg or medication
D) High triglycerides	≥150 mg/dL	≥177 mg/dL	≥150 mg/dL	≥150 mg/dL	≥150 mg/dL or specific treatment
E) Low high‐density lipoprotein	<35 mg/dL (men), <39 mg/dL (women)	<39 mg/dL	<40 mg/dL (men), <50 mg/dL (women)	<40 mg/dL (men), <50 mg/dL (women)	<40 mg/dL (men), <50 mg/dL (women), specific treatment
F) Obesity	BMI >30 kg/m2 or waist‐to‐hip ratio >0.90 (men), >0.85 (women)	Waist circumference ≥94 cm (men), ≥80 cm (women)	Waist circumference >102 cm (men), >88 cm (women)	Waist circumference ≥94 cm (men), ≥80 cm (women) for European subjects (with ethnicity‐specific values for other groups)
G) Microalbuminuria	Albumin excretion rate ≥20 μg/min or albumin‐creatinine ratio ≥30 mg/g
WHO (World Health Organization): the metabolic syndrome is diagnosed when criteria A and/or B are associated with two or more of C, D, E, F, or G. EGIR (European Group for the Study of Insulin Resistance): the metabolic syndrome is diagnosed when criterion B is associated with two or more of A, C, D, E, or F. ATP III (Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults): the metabolic syndrome is diagnosed when three or more criteria concur among A, C, D, E, and F. AACE (American Association of Clinical Endocrinologists): diagnosis of the metabolic syndrome depends on clinical judgement based on criteria A, C, D, or E and some risk factors such as family history of type 2 diabetes, hypertension or cardiovascular disease, polycystic ovary syndrome, sedentary lifestyle, nonalcoholic hepatic steatosis, acanthosis nigricans, history of gestational diabetes or glucose intolerance, non‐Caucasian ethnicity, body mass index (BMI) >25.0 kg/m2 or waist circumference >102 cm in men and >88 cm in women, or age older than 40 years. IDF (International Diabetes Federation): the metabolic syndrome is diagnosed when criterion F is associated with two or more of A, C, D, or E. *This was modified in 2004 to be ≥100 mg/dL, in accordance with the American Diabetes Association's updated definition of impaired fasting glucose (IFG) (fasting glucose ≥100 and <125 mg/dL) IGT≥impaired glucose tolerance (fasting glucose <126 mg/dL and 2‐hour postload glucose 140–199 mg/dL)

Among these definitions, the one suggested by the NCEP ATP III is the simplest, most practical, and most commonly applied. In the ATP III definition, the metabolic syndrome is diagnosed when at least three or more of the following abnormalities are present: BP ≥130/85 mm Hg, HDL <1.04 mmol/L (40 mg/dL) in men or <1.29 mmol/L (50 mg/dL) in women, fasting glucose ≥6.1 mmol/L (110 mg/dL), triglycerides >1.69 mmol/L (150 mg/dL), and waist circumference >102 cm in men or >88 cm in women. ⁵

PREVALENCE OF THE METABOLIC SYNDROME IN THE GENERAL POPULATION AND IN HYPERTENSIVE PATIENTS

Although estimates of prevalence are dependent on the exact definition used, the metabolic syndrome is undoubtedly quite prevalent.

Data from the US Third National Health and Nutrition Examination Survey (NHANES III) ⁸ indicate a high prevalence of components of the metabolic syndrome as defined by ATP III. Among 8814 adults, abdominal obesity was present in 38.6%, elevated triglycerides in 30.0%, low HDL cholesterol in 37.1%, elevated BP in 34.0%, and hyperglycemia/diabetes in 12.6% of patients. Overall, the age‐adjusted prevalence of the metabolic syndrome among adults aged 20 years and older in NHANES III was 23.7%. However, its prevalence increases with age, affecting 7% of Americans in their 20s, but up to 44% of those in their 60s. NHANES also showed that the metabolic syndrome varies by sex and ethnicity; the prevalence of the metabolic syndrome was highest in Mexican‐American women (27.2%) and lowest among African‐American men (14%). ⁸ In other US studies, 24% of subjects met the ATP III criteria and an equal proportion met the WHO criteria in the Framingham Offspring Study ⁹ ; 23% and 21%, respectively, in a non‐Hispanic white population in the San Antonio Heart Study ⁹ ; and 31% and 30%, respectively, in a population of Mexican Americans. Pooled data from 11 European study cohorts in subjects aged 30–89 years showed that 15.7% of nondiabetic men and 14.2% of nondiabetic women had the metabolic syndrome as defined by a modified WHO definition. ¹⁰ A very consistent finding in all of these studies is that the prevalence of the metabolic syndrome is highly age‐dependent.

In patients with hypertension, the metabolic syndrome is highly prevalent. In the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PUMA) study, ¹¹ a prospective observational investigation of 1742 Italian adult subjects with essential hypertension, the metabolic syndrome defined according to ATP III criteria was diagnosed in 34% of the population. Similar results were obtained in our cross‐sectional study conducted in 353 essential hypertensive's, 37% of whom had the metabolic syndrome. ¹² Moreover, Cuspidi and colleagues ¹³ found an overall prevalence of the metabolic syndrome of 30.2% in 447 hypertensive patients and, in another study by Leoncini and coworkers, ¹⁴ a total of 25% of 353 nondiabetic hypertensive subjects fulfilled the criteria for the metabolic syndrome.

THE METABOLIC SYNDROME AND CARDIOVASCULAR RISK

The high prevalence of the metabolic syndrome is of considerable concern because several studies suggest that people with the metabolic syndrome are at increased risk for developing diabetes mellitus ⁵ , ⁶ , ¹⁵ and cardiovascular disease and dying prematurely. ⁵ , ⁶ , ¹⁰ , ¹¹ , ¹⁵ , ¹⁶

Recently, Ford ¹⁵ summarized the estimates of relative risk for cardiovascular disease and diabetes reported from prospective studies in samples from the general population using definitions of the metabolic syndrome developed by the NCEP ATP III and WHO. In studies that used the exact NCEP definition of the metabolic syndrome, random‐effects estimates of combined relative risk were 2.99 (1.96–4.57) for diabetes and 1.65 (1.38–1.99) for cardiovascular disease. In studies that used the most exact WHO definition of the metabolic syndrome, the fixed‐effects estimates of relative risk were 1.93 (1.39–2.67) for cardiovascular disease; the fixed‐effects estimate was 2.60 (1.55–4.38) for coronary heart disease. The adverse prognostic impact of the metabolic syndrome has also been documented in hypertensive patients. ¹¹

In the PIUMA study, ¹¹ hypertensive participants with the metabolic syndrome ran an increased risk of developing cardiac and cerebrovascular events. The risk was less but still significant among subjects without diabetes mellitus.

It is conceivable that the increased cardiovascular risk conferred by the metabolic syndrome in hypertensive subjects may in part be mediated through preclinical cardiac and renal organ damage. Indeed, major cardiovascular events in most hypertensive patients are preceded by the development of asymptomatic cardiovascular and renal structural and functional abnormalities; these abnormalities, such as left ventricular (LV) hypertrophy, carotid atherosclerosis, arterial stiffness, and microalbuminuria, are recognized as significant independent predictors of adverse cardiovascular outcomes.

THE METABOLIC SYNDROME AND HYPERTENSIVE TARGET ORGAN DAMAGE

We recently performed a cross‐sectional study to assess the influence of the metabolic syndrome, defined according to the NCEP ATP III criteria, on some cardiac, renal, and retinal markers of target organ damage in 353 nondiabetic young and middle‐aged essential hypertensives without clinical or laboratory evidence of cardiovascular or renal diseases. ¹²

In a subset of untreated subjects of the same population, we also explored the carotid‐femoral pulse wave velocity (PWV), a measure of aortic stiffness, in patients with and without the metabolic syndrome. ¹⁷

Hypertensive patients with the metabolic syndrome showed higher LV mass on echocardiography (either normalized by body surface area or by height elevated by a power of 2.7), relative wall thickness, left atrial size (Figure 1), and greater prevalence of LV hypertrophy (57.7% vs. 25.1%; p<0.00001), lower mid‐wall fractional shortening (16.8±1.7% vs. 17.5±1.6%; p<0.002), and a longer E‐wave deceleration time (226.8±50.1% vs. 201.8±30.8%; p<0.0001) than subjects without the metabolic syndrome. ¹² These results were maintained even after correction for several confounding variables, such as age, gender distribution, severity and duration of hypertension, and previous antihypertensive therapy. In particular, after adjustment for these covariates, the likelihood of LV hypertrophy was 2.89‐fold (95% confidence interval, 1.68–4.98) higher in subjects with the metabolic syndrome than in those without it, when LV mass was indexed by height ² , ⁷ .

Figure 1.

Main echocardiographic parameters in 353 nondiabetic hypertensive patients with (black bars) (n=130) and without (gray bars) (n=223) the metabolic syndrome; p values are adjusted for age, gender, 24‐hour systolic and diastolic blood pressures, and duration of hypertension; LV=left ventricular; BSA=body surface area

Moreover, it is noteworthy that the relationship between the metabolic syndrome and LV mass was confirmed in multivariate regression models, including the metabolic syndrome together with its individual components, as independent variables ¹² ; this suggests that the metabolic syndrome may have a deleterious effect on cardiac structure over and above the potential contribution of each single component of this syndrome and that the confluence of abnormalities that comprise the metabolic syndrome may have a synergistic negative impact on LV mass.

The data of our study, obtained from a wide sample of Caucasian hypertensive patients, are in agreement with the results of three other investigations conducted in the general population ¹⁸ and in hypertensive subjects. ¹³ , ¹⁴

In the Strong Heart Study, ¹⁸ a longitudinal investigation performed in American‐Indian communities, a subset of the study population that included 1436 nondiabetic participants without evidence of cardiovascular disease (61.2% of whom had high BP), was examined to analyze the impact of the metabolic syndrome on cardiac structure and function. Patients with the metabolic syndrome showed greater LV dimension, mass, relative wall thickness, and left atrial diameter, and a higher prevalence of LV hypertrophy, with lower mid‐wall shortening than individuals who did not have the metabolic syndrome.

Furthermore, Cuspidi and colleagues ¹³ found that 447 untreated middle‐aged hypertensives with the metabolic syndrome had a more pronounced cardiac and extra‐cardiac involvement than those without the syndrome.

More recently, Leoncini and coworkers, ¹⁴ in 354 nondiabetic patients with primary hypertension, observed that subjects with the metabolic syndrome exhibited higher LV mass index and a greater prevalence of LV hypertrophy. Interestingly, they also found that the presence of the metabolic syndrome entailed a two‐fold greater risk for microalbuminuria and carotid structural abnormalities (intima–media thickening and atherosclerotic plaques). ¹⁵ Several potential mechanisms may be responsible for these findings.

The association of the metabolic syndrome with cardiac hypertrophy might be explained by insulin resistance and the accompanying compensatory hyperinsulinemia, which are regarded as the pathophysiologic key features underlying the metabolic syndrome. ³ , ⁴ , ⁵ Trophic effects of insulin on myocardial tissue have been demonstrated in cell cultures and animal models ¹⁹ and could be mediated, at least in part, by the insulin‐like growth factor‐1 receptors. ²⁰ , ²¹ However, the in vivo studies that have sought to find an association between insulin and LV mass have yielded conflicting results. ²¹ , ²² , ²³ , ²⁴

In addition, insulin may affect LV mass indirectly by increasing sodium retention ²⁵ or endothelin‐1 levels ²⁶ , ²⁷ or by inducing sympathetic activation. ²⁸ , ²⁹

Other potential biologic mediators of LV hypertrophy in subjects with the metabolic syndrome may be certain peptide hormones secreted from white adipose tissue such as angiotensin II, a potent growth factor in myocardial tissue, ³⁰ and leptin, whose mitogenic effect in cardiomyocytes has been recently evaluated with different conclusions. ²⁴ , ³¹ , ³²

There are other important findings from our study that deserve special mention: the greater level of albumin excretion rate (Figure 2) and the consequent higher prevalence of microalbuminuria (36.2% vs. 19.3%; p=0.002) observed in hypertensive subjects with the metabolic syndrome in comparison to those without it. ¹²

Figure 2.

Albumin excretion rate (in logarithmic scale) in 353 nondiabetic hypertensive patients with and without the metabolic syndrome; p value is adjusted for age, gender, 24‐hour systolic and diastolic blood pressures, and duration of hypertension. Lower and upper hinges of box plots indicate 25th and 75th percentiles. Lines across the box and numbers above the lines represent median values. Lower and upper whiskers extend to 5th and 95th percentiles.

These results concur with the above‐mentioned studies of Cuspidi ¹³ and Leoncini ¹⁴ and with a cross‐sectional evaluation of the NHANES III data in 5360 US civilian noninstitutionalized subjects, in whom a close association was found between microalbuminuria and the metabolic syndrome (defined according to NCEP ATP III criteria). ³³

The relationship between albumin excretion rate and the metabolic syndrome is so close that WHO recommendations include microalbuminuria among the criteria for diagnosing the metabolic syndrome. ⁵ However, the inclusion of microalbuminuria as part of the metabolic syndrome has been controversial because its association with insulin resistance has been described in several, but not all, reports. ⁵ , ⁶ , ³⁴

The value of microalbuminuria as a marker of target organ damage and a predictor of cardiovascular events and total mortality is well established. ¹⁶ , ³⁵

A recent European longitudinal study of the individual components of the metabolic syndrome (WHO definition) and subsequent risk of cardiovascular disease death found that microalbuminuria conferred the strongest risk of cardiovascular disease death when compared with obesity, hypertension, and dyslipidemia. ¹⁶ The finding of microalbuminuria along with other components of the metabolic syndrome may increase the specificity of this risk prediction tool and may explain the increased cardiovascular disease risk seen with this syndrome.

Another finding from our study merits a comment; there is an increased prevalence of grade I and grade II hypertensive retinopathy observed in subjects with the metabolic syndrome when compared with persons without the metabolic syndrome (Figure 3). ¹² This result is in keeping with a recent cross‐sectional investigation involving 11,265 participants in the Atherosclerosis Risk in Communities (ARIC) study, in which associations were noted between the metabolic syndrome and arteriovenous nicking, focal arteriolar narrowing, and generalized arteriolar narrowing, even in people without diabetes or hypertension. ³⁶

Figure 3.

Prevalence of hypertensive retinopathy (considered as a combination of several grades) in 353 nondiabetic hypertensive patients with and without the metabolic syndrome; p value is adjusted for age, gender, 24‐hour systolic and diastolic blood pressures, and duration of hypertension.

The prognostic significance of this finding is unclear, however, because studies exploring the association between the first two degrees of hypertensive retinopathy and cardiovascular outcomes have shown inconsistent results. ³⁷

Unlike eye ground examination, the clinical and prognostic value of increased aortic stiffness seems to be more consistently demonstrated; there is a growing awareness that large artery stiffening is a powerful predictor of cardiovascular morbidity and mortality. ³⁸

PWV is the most widely used measure of arterial stiffness. The basic principle of PWV assessment is that the pulse wave runs along the arterial tree at a speed that depends on the elasticity of the wall itself: the stiffer (i.e., less elastic) the wall, the higher the velocity of propagation. PWV measured along the aortic and aortoiliac pathway is the most clinically relevant since the aorta and its first branches are responsible for most of the pathophysiologic effects of arterial stiffness. ³⁸

When we assess the influence of the metabolic syndrome in a sample of never‐treated nondiabetic patients with essential hypertension on carotid‐femoral PWV, an index of aortic stiffness, we found faster carotid‐femoral PWV in subjects with the metabolic syndrome when compared with those without it. This difference held after controlling by ANCOVA for age, 24‐hour mean BP, and gender (p=0.02), and lost its statistical significance after further adjustment for albumin excretion rate. This latter finding may be explained, since microalbuminuria may reflect impaired endothelial function, ³⁴ , ³⁵ and evidence from several studies suggests that the endothelium is an important regulator of arterial stiffness. ³⁸ Similar results were obtained when the metabolic syndrome was defined using the WHO modified criteria (Figure 4).

Figure 4.

Carotid‐femoral pulse wave velocity in untreated nondiabetic essential hypertensives with (black bars) and without (gray bars) the metabolic syndrome, defined using criteria proposed by the Adult Treatment Panel 111 of the National Cholesterol Education Program (NCEP ATP 111) (on the left) and those suggested by the World Health Organization (WHO) (on the right). The differences remained statistically significant after adjustment for age, 24‐hour mean blood pressure, and gender.

Our data are in agreement with the results of Schillaci and colleagues ³⁹ that, in 169 newly diagnosed nondiabetic hypertensive subjects, observed a greater aortic PWV in the subgroup with the metabolic syndrome, whereas upper limb PWV did not differ in the groups with and without the metabolic syndrome.

Moreover, an independent relationship has been reported of the metabolic syndrome, defined according to NCEP ATP III, with increased stiffness of the carotid artery in subjects participating in the Baltimore Longitudinal Study on Aging. ⁴⁰

CONCLUSIONS

Several lines of evidence suggest that the metabolic syndrome may amplify hypertension‐related cardiovascular and renal changes, over and above the potential contribution of each single component of this syndrome. This may partly explain the enhanced cardiovascular risk associated with the metabolic syndrome, since these markers of target organ damage are well‐known predictors of cardiovascular events. Therefore, the simple search for the metabolic syndrome in hypertensive patients may enable the clinician to better assess absolute cardiovascular risk and to make a more informed decision regarding therapeutic strategies. Once this syndrome is properly identified, aggressive implementation of therapeutic lifestyle change and appropriate medication can greatly reduce its adverse prognostic impact.

Disclosure: This work was supported in part by a grant from the Italian Ministry for University and Scientific Research (MURST).