Department of Internal Medicine, University of Genoa, and Department of Cardio-Nephrology, Azienda Opedaliera Universitaria San Martino, Genoa, Italy
Address correspondence to: Dr. Roberto Pontremoli, Department of Internal Medicine, University of Genoa, and Department of Cardio-Nephrology, Azienda Opedaliera Universitaria San Martino, Viale Benedetto XV 6, 16132 Genoa, Italy. Phone: +39-010-353-8932; Fax: +39-010-353-8932; E-mail: roberto.pontremoli{at}unige.it
The metabolic syndrome can be found in approximately one thirdof patients who do not have diabetes but have primary hypertension.Its presence has been associated with a wide range of traditionaland nontraditional cardiovascular risk factors and early signsof cardiovascular and renal damage. Moreover, it was emphasizedrecently that the metabolic syndrome predicts an increased probabilityof sustaining a cardiovascular event or dying. In the clinicalsetting of insulin resistance, attention should be paid to themetabolic side effects of antihypertensive drugs; therefore,preference should be given to renin-angiotensin system inhibitorsand calcium channel blockers rather than to blockers and diuretics.
Metabolic syndrome is characterized by the simultaneous occurrenceof several metabolic and nonmetabolic abnormalities that resultin a marked increase in cardiovascular morbidity and mortality.The awareness and interest of the cardiovascular community inthe metabolic syndrome arose in 1988, when Reaven (1) observedhow dyslipidemia, hypertension, and hyperglycemia tended tocluster in some individuals. He called this clustering "syndromeX" and emphasized its role as a risk factor for cardiovasculardisease. Because the main pathophysiologic feature underlyingthis condition is the presence of peripheral tissue resistanceto insulin action, the syndrome also commonly is referred toas "insulin resistance syndrome."
A number of scientific agencies have proposed several workingdefinitions for the metabolic syndrome (2–5). The definitionby Adult Treatment Panel III is perhaps the most physician friendlybecause it does not require direct assessment of insulin resistanceand therefore is easier to apply in clinical practice.
Recent large epidemiologic surveys indicate that the age-adjustedprevalence of the metabolic syndrome is 24% in the United States(6), a figure that is rising rapidly, mainly because of thecontinuous increase in the prevalence of obesity (7). As a resultof the high incidence of diabetes and cardiovascular complicationsassociated with the metabolic syndrome, this condition has aremarkable impact on clinical practice, and its costs, directand indirect, draw a significant share of public health resources.
BP levels are strongly associated with insulin levels and thedegree of insulin resistance (8). It has been reported thatinsulin resistance might be involved in the pathogenesis ofprimary hypertension in up to 40 to 50% of cases. In the clinicalsetting of insulin resistance, hypertension may arise from theinteractions of several mechanisms, such as increased renalsodium reabsorption, increased sympathetic neural outflow, andimpaired ability of insulin to dilate the peripheral vasculature(9). Indeed, high BP is a classical feature of the metabolicsyndrome, and it has been reported that the metabolic syndromeis present in up to one third of hypertensive patients (10,11).
Metabolic Syndrome and Cardiovascular Risk Factors
A wide range of traditional and nontraditional cardiovascularrisk factors that may promote and foster the development ofatherosclerosis have been reported in association with the metabolicsyndrome, including atherogenic dyslipidemia, prothromboticand proinflammatory milieu, and endothelial dysfunction. Patientswith the metabolic syndrome often show elevated small and denseLDL cholesterol particles and elevated levels of apolipoproteinB (12). Small, dense LDL particles are more atherogenic thanthe large ones, and apolipoprotein B-100 is the major apolipoproteincomponent of the atherogenic lipoproteins (VLDL, LDL, and intermediatedensity lipoprotein) (13). Increased levels of clotting factors(tissue factor VII and fibrinogen), inhibition of the fibrinolyticpathway (increased plasminogen activator inhibitor-1 and decreasedtissue plasminogen activator activity), and increased plateletaggregability also have been described in the metabolic syndrome,which therefore can be considered a prothrombotic condition(14). Furthermore, the metabolic syndrome signals the presenceof a proinflammatory state. In fact, increased C reactive proteinlevels often can be found in patients with the metabolic syndrome,and there is a linear relationship between the number of componentsof the metabolic syndrome and the degree of inflammation (15).An impairment in endothelial function, as indicated by a highertranscapillary escape rate of albumin and defective forearmresponse to acetylcholine, also has been described in untreatedhypertensive patients who did not have diabetes but had themetabolic syndrome without overt cardiovascular disease (16).These abnormalities contribute to the development of asymptomaticstructural and functional abnormalities at the vascular andcardiac levels and may lead to the onset of major cardiovascularevents.
Several studies have shown a significant, independent associationbetween the metabolic syndrome and subclinical cardiovascularand renal damage both in the general population and in patientswith primary hypertension. We and others have described an associationbetween the metabolic syndrome and greater left ventricularmass index and prevalence of left ventricular hypertrophy, especiallyconcentric hypertrophy, in patients with primary hypertension(10,17). Moreover, in a group of 354 untreated hypertensivepatients without diabetes, we found a linear relationship betweenthe number of components of the metabolic syndrome and the prevalenceand the degree of left ventricular hypertrophy. We also showedthat the presence of the metabolic syndrome entails a twofoldincreased risk for left ventricular hypertrophy, even afteradjustment for several potentially confounding variables (17).Furthermore, in a large group of patients with primary hypertension,we reported that the metabolic syndrome is a significant, independentpredictor of carotid atherosclerosis (17), thus extending previouslyreported, similar results in the general population (18–20).The relationship between the metabolic syndrome and increasedurinary albumin excretion is so strong that microalbuminuriahas been taken as a criterion to define the occurrence of themetabolic syndrome (3). Cuspidi et al. (10) reported that higherurinary albumin excretion and prevalence of microalbuminuriawere associated with the occurrence of the metabolic syndromein a group of 447 hypertensive patients. More recently, we showedthat the metabolic syndrome is a significant, independent predictorof the presence of microalbuminuria in a large group of untreatedpatients with primary hypertension. Moreover, we found a linearrelationship between the number of components of the metabolicsyndrome and the prevalence and the degree of microalbuminuria(17). In the general population, the metabolic syndrome hasbeen related to higher serum creatinine and urinary albuminexcretion and lower GFR: the greater the number of componentsof the metabolic syndrome, the greater the prevalence of chronickidney disease and microalbuminuria. Furthermore, the risk forchronic kidney disease and microalbuminuria increases as thenumber of components of the metabolic syndrome increases andis 2.6- and 1.9-fold higher, respectively, in the presence ofthe metabolic syndrome (21).
There is now a large body of evidence showing that the metabolicsyndrome predisposes individuals to the development of cardiovasculardisease. For example, an analysis of 3606 individuals with afamily history of type 2 diabetes demonstrated that those withthe metabolic syndrome showed a significant increase in cardiovascularmortality (22). Similarly, in a large group of middle-aged Finnishmen over a mean follow-up of 11.6 yr, the presence of the metabolicsyndrome predicted all-cause and cardiovascular mortality evenin the absence of cardiovascular disease and diabetes at baseline(23). The Second National Health and Nutrition Examination Surveyshowed that patients with the metabolic syndrome had a higherrisk for cardiovascular death, coronary heart disease, and stroke.Furthermore, the higher the number of the metabolic syndromecriteria, the higher the incidence of mortality as a resultof cardiovascular disease (24). More recently, an analysis ofdata from the Atherosclerosis Risk in Communities study showedthat individuals who have the metabolic syndrome without diabetesor cardiovascular disease are at increased risk for long-term,poor cardiovascular outcome (25).
Both the Seventh Report of the Joint National Committee (26)and the European Society of Hypertension–European Societyof Cardiology Guidelines (27) emphasize the importance of diagnosingthe metabolic syndrome when treating hypertensive patients.The Progetto Ipertensione Umbria Monitoraggio Ambulatoriale(PIUMA) study, which included 1742 initially untreated essentialhypertensive patients without cardiovascular disease, recentlyshowed that the metabolic syndrome amplifies the risk associatedwith high BP, independent of several traditional cardiovascularrisk factors. Actually, over a mean follow-up period of 4.1yr, the presence of the metabolic syndrome was a significantindependent predictor of both cardiac (hazard ratio 1.5) andcerebrovascular (hazard ratio 2.1) events. The adverse prognosticvalue of the metabolic syndrome was attenuated but still significantamong hypertensive patients without diabetes (11).
Recognizing the metabolic syndrome in patients with hypertensionprovides a great opportunity for more aggressive treatment,including lifestyle modification and treatment of comorbid factorsso as to attain cardiovascular risk reduction. Most of the cardiovascularrisk reduction that is associated with antihypertensive drugsis the result of BP lowering alone; however, in the clinicalsetting of insulin resistance, consideration should be givento the metabolic side effects of antihypertensive drugs. Therefore,drugs that inhibit the renin-angiotensin system, such as angiotensin-convertingenzyme inhibitors and angiotensin receptor blockers, shouldbe preferred because of their proven protective effect on theincidence of new-onset diabetes. Calcium channel blockers areneutral from a metabolic standpoint and could be useful bothas first-line and as add-on treatment. Blockers and diureticsare less attractive in the context of insulin resistance becausethey are known to worsen metabolic abnormalities, even thoughthey often are necessary to achieve BP goals.
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Abstract
Introduction
blockers and diuretics. 
