Evidence is available that the condition called metabolic. Age and Target Organ Damage in Essential Hypertension: Role of the Metabolic Syndrome

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1 AJH 2007; 20: Metabolic Age and Target Organ Damage in Essential Hypertension: Role of the Metabolic Syndrome Cesare Cuspidi, Stefano Meani, Cristiana Valerio, Carla Sala, Veronica Fusi, Alberto Zanchetti, and Giuseppe Mancia Objective: We sought to investigate the association of the metabolic syndrome (MS) with cardiovascular alterations in essential hypertensives in relation to age. Methods: A total of 3266 untreated and treated hypertensive patients categorized in three age groups (I: 17 to 40 years; II: 41 to 64 years; III: 64 years) were considered for this analysis. All patients underwent extensive investigations searching for target organ damage (TOD). The MS was defined according to Advanced Technology Laboratories (ATP) III criteria. Results: In the entire population, the risk of left ventricular hypertrophy (LVH), carotid abnormalities, and microalbuminuria increased by 2.5 (P.003), 2.2 (P.005), and 1.5 times (P.01), respectively, in the presence of MS after adjusting for several confounders. Prevalence of LVH (group I: 39% v 22%; group II: 53% v Evidence is available that the condition called metabolic syndrome (MS), that is, the clustering of abnormalities in glucose metabolism, lipid metabolism, and blood pressure (BP), 1 is associated with an increased prevalence of subclinical damage in a variety of organs. Microalbuminuria, left ventricular hypertrophy (LVH), and thickening or atherosclerotic plaques of the carotid arteries are more common in individuals who fit the diagnostic criteria for MS than in those who do not. 2 6 This is clinically relevant because microalbuminuria, LVH, and carotid artery thickening or plaques are associated with an increased risk of cardiovascular fatal and nonfatal events The presence of these alterations may worsen the prognosis in subjects with MS calling for the timely adoption of suitable therapeutic interventions. Prevalence of MS is known to increase with age; however, the issue whether the alterations 35%; group III: 69% v 52%, P.01 for all), carotid thickening (group I: 8% v 2%; group II 29% v 19%; group III: 69% v 52%, P.05 for all) and microalbuminuria (group I: 20% v 11%; group II: 16% v 8%; group III: 18% v 11%, P.05 for all) was significantly higher in patients with MS than in their counterparts across all age groups. Conclusions In hypertensive patients the MS amplifies TOD regardless of patient s age, thus increasing cardiovascular risk. This synergistic effect may accelerate the early development of TOD in young hypertensives and enhance the age-associated cardiovascular alterations in the elderly. Am J Hypertens 2007;20: American Journal of Hypertension, Ltd. Key Words: Hypertension, metabolic syndrome, organ damage, age. making up MS change with age have never been analyzed in detail. Cardiac, vascular, and renal abnormalities increase progressively with age, the change being particularly pronounced in the presence of hypertension due to the alterations in organ structure induced by sustained BP elevation. 12,13 Whether the impact of MS on organ damage is similarly effective at all ages has not been studied, despite the potential therapeutic and prognostic relevance of this information. The present article reports the results obtained in 3266 essential hypertensive patients with a large age range enrolled in the Evaluation of Target Organ Damage in Hypertension (ETODH) observational registry. All patients were assessed for the prevalence of cardiac, vascular, and renal damage, as well as for the presence or absence of the MS. Data were calculated for different age groups. Received July 26, First decision August 8, Accepted September 9, From the Department of Clinical Medicine, Prevention and Applied Biotechnologies, University of Milano-Bicocca (CC, GM), Milan; Policlinico di Monza, Istituto di Medicina Cardiovascolare, Ospedale Maggiore PoliclinicoIRCCS (SM, CV, CS, VF), and Centro Interuniversitario di Fisiologia Clinica e Ipertensione (CC, CS, AZ, GM), Universitá di Milano, Milan, Italy; Istituto Auxologico Italiano, Milan, Italy. Address correspondence and reprint requests to Dr. Cesare Cuspidi, Policlinico di Monza, via Amati 111, Monza, Italy; dhipertensione@libero.it /07/$ by the American Journal of Hypertension, Ltd. doi: /j.amjhyper Published by Elsevier Inc.

2 AJH March 2007 VOL. 20, NO. 3 METABOLIC SYNDROME AND AGE 297 Methods Patients The ETODH study is an ongoing observational registry of hypertension-related target organ damage (TOD) and concomitant cardiovascular risk factors in subjects with uncomplicated essential hypertension aimed at estimating the total cardiovascular risk of each patient referred or selfreferred to our hospital outpatient clinic according to the International 14,15 and European hypertension guidelines. 16 High BP was defined as a systolic BP 140 mm Hg or diastolic BP 90 mm Hg in untreated subjects. Treated hypertensive subjects were included regardless of their BP values. The main exclusion criteria were the presence of clinical or laboratory evidence of congestive heart failure, atrial fibrillation, previous stroke, significant cardiac valve disease, previous myocardial infarction, history of coronary bypass, secondary causes of hypertension, and neoplastic disease. After their informed consent had been obtained during the initial visit, all patients were subjected to the following procedures, which were completed within 1 to 4 weeks: medical history and physical examination, clinic BP measurement, blood and urine sampling, standard 12-lead electrocardiogram, 24-h urine collection for microalbuminuria, nonmydriatic retinography, and cardiac, renal, and carotid ultrasonography. In all subjects laboratory tests for secondary hypertension were performed when considered appropriate on clinical grounds. The study protocol was approved by the Ethics Committee of one of the institutions involved. For the present analysis patients were categorized in three age groups: young (I: 17 to 40 years); middle-aged (II: 41 to 64 years); and elderly (III: 64 years). Definition of the Metabolic Syndrome Metabolic syndrome was diagnosed when three or more of the following criteria were present: abdominal obesity (waist circumference 102 cm in men and 88 in women), hypertriglyceridemia ( 150 mg/dl or 1.69 mmol/l) or on drug treatment for elevated triglycerides, reduced HDL-cholesterol ( 40 mg/dl or 1.04 mmol/l in men and 50 mg/dl or 1.29 mmol/l in women) or on drug treatment for reduced HDL-cholesterol, high BP (systolic 130 mm Hg or diastolic 85 mm Hg or on antihypertensive medication), and high fasting blood glucose ( 110 mg/dl or 6.1 mmol/l) or on drug treatment for elevated glucose. 1,17 Clinic Blood Pressure Measurement Blood pressure was measured by a physician at two different visits in the outpatient clinic using a mercury sphygmomanometer and taking the first and fifth phases of Koroktoff sounds to identify systolic and diastolic values, respectively. At each visit, three measurements were taken at 1-min intervals after the subjects had rested for 5 min in the sitting position. The average was used to define clinic systolic and diastolic BP. Echocardiography Technical details have been reported previously. 18 In brief, M-mode, two-dimensional, and Doppler echocardiographic examinations were performed with commercially available instruments (Advanced Technology Laboratories (ATL) HDI 3000 or 5000, Bothell, WA). Left ventricular mass (LVM) was estimated from end-diastolic left ventricular internal diameter (LVIDd), interventricular septum (IVSd), and posterior wall thickness (PWTd), according to the formula by Devereux and Reickek 19 and normalized to height 2.7. Relative wall thickness (RWT) was calculated as (2 PWTd/LVIDd). Patterns of LV geometry were defined according to Ganau et al 20 as follows: LV concentric remodeling, when a normal left ventricular mass index (LVMI) was combined with a RWT 0.45; eccentric LVH, when an increased LVMI was associated with a RWT 0.45; and concentric LVH, when increased LVMI occurred with a RWT The LV systolic function was assessed by endocardial fractional shortening [(LVIDd LVIDs)/LVIDd]. The LV filling was assessed by mitral flow with standard pulsed Doppler technique. The following parameters were considered: early diastolic peak flow velocity (E), late diastolic peak flow velocity (A), and their ratio (E/A). Carotid ultrasonography Technical details have been reported previously. 18 In brief, images of the extracranial carotid artery walls (common, bifurcation, and internal carotid arteries) were obtained in several projections by a high resolution, linear array 7.5 to 10 MHz probe (ATL HDI 3000 or 5000). Plaques were sought in the near and far walls of the entire extracranial tree based on the presence of a focal wall thickening. Intima media thickness (IMT) was measured in the posterior wall of both common carotid arteries 5, 10, 15, 20, and 25 mm caudally to the bifurcation. 21 To obtain a mean value of common carotid IMT all 10 measurements were averaged. Carotid RWT was calculated as (2 IMT/Dd) where Dd is the value of common carotid internal diameter (intima intima distance) during end-diastole. Microalbuminuria The 24-h urinary concentration of albumin was measured using a commercially available radioimmunoassay kit (Sclavo SPA, Cinisello Balsamo, Milan, Italy). The detection limit of the method was 0.5 mg/l. Definition of Target Organ Damage Target organ damage was defined by the presence of microalbuminuria and ultrasonographic evidence of cardiac and vascular alterations. For ultrasound data, LVH was defined when LVMI was equal or exceeded: 51 g/h 2.7 in men and 47 g/h 2.7 in women. 22 The presence of at least

3 298 METABOLIC SYNDROME AND AGE AJH March 2007 VOL. 20, NO. 3 one carotid atherosclerotic plaque or diffuse IMT was taken as evidence of vascular alteration. A plaque was defined as a focal thickening greater than 1.3 mm in any segment of either carotid artery. 16 Diffuse IMT was diagnosed when common carotid wall thickness exceeded 0.8 mm. 16 Reproducibility of Ultrasonographic Measurements As previously reported 23 in our laboratory, intraobserver and interobserver coefficients of variation for LVMI are 7.4% and 8.6%, respectively. The corresponding values for common carotid IMT are 9.2% and 10.1%, respectively. 23 Statistical Analysis Statistical analysis was performed by the SAS System (version 6.12; SAS Institute Inc., Cary, NC). Values are expressed as means SD or percentage, as appropriate. Means were compared using Student t test for independent samples. Analysis of categorical data was carried out using the 2 test or Fisher s exact test when appropriate. The differences within groups were tested using analysis of variance. To investigate the association between: (1) MS and markers of TOD, and (2) individual components of MS and TOD, multiple logistic regression analyses were performed by calculating odd ratios and their 95% confidence limits. For all analyses a P.05 was considered statistically significant. Results The ETODH registry started in January 1999 and by the end of June 2005 had enrolled 3266 subjects (51.2 % men) with untreated (28.9%) or treated essential hypertension. Mean age was years (range 17 to 90 years). Mean systolic and diastolic BP were mm Hg and mm Hg, respectively; 22.5% of the study sample were smokers, 5.3% had type 2 diabetes mellitus, and 43.5% had the MS. In the entire population the most common component of the MS (other than high BP) was a low HDL-cholesterol (45.8%) followed by abdominal obesity (30.6%), hypertriglyceridemia (27.0%), and high fasting glucose (18.1%). Table 1 shows the demographic and clinical characteristics of the patients categorized according to age and the presence or absence of MS. Systolic BP, duration of hypertension more than 1 year, and prevalence of antihypertensive treatment, blood glucose and prevalence of diabetes, and plasma lipid parameters all showed a progressive increase from young (group I) to middle age (group II) and elderly (group III) patients; whereas, diastolic BP, heart rate, prevalence of men, smoking, and being overweight showed an opposite trend. The MS was less prevalent in group I than in groups II and III (35% v 45.2% and 45.2%), which in turn showed a similar prevalence of this condition. There were 2325 subjects who were treated with antihypertensive drugs. The frequency of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers, -blockers, calcium antagonists, and diuretics use did not differ between patients with and without MS in groups I and II, whereas the frequency of diuretics and -blockers use was higher in older patients with MS than in their counterpart without it. As shown in Fig. 1 in all three age groups of hypertensive patients, a low HDL was the most common component of MS with no significant between-group difference. This was also the case for the high triglyceride and body weight components, whereas the high fasting glucose component showed a significant and marked age-related increase in prevalence. The echocardiographic and carotid artery values are shown in Table 2. As expected, echocardiographic values (septal and posterior wall thickness, LV RWT, LVM, left atrial diameter) showed a progressive increase from the young group to the middle age and elderly group, whereas the E/A value showed an opposite trend. Carotid artery diameter, thickness, and RWT were also characterized by a progressive age-related increase. In all groups values were markedly altered in patients with MS as compared to those without it; the difference being in most instances statistically significant. As shown in Fig. 2, prevalence of LVH of both concentric and eccentric type as well as prevalence of carotid thickening or plaques also increased progressively with age; all alterations being clearly more common with than without MS in nearly all age groups. Although, without showing an age-related increase, this was the case also for the prevalence of microalbuminuria. When the impact of MS on TOD was separately analyzed in men and women, prevalence rates of LVH, carotid thickening, and plaques remained significantly higher in patients with MS than in their counterparts both in men (50%, 36%, 58% v 37%, 27%, 46%, P.01 for all) as in women (58%, 29%, 58% v 32%, 18%, 43%, P.01 for all). Women with MS had an increase in LVM and carotid IMT, respectively, by 17% and 10% compared to women without MS (P.001 for both). Less pronounced differences were found in men (10%, P.003 and 7%, P.005, respectively). On the other hand, the increase in urinary albumin excretion (UAE) in patients with MS was more pronounced in men ( 41%, P.001) than in women ( 16%, P.05). Finally, prevalence rates of LVH, carotid plaques, and microalbuminuria were significantly higher in patients with MS regardless of the absence (35%, 42%, 12% v 27%, 31%, 8%, P.05) or the presence of antihypertensive treatment (59%, 62%, 18% v 38%, 51%, 11%, P.001). Correlation Analyses Multiple regression analysis showed that in the entire population, after adjusting for several confounders (gender, duration of hypertension, systolic and diastolic BP,

4 Table 1. Demographic and clinical characteristics of the study population categorized by age and the metabolic syndrome Variable MS (n 393) Value Group I (n 611) Group II (n 2002) Group III (n 653) (n 218) (n 1102) (n 900) (n 362) (n 291) Age (y) Male gender (%) BSA (m 2 ) * * * BMI (kg/m 2 ) * * * Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (beatts/min) Duration of HT ( 1 y) Blood glucose (mg/dl) * * * Total cholesterol (mg/dl) * * * HDL-cholesterol (mg/dl) * * * Triglycerides (mg/dl) * * * Overweight (%) * * * Current smoking (%) Diabetes(%) * * Untreated(%) ACEI or ARB(%) Blockers (%) Ca antagonists(%) Diuretics(%) Statins(%) Fibrates(%) Gluc lowering Agents (%) * * P.01 v ; P.05 v. AJH March 2007 VOL. 20, NO. 3 METABOLIC SYNDROME AND AGE 299

5 300 METABOLIC SYNDROME AND AGE AJH March 2007 VOL. 20, NO. 3 FIG. 1. Prevalence rates of each component of the metabolic syndrome, other than high blood pressure, in younger, middle-aged, and elderly hypertensives. smoking, and age), the risk of having LVH, carotid thickening or plaques, and microalbuminuria increased by 2.5- fold (95% CI , P.003), 2.2-fold (95% CI , P.005), and 1.5-fold (95% CI , P.01), respectively, in the presence of MS. However, when organ damage was analyzed taking into account each metabolic component of the MS, we found that: (1) abdominal obesity was the only independent predictor of LVH (OR 2.1, 95% CI , P.01); (2) high blood glucose ( 110 mg/dl) was the only independent predictor of microalbuminuria (OR 1.9, 95% CI , P.02); and (3) none of the components was an independent predictor of carotid atherosclerosis. Discussion Our study of a large cohort of untreated and treated uncomplicated hypertensive patients provides several new findings. First, it confirms that alterations in LV structure as assessed by absolute and RWT, LVMI, or the presence or absence of LVH were more frequent in patients with MS than in those without MS. Second, the more pronounced cardiac involvement of hypertensives with MS was paralleled by an increased prevalence of microalbuminuria and carotid artery wall thickening or plaques, with the occurrence of at least one type of organ damage in most individuals. Third, although organ damage became progressively more common with age, the greater and simultaneous prevalence of cardiac, vascular, and renal abnormalities in individuals with MS was observed in young, middle-age, and elderly hypertensives, thereby characterizing all age groups. This confirms the reports by other groups that when superimposed to hypertension MS leads to a prevalence of renal, cardiac, and vascular subclinical damage. 6,24 It extends previous information, however, by showing in a large cohort of patients that this damage is greater than that due to the BP elevation alone. The contribution of MS to the prevalence of organ damage is not limited to elderly, but it involves to a similar degree Table 2. Cardiac and carotid ultrasonographic parameters of the study population categorized by age and the metabolic syndrome Value Group I (n 611) Group II (n 2002) Group III (n 653) (n 291) (n 362) (n 900) (n 1102) (n 218) (n 393) Variable LVIDd (mm) * IVSTd (mm) * * * PWTd (mm) * * * RWT * * LV mass (g) * * * LVM/h (g/m 2.7 ) * * * AR Diam. (mm) LA Diam. (mm) * * * E/A ratio CCA IMT (mm) * CCA Diam. (mm) CCA RWT * AR aortic root; LA left atrium. * P.01 v ; P.05 v.

6 AJH March 2007 VOL. 20, NO. 3 METABOLIC SYNDROME AND AGE 301 FIG. 2. Prevalence rates of left ventricular hypertrophy (LVH), concentric and eccentric LVH, carotid thickening, carotid plaques, and microalbuminuria in younger, middle-aged, and elderly hypertensives with (black bars) and without (white bars) metabolic syndrome. middle-age and young individuals as well. This allows us to conclude that organ alterations with established prognostic significance such as those addressed in the present study appear to characterize patients with the MS and presumably contribute to the substantial increase in cardiovascular fatal and nonfatal events reported in these patients. 25 These damages should be searched routinely in hypertensives with MS, given that absence of damage in one organ does not exclude its presence in another, 26 and that damage in multiple organs has a worse prognosis than single ones. 27 Diagnostic procedures should be extensive also in younger patients because the adverse role of MS on organ structure takes place when the exposure to this condition is shorter. Several other results of our study deserve to be mentioned. First, prevalence of MS (40%) was greater than that reported by other studies. This is probably because our sample was characterized by an older age and higher BP values (ie, by two variables correlated closely with the prevalence of MS 28 and metabolic abnormalities). Second, patients with and without MS were similar for gender, known duration of hypertension, smoking habit, as well as systolic and diastolic BP. This supports the view that the excess prevalence and degree of organ damage was not

7 302 METABOLIC SYNDROME AND AGE AJH March 2007 VOL. 20, NO. 3 due to a differential BP load or to other demographic and clinical variables affecting cardiovascular structure, but related to synergic influence of metabolic abnormalities typical of MS. It is noteworthy that the risk of having organ damage associated with MS itself exceeded that independently related with its individual components. Multiple logistic regression analysis indicated that MS entails a greater risk of TOD than each one of its metabolic components. A novel finding of our study is that MS was associated with increased odds for LVH that, although variable across all age groups, was progressively more frequent from the elderly to the middle-age and young subjects. This supports that MS is a powerful determinant of LVH, regardless of the duration to which subjects are exposed to this condition. Third, the differences in the prevalence of organ damage between patients with and without MS in younger subjects, at variance from middleage and elderly subjects, were less evident for carotid than for cardiac and renal abnormalities, which were clearly present between subjects with and without MS in all three age groups. This could be because development of carotid damage induced by MS takes more time than the development of renal and cardiac damage. At difference from other previous reports indicating that the effect of MS on early atherosclerosis 29 and left ventricular structure 30 are prevalent in women, we found that MS was associated with an excess of TOD in both genders, with a more pronounced impact on cardiac and carotid structure in women and on renal dysfunction (ie, microalbuminuria) in men. A higher prevalence of MS in our study sample compared to these other studies (16% and 27%, respectively) may partly explain this discrepancy; however, our results do not support the view that MS is an innocent condition in men. Our study has some limitations. First, because our study is based on hypertensives referred to a special center the results may not be extended to the general population. Second, the inclusion of patients taking antihypertensive treatment may have altered the relationship between MS and organ damage. Although the treatment-related BP reduction might have reduced the prevalence and degree of damage, we found that cardiac and extracardiac TOD was significantly greater in patients with MS independently of the antihypertensive drugs and the difference in organ involvement was even more pronounced in treated than in untreated individuals. Finally, although in our hypertensive patients a low HDL-cholesterol was the most common additional component of MS in all age groups, the prevalence of other components increased with age. For example, high fasting glucose was six- and fourfold more frequent, respectively, in elderly and middle-age than in younger participants, therefore the burden of MS components may have differently affected organ damage in the various age groups. In conclusion, our study carried out in a large cohort of hypertensives with a high prevalence of MS, indicates that the syndrome amplifies organ damage regardless of patient s age and gender, thus increasing cardiovascular risk. This synergistic effect may accelerate in young hypertensives the early development of TOD and enhance in the elderly the age-associated preclinical cardiovascular abnormalities. References 1. 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