Influence of Gender on the Relationships between Metabolic Syndrome and Left Ventricular Mass in Essential Hypertensive Subjects

Although the definition and clinical importance of the metabolic syndrome (MetS) are still under debate [1], there is clear evidence that MetS considerably increases the risk of cardiovascular (CV) and renal events, in general population and also in subjects with high blood pressure (BP), even in absence of diabetes [2-5]. In some studies the CV morbidity and mortality risk associated with MetS was found to be higher in the female sex [3]. Several lines of evidence suggest that this enhanced CV risk may partially be mediated by the increased prevalence of preclinical CV and renal damage observed in individuals with the MetS [6-14]. Recently, the results of the Framingham Offspring study highlighted the importance of subclinical cardiovascular changes in mediating the CV risks associated with MetS, showing that subjects with MetS who had preclinical disease had a 2.7-fold increased CV risk, compared with individuals without preclinical disease, MetS, or diabetes (who served as referent). In contrast, participants with the presence of MetS or diabetes but without any preclinical CV disease were not at a statistically significant increased risk compared with the referent group [14]. Among the various markers of preclinical cardiovascular damage, LV hypertrophy (LVH) is one of the most investigated [5-7,9-14]. It is well known that LVH, detected either by electrocardiography or echocardiography, is a strong predictor of cardiovascular morbidity and mortality [15]. Several studies have demonstrated that the MetS is associated with a high prevalence of LVH in hypertensive patients and in general population. The effect of the metabolic syndrome on left ventricular structure has been reported to be partly independent of the effect of hemodynamic and non-hemodynamic determinants of left ventricular mass [5-7,9-14], including BP values over 24 hours [5,7,10,12] and intra- arterial BP levels [13]. More recently, it has been also documented, in a longitudinal study conducted in general population, that the MetS markedly increases the odds of developing LVH. The adjusted risk to develop new onset LVH was 2.6 times greater in individuals with than in those without the MetS [16]. Only in a few studies was the influence of MetS on LVM analyzed separately in men and women [5,10-12,17]. Recently, we evaluated cross-sectionally in both sexes the relationships of MetS with LV mass and LV hypertrophy in 475 patients with essential hypertension, of whom 40% had MetS [17]. The definition based on Adult Treatment Panel III guidelines, recently slightly revised by an American Heart Association /National Heart, Lung, and Blood Institute scientific statement [2], was used to identify subjects with MetS. Measurements were obtained with patients off antihypertensive medications and included 24-hour BP monitoring and an echocardiogram. LV mass was indexed both by height elevated by a power of 2.7 (LVMH2.7) and by body surface area (LVMI). A cut-off point of 51 g/m2.7 in either gender was set to separate normal from LVH. Left ventricular hypertrophy was defined also as LVMI ≥ 125 g/m2 for men and ≥ 110 g/m2 for women, as suggested by the 2007 guidelines of the European Society of Hypertension [18]. In the group of female subjects, participants with MetS showed significantly higher values of LV mass, either normalized for height2.7 (Figure 1) or for body surface area (Figure 2) [17]. In male gender slightly less pronounced differences, but equally significant, were observed in the two subgroups of hypertensive patients with and without MetS, regarding left ventricular mass, independently of the method used for indexation (Figures 1-2) [17]. Also in the subset of hypertensive patients never pharmacologically treated for high BP, LVMH2.7 and LVMI were higher in both females and males with MetS compared with their counterparts without it (all p < 0.005) [17]. In the whole population, a 2-factor ANOVA model showed a significant effect of MetS (p < 0.001), but not of gender on LVMH2.7. The analysis of the interaction term “gender x MetS” disclosed no significant effect of sex on the association between MetS and LVMH2.7, both before (p = 0.18) and after adjustment for age, previous pharmacological antihypertensive therapy, duration of hypertension and 24-h systolic BP (p = 0.10). Similar results where obtained when in the same 2-factor ANOVA model the dependent variable LVMH2.7 was replaced by LVMI [17]. The prevalence of LVH, defined as LVMH2.7 ≥ 51 g/m2.7, was greater in women and men with MetS than in those without it (48.2 versus 18.6% in females and 42.9% versus 22.8% in males; all p < 0.001) [17]. Similar conclusions were reached when LVH was defined as LVMI ≥ 110 g/m2 in women and ≥ 125 g/m2 in men (Figure 3). The relationship between MetS and LVMH2.7 remained significant in both sexes (in females β = 0.26, p < 0.001; in males β = 0.21, p < 0.001) in stepwise linear multiple regression analyses, even after adjustment for 24-hour systolic blood pressure, 24-hour heart rate, age, duration of hypertension, previous antihypertensive therapy, total cholesterol, and glycemia. Similar results were obtained by using LVMI instead of LVMH2.7, as dependent variable (in females β = 0.15, p = 0.02; in males β = 0.15, p = 0.009) [17]. Some previous investigations explored the potential influence of gender on MetS related LV hypertrophy, with conflicting results [5,10-12,17]. In a study conducted on 618 hypertensive patients it was found a remarkable sex difference in the association between MetS and LVH; indeed, in that study, MetS was a strong determinant of LV mass in women but not in men [10]. In contrast, in the Atherosclerosis Risk in Communities (ARIC) Study, performed in a group of 1572 black adults, LV mass indexed by height gradually increased with increasing number of MetS components, in a similar manner in both sexes [11]. Being the population of this study constituted by black people, these results may not be extended to other populations, in regard to the documented greater prevalence of metabolic disorders and cardiac hypertrophy of this race. However, similar conclusions were reached in the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) Study, conducted in 2,014 subjects from the Italian general population of Monza [5]. Moreover, in a larger cohort of 3,266 white hypertensive patients, it was observed that women with MetS had an increase in LVMH2.7 by 17% compared to women without MetS. Less pronounced (10%), but equally significant, differences were observed in men [12]. Our results are in agreement with these latter findings and provide new information, showing that the MetS is associated with increased odds for LVH in both men and women, regardless of the methods of indexation for left ventricular mass [17]. Therefore, our observations do not support the view that MetS may be considered an innocent condition for the heart in men.