COMMENTARIES

Relationships of Plasma Aldosterone with Metabolic Syndrome and Left Ventricular Mass in Essential Hypertensive Patients

Giuseppe Mulč, M.D., Emilio Nardi, M.D., Paola Cusimano, M.D., Santina Cottone, M.D., Giovanna Seddio, M.D., Calogero Geraci, M.D., Alessandro Palermo, M.D., and Giovanni Cerasola, M.D., Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche, Cattedra di Medicina Interna. European Society of Hypertension Excellence Centre, Universitŕ di Palermo, Italy

Please address correspondence to:
Giuseppe Mulč, M.D.
Via Monte San Calogero, 29
90146 Palermo, Italy
Tel: (+39) 091 6554578
Fax: (+39) 091 6554331
Email: giusemme@unipa.it

Giuseppe Mulč


Introduction

 

Although some controversies in the pathogenesis and clinical importance of metabolic syndrome (MetS) still remain [1], it is accepted that MetS carries an increased risk of cardiovascular (CV) diseases, even in the absence of diabetes [2-4]. It is conceivable that the increased cardiovascular risk conferred by the MetS may in part be mediated through preclinical cardiovascular and renal damage. Indeed, major cardiovascular events in most subjects 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 more often observed in subjects with MetS than in those without it, and they are recognized as significant independent predictors of adverse cardiovascular outcomes [5-8].

          Recently, the results of the Framingham Offspring study underline the important role of preclinical cardiovascular changes in mediating the CV risks associated with MetS, showing that individuals with MetS who had subclinical disease experienced a 2.7-fold increased CV risk, compared with participants without subclinical disease, MetS, or diabetes (who served as referent). In contrast, individuals with the presence of MetS or diabetes but without any subclinical vascular disease were not at a statistically significant increased risk compared with the referent group [8].

          Among the various markers of preclinical cardiovascular damage, LV hypertrophy (LVH) is one of the most investigated [5-8]. It has been demonstrated often in the context of arterial hypertension that patients with MetS exhibit higher LV mass than those without MetS, regardless of the methods of indexation for LV mass. These results were equally significant in men and women, independently of age, blood pressure, and other potential confounding factors [6].

          The mechanisms responsible for the increased occurrence of subclinical CV changes in subjects with MetS are only known in part [2,4,7].

          A growing body of evidence links aldosterone excess to cardiovascular remodeling and injury [9].

 

Plasma Aldonsterone and Metabolic Syndrome

 

Although the role of aldosterone in BP regulation is well known, the association of aldosterone with MetS has been explored only recently [10-14]. In 1994 Egan et al. studied 29 subjects of unidentified ethnicity with CV risk factor clustering and found higher renin and aldosterone levels when compared with appropriate control individuals [10]. In a more recent study performed in the Seychelles, populated predominantly by people of East African descent, PRA and plasma aldosterone concentration (PAC) were associated with different components of the MetS, but only plasma aldosterone was associated with the MetS per se, independently of its separate components [11]. This result was confirmed by Kidambi at al. in a sample of 397 African-American subjects [12]. Furthermore, in this study a relationship of aldosterone with blood pressures, waist circumference, and insulin resistance, assessed by HOMA index, was found [12]. In contrast, in a subanalysis of the TROPHY (Trial of Preventing Hypertension) study, including 141 individuals with high-normal BP, aldosterone or PRA did not differ between subjects with MetS and controls without MetS [13].

          More recently, we evaluated cross-sectionally the relationships of PAC to MetS and LV mass in 450 Caucasian patients with essential hypertension [14]. 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, plasma renin activity and aldosterone, and an echocardiogram. Secondary hypertension was ruled out by clinical examination, urinalysis, and determination of serum creatinine and electrolytes, plasma renin activity (PRA), plasma aldosterone, renal echography, and where appropriate, by performing plasma catecholamine assay, echo-Doppler of renal arteries and renoscintigraphy. Primary aldosteronism was excluded on the basis of an aldosterone/renin ratio > 40.

          Compared with the subjects without metabolic syndrome (n = 249), those with MetS (n = 201) had higher levels of age-adjusted PAC (Figure 1) and greater LV mass indexed for both body surface area (LVMI) (106 ± 34 vs 97 ± 31 g/m2; p = 0.006) and height2.7 (LVMH2.7) (63 ± 21 vs 55 ± 18 g/m2.7; p < 0.001). The difference regarding PAC was independent from PRA and was detected also in a subset of hypertensive individuals never pharmacologically treated for high BP.

 


 

Figure 1. Age-adjusted values of plasma aldosterone concentration in subjects without metabolic syndrome (MetS) (yellow bars) and in those with MetS (red bars). Data in figure are given as means ± SEM.

          

          However, we found that the association of the MetS with PAC was mainly related to one of its key individual components, which is obesity, because it lost statistical significance after adjustment in multivariate analysis for waist circumference or BMI [14]. This result seems to be biologically plausible, because several mechanisms may explain whereby aldosterone is potentially linked to obesity.   Indeed, it has been demonstrated that a variety of adipose tissue-derived factors can stimulate aldosterone synthesis. Goodfriend et al. [15] reported that epoxy-keto derivative of linoleic acid (EKODE), one of the oxidized products of fatty acids, not native linoleic acid, stimulates aldosterone secretion in rat adrenal cells. They hypothesized that the site of oxidative modification might be the liver and showed that incubation of linoleic acid with hepatocytes gave rise to compounds that enhanced aldosterone production in adrenal cells [15]. Furthermore, in vitro experiments documented that human adipocytes secrete potent mineralcorticoid releasing factors, not yet well identified [16]. On the other hand, the low levels of plasma natriuretic peptides observed in individuals with obesity and MetS [17] might predispose to increased adrenal production of aldosterone, because the stimulatory effect of EKODE on aldosteronogenesis is inhibited by atrial natriuretic peptide [15].

          Moreover, human adipose tissue produces several components of the renin-angiotensin system, mainly angiotensinogen, which can also be secreted into the bloodstream, especially during β-adrenergic stimulation, contributing to the circulating pool of angiotensinogen and probably of plasma aldosterone [18].

          Furthermore, insulin resistance and the accompanying compensatory hyperinsulinemia, which are regarded as the pathophysiological key features underlying visceral obesity and MetS, may contribute to increase PAC, because insulin is known to stimulate aldosterone synthesis in vitro [19] and reciprocal relationships among aldosterone, insulin resistance, and hyperinsulinemia have been described in clinical and experimental studies [12,20-21]

          Moreover, it is noteworthy that in the Framingham Offspring Study, including predominantly white participants, higher circulating aldosterone levels predisposed persons to the subsequent development of the MetS [22].

 

Plasma Aldosterone and Left Ventricular Mass

 

Other important results of our study need to be discussed. In patients with and in those without MetS, LVMI (Figure 2) and LVMH2.7 correlated significantly with plasma aldosterone levels (all p < 0.01). Whereas in the group with the MetS these associations remained statistically significant (p ≤ 0.007 for both LVMI and LVMH2.7), after adjustment for various potential confounders, including BMI and blood pressures in multiple regression analyses, in the subjects without MetS the same relationships became of borderline statistical significance [14].

 


 

Figure 2: Relationship between plasma aldosterone concentration and left ventricular mass indexed for body surface area (LVMI) in essential hypertensive patients with metabolic syndrome. Dotted hyperbolic lines represent the 95% confidence bands around the regression line.

 

          Several lines of evidence suggest a key role for aldosterone in LV remodeling [10]. In morphological findings obtained from in vivo and in vitro studies, increased levels of aldosterone in the circulation were found to be related with the excessive accumulation of collagen causing myocardial fibrosis [23]. However, although there is evidence that primary aldosteronism is associated with LVH [24], it is not clear whether aldosterone plays an independent role in the development of LVH in patients with essential hypertension. Several investigations exploring this issue in the past achieved inconsistent results [25-26]. Some of studies these were limited by small samples or incomplete adjustment for confounders.

          Our findings seem to suggest that in essential hypertensive patients, plasma aldosterone may contribute to increase LV mass independently of its impact on systemic BP. This was particularly true in the group of subjects with the MetS, where the association between PAC and LV mass, regardless of the method used for indexation, remained statistically significant even after multivariate adjustment. Therefore, the elevated levels of aldosterone may help to explain the increased LV mass observed in the subjects with the MetS and, in this way, may contribute to enhance the cardiovascular risk associated with the MetS.

          Our results may suggest that, in addition to lifestyle interventions designed to reduce body weight, treatment with aldosterone antagonists may have potential beneficial effects in the hypertensive subjects with the MetS. Additional studies are needed to verify this hypothesis.

References

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