Editorial
Adiponectin and Aldosterone in Left Ventricular Hypertrophy: An Intriguing Interplay
Angiology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319714527785 ang.sagepub.com
Panagiotis Anagnostis, MD1,2, Niki Katsiki, MD, PhD2, Vasilios G. Athyros, MD, PhD2, and Asterios Karagiannis, MD, PhD2
Peer et al in this issue of Angiology assess the value of various biomarkers in the development of left ventricular hypertrophy (LVH) in a hypertensive nondiabetic cohort.1 Despite limitations, such as the small sample size and cross-sectional design, they concluded that adiponectin and aldosterone, in particular aldosterone to renin ratio, were independent predictors of LVH.1 Adiponectin is a white adipose tissue-derived 30-kDa protein that exerts insulin-sensitizing, anti-inflammatory, and antiatherosclerotic properties.2 It is downregulated in obesity (including metabolic syndrome [MetS], type 2 diabetes mellitus [T2DM], and fatty liver disease] and its levels have been inversely associated with high-density lipoprotein cholesterol and homeostatic model assessment insulin resistance (HOMA-IR) index.2-4 It has also been recognized as an independent cardiovascular disease risk factor.2,5 Adiponectin levels seem to be decreased in patients with coronary heart disease and stroke5 although adiponectin gene polymorphisms may also contribute to this relationship.6,7 Aldosterone mainly regulates sodium excretion by acting on its mineralocorticoid receptor (MR) at the distal nephron. It is secreted by the adrenal zona glomeruloza under the stimulation of angiotensin II (AT-II), potassium, and adrenocorticotropic hormone (ACTH).8 However, MRs have been identified in other tissues, such as heart (cardiomyocytes) and vasculature, including both endothelial and vascular smooth muscle cells (VSMCs).8 Except for acting on gene expression, some nongenomic effects have also been described for aldosterone, both on VSMC and endothelial cells, as well as on the heart, explaining in part the aldosterone-induced vasoconstriction via a rapid increase in intracellular calcium and Naþ–Kþ–2Cl cotransporter activity, respectively.8 Aldosterone excess has been associated with endothelial damage and cardiovascular injury, including inflammation, oxidative stress, cardiac hypertrophy, and fibrosis, mainly through its MRs, apart from sodium retention and hypertension.9,10 It also increases angiotensinconverting enzyme (ACE) and angiotensin I receptor messenger RNA (mRNA) expression in the heart and vasculature.11 Furthermore, increased aldosterone concentrations have been associated with the development of MetS and T2DM.9 Aldosterone decreases glucose-stimulated insulin release12 and
insulin receptor expression in adipocytes and monocytes in an MR-dependent way.13 Primary aldosteronism (PA) is associated with decreased insulin sensitivity compared with essential hypertension, which seems to improve after surgical treatment.14 Interestingly, patients with PA have increased cardiovascular morbidity compared with age- and sexmatched controls with essential hypertension, indicating the multifocal role of aldosterone in the cardiovascular system.15
Interplay Between Adiponectin and Aldosterone The findings of Peer at al1 raise questions regarding the contribution of these 2 hormones in the pathogenesis of LVH. It could be that obesity, which is associated with hypoadiponectinemia, causes hyperactivation of the renin–angiotensin– aldosterone system (RAAS) resulting in hypertension and LVH.16 Another mechanism could be based on the upregulation of hypothalamus–pituitary–adrenal (HPA) axis, which has been reported in obesity and provides a hypothesis for the pathogenesis of MetS.17 Hyperactivation of HPA may increase aldosterone production via stimulation of adrenal zona glomeruloza by ACTH, providing a plausible link between cardiac hypertrophy and fibrosis in patients with MetS and hypoadiponectinemia.17 Furthermore, an association between high aldosterone and increased fat mass has been reported.18 However, apart from the coexistence of hypoadiponectinemia with aldosterone excess in obesity states, a more complex interplay seems to exist. Human adipocytes stimulate adrenocortical steroidogenesis and aldosterone secretion by aldosterone-releasing factors, independent of AT-II.19,20 Elevated concentrations of circulating angiotensinogen, renin, and aldosterone as well as ACE activity have been reported in 1
Division of Endocrinology, Police Medical Centre, Thessaloniki, Greece Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
2
Corresponding Author: Panagiotis Anagnostis, Division of Endocrinology, Police Medical Centre, Sarantaporou 10, Thessaloniki 54640, Greece. Email: [email protected]
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obese patients.21 Angiotensinogen has also been implicated in the pathogenesis of MetS.20 An overexpression of RAAS in visceral adipose tissue (VAT) has also been supported.22 On the other hand, both brown and white adipose tissue express MRs and aldosterone appears to induce adipogenesis and adipocyte differentiation and may modulate adiponectin production via these receptors.20,21 Animal studies have shown that hypoadiponectinemia further augments aldosterone-induced LVH and exacerbates diastolic dysfunction and diastolic heart failure.23 It also increases expression of inflammatory proteins, such as interferon g and tumor necrosis factor a and myocardial atrial natriuretic peptide, which are implicated in the process of cardiac remodeling.22 On the other hand, it has been demonstrated that mRNA and protein of adiponectin receptors (AdipoR1 and AdipoR2) are also expressed in cardiomyocytes,24 as well as, in human adrenal cortex, and in aldosterone-producing adenomas.25,26 Adiponectin infusion reduces basal production of corticosterone and aldosterone and inhibits ACTH-induced steroid secretion, accompanied by a parallel increased expression of the key genes involved in steroidogenesis, such as 11b-hydroxylase (CYP11B1) and aldosterone synthase genes. These findings indicate a modulatory role of adiponectin in steroidogenesis.26 On the other hand, aldosterone infusion in mice reduces adiponectin production from adipose tissue.23 Useful data further supporting the interplay between adiponectin and aldosterone have emerged from studies in patients with PA. Lower plasma adiponectin and higher resistin (an adipokine associated with systemic inflammation and insulin resistance)2 concentrations have been reported in patients with PA compared to normotensive patients and those with essential hypertension, providing a plausible explanation for the increased insulin resistance observed in PA.27 These data were also confirmed by another study in patients with PA, which showed lower adiponectin concentrations and increased insulin resistance (demonstrated by HOMA-IR) compared to patients with low-renin essential hypertension.28 Moreover, the gene encoding adiponectin, ADIPOQ, as well as the genes implicated in lipid metabolism, such as those encoding cytosolic phosphoenolpyruvate carboxykinase 1, were found to be downregulated in VAT in patients with PA, compared with age-, sex-, and body mass index-matched controls.29 In this study, peroxisome proliferator-activated receptor g (PPARg) was also downregulated, which may also play a role in the downregulation of the other genes.29 In a similar context, adiponectin gene polymorphisms have been associated with specific phenotypes in patients with PA. In particular, the 276T/T genotype has been associated with worse metabolic profile and a higher risk of the MetS compared to patients with essential hypertension.30 In contrast, 45T/G þ G/G genotypes are related to lower waist circumference and HOMA-IR values and serum aldosterone levels.30 We found only 1 study investigating the association of adiponectin gene polymorphisms with myocardial fibrosis. The authors of this study reported that genotype (GG þ GT) of singlenucleotide polymorphism (SNP) þ45 T/G (rs2241766) variant in exon 2 was a major risk factor for myocardial fibrosis in
patients with hypertension.31 SNP11377GG and SNP45TG þ GG genotypes have been associated with increased risk of MetS and increased carotid artery intima–media thickness in T2DM although data are generally inconclusive.6
Can We Target Both Aldosterone and Adiponectin in Order to Improve LVH? The above-mentioned data raise the question whether both aldosterone inhibition and increase in adiponectin concentrations are feasible and potentially beneficial in patients with LVH. Both surgical and medical treatment of patients with PA having spironolactone seem to restore insulin sensitivity to a similar extent.14 Inhibition of RAAS at the level of either ACE or AT-II receptors or MRs seems to abrogate many of the adverse effects of aldosterone on the heart and vasculature.32-34 Telmisartan may delay myocardial fibrosis, by reducing myocardial local AT-II levels by directly blocking AT-II receptors. It can also decrease myocardial collagen fibrosis and delay hypertensive LVH.32 A recent meta-analysis of randomized controlled trials showed that telmisartan improves HOMA-IR and increases adiponectin levels in patients with MetS.33 Interestingly, the 4E-Left Ventricular Hypertrophy Study compared the effects of the ACE inhibitor enalapril with the MR antagonist eplerenone or their combination in patients with hypertension in terms of LVH regression. Both enalapril and eplerenone decreased left ventricular mass assessed by magnetic resonance imaging but their combination was more effective than eplerenone alone.34 Regarding their effect on adiponectin, eplerenone has been shown in vitro to inhibit the aforementioned decreased expression of ADIPOQ gene by aldosterone in patients with PA.29 In addition, animal studies have shown that enalapril may prevent the high-fat diet-induced decrease in adiponectin levels and improve insulin sensitivity, an effect that was not evident with aliskiren or losartan.35 In another study, ramipril and valsartan increased plasma adiponectin levels significantly higher than metoprolol, amlodipine, or doxazosin.36 Since a downregulation of PPARg and ADIPOQ genes has been reported in patients with PA, a potentially beneficial role of PPARg agonists such as thiazolidinediones may be speculated. In 1 study, rosiglitazone improved cardiac structure and function in Zucker diabetic fatty rats and increased adiponectin levels but did not improve left ventricular mass.37 Finally, there are some data indicating a potential beneficial role of statins, mainly atorvastatin and rosuvastatin, on adiponectin levels.2 Apart from oral hypoglycemic, antihypertensive, and hypolipidemic drugs, adiponectin concentrations may be affected by insulin therapy and antiobesity agents.38,39 Regarding LVH, statins were shown to reverse hypertension-induced cardiac remodeling40 and LVH in animal models of hypertrophic cardiomyopathy (HCM).41 However, this effect was not demonstrated in humans with HCM.42 In another study, adding atorvastatin to amlodipine further reversed LVH in patients with hypertension having familial hypercholesterolemia.43 In contrast, rosuvastatin did not have any significant effect on LVH in 1 study of patients with hypertension.44
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In conclusion, a complex interplay between aldosterone and adiponectin may be involved in the pathogenesis of LVH. This is mainly supported by the expression of MRs in adipose tissue and AdipoR1 and AdipoR2 in adrenal glands, by the role of adiponectin gene polymorphisms and by the metabolic profile in patients with PA. Simultaneous reduction in aldosterone levels or inhibition of its action, along with an increase in adiponectin levels, might provide cardiovascular protection in patients with LVH. References 1. Peer M, Matasb Z, Harpaz D, Shargorodsky M. Adiponectin as an independent predictor of left ventricular hypertrophy in hypertensive non-diabetic patients [published online February 26, 2014]. Angiology. 2014. 2. Athyros VG, Tziomalos K, Karagiannis A, Anagnostis P, Mikhailidis DP. Should adipokines be considered in the choice of the treatment of obesity-related health problems? Curr Drug Targets. 2010;11(1):122-135. 3. Wolfson N, Gavish D, Matas Z, Boaz M, Shargorodsky M. Relation of adiponectin to glucose tolerance status, adiposity, and cardiovascular risk factor load. Exp Diabetes Res. 2012;2012:250621. 4. Katsiki N, Yovos JG, Gotzamani-Psarrakou A, Karamitsos DT. Adipokines and vascular risk in type 2 diabetes mellitus. Angiology. 2011;62(8):601-604. 5. Zhang BC, Liu WJ, Che WL, Xu YW. Serum total adiponectin level and risk of cardiovascular disease in Han Chinese populations: a meta-analysis of 17 case-control studies. Clin Endocrinol (Oxf). 2012;77(3):370-378. 6. Anagnostis P, Athyros VG, Kita M, Karagiannis A. Is there any association between adiponectin gene polymorphisms and cardiovascular disease? Angiology. 2013;64(4):253-256. 7. Rizk NM, El-Menyar A, Marei I, et al. Association of adiponectin gene polymorphism (þT45G) with acute coronary syndrome and circulating adiponectin levels. Angiology. 2013;64(4):257-265. 8. Marney AM, Brown NJ. Aldosterone and end-organ damage. Clin Sci (Lond). 2007;113(6):267-278. 9. Karagianis A. Treatment of primary aldosteronism: where are we now? Rev Endocr Metab Disord. 2011;12(1):15-20. 10. Nishizaka MK, Zaman MA, Green SA, Renfroe KY, Calhoun DA. Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism. Circulation. 2004;109(23):2857-2861. 11. Harada E, Yoshimura M, Yasue H, et al. Aldosterone induces angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes. Circulation. 2001;104(2):137-139. 12. Pierluissi J, Navas FO, Ashcroft SJ. Effect of adrenal steroids on insulin release from cultured rat islets of Langerhans. Diabetologia. 1986;29(2):119-121. 13. Campion J, Maestro B, Mata F, Davila N, Carranza MC, Calle C. Inhibition by aldosterone of insulin receptor mRNA levels and insulin binding in U-937 human promonocytic cells. J Steroid Biochem Mol Biol. 1999;70(4-6):211-218. 14. Catena C, Lapenna R, Baroselli S, et al. Insulin sensitivity in patients with primary aldosteronism: a follow-up study. J Clin Endocrinol Metab. 2006;91(9):3457-3463.
15. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45(8): 1243-1248. 16. Calhoun DA, Jones D, Textor S, et al; American Heart Association Professional Education Committee. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American heart association professional education committee of the council for high blood pressure research. Circulation. 2008; 117(25):e510-e526. 17. Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009; 94(8):2692-2701. 18. Goodfriend TL, Kelley DE, Goodpaster BH, Winters SJ. Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Obes Res. 1999;7(4):355-362. 19. Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, et al. Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci USA. 2003;100(24):14211-14216. 20. Essick EE, Sam F. Cardiac hypertrophy and fibrosis in the metabolic syndrome: a role for aldosterone and the mineralocorticoid receptor. Int J Hypertens. 2011;2011:346985. 21. Ronconi V, Turchi F, Bujalska IJ, Giacchetti G, Boscaro M. Adipose cell–adrenal interactions: current knowledge and future perspectives. Trends Endocrinol Metab. 2008;19(3):100-1103. 22. Giacchetti G, Faloia E, Mariniello B, et al. Overexpression of the renin–angiotensin system in human visceral adipose tissue in normal and overweight subjects. Am J Hypertens. 2002;15(5):381-388. 23. Sam F, Duhaney TA, Sato K, et al. Adiponectin deficiency, diastolic dysfunction, and diastolic heart failure. Endocrinology. 2010;151(1):322-331. 24. Ding G, Qin Q, He N, et al. Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor gamma. J Mol Cell Cardiol. 2007;43(1):73-84. 25. Rossi GP, Sticchi D, Giuliani L, et al. Adiponectin receptor expression in the human adrenal cortex and aldosteroneproducing adenomas. Int J Mol Med. 2006;17(6):975-980. 26. Li P, Sun F, Cao HM, et al. Expression of adiponectin receptors in mouse adrenal glands and the adrenocortical Y-1 cell line: adiponectin regulates steroidogenesis. Biochem Biophys Res Commun. 2009;390(4):1208-1213. 27. Iacobellis G, Petramala L, Cotesta D, et al. Adipokines and cardiometabolic profile in primary hyperaldosteronism. J Clin Endocrinol Metab. 2010;95(5):2391-2398. 28. Fallo F, Della Mea P, Sonino N, et al. Adiponectin and insulin sensitivity in primary aldosteronism. Am J Hypertens. 2007; 20(8):855-861. 29. Williams TA, Monticone S, Urbanet R, et al. Genes implicated in insulin resistance are down-regulated in primary aldosteronism patients. Mol Cell Endocrinol. 2012;355(1):162-168. 30. Ronconi V, Turchi F, Rilli S, et al. Metabolic syndrome in primary aldosteronism and essential hypertension: relationship to adiponectin gene variants. Nutr Metab Cardiovasc Dis. 2010; 20(2):93-100.
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31. Yan CJ, Li SM, Xiao Q, et al. Influence of serum adiponectin level and SNP þ45 polymorphism of adiponectin gene on myocardial fibrosis. J Zhejiang Univ Sci B. 2013;14(8):721-728. 32. Zhang Y, Shao L, Ma A, et al. Telmisartan delays myocardial fibrosis in rats with hypertensive left ventricular hypertrophy by TGF-b1/Smad signal pathway. Hypertens Res. 2014;37(1):43-49. 33. Takagi H, Niwa M, Mizuno Y, Goto SN, Umemoto T; ALICE (All-literature investigation of cardiovascular evidence) group. Telmisartan as a metabolic sartan: the first meta-analysis of randomized controlled trials in metabolic syndrome. J Am Soc Hypertens. 2013;7(3):229-235. 34. Pitt B, Reichek N, Willenbrock R, et al. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation. 2003;108(15):1831-1838. 35. Frantz ED, Crespo-Mascarenhas C, Barreto-Vianna AR, Aguila MB, Mandarim-de-Lacerda CA. Renin–angiotensin system blockers protect pancreatic islets against diet-induced obesity and insulin resistance in mice. PLoS One. 2013;8(7):e67192. 36. Yilmaz MI, Sonmez A, Caglar K, et al. Effect of antihypertensive agents on plasma adiponectin levels in hypertensive patients with metabolic syndrome. Nephrology (Carlton). 2007;12(2):147-153. 37. Wang X, Liu X, Zhan Y, et al. Pharmacogenomic, physiological, and biochemical investigations on safety and efficacy biomarkers associated with the peroxisome proliferator-activated receptorgamma activator rosiglitazone in rodents: a translational medicine investigation. J Pharmacol Exp Ther. 2010;334(3):820-829. 38. Katsiki N, Mikhailidis DP, Gotzamani-Psarrakou A, Didangelos TP, Yovos JG, Karamitsos DT. Effects of improving glycemic
39.
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control with insulin on leptin, adiponectin, ghrelin and neuropeptide Y levels in patients with type 2 diabetes mellitus: a pilot study. Open Cardiovasc Med J. 2011;5:136-147. Katsiki N, Mikhailidis DP, Gotzamani-Psarrakou A, Yovos JG, Karamitsos D. Effect of various treatments on leptin, adiponectin, ghrelin and neuropeptide Y in patients with type 2 diabetes mellitus. Expert Opin Ther Targets. 2011;15(4):401-420. Geng J, Zhao Z, Kang W, Wang W, Zhang Y, Zhiming GE. Atorvastatin reverses cardiac remodeling possibly through regulation of protein kinase D/myocyte enhancer factor 2D activation in spontaneously hypertensive rats. Pharmacol Res. 2010;61(1): 40-47. Senthil V, Chen SN, Tsybouleva N, et al. Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circ Res. 2005;97(3): 285-292. Nagueh SF, Lombardi R, Tan Y, Wang J, Willerson JT, Marian AJ. Atorvastatin and cardiac hypertrophy and function in hypertrophic cardiomyopathy: a pilot study. Eur J Clin Invest. 2010; 40(11):976-983. Ge CJ, Lu SZ, Chen YD, Wu XF, Hu SJ, Ji Y. Synergistic effect of amlodipine and atorvastatin on blood pressure, left ventricular remodeling, and C-reactive protein in hypertensive patients with primary hypercholesterolemia. Heart Vessels. 2008;23(2): 91-95. Folkeringa RJ, de Vos C, Pinto YM, et al.No effect of rosuvastatin on left ventricular hypertrophy in patients with hypertension: a prospective randomised open-label study with blinded endpoint assessment. Int J Cardiol. 2010;145(1):156-158.
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Adiponectin and Aldosterone in Left Ventricular Hypertrophy: An Intriguing Interplay
Angiology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319714527785 ang.sagepub.com
Panagiotis Anagnostis, MD1,2, Niki Katsiki, MD, PhD2, Vasilios G. Athyros, MD, PhD2, and Asterios Karagiannis, MD, PhD2
Peer et al in this issue of Angiology assess the value of various biomarkers in the development of left ventricular hypertrophy (LVH) in a hypertensive nondiabetic cohort.1 Despite limitations, such as the small sample size and cross-sectional design, they concluded that adiponectin and aldosterone, in particular aldosterone to renin ratio, were independent predictors of LVH.1 Adiponectin is a white adipose tissue-derived 30-kDa protein that exerts insulin-sensitizing, anti-inflammatory, and antiatherosclerotic properties.2 It is downregulated in obesity (including metabolic syndrome [MetS], type 2 diabetes mellitus [T2DM], and fatty liver disease] and its levels have been inversely associated with high-density lipoprotein cholesterol and homeostatic model assessment insulin resistance (HOMA-IR) index.2-4 It has also been recognized as an independent cardiovascular disease risk factor.2,5 Adiponectin levels seem to be decreased in patients with coronary heart disease and stroke5 although adiponectin gene polymorphisms may also contribute to this relationship.6,7 Aldosterone mainly regulates sodium excretion by acting on its mineralocorticoid receptor (MR) at the distal nephron. It is secreted by the adrenal zona glomeruloza under the stimulation of angiotensin II (AT-II), potassium, and adrenocorticotropic hormone (ACTH).8 However, MRs have been identified in other tissues, such as heart (cardiomyocytes) and vasculature, including both endothelial and vascular smooth muscle cells (VSMCs).8 Except for acting on gene expression, some nongenomic effects have also been described for aldosterone, both on VSMC and endothelial cells, as well as on the heart, explaining in part the aldosterone-induced vasoconstriction via a rapid increase in intracellular calcium and Naþ–Kþ–2Cl cotransporter activity, respectively.8 Aldosterone excess has been associated with endothelial damage and cardiovascular injury, including inflammation, oxidative stress, cardiac hypertrophy, and fibrosis, mainly through its MRs, apart from sodium retention and hypertension.9,10 It also increases angiotensinconverting enzyme (ACE) and angiotensin I receptor messenger RNA (mRNA) expression in the heart and vasculature.11 Furthermore, increased aldosterone concentrations have been associated with the development of MetS and T2DM.9 Aldosterone decreases glucose-stimulated insulin release12 and
insulin receptor expression in adipocytes and monocytes in an MR-dependent way.13 Primary aldosteronism (PA) is associated with decreased insulin sensitivity compared with essential hypertension, which seems to improve after surgical treatment.14 Interestingly, patients with PA have increased cardiovascular morbidity compared with age- and sexmatched controls with essential hypertension, indicating the multifocal role of aldosterone in the cardiovascular system.15
Interplay Between Adiponectin and Aldosterone The findings of Peer at al1 raise questions regarding the contribution of these 2 hormones in the pathogenesis of LVH. It could be that obesity, which is associated with hypoadiponectinemia, causes hyperactivation of the renin–angiotensin– aldosterone system (RAAS) resulting in hypertension and LVH.16 Another mechanism could be based on the upregulation of hypothalamus–pituitary–adrenal (HPA) axis, which has been reported in obesity and provides a hypothesis for the pathogenesis of MetS.17 Hyperactivation of HPA may increase aldosterone production via stimulation of adrenal zona glomeruloza by ACTH, providing a plausible link between cardiac hypertrophy and fibrosis in patients with MetS and hypoadiponectinemia.17 Furthermore, an association between high aldosterone and increased fat mass has been reported.18 However, apart from the coexistence of hypoadiponectinemia with aldosterone excess in obesity states, a more complex interplay seems to exist. Human adipocytes stimulate adrenocortical steroidogenesis and aldosterone secretion by aldosterone-releasing factors, independent of AT-II.19,20 Elevated concentrations of circulating angiotensinogen, renin, and aldosterone as well as ACE activity have been reported in 1
Division of Endocrinology, Police Medical Centre, Thessaloniki, Greece Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
2
Corresponding Author: Panagiotis Anagnostis, Division of Endocrinology, Police Medical Centre, Sarantaporou 10, Thessaloniki 54640, Greece. Email: [email protected]
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obese patients.21 Angiotensinogen has also been implicated in the pathogenesis of MetS.20 An overexpression of RAAS in visceral adipose tissue (VAT) has also been supported.22 On the other hand, both brown and white adipose tissue express MRs and aldosterone appears to induce adipogenesis and adipocyte differentiation and may modulate adiponectin production via these receptors.20,21 Animal studies have shown that hypoadiponectinemia further augments aldosterone-induced LVH and exacerbates diastolic dysfunction and diastolic heart failure.23 It also increases expression of inflammatory proteins, such as interferon g and tumor necrosis factor a and myocardial atrial natriuretic peptide, which are implicated in the process of cardiac remodeling.22 On the other hand, it has been demonstrated that mRNA and protein of adiponectin receptors (AdipoR1 and AdipoR2) are also expressed in cardiomyocytes,24 as well as, in human adrenal cortex, and in aldosterone-producing adenomas.25,26 Adiponectin infusion reduces basal production of corticosterone and aldosterone and inhibits ACTH-induced steroid secretion, accompanied by a parallel increased expression of the key genes involved in steroidogenesis, such as 11b-hydroxylase (CYP11B1) and aldosterone synthase genes. These findings indicate a modulatory role of adiponectin in steroidogenesis.26 On the other hand, aldosterone infusion in mice reduces adiponectin production from adipose tissue.23 Useful data further supporting the interplay between adiponectin and aldosterone have emerged from studies in patients with PA. Lower plasma adiponectin and higher resistin (an adipokine associated with systemic inflammation and insulin resistance)2 concentrations have been reported in patients with PA compared to normotensive patients and those with essential hypertension, providing a plausible explanation for the increased insulin resistance observed in PA.27 These data were also confirmed by another study in patients with PA, which showed lower adiponectin concentrations and increased insulin resistance (demonstrated by HOMA-IR) compared to patients with low-renin essential hypertension.28 Moreover, the gene encoding adiponectin, ADIPOQ, as well as the genes implicated in lipid metabolism, such as those encoding cytosolic phosphoenolpyruvate carboxykinase 1, were found to be downregulated in VAT in patients with PA, compared with age-, sex-, and body mass index-matched controls.29 In this study, peroxisome proliferator-activated receptor g (PPARg) was also downregulated, which may also play a role in the downregulation of the other genes.29 In a similar context, adiponectin gene polymorphisms have been associated with specific phenotypes in patients with PA. In particular, the 276T/T genotype has been associated with worse metabolic profile and a higher risk of the MetS compared to patients with essential hypertension.30 In contrast, 45T/G þ G/G genotypes are related to lower waist circumference and HOMA-IR values and serum aldosterone levels.30 We found only 1 study investigating the association of adiponectin gene polymorphisms with myocardial fibrosis. The authors of this study reported that genotype (GG þ GT) of singlenucleotide polymorphism (SNP) þ45 T/G (rs2241766) variant in exon 2 was a major risk factor for myocardial fibrosis in
patients with hypertension.31 SNP11377GG and SNP45TG þ GG genotypes have been associated with increased risk of MetS and increased carotid artery intima–media thickness in T2DM although data are generally inconclusive.6
Can We Target Both Aldosterone and Adiponectin in Order to Improve LVH? The above-mentioned data raise the question whether both aldosterone inhibition and increase in adiponectin concentrations are feasible and potentially beneficial in patients with LVH. Both surgical and medical treatment of patients with PA having spironolactone seem to restore insulin sensitivity to a similar extent.14 Inhibition of RAAS at the level of either ACE or AT-II receptors or MRs seems to abrogate many of the adverse effects of aldosterone on the heart and vasculature.32-34 Telmisartan may delay myocardial fibrosis, by reducing myocardial local AT-II levels by directly blocking AT-II receptors. It can also decrease myocardial collagen fibrosis and delay hypertensive LVH.32 A recent meta-analysis of randomized controlled trials showed that telmisartan improves HOMA-IR and increases adiponectin levels in patients with MetS.33 Interestingly, the 4E-Left Ventricular Hypertrophy Study compared the effects of the ACE inhibitor enalapril with the MR antagonist eplerenone or their combination in patients with hypertension in terms of LVH regression. Both enalapril and eplerenone decreased left ventricular mass assessed by magnetic resonance imaging but their combination was more effective than eplerenone alone.34 Regarding their effect on adiponectin, eplerenone has been shown in vitro to inhibit the aforementioned decreased expression of ADIPOQ gene by aldosterone in patients with PA.29 In addition, animal studies have shown that enalapril may prevent the high-fat diet-induced decrease in adiponectin levels and improve insulin sensitivity, an effect that was not evident with aliskiren or losartan.35 In another study, ramipril and valsartan increased plasma adiponectin levels significantly higher than metoprolol, amlodipine, or doxazosin.36 Since a downregulation of PPARg and ADIPOQ genes has been reported in patients with PA, a potentially beneficial role of PPARg agonists such as thiazolidinediones may be speculated. In 1 study, rosiglitazone improved cardiac structure and function in Zucker diabetic fatty rats and increased adiponectin levels but did not improve left ventricular mass.37 Finally, there are some data indicating a potential beneficial role of statins, mainly atorvastatin and rosuvastatin, on adiponectin levels.2 Apart from oral hypoglycemic, antihypertensive, and hypolipidemic drugs, adiponectin concentrations may be affected by insulin therapy and antiobesity agents.38,39 Regarding LVH, statins were shown to reverse hypertension-induced cardiac remodeling40 and LVH in animal models of hypertrophic cardiomyopathy (HCM).41 However, this effect was not demonstrated in humans with HCM.42 In another study, adding atorvastatin to amlodipine further reversed LVH in patients with hypertension having familial hypercholesterolemia.43 In contrast, rosuvastatin did not have any significant effect on LVH in 1 study of patients with hypertension.44
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