Abstract
The causes of adrenal Cushing’s syndrome (CS) encompass a wide spectrum of adrenal cortisol proliferations that exhibit clinical and molecular heterogeneity. The aims of our study were to investigate whether clinical and molecular heterogeneity influences endothelial function and metabolic abnormalities in patients with cortisol-producing adenoma (CPA). We retrospectively enrolled 25 patients with CPA and 45 patients with essential hypertension (EH). All CPAs were studied by direct sequencing of PRKACA. Flow-mediated vasodilation (FMD), an index of vascular endothelial function, was significantly lower in CS and subclinical CS (SCS) groups than in the EH group. FMD impairment did not differ significantly between CS and SCS groups. No differences in FMD were seen between PRKACA mutant and wild-type groups. FMD correlated negatively with hemoglobin A1c (HbA1c) in both PRKACA mutant and wild-type groups, as well as in CS and SCS groups. After adrenalectomy, systolic blood pressure (SBP) and HbA1c decreased significantly from baseline in the CS group, and SBP and low-density lipoprotein cholesterol (LDL-C) decreased significantly from baseline in the SCS group. While SBP and LDL-C decreased significantly from baseline in patients with wild-type PRKACA, only HbA1c decreased from baseline in patients harboring PRKACA mutations. Our data showed that patients with CPA have impaired endothelial function compared with EH patients and suggest the need for strict monitoring of atherosclerosis, even in patients with SCS or without PRKACA mutation.
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Dekkers OM, Horváth-Puhó E, Jørgensen JO, Cannegieter SC, Ehrenstein V, Vandenbroucke JP, Pereira AM, Sørensen HT (2013) Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab 98:2277–2284
Bancos I, Prete A (2021) Approach to the patient with adrenal incidentaloma. J Clin Endocrinol Metab 106:3331–3353
Faggiano A, Pivonello R, Spiezia S, De Martino MC, Filippella M, Di Somma C, Lombardi G, Colao A (2003) Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab 88:2527–2533
Yanase T, Oki Y, Katabami T, Otsuki M, Kageyama K, Tanaka T, Kawate H, Tanabe M, Doi M, Akehi Y, Ichijo T (2018) New diagnostic criteria of adrenal subclinical Cushing’s syndrome: opinion from the Japan endocrine society. Endocr J 65(4):383–393
Di Dalmazi G, Pasquali R (2015) Adrenal adenomas, subclinical hypercortisolism, and cardiovascular outcomes. Curr Opin Endocrinol Diabetes Obes 22:163–168
Beuschlein F, Fassnacht M, Assié G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Bertherat RM, J, Strom TM, Allolio B, (2014) Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N Engl J Med 370:1019–1028
Mete O, Duan K (2018) The many faces of primary aldosteronism and Cushing syndrome: a reflection of adrenocortical tumor heterogeneity. Front Med (Lausanne) 5:54
Kamilaris CDC, Hannah-Shmouni F, Stratakis CA (2020) Adrenocortical tumorigenesis: lessons from genetics. Best Pract Res Clin Endocrinol Metab 34:101428
Rege J, Hoxie J, Liu CJ, Cash MN, Luther JM, Gellert L, Turcu AF, Else T, Giordano TJ, Udager AM, Rainey WE, Nanba K (2022) Targeted mutational analysis of cortisol-producing adenomas. J Clin Endocrinol Metab 107:e594–e603
Li X, Wang B, Tang L, Lang B, Zhang Y, Zhang F, Chen L, Ouyang J, Zhang X (2016) Clinical characteristics of PRKACA mutations in Chinese patients with adrenal lesions: a single-centre study. Clin Endocrinol (Oxf) 85:954–961
Baba R, Oki K, Gomez-Sanchez CE, Otagaki Y, Itcho K, Kobuke K, Kodama T, Nagano G, Ohno H, Yoneda M, Hattori N (2021) Genotype-specific cortisol production associated with Cushing’s syndrome adenoma with PRKACA mutations. Mol Cell Endocrinol 538:111456
Thiel A, Reis AC, Haase M, Goh G, Schott M, Willenberg HS, Scholl UI (2015) PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases. Eur J Endocrinol 172:677–685
Horikoshi T, Nakamura T, Yoshizaki T, Watanabe Y, Uematsu M, Kobayashi T, Nakamura K, Saito Y, Obata JE, Kugiyama K (2021) Impact of persistent endothelial dysfunction in an infarct-related coronary artery on future major adverse cardiovascular event occurrence in STEMI survivors. Heart Vessels 36:472–482
Tanaka A, Tomiyama H, Maruhashi T, Matsuzawa Y, Miyoshi T, Kabutoya T, Kario K, Sugiyama S, Munakata M, Ito H, Ueda S, Vlachopoulos C, Higashi Y, Inoue T, Node K (2018) Physiological diagnostic criteria for vascular failure. Hypertension 72:1060–1071
Xiao K, Liu M, Sun X, Zhang Y, Si J, Shi N, Sun L, Miao Z, Zhang H, Zhao T, Liu Z, Fan Z, Gao J, Li J (2023) Association of vascular endothelial function and quality of life in patients with ischemia and non-obstructive coronary artery disease. Heart Vessels 38:617–625
Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM (2008) The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:1526–1540
Watanabe D, Morimoto S, Morishima N, Ichihara A (2021) Clinical impacts of endothelium-dependent flow-mediated vasodilation assessment on primary aldosteronism. Endocr Connect 10:578–587
Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Iwamoto A, Kajikawa M, Matsumoto T, Oda N, Kishimoto S, Matsui S, Hashimoto H, Aibara Y, Yusoff FBM, Hidaka T, Kihara Y, Chayama K, Noma K, Nakashima A, Goto C, Tomiyama H, Takase B, Kohro T, Suzuki T, Ishizu T, Ueda S, Yamazaki T, Furumoto T, Kario K, Inoue T, Koba S, Watanabe K, Takemoto Y, Hano T, Sata M, Ishibashi Y, Node K, Maemura K, Ohya Y, Furukawa T, Ito H, Ikeda H, Yamashina A, Higashi Y (2017) Endothelial function is impaired in patients receiving antihypertensive drug treatment regardless of blood pressure level: FMD-J study (flow-mediated dilation Japan). Hypertension 70:790–797
Nakajima Y, Okamura T, Gohko T, Satoh T, Hashimoto K, Shibusawa N, Ozawa A, Ishii S, Tomaru T, Horiguchi K, Okada S, Takata D, Rokutanda N, Horiguchi J, Tsushima Y, Oyama T, Takeyoshi I, Yamada M (2014) Somatic mutations of the catalytic subunit of cyclic AMP-dependent protein kinase (PRKACA) gene in Japanese patients with several adrenal adenomas secreting cortisol [rapid communication]. Endocr J 61:825–832
Baykan M, Erem C, Gedikli O, Hacihasanoglu A, Erdogan T, Kocak M, Durmuş I, Korkmaz L, Celik S (2007) Impairment of flow-mediated vasodilatation of brachial artery in patients with Cushing’s syndrome. Endocrine 31:300–304
Akaza I, Yoshimoto T, Tsuchiya K, Hirata Y (2010) Endothelial dysfunction aassociated with hypercortisolism is reversible in Cushing’s syndrome. Endocr J 57:245–252
Tachibana H, Washida K, Kowa H, Kanda F, Toda T (2016) Vascular function in alzheimer’s disease and vascular dementia. Am J Alzheimers Dis Other Demen 31:437–442
Chandran DS, Jaryal AK, Jyotsna VP, Deepak KK (2011) Impaired endothelium mediated vascular reactivity in endogenous Cushing’s syndrome. Endocr J 58:789–799
Fallo F, Sonino N (2009) Should we evaluate for cardiovascular disease in patients with Cushing’s syndrome? Clin Endocrinol (Oxf) 71:768–771
Hatakeyama H, Inaba S, Takeda R, Miyamori I (2000) 11beta-hydroxysteroid dehydrogenase in human vascular cells. Kidney Int 57:1352–1357
Liu Y, Mladinov D, Pietrusz JL, Usa K, Liang M (2009) Glucocorticoid response elements and 11 beta-hydroxysteroid dehydrogenases in the regulation of endothelial nitric oxide synthase expression. Cardiovasc Res 81:140–147
Tsuiki M, Tanabe A, Takagi S, Naruse M, Takano K (2008) Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing’s syndrome. Endocr J 55:737–745
Di Dalmazi G, Pagotto U, Pasquali R, Vicennati V (2012) Glucocorticoids and type 2 diabetes: from physiology to pathology. J Nutr Metab 2012:525093
Tuttle KR, Agarwal R, Alpers CE, Bakris GL, Brosius FC, Kolkhof P, Uribarri J (2022) Molecular mechanisms and therapeutic targets for diabetic kidney disease. Kidney Int 102:248–260
Nakanishi T, Ishigami Y, Otaki Y, Izumi M, Hiraoka K, Inoue T, Takamitsu Y (2002) Impairment of vascular responses to reactive hyperemia and nitric oxide in chronic renal failure. Nephron 92:529–535
Tanaka T, Satoh F, Ujihara M, Midorikawa S, Kaneko T, Takeda T, Suzuki A, Sato M, Shimatsu A (2020) A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing’s syndrome other than Cushing’s disease. Endocr J 67:841–852
Matore BW, Banjare P, Singh J, Roy PP (2022) In silico selectivity modeling of pyridine and pyrimidine based CYP11B1 and CYP11B2 inhibitors: a case study. J Mol Graph Model 116:108238
Sakuma I, Suematsu S, Matsuzawa Y, Saito J, Omura M, Maekawa T, Nakamura Y, Sasano H, Nishikawa T (2013) Characterization of steroidogenic enzyme expression in aldosterone-producing adenoma: a comparison with various human adrenal tumors. Endocr J 60:329–336
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We are grateful to the staff of the Department of Endocrinology and Hypertension at Tokyo Women’s Medical University for their assistance.
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This work was funded by JSPS KAKENHI with Grant number 19K08497.
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Watanabe, D., Morimoto, S., Morishima, N. et al. Cardiovascular risk assessments in patients with cortisol-producing adenoma: impact of clinical features and genetic characteristics. Heart Vessels 39, 65–74 (2024). https://doi.org/10.1007/s00380-023-02309-x
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DOI: https://doi.org/10.1007/s00380-023-02309-x