Parathyroid gland disorders and cardiovascular disease

The review provides systematic information on the relation between pathology of parathyroid glands and cardiovascular disease (CVD). Recent studies have shown that actions of parathyroid hormone (PTH) and calcium affect the heart and vasculature through downstream actions of their receptors in the myocardium and endothelial cells, which lead to higher incidence of CVD among patients with parathyroid gland disorders (PGD). The mechanisms underlying this association also include insulin resistance and altered renin-angiotensinaldosterone axis among patients with primary hyperparathyroidism. However, low calcium and PTH level in hypoparathyroid patients are characterized by higher values of arterial stiffness, electrocardiogram abnormalities, vascular atherosclerosis and remodeling. These factors contribute to low quality of life among those patients. Knowledge of cardiovascular disease pathogenesis in patients with hyper- or hypoparathyroidism could help to improve quality of diagnostic and treatment and decrease the burden of cardiac risk factors. This review will be of interest to endocrinologists and cardiologists, and other specialists.

1. Melton LJ 3rd. The epidemiology of primary hyperparathyroidism in North America. J Bone Miner Res. 2002;17 Suppl 2: N 12–N 17.

2. The Human Protein Atlas [Internet]. Available from: http://www.proteinatlas.org/

3. Gardella TJ, Vilardaga JP. International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors family B G protein-coupled receptors. Pharmacol Rev. 2015;67(2):310–337. doi:10.1124/pr.114.009464

4. Schlüter KD, Piper HM. Cardiovascular actions of parathyroid hormone and parathyroid hormone-related peptide. Cardiovasc Res. 1998;37(1):34–41. doi:10.1016/s0008-6363(97)00194-6

5. Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci. 2005;42(1):35–70. doi:10.1080/10408360590886606

6. Riccardi D, Kemp PJ. The calcium-sensing receptor beyond extracellular calcium homeostasis: conception, development, adult physiology, and disease. Annu Rev Physiol. 2012;74:271–297. doi:10.1146/annurev-physiol-020911-153318

7. Schepelmann M, Yarova PL, Lopez-Fernandez I, Davies TS, Brennan SC, Edwards PJ et al. The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure. Am J Physiol Cell Physiol. 2016;310(3): C 193–C 204. doi:10.1152/ajpcell.00248.2015

8. Schreckenberg R, Schlüter KD. Calcium sensing receptor expression and signalling in cardiovascular physiology and disease. Vascul Pharmacol. 2018; S 1537–1891(17)30323–3. doi:10.1016/j.vph.2018.02.007

9. Greenberg HZ, Shi J, Jahan KS, Martinucci MC, Gilbert SJ, Ho WSV et al. Stimulation of calcium-sensing receptors induces endothelium-dependent vasorelaxations via nitric oxide production and activation of IKCa channels. Vascul Pharmacol. 2016;80:75–84. doi:10.1016/j.vph.2016.01.001

10. Alam MU, Kirton JP, Wilkinson FL, Towers E, Sinha S, Rouhi M et al. Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovasc Res. 2009;81(2):260–268. doi:10.1093/cvr/cvn279

11. Bilezikian JP, Cusano NE, Khan AA, Liu JM, Marcocci C, Bandeira F. Primary hyperparathyroidism. Nat Rev Dis Primers. 2016;2:16033. doi:10.1038/nrdp.2016.33

12. Dedov II, Melnichenko GA, Mokrysheva NG, Rozhinskaya LY, Kusnezov NS, Pigarova EA et al. Primary hyperparathyroidism: the clinical picture, diagnostics, differential diagnostics, and methods of treatment. Probl Endocrinol. 2016;62(6):40–77. In Russian. doi:10.14341/probl201662640-77

13. Fraser WD. Hyperparathyroidism. Lancet. 2009;374 (9684):145–158. doi:10.1016/S0140-6736(09)60507-9.

14. AACE/AAES Task Force on Primary Hyperparathyroidism. The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract. 2005;11(1):49–54. doi:10.4158/EP.11.1.49

15. Mokrysheva NG, Rozhinskaia LI, Peretokina EV, Rostomyan LG, Mirnaya VS, Pronin VS et al. The results of analysis of the major epidemiological characteristics of primary hyperparathyroidism in Russia based on the registry data. Probl Endocrinol. 2012;58(5):16–20. In Russian. doi:10.14341/probl201258516-20

16. Yanevskaya LG, Karonova TL, Sleptsov IV, Boriskova ME, Bakhtiyarova AL, Ivanova EV et al. Primary hyperparathyroidism: clinical forms and their features. Retrospective study. Clin Exp Thyroidol. 2019;15(1):19–29. In Russian. doi:10.14341/ket10213

17. Andersson P, Rydberg E, Willenheimer R. Primary hyperparathyroidism and heart disease a review. Eur Heart J. 2004;25(20):1776–1787. doi:10.1016/j.ehj.2004.07.010

18. Leifsson BG, Ahrén B. Serum calcium and survival in a large health screening program. J Clin Endocrinol Metab. 1996;81(6):2149–2153. doi:10.1210/jcem.81.6.8964843

19. Lind L, Skarfors E, Berglund L, Lithell H, Ljunghall S. Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol. 1997;50(8):967–973. doi:10.1016/s0895–4356(97)00104–2

20. Hagström E, Hellman P, Larsson TE, Ingelsson E, Berglund L, Sundström J et al. Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation. 2009;119(21):2765–2771. doi:10.1161/CIRCULATIONAHA.108.808733

21. Bansal N, Zelnick L, Robinson-Cohen C, Hoofnagle AN, Ix JH, Lima JA et al. Serum parathyroid hormone and 25-hydroxyvitamin D concentrations and risk of incident heart failure: the Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc. 2014;3(6):e001278. doi:10.1161/JAHA.114.001278

22. Brown SJ, Ruppe MD, Tabatabai LS. The parathyroid gland and heart disease. Methodist Debakey Cardiovasc J. 2017;13(2):49– 54. doi:10.14797/mdcj-13-2-49

23. Yao L, Folsom AR, Pankow JS, Selvin E, Michos ED, Alonso A et al. Parathyroid hormone and the risk of incident hypertension: the atherosclerosis risk in communities study. J Hypertens. 2016;34(2):196–203. doi:10.1097/HJH.0000000000000794

24. Brown J, de Boer IH, Robinson-Cohen C, Siscovick DS, Kestenbaum B, Allison M et al. Aldosterone, parathyroid hormone, and the use of renin-angiotensin-aldosterone system inhibitors: the multi-ethnic study of atherosclerosis. J Clin Endocrinol Metab. 2015;100(2):490–499. doi:10.1210/jc.2014–3949

25. Witte KK, Byrom R, Gierula J, Paton MF, Jamil HA, Lowry JE et al. Effects of vitamin D on cardiac function in patients with chronic HF: the VINDICATE Study. J Am Coll Cardiol. 2016;67(22):2593–2603. doi:10.1016/j.jacc.2016.03.508

26. Dobreva EA, Bibik EE, Eremkina AK, Rebrova OYu, Nikankina LV, Malysheva NM et al. Correlations between parameters of calcium metabolism and renin-angiotensin-aldosterone system in patients with primary hyperparathyroidism in the pre- and early postoperative periods. Arterial’naya Gipertenziya = Arterial Hypertension. 2019;25(6):630–638. In Russian. doi:10.18705/1607-419X-2019-25-6-630-638

27. Vlachakis ND, Frederics R, Valasquez M, Alexander N, Singer F, Maronde RF. Sympathetic system function and vascular reactivity in hypercalcemic patients. Hypertension. 1982;4(3):452–458. doi:10.1161/01.hyp.4.3.452

28. Kiernan TJ, O’Flynn AM, McDermott JH, Kearney P. Primary hyperparathyroidism and the cardiovascular system. Int J Cardiol. 2006;113(3): E 89–E 92. doi:10.1016/j.ijcard.2006.05.033

29. Morgan HE, Baker KM. Cardiac hypertrophy. Mechanical, neural, and endocrine dependence. Circulation. 1991;83(1):13–25. doi:10.1161/01.cir.83.1.13

30. Schlüter KD, Piper HM. Trophic effects of catecholamines and parathyroid hormone on adult ventricular cardiomyocytes. Am J Physiol. 1992;263(6 Pt 2): H1739–H1746. doi:10.1152/ajpheart.1992.263.6.H1739

31. Stefenelli T, Abela C, Frank H, Koller-Strametz J, Globits S, Bergler-Klein J et al. Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up. J Clin Endocrinol Metab. 1997;82(1):106–112. doi:10.1210/jcem.82.1.3666

32. Persson A, Bollerslev J, Rosen T, Mollerup CL, Franco C, Isaksen GA et al. Effect of surgery on cardiac structure and function in mild primary hyperparathyroidism. Clin Endocrinol (Oxf). 2011;74(2):174–180. doi:10.1111/j.1365-2265.2010.03909.x

33. Silverberg SJ, Walker MD, Bilezikian JP. Asymptomatic primary hyperparathyroidism. J Clin Densitom. 2013;16(1):14–21. doi:10.1016/j.jocd.2012.11.005

34. Mishra AK, Agarwal A, Kumar S, Mishra SK. Assessment of cardiovascular system abnormalities in patients with advanced primary hyperparathyroidism by detailed echocardiographic analysis: a prospective study. World J Endocr Sur. 2017;9:46–50. doi:10.5005/jp-journals-10002-1209

35. Nilsson IL, Aberg J, Rastad J, Lind L. Endothelial vasodilatory dysfunction in primary hyperparathyroidism is reversed after parathyroidectomy. Surgery. 1999;126(6):1049–1055. doi:10.1067/msy.2099.101422

36. Kosch M, Hausberg M, Vormbrock K, Kisters K, Gabriels G, Rahn KH et al. Impaired flow-mediated vasodilation of the brachial artery in patients with primary hyperparathyroidism improves after parathyroidectomy. Cardiovasc Res. 2000;47(4):813–818. doi:10.1016/s0008-6363(00)00130-9

37. Carrelli AL, Walker MD, Di Tullio MR, Homma S, Zhang C, McMahon DJ et al. Endothelial function in mild primary hyperparathyroidism. Clin Endocrinol (Oxf). 2013;78(2):204–209. doi:10.1111/j.1365-2265.2012.04485.x

38. Hazinski MF, Nadkarni VM, Hickey RW, O’Connor R, Becker LB, Zaritsky A. 2005 American Heart Association Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 10. 1: Life-threatening electrolyte abnormalities. Circulation. 2005;112(24): IV-121-IV-125. doi:10.1161/CIRCULATIONAHA.105.166563

39. Chiu KC, Chuang LM, Lee NP, Ryu JM, McGullam JL, Tsai GP et al. Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level. Metabolism. 2000;49(11):1501–1505. doi:10.1053/meta.2000.17708

40. Taylor WH, Khaleeli AA. Coincident diabetes mellitus and primary hyperparathyroidism. Diabetes Metab Res Rev. 2001;17(3):175–180. doi:10.1002/dmrr.199

41. Haap M, Heller E, Thamer C, Tschritter O, Stefan N, Fritsche A. Association of serum phosphate levels with glucose tolerance, insulin sensitivity and insulin secretion in non-diabetic subjects. Eur J Clin Nutr. 2006;60(6):734–739. doi:10.1038/sj.ejcn.1602375

42. Kalla A, Krishnamoorthy P, Gopalakrishnan A, Garg J, Patel NC, Figueredo VM. Primary hyperparathyroidism predicts hypertension: results from the National Inpatient Sample. Int J Cardiol. 2017;227:335–337. doi:10.1016/j.ijcard.2016.11.080

43. Yu N, Leese GP, Donnan PT. What predicts adverse outcomes in untreated primary hyperparathyroidism? The Parathyroid Epidemiology and Audit Research Study (PEARS). Clin Endocrinol (Oxf). 2013;79(1):27–34. doi:10.1111/cen.12206

44. Vestergaard P, Mollerup CL, Frøkjaer VG, Christiansen P, Blichert-Toft M, Mosekilde L. Cardiovascular events before and after surgery for primary hyperparathyroidism. World J Surg. 2003;27(2):216–222. doi:10.1007/s00268-002-6541-z

45. Øgard CG, Engholm G, Almdal TP, Vestergaard H. Increased mortality in patients hospitalized with primary hyperparathyroidism during the period 1977–1993 in Denmark. World J Surg. 2004;28(1):108–111. doi:10.1007/s00268-003-7046-0

46. Bilezikian JP, Khan A, Potts JT, Clarke BL, Shoback D, Jüppner H et al. Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res. 2011;26(10):2317–2337. doi:10.1002/jbmr.483

47. Clarke BL, Brown EM, Collins MT, Jüppner H, Lakatos P, Levine MA et al. Epidemiology and diagnosis of hypoparathyroidism. J Clin Endocrinol Metab. 2016;101(6):2284–2299. doi:10.1210/jc.2015-3908

48. Bansal B, Bansal M, Bajpai P, Garewal HK. Hypocalcemic cardiomyopathy-different mechanisms in adult and pediatric cases. J Clin Endocrinol Metab. 2014;99(8):2627–2632. doi:10.1210/jc.2013–3352

49. Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol. 2004;15(12):2959–2964. doi:10.1097/01.ASN.0000145894.57533.C4

50. Underbjerg L, Sikjaer T, Rejnmark L. Long-term complications in patients with hypoparathyroidism evaluated by biochemical findings: a case-control study. J Bone Miner Res. 2018;33(5):822–831. doi:10.1002/jbmr.3368

51. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. The epidemiology of nonsurgical hypoparathyroidism in Denmark: a nationwide case finding study. J Bone Miner Res. 2015;30(9):1738–1744. doi:10.1002/jbmr.2501

52. Bergenfelz A, Nordenström E, Almquist M. Morbidity in patients with permanent hypoparathyroidism after total thyroidectomy. Surgery. 2020;167(1):124–128. doi:10.1016/j.surg.2019.06.056

53. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow-up study. J Bone Miner Res. 2013;28(11):2277–2285. doi:10.1002/jbmr.1979