*2.3. Role of Parathyroid Hormone*

Secondary hyperparathyroidism is a frequent complication of CKD characterized by an increase in PTH synthesis and secretion and by parathyroid gland hyperplasia. High levels of PTH have an impact on the cardiovascular system apart from the regulation of calcium and phosphate homeostasis [54]. Elevated PTH levels are a common finding in uremic patients which appears much earlier than hyperphosphatemia. PTH and FGF23 have both phosphaturic effects. The difference remains that only PTH has an impact on increased serum calcium. While PTH receptor (PTH1R), is present in bone and kidney, the klotho coreceptor is only expressed in the kidney [7,31]. In addition, PTH stimulates calcitriol synthesis that further contributes to increased serum calcium, whereas FGF23 has an opposite effect on vitamin D and calcium. In the physiologic state, FGF23 acts on the parathyroid gland by reducing gene expression and secretion while in the absence of Klotho, the parathyroid gland shows resistance to FGF23, so enhances PTH secretion.

Experimental data have shown that PTH may directly affect the myocardium although the effect of PTH on the CV system is still under study.

PTH was shown to affect directly rat myocardial cells causing early death of cells by increasing calcium entry into the heart cells [55]. Calcium ions are crucial to myocardial excitation–contraction coupling and cardiac contraction and relaxation [56].

There are early reports by Amman et al. regarding the non-hemodynamic e ffect of PTH on cardiac fibrosis which was related to diastolic LV function [9]. An experimental rat model of CKD (5/6 nephrectomy) reported that continuous infusion of supraphysiological rates of synthetic PTH in animals with parathyroidectomy was associated with an extensive progression of VC—independently of serum Pi levels or the presence of uremia [57]. Moreover, the higher PTH levels have direct trophic effects on cardiomyocytes, interstitial fibroblasts, and smooth muscle cells of intramyocardial arterioles, promoting cardiac hypertrophy and fibrosis. PTH activates fibroblasts and regulates pro-fibrotic factors, such as aldosterone and angiotensin II (PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa directly by binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced e ffects) [54,58]. Additionally, PTH potentially would activate protein kinase C, which further on activates other proteins, such as TGF-b, that in turn, promote the proliferation of fibroblasts, collagen synthesis, and fibrosis [59,60]. In vitro studies have found that PTH shows to have chronotropic, inotropic, as well as hypertrophic e ffects on cardiomyocytes [55] and based on research it was represented that there is a source for a direct role of PTH on cardiac electrophysiology outside of its e ffect on serum calcium [61].

Furthermore, ex-vivo experiments have shown the interaction between PTH and norepinephrine release in isolated human atria and renal cortex tissue through activation of the PTH1-receptor subtype. This e ffect would be an explanation for another potential underlying mechanism of the sympathetic overactivity and the associated cardiovascular mortality seen in patients with ESRD [62].

In hemodialysis patients, like in the rat model, the e ffect of PTH on the myocardium and cardiac fibrosis was well perceived. The hormone was shown to raise the beating rate of myocardial cells and induced their death after prolonged hormonal exposure; PTH stimulates the cyclic AMP production and impairs energy production, transfer, and utilization by myocardial cells [63] and myofibrillar activity of creatine kinase [64]. The presence of sHPTH has also been shown to correlate with enhanced myocardial calcium content and impaired ventricular systolic and diastolic function [65].

Despite a theoretical inverse association between plasma PTH concentration and left ventricular function, parathyroidectomy is not consistently associated with improvement in cardiac contractile function [66]. This suggests that changes induced by PTH could be irreversible in the case of long-standing severe hyperparathyroidism, or other factors contributing to myocardial dysfunction were more important than PTH excess or PTH interferes with the other risk factors of CVD. Despite a theoretical inverse relation between plasma PTH concentration and left ventricular function, parathyroidectomy is not consistently associated with improvement in cardiac contractile function [66]. This suggests in the case of long-standing severe hyperparathyroidism changes induced by PTH could be irreversible, or other factors with an impact on myocardial dysfunction are more important than PTH excess or PTH interferes with the other risk factors of CVD. Furthermore, the inconclusive results of the EVOLVE trial have been linked with this uncertainty since in intent-to-treat analysis a significant advantage of cinacalcet treatment over best presently available standard treatment in the combined primary endpoint (cardiovascular events plus death) was not shown, despite a marked decrease in serum PTH [67]. However, in the subanalysis, when it was adjusted for major confounders such as age and study drug discontinuation, the better control of hyperparathyroidism correlated with a significant advantage in hard outcomes. It was reported that PTH increases with age, weight, BMI, SBP, and LDL, all risk factors for CVD. Increased SBP would be a hemodynamic e ffect of PTH on cardiac remodeling [68,69]. Evidence suggests that PTH has vascular e ffects [68]. Here its potential e ffects on endothelial dysfunction, and increased serum levels of endothelin-1 and IL-6 could be mentioned. In addition, PTH may stimulate the vascular smooth muscle cells to produce factors including collagen and beta-1 integrin which could, in turn, remodel the peripheral vasculature. Another potential e ffect of PTH would be the increase of renin release and activation of the renin–angiotensin system, a process mediated by serum calcium and renal 1-alpha hydroxylase [69]. Aman et al. have underlined the e ffect of PTH as the major determining factor of coronary artery lesions, ranging from the discontinuity of the elastic lamina to the calcification of the medial layer, confirming the agreeable action of PTH [70].

In conclusion, there are clinical and experimental reports which support the hypothesis that PTH behaves as a systemic uremic toxin, with direct and indirect e ffects on uremic cardiomyopathy. PTH acts through four major cardiovascular e ffects; contractile disturbance, cardiomyocyte hypertrophy, cardiac interstitial fibrotic, and vasodilator e ffect. Severe sHPTH is an important threat to CKD patient outcomes a ffecting CV morbidity and mortality and remains an important therapeutic target to prevent bone and CV complications in such patients.
