DISCUSSION
This is the first study to show that both intra-atrial and inter-atrial conduction times were prolonged in PHPT patients. In addition, we found that both intra-atrial EMD and inter-atrial EMD were significantly correlated with calcium and PTH levels.
As is known, PHPT is an endocrinological disease that is typically characterized by high or non-suppressed parathyroid hormone levels (PTH) together with high serum calcium levels (1). As far as we know, there are no ECG and echocardiography studies conducted to assess atrial arrhythmia risk in PHPT patients in literature. Although hypercalcemia is well known to cause cardiac conduction disturbances and arrhythmias; surprisingly, follow-up studies of long-term cardiovascular results of this disease have not been conducted. Due to the physiological effects of both parathyroid hormone (PTH) and calcium on the cardiomyocyte, cardiac conduction system, and pancreatic beta cells, disorders such as hypertension, arrhythmias, left ventricular hypertrophy, heart failure, glucose metabolism disorder and metabolic syndrome can be seen throughout the course of the disease (9). Furthermore, studies investigating the effects of PHPT on the cardiovascular system have shown impairment in endothelial and vascular functions (10). In addition to all these effects, increase in sympathetic activity and activation of the renin angiotensin and aldosterone system (RAS) due to increased catecholamines have been shown in PHPT (11, 12).Furthermore, recent studies have shown impairment in LA functions of PHPT patients (13). These undesirable effects that can be seen in PHPT are known as risk factors for the development of AF(4) . The studies searching the effects of PTH and calcium on the heart have shown that both of them cause changes in both endothelial cells and myocardial cells. PTH may have such effects on calcium; it may also be seen in connection with its effects on the cells directly (14, 15 ). Hypercalcemia poses a risk for cardiac arrhythmia without regarding whether it occurs due to PHPT or other reasons of hypercalcemia (16, 17 ). Although there are concerns over the development of more ventricular arrhythmia in PHPT, atrial arrhythmia may also be observed in the course of the disease.
Non-invasive measurement of atrial EMD by TDI has been found successful in evaluating the risk of AF as an alternative to invasive electrophysiological measurements (5 ). Cui QQ et al. showed that the atrial conduction delay measured by TDI was significantly longer in patients with paroxysmal AF compared to the control group(18). Roshanalli et al. showed that the atrial electromechanical interval is a predictor of AF developing after coronary artery bypass grafting, and preoperative administration of amiodarone to patients with a longer atrial electromechanical interval reduces the incidence of postoperative AF (19). In addition, it has been shown in previous studies that atrial EMD is prolonged in many clinical disorders such as mitral stenosis, diabetes mellitus, hypertension, psoriasis, and Inflammatory Bowel Disease(20-24 ). In addition, the incidence of AF in these diseases has increased significantly compared to the normal population. In conclusion, atrial EMD is prolonged in paroxysmal AF and is considered a predictor of new-onset AF (25 ). In our study, we showed that intra-atrial and inter-atrial EMD, a technique that predicts the risk of future AF development, was significantly longer in patients with PHPT compared to controls.
We also found a significant correlation between both inter-atrial EMD and intra-atrial EMD and calcium. In previous studies, the increase in calcium release from the sarcoplasmic reticulum in atrial myocytes was found to be related to the development of AF (26, 27 ). Although hypercalcemia is well known to cause cardiac conduction disturbances and arrhythmias, clinical observations of conduction disturbances caused by hypercalcemia are surprisingly rare. Case reports have shown various conduction disorders such as atrioventricular nodal conduction defects, sinus node disease and atrial fibrillation, depending on the severity of hypercalcemia in patients with PHPT, but the prevalence of these disorders is unknown (28 ). It is known that cardiac relaxation is impaired in individuals with hypercalcemia as a result of its deleterious effects on the myocardium through excessive increase of intracellular calcium or calcium accumulation in the myocardium(29) . In addition to myocardial involvement, hypercalcemia may also cause involvement in atrial conduction paths, leading to prolongation in Atrial EMD. In addition, Curione M et al. showed that hypercalcemia developed adverse effects on cardiac electrical stability in patients with PHPT (30). Therefore, we can think that hypercalcemia plays an important role in the prolongation of atrial EMD. This suggests that the increase in calcium levels in PHPT patients may be determinant for the possible development of AF.
Another important result of our study is that we found that PTH levels are associated with atrial EMD. PTH is vital for calcium hemostasis. However, PTH itself is now known to cause hypertrophy of cardiac myocytes and vascular smooth muscle even without hypercalcemia. Moreover, parathyroid hormone accelerates heart rate, an effect mediated by PTH’s direct effect on the sinus node and conduction system. PTH also exerts inotropic effects, possibly as a result of increased coronary blood flow due to the vasodilatory effect of PTH on the coronary circulation (31). Furthermore, it has been shown that blood biochemical measurements have revealed high cytokine levels in patients with high PTH level (32). This suggests that there is also an inflammatory process in PHPT patients. Because of all these effects, the possibility of developing arrhythmia secondary to PTH increase may scale up. In addition, serum PHT levels have been shown to be associated with AF in recent studies (33-36 ). Rienstra M et al. have found that PTH levels were significantly higher in patients who develop atrial fibrillation (35 ). Lee et al. showed in their public-based study that the increase in PTH levels increased the incidence of AF (36) . In the study conducted by Pepe and Cipriani et al., more frequent atrial extrasystole in 24-hour ECG monitoring of PHPT patients was determined and such arrhythmias were shown to be reduced with decrease in post- Parathyroidectomy PTH levels (37). The relevant effects of PTH consequently lead to the occurrence of electrical and structural remodeling in myocardial cells. All of these effects cause hypertrophy, fibrosis and functional disorders in the cardiovascular structures in time and are suggested to have facilitated the occurrence of atrial arrhythmia. Therefore, we can think that PTH plays an important role in the prolongation of atrial EMD, a well-known predictor of AF. This suggests that the increase in PTH levels PHPT patients may be determinant for the possible development of AF.
Although our study is not a follow-up study, we have observed that intra-atrial and inter-atrial EMD, which is a technique that predicts the cardiac arrhythmias, was significantly longer in patients with PHPT. It was also found that there is a significant correlation between both inter-atrial EMD and intra-atrial EMD and calcium and PTH levels. In other words, both high PTH and high calcium levels seem to have individually the potential to cause arrhythmogenic effects. When our outcomes are considered with literature, it is suggested that PHPT patients are at risk in terms of atrial fibrillation.
This study has the following limitations: it is hard to estimate how long the participants have been exposed to calcium and PTH. Furthermore, as the number of participants is low, it is not possible to determine the cut-off value of PTH with respect to the level and exposure period of its cardiac effects. The orbit of the disease may change in presymptomatic patients and with an intervention in the level of hypercalcemia. We looked at atrial EMD, which is a good marker for AF development, but the development of AF has not been directly investigated. Long-term follow-up is required to identify cases that will cause AF.