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.