5. Discussion

In this study, we evaluated the relationship between echo parameters of subclinical myocardial dysfunction, endothelial dysfunction parameters, and MRI T2 * values which is the gold standard for cardiac iron deposition.
Among the measured variables, all LVEF values obtained with 2DE were normal (≥50%) and not significantly associated with MRI T2* values. This finding is in agreement with previous studies which indicates its inefficiency in predicting abnormal cardiac iron deposition (14). This is likely due to limitations of 2DE compared to 3DE for measuring LVEF which lead to systematic overestimation of volumes and LVEF2D (15). On the other hand, since echocardiographic measurement of LVEF with 2DE may be inaccurate in patients with regional wall motion abnormalities or mechanical dyssynchrony, precence of heart failure can not be ruled out even with normal LVEF2D (15).
In our study, in contrast to other published studies (16,17), levels of serum ferritin were significantly different between two groups and negatively correlated with MRI T2*. Our finding is similar to Wahidiyat et al. -large-scale population-based- study which found statistically significant correlation between serum ferritin level and liver and cardiac T2* (18). This may indicate an ongoing remodeling process even in patients with preserved LVEF2D and it is important to identify patients while their cardiomyopathy is still reversible.
In the present study, while LVEF2D was preserved and not significantly associated with MRI T2*, LVEF3D, SDI12 and SDI16 was significantly different between two groups and negatively correlated with MRI T2* findings. These relationships suggest that iron overload may play an important role in the pathogenesis of ventricular dyssynchrony (19,20). In light of evidence, we know that ventricular dysynchrony has an independent mechanism of decrease in left ventricular systolic function and is an important parameter in determining patients with severely decreased left ventricular systolic function (21-23). Furthermore Bae et al. demonstrated a significant improvement of ventricular dysynchrony after the antihypertensive treatment when compared to the baseline ventricular dysynchrony in hypertensive patients with preserved LV systolic function (24). These findings show importance of properly assessment of cardiac function particularly in this population.
While heart disease is the main cause of death in β-TM, vascular endothelial pathologies as well as myocardial parenchymal injury has been reported as the one of the main cause of cardiovascular complications (25,26). Its known that, vascular bed function and integrity were affected by chronic hemolysis because both hemolysis and iron overload are the main causes of oxidative damage in β-TM patients. Plasma-free hemoglobin, released as a result of chronic intravascular hemolysis, directly causes the formation of reactive oxygen species that catalyze oxidative damage in vascular cellular structures. In addition, it has been observed that free hemoglobin reacts with NO, causes NO deactivation and limits NO diffusion from the endothelium to smooth muscle cells (27). Similarly, the release of erythrocyte arginase during intravascular hemolysis may limit the cellular availability of L-arginine, a substrate for NO synthesis, and cause insufficient NO production (28). This imbalance between NO production and consumption causes a decrease in NO bioavailability and ultimately leads to the development of endothelial dysfunction by inhibiting vasodilation (29). Endothelial dysfunction probably contributes in part to the increase in arterial stiffness. Not surprisingly, flow-mediated dilatation of the brachial artery and aortic strain are important research tools for assessing vascular biology and endothelial function and detects early stages of atherosclerosis. (30,31). In the present study we found that FMD and aortic strain values were significantly different between two groups and negatively colerated with T2* values. Stakos et al. (32) showed in their study that, patients with β-TM and normal cardiac iron levels documented by T2* and no clinical signs of cardiac dysfunction, have also increased aortic stiffness compared with normal control subjects. FMD was found significantly impaired in patients with β-TM compared with healty control group in another study (33). While our findings may lead to the hypothesis that the aorta and peripheral arteries exhibit an accelerated aging rate in negative correlation with cardiac T2 values, this group of patients, including patients with normal T2 findings, may undergo a lifelong process of vascular remodeling. Knowledge about the complexity of the underlying mechanisms can help prevent or treat potential complications.