Discussion
The main findings of our study were as follows: (1) Individuals with ERP had significantly higher LV dimensions, LV wall thickness, RV dimension; (2) a significant inverse interaction was observed between ERP and GLS; (3) ERP had an impact on regional longitudinal and circumferential SR values. The lower longitudinal SRS, SREand SRA were mainly found at the A3C and the lower circumferential SRS and SRE were mainly seen in the basal segment of LV. To our knowledge, this is the first study for demonstrating an important relationship between ERP and both LV longitudinal and circumferential strain and SR parameters.
ERP is associated with an increased risk of sudden cardiac arrest due to idiopathic ventricular fibrillation in the general population1,5,17. Unfortunately, these arrhythmic events can be seen in the young people without cardiac disease such as ischemic heart diseases, cardiomyopathies 18. However, Trenkwalder et al. and McNamara et al. showed that the morphological changes of LV began to be seen in ERP subjects 9,10. In these subjects, ventricular dysfunction can not be determined with the use of conventional echocardiographic modalities 18,19. STE and TDI can clearly detect subtle ventricular dysfunction by calculating the ventricular strain and SR which are more sensitive indicators than LVEF 20,21.
In our study, we found that both LV and RV dimensions, and LV wall thickness were significantly increased in subjects with ERP. In addition, it was observed that LV mass and RWT were significantly higher in ERP group. Our results are consistent with the previous studies9,22,23. These results suggest that ERP can lead to LV structural changes. As we known, LV radius, LV wall thickness and hemodynamic conditions impose onto LV- wall stress (WS)24. In ERP group, increased LV volumes may lead to proliferation of LV myocardium to normalize LV- WS. These structural changes may be accompanied by oxygen demand- supply mismatch which leads to myocardial systolic dysfunction, even before LVEF reduces.
The most important finding of our study was that ERP participants had a significantly lower GLS. There are plausible mechanisms for why ERP produced impaired GLS. Firstly, ERP can mediate impaired GLS through its effects on LV structural changes. Especially, the increased LVESV and LVEDV can lead to increased WS followed by impaired GLS. Because, ventricular strain and SR has been known as WS dependent indicators. In line with our work, several studies have also reported a significant inverse relationship between WS and strain and SR parameters25-28. The second mechanism for impaired GLS values may be that mutations in genes can cause both ion channel dysfunction and myocardial dysfunction 29,30. Chen et al. showed that CACNA1C/ DES/ MYPN mutations are the pathogenic substrates for the clinical manifestation in the hypertrophic cardiomyopathy patients with ERP 29. ERP could be a heritable condition with variable penetrance and incomplete phenotypic manifestation. In such patients, impaired GLS may also guide further genetic analysis. To our knowledge, our study was the first to evaluate the relationship between GLS and ERP and also to explain the possible underlying mechanisms for impaired GLS in ERP subjects. However, unlike to these findings, Gulel et al. reported that myocardial deformation parameters including longitudinal and circumferential S/ SR were not affected by ERP31. The main reason for this unexpected result in Gulel et al. may be due to lower number participants in their study. In addition, mean age was lower in Gulel’s study. The possibility of ERP induced morphological and functional changes on the myocardium may increased with advancing age.
The significantly lower longitudinal SRS,SRE and SRA at the A3C in ERP can be consistent with the significantly higher IL wall dimension in ERP group due to WS relationship. In addition, these findings may be consistent with the animal studies which showed higher levels of transient outward potassium current (Ito) in the inferior wall and lateral wall of canine myocardium 32. Because, long non- coding RNAs which has been known as myocardial K+ channel regulators may play an important role in subtle myocardial dysfunction in the region with higher Ito density 33.
The association between ERP and impaired basal segment circumferential SRS and SRE deserves further comment. We previously explained that the morphological changes related to ERP could be affected by ion channel density. The density of potassium (K+) channel varies from apical segment to basal segment of LV34,35. The density of K+ channel in apical segment is approximately twice as high as in basal segment 35. In accordance with our previous findings, in ERP group, the lower frequency of basal segment ion channel density may be associated with a thinner wall thickness in basal segment than that in apical segment. In addition, basal segment has the largest radius as compared to mid and apical segment of LV. The combined effect of basal segment’s ion channel density and large radius may cause significantly higher WS in the basal segment of LV in subjects with ERP than those without ERP, resulting in the fact that LV basal segment needs more energy for both contraction and relaxation than mid and apical segment do. Consequently, the presence of ERP accompanied by worse basal segment circumferential SRS and SRE.