High altitude heart disease (HAHD) was a chronic high-altitude disease, which referred to the right ventricular hypertrophy caused by persistent pulmonary hypertension and myocardial cell hypoxia after people in plain areas migrated to the low-pressure and hypoxic environment at high altitude, and finally the right ventricular dysfunction caused by decompensation, in the late stage, serious cardiovascular system dysfunction such as left ventricular hypertrophy and expansion and total heart failure can also occurred [16]. The course of high altitude heart disease was slow, and the incidence increased gradually with the extension of living time at high altitude. HAHD had many pathogenesis mechanisms, and the fundamental reason was that the stress reactions regulated the cardiovascular system through nerves, body fluids, endocrine systems, etc., resulting in the increase of heart rate, pulmonary arterial pressure, and red blood cells(RBC), improving the oxygen carrying capacity of red blood cells to meet tissue oxygen supply [17,18,19]. Hypoxia could induce the synthesis of erythropoietin (EPO) mediated by hypoxia inducible factor (HIF), thus stimulating the production of red blood cells and increasing the levels of hemoglobin (HGB) and hematocrit (HCT ) [20]. The increase of red blood cells helped to improve the oxygen carrying and transport capacity in blood. However, the excessive increase of HGB and HCT levels would also increase blood viscosity and the additional burden on the heart, which would eventually reduce cardiac output and aggravate hypoxia, and further develop into HAHD [16]. Hypoxic pulmonary hypertension and thickening of pulmonary arterioles were the key link and fundamental feature of the pathogenesis of HAHD. Long-term hypoxia stimulation could lead to pulmonary artery hyperplasia and pulmonary vascular remodeling [21, 22]. Pulmonary vascular remodeling could cause an increase in pulmonary artery pressure and right ventricular afterload, resulting in right ventricular hypertrophy and dysfunction, and ultimately left heart dysfunction and failure. Of note, testosterone had also been reported to increase RBC, HGB and HCT levels by stimulating EPO [23], while estrogen appeared to have the opposite effects [24]. In this study, we included male SD rats as the research object, in addition to hypoxia stimulation, testosterone may also participate in and improve the blood oxygen transport capacity of rats at high altitude, which would be interesting to find out whether female plateau rats have similar changes in oxygen transport capacity in future studies.

In a previous study from our group found that RVEDV, RVESV and RVSV of rats were significantly increased after continuous exposure to hypoxia for 12 weeks, while RVEF remained normal, and the levels of RBC, HGB and HCT in blood of rats were significantly increased [15], indicating that chronic hypoxia at high altitude had changed the structure and function of the right ventricle, in order to adapt to hypoxia at high altitude, the pumping function of the right ventricle increased compensably, and the myocardial contractility remained unchanged. However, due to the increase of cardiac output and afterload, the overall strain of the myocardium decreased.

It had been reported that myocardial strain was an important predictor of cardiovascular disease [25, 26]. Previous studies on high altitude heart disease mainly focused on the right heart, while few studies on the changes of myocardial stress in the left heart caused by high altitude hypoxia. Therefore, we used 7T CMR-TT technology to explore the effects of high altitude hypoxia on left ventricular function and myocardial strain in rats. The results showed that LVGRS and LVGLS decreased, while LVEDV, LVESV, LVSV, LVGCS and EF remained at normal levels, which showed that the left ventricular strain of rats had changed, and the left ventricular myocardial injury occurred after continuous exposure to high altitude for 12 weeks. However, in order to meet the tissue oxygen supply, the left ventricular systolic function was still preserved. There was inconsistency between EF and myocardial strain in the evaluation of cardiac function. A study performed a combined mathematical and echocardiographic study to understand the inconsistencies between EF and strains, which had shown that increased wall thickness and/or reduced EDV augment EF, and therefore could maintain a normal EF despite reduced shortening. EF was quadratically dependent on circumferential shortening and only linearly dependent on longitudinal shortening; hence, EF was less sensitive to a reduction in longitudinal shortening, this study also suggested that strain measurements reflect systolic function better than EF in patients with preserved EF [27].

In this study, we also found that LVGRS and LVGLS decreased differently, and LVGLS decreased more significantly, indicating that LVGLS was more sensitive to assess early cardiac function injury than LVGRS and LVGCS, which may be related to the different arrangement of myocardial bundles. Torrent Guasp et al. [28] found that the characteristics of left ventricular myocardial contraction were related to the arrangement of myocardium. There were two kinds of arrangement of left ventricular myocardial bundles, namely, the longitudinal myocardial bundle forming the endocardium and epicardium and the circumferential myocardial bundle forming the middle layer of the myocardium. The longitudinal myocardial bundle runs from the basal segment to the apical segment, bypasses the apex and returns to the basal segment, forming a spiral structure [29]. In addition, the degree and direction of myocardial deformation were different due to the different directions of endocardial and epicardial myocardial fibers. The contraction of endocardial fibers leaded to the longitudinal shortening of the myocardium, and the contraction of epicardial fibers leaded to the circumferential shortening of the myocardium, which could make the myocardial radial increase [30]. Duo to the coronary artery had its own unique shape, the farthest blood supply area was the endocardium, when myocardial hypoxia occurred, the endocardial myocardium was first affected, followed by the epicardial myocardium, so the reduction of longitudinal strain was more significant [30].

Based on the true replication of high altitude hypobaric and hypoxic environment, we observed the changes of cardiac function of rats under hypobaric and hypoxic environment. This study provided experimental and theoretical basis for the future study of high altitude heart disease. However, this study still has some limitations. Firstly, due to the lack of 7.0T MRI scanning equipment in the plateau area, after being raised in a high altitude environment for 12 weeks, we transported plateau rats to the plain area for CMR scanning and data acquisition, which takes about 14 h and may have an impact on our experimental data. Secondly, we did not assess pulmonary artery pressure, arterial partial pressure of oxygen and / or oxygen saturation, nor did we observe the relationship between pulmonary artery pressure and changes in right ventricular function, which will be our next research plan.