Establishing the nature of reversible cardiac remodeling in a rat model of hypobaric hypoxia-induced right ventricular hypertrophy

[摘要] Physiological cardiac hypertrophy is characterized by the heart's ability to increase mass in a reversible fashion without leading to heart failure. In contrast, pathological cardiac hypertrophy leads to the onset of heart failure. For this study, we investigated a model of physiological hypobaric hypoxia-mediated right ventricular (RV) hypertrophy (RVH). Here our hypothesis was that the hypertrophic response and associated changes triggered in the RV in response to chronic hypobaric hypoxia (CHH) (increased RV mass, function and respiratory capacity) are reversible. To test our hypothesis we exposed male Wistar rats to 3 weeks of CHH and thereafter removed the hypoxic stimulus for 3 and 6 weeks, respectively. Adaptation to 3 weeks of CHH increased the RV to left ventricle (LV) plus interventricular septum ratio by increased (223.5 ± 7.03 vs. 397.4 ± 29.8, p<0.001 versus normoxic controls), indicative of RVH. Hematocrit levels, RV systolic pressure and RV developed pressure (RVDP) were increased in parallel. Mitochondrial respiratory capacity was not significantly altered when using both carbohydrate and fatty acid oxidative substrates. After the 3-week normoxia recovery period, the RV to LV ratio was increased but to a lesser extent compared to the 3-week hypoxic time-point, i.e. 244.7 ± 11.2 vs. 349.64 ± 3.8, p<0.001 versus normoxic controls. Moreover, hematocrit levels were completely normalized. However, the RV systolic pressure and the functional adaptations, i.e. increased RVDP induced by CHH exposure still persisted in the 3-week recovery (3HRe) group. Also, pyruvate utilization was increased versus matched controls (p<0.04 vs. matched controls).Interestingly, we found that at the 6-week recovery time point functional parameters were largely normalized. However, the RV to LV ratio was still increased by 269.3 ± 14.03 vs. 333.9 ± 11.7, p<0.0001 vs. matched controls. Furthermore, palmitoylcarnitine utilization was increased (p<0.03 vs. matched controls).In conclusion, we found that exposure to CHH resulted in various adaptive physiological changes, i.e. enhanced hematocrit levels, increased RV mass linked to greater RV contractility and respiratory function. It is important to note that all these changes only occurred in the RV and not in the LV. Furthermore, when a normoxic recovery period (3 and 6 weeks, respectively) were initiated, these physiological parameters largely normalized. Together, the findings of this thesis clearly show the establishment of a reversible model of RV physiological hypertrophy. Our future work will focus on disrupting signaling pathways underlying this process and to thereafter ascertain whether reversibility is abolished. Elucidation of such targets should provide a unique opportunity to develop novel therapeutic agents to treat patients and thereby reduce the burden of heart disease.

[发布机构] Stellenbosch University