Intrinsic protection against arrhythmia in a rat model of pulmonary arterial hypertension independent of hypoxia inducible factor 2-alpha activity
A Sohi, Z Hua, Y Shyam, M Keles, H A Prabhu, V Kappadan, E Zounis, Z Habib, C Brown, Y Abdelghani, E Zhang, D Agha-Jaffar, N S Peters, F S Ng, A CowburnAbstract
Background
Pulmonary Arterial Hypertension (PAH) characterised by a mean resting pulmonary arterial pressure of >20 mmHg leads to excess pressure on the right ventricle, eventually leading to Right Heart Failure (RHF). RHF elevates the risk of arrhythmia and mortality. Pre-clinical studies show that Hypoxia Inducible Factor 2-alpha (HIF2a), a transcription factor that elicits adaptation to hypoxia, contributes to the development of PAH.
Purpose
This study aimed to define the role of HIF2a on cardiac electrophysiological remodelling in a chronic model of PAH.
Methods
Male rats administered a single dose of saline (CTR) or monocrotaline (MCT), an agent that induces PAH, were treated from 2-weeks post-injection twice daily with vehicle (VEH) or a HIF2a inhibitor (HIF2a-i). 4-weeks post-injection, end-point echocardiograms were conducted; hearts were then explanted and Langendorff perfused. Action potentials of dynamically paced hearts were mapped, followed by Programmed Electrical Stimulation (PES) of the right ventricle. 2-way ANOVA; mean ± s.d. unless otherwise stated.
Results
There was no significant difference amongst groups for fractional shortening nor ejection fraction. Echocardiographic measure of fractional area change of the right ventricle (RV) was significantly lower in MCT VEH (38.24% ± 17.20) and MCT HIF2a-i (42.09% ± 10.99) than CTR VEH (60.03% ± 2.82) and CTR HIF2a-i (56.25% ±5.68), respectively. Significantly shorter Action Potential Duration (APD80) was exhibited in CTR HIF2a-i (79.11ms ± 14.83) than CTR VEH (93.99ms ± 11.08) and MCT HIF2a-i (105.3ms ± 12.37) (p<0.05). Heterogeneity indices of APD80 across the heart’s surface was significantly greater in CTR VEH (0.61 ± 0.18) and CTR HIF2a-i (0.53 ± 0.17) than MCT VEH (0.37 ± 0.11) and MCT HIF2a-i (0.38 ± 0.11), respectively (p<0.05), suggestive of higher risk for arrhythmia in CTR hearts. Greater PES scores were observed in CTR VEH (6.0, 3.0 – 6.0 IQR) and CTR HIF2a-i (5.0, 0.5 – 6.0 IQR) than MCT VEH (0.0, 0.0 – 1.0 IQR) and MCT HIF2a-i (0.0, 0.0 – 0.0 IQR), respectively, indicative of greater propensity for arrhythmias in CTR hearts than MCT diseased hearts.
Conclusions
Left ventricular function in the MCT rat model was preserved, while the RV indicated remodelling and impaired function. Inhibition of HIF2a was found to significantly shorten APD in healthy CTR hearts with no effect in MCT. This study found CTR hearts were to be more pro-arrhythmic and heterogenous for APD than MCT diseased hearts. This is suggestive of electrophysiological protection in MCT diseased hearts. It is hypothesised that the Langendorff hearts were hypo-perfused, thus producing a hypoxic/malnourished environment; the MCT hearts had adapted to hostilities over 4 weeks, while the CTR hearts were unprepared for such conditions. Further investigations are needed to investigate this hypothesis and the conditions that elicit electrophysiological protection in MCT diseased hearts.Echocardiogram and Fulton IndexAction Potentials and PES