Key result
Treprostinil significantly reduced right ventricular hypertrophy, decreased pulmonary and right atrial pressures, and improved right ventricular systolic contractility in a rat model of severe PAH.
Why the study?
It was unknown whether prostacyclin analogs confer protection through RV myocardio-specific mechanisms, and their use in severe PAH models had not been adequately tested.
Does treprostinil improve right ventricular hypertrophy and dysfunction in a rat model of severe pulmonary arterial hypertension?
Does treprostinil improve right ventricular hypertrophy and dysfunction in a rat model of severe pulmonary arterial hypertension?
Answers are grounded in this paper and cite their sources.
In a severe rat model of PAH, treprostinil reduced right ventricular hypertrophy and improved intrinsic RV systolic contractility and fibrotic responses.
Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has not been adequately tested. To further identify underlying responses to prostacyclin, a prostacyclin analogue, treprostinil, was used in a preclinical rat Sugen-chronic hypoxia (SuCH) model of severe PAH that closely resembles the human disease. Male Sprague-Dawley rats were implanted with osmotic pumps containing vehicle or treprostinil, injected concurrently with a bolus of Sugen (SU5416) and exposed to 3-week hypoxia followed by 3-week normoxia. RV function was assessed using pressure-volume loops and hypertrophy by weight assessed. To identify altered mechanisms within the RV, tissue samples were used to perform a custom RNA array analysis, histological staining, and protein and transcript level confirmatory analyses. Treprostinil significantly reduced SuCH-associated RV hypertrophy and decreased the rise in RV systolic pressure, mean pulmonary arterial (mPAP), and right atrial (RAP) pressure. Prostacyclin treatment was associated with improvements in RV stroke work, maximum rate of ventricular pressure change (max dP/dt) and the contractile index, and almost a complete reversal of SuCH-associated increase in RV end-systolic elastance, suggesting the involvement of load-independent improvements in intrinsic RV systolic contractility by prostacyclin treatment. An analysis of the RV tissues showed no changes in cardiac mitochondrial respiration and ATP generation. However, custom RNA array analysis revealed amelioration of SuCH-associated increases in newly identified TBX20 as well as the fibrotic markers collagen1α1 and collagen 3α1 upon treprostinil treatment. Taken together, our data support decreased afterload and load-independent improvements in RV function following prostacyclin administration in severe PAH, and these changes appear to associate with improvements in RV fibrotic responses.
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Vanderpool et al. (2022) studied Severe pulmonary arterial hypertension. Treprostinil vs. Vehicle was evaluated. Treprostinil significantly reduced right ventricular hypertrophy, decreased pulmonary and right atrial pressures, and improved right ventricular systolic contractility in a rat model of severe PAH.
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