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Pulmonary Vascular Disease |

Reversal of Right Ventricular Hypertrophy and Dysfunction by Remodulin in a Rat Model of Severe Angioproliferative Pulmonary Arterial Hypertension

Imad Al Ghouleh, PhD; Rebecca Vanderpool, PhD; Jeffrey Baust, MS; Sruti Shiva, PhD; Stevan Tofovic, MD; Jian Hu, MD; Mark Gladwin, MD; Patrick Pagano, PhD
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University of Pittsburgh, Pittsburgh, PA


Chest. 2015;148(4_MeetingAbstracts):929A. doi:10.1378/chest.2262571
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Abstract

SESSION TITLE: PAH and the Heart

SESSION TYPE: Original Investigation Slide

PRESENTED ON: Wednesday, October 28, 2015 at 08:45 AM - 10:00 AM

PURPOSE: Prostacyclin analogues are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they confer protection exclusively via attenuating pulmonary vascular remodeling and constriction or if right ventricle (RV) myocardio-specific mechanisms are also involved. Moreover, their use in severe models of PAH has not been adequately tested. To address gaps in knowledge of the underlying responses to prostacyclin, the analogue Remodulin (Rem, treprostinil) was used in a pre-clinical rat Sugen-hypoxia (SuHx) model of angioproliferative severe PAH that closely resembles the human disease.

METHODS: Male Sprague-Dawley rats (300g) were implanted with ALZET osmotic pumps containing vehicle or Rem (900ng/kg/min), injected concurrently with a bolus of Sugen (SU5416; 20mg/kg) and exposed to 3 wk hypoxia (10%O2) followed by 3 wk normoxia (21% O2). RV function was assessed using pressure-volume loops measured using an admittance catheter and hypertrophy assessed by Fulton Index (FI; RV/LV+Septum wet weight).

RESULTS: Rem significantly reduced SuHx-associated RV hypertrophy and rise in systolic pressure (FI: 0.26±0.02, 0.58±0.04 & 0.37±0.05, P <0.001; mmHg: 25.3±0.9, 77.6±8.0 & 40.8±7.3, P <0.001, for normoxia, SuHx & SuHx+Rem, respectively). Mean pulmonary arterial (mPAP) and right atrial (RAP) pressures were also reduced (mmHg, mPAP: 16.9±0.5, 51.0±5.2 & 27.0±4.8, P <0.001; RAP: 1.9±0.3, 5.0±0.7 & 3.0±0.3, P <0.01, for normoxia, SuHx & SuHx+Rem, respectively). These associated with improved RV afterload including decreased stroke work and peak power index. RV contractile index (max dP/dt normalized to mPAP) also improved (90.9±3.9, 62.9±3.1 & 79.6±5.0, P <0.05, for normoxia, SuHx & SuHx+Rem, respectively) supporting load-independent RV function restoration. Finally, there was a reversal of SuHx-associated increases in RV end-systolic elastance (Ees, mmHg/mL: 0.13±0.06, 0.54±0.16 & 0.20±0.07, P <0.05, for normoxia, SuHx & SuHx+Rem, respectively) further supporting load-independent improvements in intrinsic RV systolic contractility.

CONCLUSIONS: Taken together, our data support decreased afterload and load-independent improvements in RV function following Rem administration in severe PAH.

CLINICAL IMPLICATIONS: The current findings shed light on the cardiopulmonary effects of prostacyclin analogues and open the door for future investigation into myocardium-specific protective pathways specifically activated by prostacyclin. Support: United Therapeutics Corp.

DISCLOSURE: Imad Al Ghouleh: Grant monies (from industry related sources): The project was funded by a grant from United Therapeutics Corporation. PI: Dr. Mark Gladwin. Rebecca Vanderpool: Grant monies (from industry related sources): The project was funded by a grant from United Therapeutics Corporation. PI: Dr. Mark Gladwin. Jeffrey Baust: Grant monies (from industry related sources): The project was funded by a grant from United Therapeutics Corporation. PI: Dr. Mark Gladwin. Sruti Shiva: Grant monies (from industry related sources): The project was funded by a grant from United Therapeutics Corporation. PI: Dr. Mark Gladwin. Stevan Tofovic: Grant monies (from industry related sources): The project was funded by a grant from United Therapeutics Corporation. PI: Dr. Mark Gladwin. Jian Hu: Grant monies (from industry related sources): The project was funded by a grant from United Therapeutics Corporation. PI: Dr. Mark Gladwin. Mark Gladwin: Grant monies (from industry related sources): The project was funded by a grant from United Therapeutics Corporation. PI: Dr. Mark Gladwin. Patrick Pagano: Grant monies (from industry related sources): The project was funded by a grant from United Therapeutics Corporation. PI: Dr. Mark Gladwin.

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