title: Longitudinal in vivo SPECT/CT imaging reveals morphological changes and cardiopulmonary apoptosis in a rodent model of pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) has a complex pathogenesis involving both heart and lungs. Animal models can reflect aspects of the human pathology and provide insights into the development and underlying mechanisms of disease. Because of the variability of most animal models of PAH, serial in vivo measurements of cardiopulmonary function, morphology, and markers of pathology can enhance the value of such studies. Therefore, quantitative in vivo SPECT/CT imaging was performed to assess cardiac function, morphology and cardiac perfusion utilizing (201)Thallium ((201)Tl) in control and monocrotaline-treated rats. In addition, lung and heart apoptosis was examined with (99m)Tc-Annexin V ((99m)Tc-Annexin) in these cohorts. Following baseline imaging, rats were injected with saline or monocrotaline (50 mg/kg, i.p.) and imaged weekly for 6 weeks. To assess a therapeutic response in an established pulmonary hypertensive state, a cohort of rats received resveratrol in drinking water (3 mg/kg/day) on days 28-42 post-monocrotaline injection to monitor regression of cardiopulmonary apoptosis. PAH in monocrotaline-treated rats was verified by conventional hemodynamic techniques on day 42 (right ventricular systolic pressure (RSVP) = 66.2 mmHg in monocrotaline vs 28.8 mmHg in controls) and in terms of right ventricular hypertrophy (RV/LVS = 0.70 in monocrotaline vs 0.32 in controls). Resveratrol partially reversed both RVSP (41.4 mmHg) and RV/LVS (0.46), as well as lung edema and RV contractility +dP/dt(max). Serial (99m)Tc-Annexin V imaging showed clear increases in pulmonary and cardiac apoptosis when compared to baseline, which regressed following resveratrol treatment. Monocrotaline induced modest changes in whole-heart perfusion as assessed by (201)TI imaging and cardiac morphological changes consistent with septal deviation and enlarged RV. This study demonstrates the utility of functional in vivo SPECT/CT imaging in rodent models of PAH and further confirms the efficacy of resveratrol in reversing established monocrotaline-induced PAH presumably by attenuation of cardiopulmonary apoptosis.
authors: Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America. mpaffett@salud.unm.edu
authors: Michael L
authors: ML
authors: Paffett
authors: Jacob
authors: J
authors: Hesterman
authors: Gabriel
authors: G
authors: Candelaria
authors: Selita
authors: S
authors: Lucas
authors: Tamara
authors: T
authors: Anderson
authors: Daniel
authors: D
authors: Irwin
authors: Jack
authors: J
authors: Hoppin
authors: Jeffrey
authors: J
authors: Norenberg
authors: Matthew J
authors: MJ
authors: Campen
mesh_terms: D000818:Animals; D017302:Annexins / Q000378:metabolism; D017209:Apoptosis; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging* / Q000473:pathology* / Q000503:physiopathology; D008168:Lung / Q000000981:diagnostic imaging / Q000473:pathology*; D008297:Male; D016686:Monocrotaline; D009206:Myocardium / Q000473:pathology*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use; D013599:Systole / Q000187:drug effects; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D017302:Annexins; D013267:Stilbenes; D016686:Monocrotaline; D000077185:Resveratrol