Understanding longitudinal biventricular structural and functional changes in a pulmonary hypertension Sugen–hypoxia rat model by cardiac magnetic resonance imaging

Abstract

Cardiac magnetic resonance-derived ventricular variables are predictive of mortality in pulmonary arterial hypertension. Rodent models which emphasize ventricular function, allowing serial monitoring, are needed to identify pathophysiological features and novel therapies for pulmonary arterial hypertension. We investigated longitudinal changes in the Sugen–hypoxia model during disease progression. Sprague Dawley rats ( n = 32) were divided into two groups. (1) Sugen–hypoxia: a dose of subcutaneous Sugen-5416 and placed in hypobaric hypoxia for two weeks followed by normoxia for three weeks. (2) Normoxia: maintained at normal pressure for five weeks. Rats were examined at five or eight weeks with right-heart catheter, cardiac magnetic resonance, and autopsy. Compared to normoxic controls (23.9 ± 4.1 mmHg), right ventricular systolic pressure was elevated in Sugen–hypoxia rats at five and eight weeks (40.9 ± 15.5 mmHg, p = 0.026; 48.9 ± 9.6 mmHg, p = 0.002). Right ventricular end-systolic volume index was increased in eight weeks Sugen–hypoxia (0.28 ± 0.04 µlcm–2, p = 0.003) compared to normoxic controls (0.18 ±0.03 mlcm–2). There was progressive dilatation of the right ventricular at eight weeks Sugen–hypoxia compared to normoxic controls (0.75 ± 0.13 µlcm–2 vs 0.56 ± 0.1 µlcm–2 p = 0.02). Ventricle mass index by cardiac magnetic resonance at five weeks (0.34 ± 0.06, p = 0.003) and eight weeks Sugen–hypoxia (0.34 ± 0.06, p = 0.002) were higher than normoxic controls (0.21 ± 0.04). Stroke volume, right ventricular ejection fraction, and left ventricular variables were preserved in Sugen–hypoxia. Ventricular changes during the course of illness in a pulmonary arterial hypertension rodent model can be examined by cardiac magnetic resonance. These changes including right ventricular hypertrophy and subsequent dilatation are similar to those seen in pulmonary arterial hypertension patients. Despite the persisting pulmonary hypertension, there are features of adaptive cardiac remodeling through the study duration.

Exploring the failing right ventricle in pulmonary hypertension by cardiac magnetic resonance: An in vivo study utilizing Macitentan

“…Our Su/Hx rat model replicated the lower RVEF observed in a modified Su/Hx mouse protocol carried 22 as well as within clinic in PAH patients. 26 Previously, our group had undertaken CMRs in Su/Hx rats, 13 which found no changes in RVEF. Possible reasons for this difference are the previous study had a shorter 2-week hypoxic phase and it is previously been published that increasing the duration of hypoxia significantly modifies PH indices in Su/Hx rats.…”

“…The use of CMR in animal models could provide more accurate measurements of ventricular volumes and function 12 . This has been demonstrated recently by our own group in the Su/Hx rat model 13 …”

“…12 This has been demonstrated recently by our own group in the Su/ Hx rat model. 13 Macitentan is a well-established dual endothelin receptor antagonist, which helps mitigate the vasoconstrictive and mitogenic effects of elevated endothelin-1 (ET-1) in PAH. 14,15 Macitentan has been shown to reduce or prevent increases in pulmonary vascular remodeling, RV systolic pressure, and RV hypertrophy, assessed by gross histology, in preclinical models of PH, such as monocrotaline 8,16 and Sugen 5416 (Su) combined with chronic hypoxia (Su/Hx) models of PH, 11 as well as reducing morbidity and mortality in PAH patients.…”

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

“…Proteomics analysis revealed that a significant downregulation of adenylate kinase 1 (ADK1), which translates into inefficient cardiac energetics, might be the molecular substrate for the premature deterioration of RV function in Fisher rats [ 86 ]. In Sprague Dawley rats, RV hypertrophy and increased filling pressures are present after 5 weeks, with a subsequent RV enlargement by 8 weeks, but still preserved RV stroke volume and ejection fraction [ 85 ]. Rodent hypoxia-based pulmonary hypertension models have been exhaustively addressed by several reviews [ 79 , 84 , 138 ].…”

Hypoxia-Induced Cardiomyocyte Apoptosis Exacerbates Cardiomyocyte Hypertrophy and Myocardial Injury through p38 MAPK Pathway in SD Rats

“…Cardiac function was measured in rats anesthetized with isoflurane, briefly, the catheter was inserted into the jugular vein, and guided into the right ventricle, then hemodynamic data were measured, include RVSP (Right Ventricular Systolic Pressure), max dp/dt and min dp/dt [11,12], heart rate (HR), right ventricular end-diastolic pressure (RVEDP), pulmonary artery systolic pressure, mean pulmonary artery pressure. The right ventricle and the left ventricle plus interventricular septum were separated and weighed respectively to calculate RV/(LV+S) as right ventricular hypertrophy index.…”