Abstract 19152: Development of Secondary Pulmonary Hypertension and Right Ventricular Dysfunction in a Mouse Model of Ischemic Heart Failure

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Introduction: Heart failure (HF) is the most common cause of pulmonary hypertension (PH). In HF, elevated pulmonary artery pressures are associated with increased morbidity and mortality. Many of the mechanisms of pulmonary vascular remodeling in secondary PH are unknown. Currently there are few therapies for secondary PH beyond optimization of medical therapies for left HF (LHF). We sought to develop a small animal model of PH due to LHF in order to characterize the pulmonary vascular biomechanics and changes in RV function.

Methods: LHF was created in 6-week old C57/Bl6 mice using a Left anterior descending artery (LAD) ligation model of myocardial infarction (MI). Sham animals underwent thoracotomy alone. Biventricular function was examined using echocardiography. Right ventricular (RV) pressure-volume (P-V) loop analysis was used to evaluate RV function. Pulmonary arterial fibrosis was assessed by trichrome staining.

Results: There was significant 36% decrease in LV ejection fraction (p<0.01) and doubling of LV volumes (p<0.02) at 12 weeks Post-MI. Elevation of both LV diastolic pressure and RV systolic pressure demonstrated the development of secondary PH (Table 1). There was RV contractile dysfunction with a 38% decrease in RV end systolic elastance (Ees). Importantly, there was increased pulmonary vascular arterial elastance (Ea) and increased total pulmonary vascular resistance (tPVR), which were associated with a 40% in perivascular pulmonary arterial fibrosis.

Conclusion: This study utilized the LAD ligation model of ischemic left heart failure in order to study and characterize the development of secondary PH due to LHF. We demonstrate development of RV dysfunction, increased RV afterload, and pulmonary fibrosis, key pathologic features of human secondary PH. Future studies with this novel animal model will provide improved understanding of the pathophysiology of this deadly disease as well as help to identify novel therapeutic targets.

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