BALB/cJBom Treated with Angiotensin II and High Salt Diet Develop Pulmonary Hypertension and Right Sided Heart Failure while C57BL/6J Mice do not
Authors: Becirovic‐Agic Mediha , Jönsson Sofia , Tveitarås Maria K. , Skogstrand Trude , Karlsen Tine V. , Lidén Åsa , Leh Sabine , Reed Rolf K. , Hultström Michael 
Published: June 2021

Pulmonary arterial hypertension (PAH) is caused by increased pulmonary vascular resistance that can develop as part of other pathologies such as pulmonary embolism and heart failure, or because of pulmonary vascular remodeling. Right ventricle failure is the primary cause of death in patients with pulmonary hypertension. Interestingly, despite similar right ventricle systolic pressure and degree of hypertrophy, some patients rapidly develop right ventricle failure while others show prolonged periods of stability. Here we present a new mouse model of acute decompensated pulmonary hypertension displaying genetic predisposition to right‐sided heart failure.

In a previous study we have seen that BALB/cJBom mice are more sensitive to a combination treatment of angiotensin II and high salt diet (AngII+Salt) compared to C57BL/6J. During the treatment BALB/cJBom mice develop massive edema and display very high mortality. The aim of present study was to elucidate the physiological and genetic mechanism responsible for the increased sensitivity in BALB/cJBom. BALB/cJBom and C57BL/6J mice were treated with AngII (0.5 μg/min/kg) and high salt diet (3%) and cardiac function was measured with echocardiography every day for seven days. BALB/cJBom treated with AngII+Salt display an increased pulmonary vascular resistance and right ventricle systolic pressure 24 hours following treatment initiation, assessed with Pulsed wave Doppler measurement of pulmonary artery flow. Increased pulmonary vascular resistance precedes diastolic dysfunction and reduced cardiac output, that is seen at day two and three respectively. Ejection fraction is not affected by AngII+Salt treatment. AngII+Salt does not affect cardiac function in C57BL/6J except increasing heart rate. This indicates a genetic susceptibility to pulmonary hypertension and right‐sided heart failure in BALB/cJBom. Linkage analysis identified a quantitative trait loci (QTL) at chromosome 3 which could explain the variation in change in cardiac output. Urine and sodium excretion, measured with metabolic cages when reduced cardiac output was established, was lower in BALB/cJBom mice treated with AngII+Salt than in C57BL/6J. Some BALB/cJBom mice did not excrete any urine during the 24‐hour measurement period, indicating acute kidney injury. QTLs on chromosome 2 and 3 were linked to changes in water and sodium regulation.

In conclusion, BALB/cJBom treated with AngII+Salt develop decompensated pulmonary hypertension which is genetically predisposed. A QTL on chromosome 3 is linked to reduction in cardiac output during the setting of decompensated pulmonary hypertension. BALB/cJBom treated with AngII+Salt may work as an animal model to study the adaptive capacity of the right ventricle in pulmonary hypertension.

Support or Funding Information

Regional Health Authority in Western Norway

Åke Wiberg foundation

Swedish heart‐lung foundation

Swedish Society of Medicine

Marcus Borgström foundation

Swedish Society for Medical Research

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.