Characterization of Congestive Heart Failure Phenotype in a Murine Model of JAK2V617F-positive Myeloproliferative Neoplasm

Background: Murine models are commonly utilized to study cardiovascular disease (CVD); however, many established models involve invasive surgery or genetic manipulation to induce hyperlipidemia. These methods may not accurately represent the progressive cardiovascular issues arising from mutated blood-forming cells. The Tie2-Cre/-FF1/- (Tie2FF1) mice express the JAK2V617F mutation in both hematopoietic and endothelial cells.

They develop spontaneous CVD without dietary modifications. Methods: A thorough, non-invasive cardiovascular assessment was conducted on 1-year-old Tie2FF1 mice and their age-matched controls. The evaluation included transthoracic echocardiography, Doppler ultrasound to measure coronary flow reserve, a detailed study of coronary arteriolar structure and perivascular fibrosis, endocardial histology, subendocardial collagen deposition, and hepatic and pulmonary congestion histology.

Results: The Tie2FF1 mice exhibited left ventricular dilation, increased cardiac mass, and slightly diminished systolic function. Notably, there was no evidence of obstructive epicardial coronary disease. The mice also displayed coronary microvascular remodeling, characterized by narrowed arteriolar diameters and heightened perivascular fibrosis, accompanied by a reduced coronary flow reserve in an exploratory group.

Additionally, the mice showed disrupted endocardial endothelial cells and increased subendocardial fibrosis. Furthermore, Tie2FF1 mice had heavier lungs and livers, fluid accumulation in the lungs, thickening of the alveolar septa, pulmonary vascular fibrosis, expansion of the hepatic sinusoids, and swelling of the centrilobular hepatocytes.

These observations offer concrete evidence of clinically significant heart failure. Significance: The results confirm that Tie2FF1 mice serve as a spontaneous, non-invasive model displaying characteristics of both coronary microvascular and endocardial endothelial dysfunction, as well as heart failure with a modestly reduced left ventricular ejection fraction.

The comprehensive approach outlined in this study provides a practical strategy for thorough murine cardiovascular phenotyping, surpassing conventional atherosclerosis- and surgery-based models.