Endocardial Endothelial Dysfunction Progressively Disrupts Initially Anti then Pro-Thrombotic Pathways in Heart...

Area of Science:

• Cardiovascular Biology
• Thrombosis Research
• Endothelial Dysfunction

Background:

• Endocardial endothelial dysfunction in heart failure (HF) is understudied.
• An experimental model for endocardial thrombosis is lacking.

Purpose of the Study:

• To determine if disrupting the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis during acute decompensation.
• To investigate if altered von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes.

Main Methods:

• Utilized echocardiography to monitor HF development and detect endocardial thrombi in CREBA133 mice.
• Confirmed endocardial thrombi incidence using immunohistochemistry and histology.
• Assessed tail-bleeding index, APC generation, and expression of APC-related receptors.

Main Results:

• CREBA133 mice exhibited a high incidence of endocardial thrombi during early and acute decompensated HF phases, with a shorter tail-bleeding index.
• APC generation and key APC pathway receptor expression were suppressed in the endocardium of acutely decompensated HF mice.
• Stable compensated HF mice showed attenuated vWF protein content, secretion, vWF-dependent platelet agglutination, and reduced thrombin generation.

Conclusions:

• CREBA133 mice serve as a model for HF and associated endocardial endothelial dysfunction.
• Suppression of the APC pathway promotes endocardial thrombosis in early and acute decompensated HF.
• In stable compensated HF, reduced endothelial vWF expression and extrusion may decrease endocardial thrombosis incidence.