In chronic heart failure patients, thromboembolic events are the most common complication, resulting in increased hospitalization rates and mortality. Prevention of cardiac thrombosis in heart failure (HF) patients with anticoagulant therapy is controversial because of the increased risk of bleeding. Cardiac endothelial cells normally promote anticoagulation through multiple pathways including activated protein C (APC) generation on their luminal surface. In HF, the endothelial surface becomes increasingly prothrombotic partly due to altered endothelial anticoagulation. Alterations in APC and thrombin generation, and increased von Willebrand factor (vWF) extrusion from the endothelium, are likely consequences of a prothrombotic endothelium. A recombinant form of APC has been used in clinical trials but is associated with an increased risk of bleeding. An alternative therapeutic approach may involve promotion of multiple endogenous endothelial anticoagulant pathways. Cardiac sympathetic nerves make close appositions with endocardial endothelial cells (EECs) that line the cardiac chambers; these direct connections are unlike those with vascular endothelium where smooth muscle separates nerve from endothelial cell. Sympathetic nerves regulate many aspects of normal endothelial function likely through release of norepinephrine (NE) and neuropeptides such as neuropeptide Y (NPY) and galanin. We suspect that neuropeptides promote the anticoagulant function of endothelial cells. We hypothesize that neuropeptide release is suppressed in HF promoting endothelial dysfunction and a reduction in anticoagulation function. We test this hypothesis with human HF and control ventricular tissue and plasma, and in a mouse model of HF. We will determine: (i) the spatial and functional link between endocardial thrombosis and aberrant ventricular innervation; examined in HF mice with a novel combined contrast-enhanced ultrasound and microPET approach; (ii) the mechanisms, both direct and indirect, through which neuropeptides promote endothelial anticoagulation; examined in cultured human heart failure EECs; (iii) the promotion of endothelial anticoagulant function by neuropeptide treatment in vivo in HF mice; (iv) whether plasma neuropeptide levels in HF subjects can be used as early biomarkers of a prothrombotic state. Significance: A critical link between subendocardial nerve activity and endothelial anticoagulant function will be identified in these studies. Preliminary data suggest that neuropeptides promote endothelial anticoagulant function, and this function is disrupted in HF. If this is the case, neuropeptide treatment may provide a novel therapy for reducing thromboembolic complications in HF patients. Establishing a relationship between circulating neuropeptide levels and thrombus formation will identify novel early biomarkers of thromboembolic risk in HF patients.
In heart failure, the lining of the heart and blood vessels is more prone to formation of clots that can cause a stroke or a blockage in normal blood flow. Nerves in the heart regulate heart rate, but may also protect the heart from developing clots. We will use human and mouse heart failure tissue to look at how protection of clot formation by nerves may be disrupted in heart failure, and how neuronal factors may be used for therapy.
