Atorvastatin Reduces In Vivo Fibrin Deposition and Macrophage Accumulation, and Improves Primary Patency Duration and Maturation of Murine Arteriovenous Fistula
Authors: Cui Jie , Kessinger Chase W. , Jhajj Harkamal S. , Grau Madeleine S. , Misra Sanjay , Libby Peter , McCarthy Jason R. , Jaffer Farouc A. 
Published: March 2020

Significance Statement
Experimental studies have established that inflammatory and thrombogenic responses play critical roles in patency and maturation of arteriovenous fistulas placed surgically for dialysis vascular access. In this study of mice given atorvastatin or PBS starting 7 days before creation of an arteriovenous fistula, use of atorvastatin was associated with favorable outward remodeling, preserved arteriovenous blood flow, and longer duration of primary arteriovenous fistula patency. These statin-mediated benefits occurred following reductions in the thrombogenic and inflammatory macrophage response detected within 2 weeks after arteriovenous fistula creation. These findings provide insights into in vivo molecular mechanisms that underlie primary arteriovenous fistula failure, provide a foundation to test novel pharmacotherapeutics that aim to improve arteriovenous fistula maturation, and support further clinical evaluation of statin therapy to improve maturation and patency.

Background
Arteriovenous fistulas placed surgically for dialysis vascular access have a high primary failure rate resulting from excessive inward remodeling, medial fibrosis, and thrombosis. No clinically established pharmacologic or perisurgical therapies currently address this unmet need. Statins’ induction of multiple anti-inflammatory and antithrombotic effects suggests that these drugs might reduce arteriovenous fistula failure. Yet, the in vivo physiologic and molecular effects of statins on fistula patency and maturation remain poorly understood.

Methods
We randomized 108 C57Bl/6J mice to receive daily atorvastatin 1.14 mg/kg or PBS (control) starting 7 days before end-to-side carotid artery–jugular vein fistula creation and for up to 42 days after fistula creation. We then assessed longitudinally the effects of statin therapy on primary murine fistula patency and maturation. We concomitantly analyzed the in vivo arteriovenous fistula thrombogenic and inflammatory macrophage response to statin therapy, using the fibrin-targeted, near-infrared fluorescence molecular imaging agent FTP11-CyAm7 and dextranated, macrophage-avid nanoparticles CLIO-VT680.

Results

In vivo molecular-structural imaging demonstrated that atorvastatin significantly reduced fibrin deposition at day 7 and macrophage accumulation at days 7 and 14, findings supported by histopathologic and gene-expression analyses. Structurally, atorvastatin promoted favorable venous limb outward remodeling, preserved arteriovenous fistula blood flow, and prolonged primary arteriovenous fistula patency through day 42 (P<0.05 versus control for all measures).

Conclusions
These findings provide new in vivo evidence that statins improve experimental arteriovenous fistula patency and maturation, indicating that additional clinical evaluation of statin therapy in patients on dialysis undergoing arteriovenous fistula placement is warranted.