Jie Cui, MD, MScNephrology Division
Cardiovascular Research CenterMassachuestts General Hospital
ASDIN 02/2017
Statin therapy Decreases Vascular Inflammation andProlongs Patency in Murine Arteriovenous Fistula
Background
• The primary failure rate of AVF isaround 50%.
• The patency after percutaneousangioplasty is not satisfactory. Nomedical therapies proven.
• Annual cost of vascular accessmaintenance is around $2 billion inthe U.S.A the U.S
AVF
AVG
Background
Background
Inflammation plays a role in neointimal hyperplasia and thrombosis
• Patients with unsuccessful AVF have higher CRP and fibrinogen level.1
• Thromboses AVFs have more macrophages and lymphocytes compared to nonthrombosed fistulas. 2
• The patency and luminal area/total cross-sectional area were all higher in MCP1-/-micecompared to MCP1+/+ mice.3
1. Kaygin MA et al. The relationship between arteriovenous fistulae success and inflammation. Ten Fail 2013 Sep; 35(8): 1085-8
2. Chi-Jen Chang et al. Thromboses arteriovenous fistula for hemodialysis access is characterized by a marked inflammatory activity. KI, vol 68(2005), 1312-1314
3. Julio P.Juncos et al. MCP-1 contributes to arteriovenous fistula failure. JASN. 2011 Jan; 22(1): 43-48
Factors that predict AVF maturation
Hemodynamic changes of vessel diameter and blood flow
2 weeks:634-750 ml/min1
4 weeks: diameter 0.45cm, blood flow 700ml/min 2
12 weeks: diameter 0.47cm, blood flow 675ml/min
If blood flow rate >500ml/min at 6 to 8 weeks, 70% of AVF is usable for hemodialysis
1 Lin SL. et al. Effects of age and diabetes on blood flow rate andprimary outcome of newly created hemodialysis arteriovenous fistula. Am J Nephrol 18: 96-100, 19982 Robbin ML et al. Hemodialysis arteriovenous fistula maturity: US evaluation. Radiology 255;59-64,2002
Clinical Significances
• New imaging approaches to predict AVF failure could betteridentify high risk AVF failure patients for novel AVF therapies.
• New therapies to improve AVF patency could markedly improveESRD patients’ survival and health care expenditure
• Establish clinical relevant murine AVF model to investigateinflammation and thrombotic mechanisms of AVF failure invivo
• Develop molecular imaging approaches to predict AVFfailure
• Evaluate anti-inflammatory agent to prolong AVF patency
Aims
AVF model
• New AVF model: end to sideinternal jugular vein-carotidartery anastomosis
• Evaluate venous stenosis andthrombus formation
• Evaluate blood flow changes Venous outflow
Figure. Trends of blood flow in the venous outflow after arteriovenous fistula creation.A. The mean blood flow measured by Transonic flow probe immediately post-surgerywas 1.24±0.47 ml/min. The blood flow decreased on day 7 (1.05±0.71 ml/min), day 14(0.47±0.51ml/min) and day 21 (0.19±0.23 ml/min). B. The blood flow in the fistula onday 14 was correlated with day 7 blood flow (r=0.80, p=0.02).
AB
Blood Flow Changes
Distribution of inflammatory cells
D7
D14
CD68 F4/80 NIMP
*
*
Structure
Distribution
Cross-linked iron oxide:stable under harshconditions (do notchange in size, bloodhalf-life, or loss of itsdextran coat)
Cross-linked iron oxide (CLIO)
CLIO-VT680 CD68 CLIO-VT680
CD68
Day 1AVF
surgery
Day 6CLIO-VT680
injection
Day 14Sac
Day 7Imaging
250μm
250μm 250μm
250μm 250μm
250μm 250μm
Figure: In vivo epifluorescence imaging of arteriovenous fistula outflow using CLIO-VT680. A. CLIO-VT680 was injected on day 6 post-AVF creation (10mg/kg). A. In vivo epiflorescence imaging wasperformed 24 hours later. B. The mean signal intensity of venous outflow in AVF side was muchhigher than the control vein (p<0.0001)
FITC
CLIO
FITCCLIO
A
B C
p<0.001
Study Protocol
B
Figure. The blood flow changes from day 7 to Day 14 was correlated with day 7 CLIO-VT680target to back ground ratio (p=0.02, r=-0.57). B. If day 7 TBR<4, the average changes of bloodflow from day 7 to day 14 was 0.09±0.21 ml/min). If day 7 TBR>4, the average changes of bloodflow from day 7 to day 14 was -0.8±0.27 ml/min), p=0.02.
A B
p=0.02r=-0.57
p=0.02
Blood flow changes correlates with CLIO-VT680 TBR
Statin
• Statin— anti-inflammatory pleiotropic properties• Animal study: decrease neointimal hyperplasia1
• Human study: Controversial2,3,4
• Higher dose may be required to achieve the clinical effects
1. Yamanouchi D. et al. Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition. J Vasc Surg. 2005 Oct; 42(4):757-642. Roberto Pisoni et al. Statin therapy is not associated with improved vascular access outcomes. CJASN Aug 2010. vol 5. no. 8 1447-1450;3. Righetti M et al. Some old drugs improve late primary patency rate of native arteriovenous fistulas in hemodialysis patients. Ann Vasc Surg 23: 491-497, 204. Martinez L et al. Distinct Impact of three different statins on arteriovenous fistula outcomes: a retrospective analysis. JVA 2016 Nov 2; 17(6): 471-476
p=0.03
Day 1AVF
surgery
Day 14Sac
Day -7Atorvastatin1.14mg/kg
Study Protocol
Figure. The volume of neointimal hyperplasia was comparable in PBS treated mice and statin treatedmice in both day 7 and day 14 (p>0.05).
Day 7Sac
Figure. In mice treated with PBC, the meanblood flow changes from day 7 to day 14was -0.8±0.32 ml/min. However, in micetreated with statin, the mean blood flowchanges is 0.14±0.18 (p=0.02).
Blood flow changes in Statin vs PBS
p=0.02
p=0.02
Figure. The primary patency of AVF in micetreated with statin was much higher than
Statin increases venous outflow area
Figure. The venous outflow area was bigger in statin treated mice compared to PBS treated mice.
p=0.03
Figure. The CLIO-VT680 target to background ratio of venous outflow/control vein inPBS and statin treated mice on day 7. A. CLIO-VT680 target to background ratio washigher in PBS treated group compared to statin treated group (p=0.03). B. TBR wasmeasured every 120um from the anastomosis to the distal of the venous outflow,which showed PBS treated group had higher CLIO-VT680 signals compared to statintreated group.
Statin decreased adventitial inflammatory response
p=0.03
Day 1AVF
surgery
Day 6CLIO-VT680
injection
Day 14Sac
Day 7Imaging
Day -7Atorvastatin1.14mg/kg
FITC
CLIO
FITCCLIO
Platelet activities and Fibrinogenesis
Figure. Platelet activities and fibrinogenesis were comparable in statin treated andPBS treated group.
1.Inflammatory response in adventitium post-AVF can beimaged in vivo.
2.The inflammatory response on day 7 correlated withblood flow changes from day 7 to day 14.
3.Statin can decrease inflammatory response andprolonged AVF patency in murine animal model
Conclusions
AcknowledgementsMGH CSB
Jason R. McCarthy, PhDCharles P. Lin, PhD
Matthias Nahrendorf, PhDRalph Weissleder, MD
MGH Nephrology
Amin Arnaout, MDRavi Thadhani, MD
MGH CVRC/Cardiology
Farouc Jaffer, MD, PhDChase Kessinger, PhD
Harkamal Jhajj, BSAdam Mauskapf, BS
Victor Guanming Qi, MD, PhD
BWH Cardiology
Peter Libby, MD
BWH Nephrology
Joseph Bonventre, MD, PhD
Funding
American Society of Nephrology Ben. J Lipps Research Fellowship GrantAmerican Society of Diagnostic and Interventional Nephrology Fellowship Grantt