Evaluation of skeletal muscle perfusion in canine hind limb ischemia model using color-coded digital subtraction angiography

Accepted Manuscript Evaluation of skeletal muscle perfusion in canine hind limb ischemia model using color-coded digital subtraction angiography

Tao Wang, Haobo Su, Wensheng Lou, Jianping Gu, Xu He, Liang Chen, Guoping Chen, Jinhua Song, Wanyin Shi, Chishing Zee, Bihong T. Chen PII: DOI: Reference:

S0026-2862(18)30212-7 https://doi.org/10.1016/j.mvr.2018.12.003 YMVRE 3851

To appear in:

Microvascular Research

Received date: Revised date: Accepted date:

15 September 2018 16 December 2018 17 December 2018

Please cite this article as: Tao Wang, Haobo Su, Wensheng Lou, Jianping Gu, Xu He, Liang Chen, Guoping Chen, Jinhua Song, Wanyin Shi, Chishing Zee, Bihong T. Chen , Evaluation of skeletal muscle perfusion in canine hind limb ischemia model using color-coded digital subtraction angiography. Ymvre (2018), https://doi.org/10.1016/ j.mvr.2018.12.003

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ACCEPTED MANUSCRIPT Title: Evaluation of Skeletal Muscle Perfusion in Canine Hind Limb Ischemia Model Using Color-Coded Digital Subtraction Angiography

Tao Wang

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, Haobo Su1 , Wensheng Lou1 , Jianping Gu1 , Xu He1 , Liang Chen1 ,

Department of Interventional Radiology, Nanjing First Hospital, Nanjing Medical

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Guoping Chen1 , Jinhua Song1 , Wanyin Shi1 , Chishing Zee2, Bihong T. Chen3

University, Nanjing, Jiangsu, China

Department of Radiology, Keck School of Medicine, University of Southern

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California, Los Angeles, CA, United States

Department of Diagnostic Radiology, City of Hope National Medical Center, Duarte,

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CA, United States

Corresponding author:

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Haobo Su

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Department of Interventional Radiology, Nanjing First Hospital, Nanjing Medical University, No.68, Changle Road, Nanjing, 210006, Jiangsu, China. E-mail: [email protected] Tel: 86-025-87726269 Word count: 3676 words Tables and figures: 1 figure and 3 tables 1

ACCEPTED MANUSCRIPT ABSTRACT Objective: To evaluate perfusion alterations in skeletal muscle in a canine hind limb ischemia model using color-coded digital subtraction angiography (CC-DSA). Methods: Twelve beagles underwent embolization at the branch of their left deep

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femoral artery. Right hind limbs were used as the control group. Angiography was

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performed before and immediately after embolization. Upon CC-DSA analysis, time

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to peak (TTP) was measured before embolization in both sides of the beagles’ hind limbs at the middle iliac artery, and the distant, middle and proximal femoral artery.

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Regions of interest (ROI) peak and ROI peak time were symmetrically computed in

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proximal and distal thigh muscles before and immediately after embolization. The data were analyzed and compared using the Wilcoxon signed rank test.

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Results: Before embolization, ROI peak in the proximal thigh was lower than in the

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ipsilateral distal thigh, whereas ROI peak time in the proximal thigh was longer than in the distal thigh. In the iliac femoral artery, there was no significant difference in

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ROI peak, ROI peak time, or TTP between right and left sides. After embolization,

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ROI peaks in proximal and distal skeletal muscles of the left hind limb were significantly lower than on the contralateral side. ROI peak time was significantly longer in the left proximal and left distal thigh compared to the contralateral side. There were no significant changes in ROI peak or ROI peak time in the right proximal and right distal thigh compared to pre-embolization values. Changes in ROI peak and ROI peak time were larger in the left proximal than in the left distal thigh.

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ACCEPTED MANUSCRIPT Conclusion: CC-DSA provided real-time measurement of changes in vascular hemodynamics and skeletal muscle perfusion without increasing X-ray usage or contrast agent dose.

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Keywords: skeletal muscle perfusion; Digital Subtraction Angiography; Limb

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Ischemia

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ACCEPTED MANUSCRIPT Introduction Lower extremity ischemia is a common peripheral vascular disease. The rate of incidence for individuals over 60 years of age is 20% and increases with age [1]. It can be caused by artery arteriosclerosis, arterial embolism, and other factors that

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decrease blood flow and nutrient delivery to skeletal muscle and nerves. The clinical

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manifestations include lower extremity pain, intermittent claudication, ulcers, and

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gangrene [2]. Endovascular therapy is a preferred treatment for ischemic arterial lesions in the lower extremities due to its minimal invasiveness, efficacy, high salvage

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rate, and low fatality rate [3]. The assessment of effectiveness of lower extremity

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interventional therapy is comprehensive and multi-modal. Available assessment methods include clinical examinations (symptom improvement, arterial pulsation,

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plate walking distance), ankle-brachial index (ABI), transcutaneous oxygen pressure

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(TcP02), Doppler ultrasound, computed tomographic angiography (CTA), magnetic resonance angiography (MRA), and digital subtraction angiography (DSA). However,

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real-time and accurate evaluation of skeletal muscle perfusion after revascularization

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still remains limited [4].

Alteration in hemodynamics can be measured by dynamic DSA, in which color-coded dynamic data is processed [5]. Color-coded DSA (CC-DSA) has been applied for diagnosis and treatment assessment of cerebrovascular disease, tumors, aortic dissection, and lower extremity arterial stenosis. However, these applications only evaluate vascular hemodynamics. Furthermore, few studies have evaluated changes in 4

ACCEPTED MANUSCRIPT skeletal muscles [6-11]. The animal hind limb ischemia models, which model peripheral arterial disease in humans, are widely used to assess diagnosis and treatment of limb ischemic diseases. Some previous animal models of hind limb ischemia had the entire femoral artery and its branches on one side ligated or excised.

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To create a model in which pathogenesis would be more similar to arteriosclerosis in

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lower extremities, others have used a high-fat diet to induce ischemia. However, these

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latter models are limited in scope, take long periods of time to develop, and have had low reproducibility [12, 13]. A hind limb ischemia model that evaluates vascular

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hemodynamics and real-time changes in skeletal muscle perfusion is needed.

Our study was designed to establish a hind limb ischemia model by injecting a

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polyvinyl alcohol (PVA) particle embolic agent into the right femoral artery to

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evaluate skeletal muscle perfusion using CC-DSA and to determine the efficacy of

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real-time assessment of revascularization during interventional therapy.

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Materials and methods

Preparation of canine hind limb ischemia model This study was approved by the Nanjing First Hospital Ethics Committee at Nanjing Medical University. Twelve beagles (6 males and 6 females) weighting 7-10kg were provided by the Nanjing First Hospital Animal Experiment Center.

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ACCEPTED MANUSCRIPT Animals were anesthetized through intramuscular injection of ketamine (10mg/kg) and intravenous infusion of 3% pentobarbital sodium (20~30mg/kg) in the forelimbs. The animals were held supine on the catheter bed of the German Siemens Artis angiography system. A 4F vascular sheath (Terumo, Japan) and 4F pigtail catheter

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(Cordis, United States) were placed in the right femoral artery through the right

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inguinal area after disinfection. The head of the catheter was delivered to the inferior

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segment of the abdominal aorta, into which contrast agent was injected. The pigtail catheter was then replaced with a 4F H1 catheter (Cordis, United States) via a

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guidewire (Terumo, Japan). The head of the 4F H1 catheter was directed into the left

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femoral artery, whereas a microcatheter (Terumo, Japan) was inserted and placed into the beginning section of a branch of the left femoral deep artery. The polyvinyl

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alcohol (PVA, 30mg, 350-560um) particle embolic agent (Hangzhou Alicon Pharm

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Sci&Ten Co.Ltd, China) was injected through the microcatheter, which was replaced by a 4F pigtail catheter after injection. The contrast was injected again for review and

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the catheter and vascular sheath were then removed [14-16]. Angiography was

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performed according to a standardized protocol: (1) The head of the 4F pigtail catheter was placed 2 cm above the distal branch of the abdominal aorta before and after embolization; (2) The target distance and hind limb arterial angiography segment were kept constant; (3) 15ml of Iodine Buddha alcohol (320mgi/ml, Jiangsu Hengrui Medicine Co., Ltd, China) were injected at a rate of 4 ml/s; (4) Images were acquired before the venous period at 3 frames/s; (5)The limb was immobilized before angiography to reduce movement artifacts [17]. 6

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Image data collection Angiographic data were analyzed using the analysis software (Syngo iFlow VC21) in the German Siemens Artis Vascular Imaging System workstation. Time-density curve

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(TDC) and the time to peak (TTP) of each pixel were computed. The peak value

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refers to the difference between the maximum enhancement value and the value at the

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phase of the mask image. The above parameters were color-coded using chroma, saturation, and brightness color models. Chroma represented TTP × 240/360,

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saturation was constant, and brightness indicated the peak value. Chroma, saturation,

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and brightness values of each pixel were converted into red, green, and blue. Brightness represented the concentration of contrast agents and hue represented the

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TTP of different contrasts [18, 19].

The analysis was performed by two physicians with over eight years of experience in

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interventional diagnosis and treatment. TTP measurements before embolization in the

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middle iliac artery, proximal femoral artery, middle femoral artery, and distal femoral artery were the same in both hind limbs. Regions of Interest (ROI, 50mm2) were symmetrically placed in proximal and distal thigh muscles before and immediately after embolization. Large vessels and bones were avoided. ROI peak signal intensity and ROI peak time in the thigh muscles were measured (Figure 1). For each set of manually drawn ROIs, the time versus intensity graph was produced automatically by the software and the parameters could be directly measured and displayed. The ROI 7

ACCEPTED MANUSCRIPT analysis was an average of all the pixel points within the region of interest. A time intensity sequence enabled the creation of a density curve diagram for the time in which the benchmarks were at peak value, the period leading up to maximum value, called the “time-to-peak (TTP)” (Figure 1B). ROI peak time was defined as the time

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that contrast intensity of selected ROI reached the peak value. Time to peak (TTP)

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indicated the time that contrast intensity of one selected image pixel reached the

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maximal value. ROI peak indicated contrast intensity of selected ROI reached the

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ROI reached the peak value[18,19].

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maximal value. ROI peak times indicated the time that contrast intensity of selected

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Figure 1. A representative Color-Coded Digital Subtraction Angiography (CC-DSA) map with region of interest (ROI), time-to-peak (TTP) measurement and time versus ROI contrast intensity graph. (A) On this CC-DSA map, ROIs and TTP measurements were indicated after the insertion of the 4F vascular sheath and the 4F pigtail catheter through the right 9

ACCEPTED MANUSCRIPT femoral artery. The circles highlighted ROI measurements. Before embolization, ROI (50mm2) were symmetrically situated in the proximal and distal thigh muscles. After embolization, the lateral vascular network of the left hind limb was significantly reduced and sparse as seen in ROI 2 and ROI 4. ROI (50mm2) were situated in the

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same places as pre-embolization.

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(B) Time versus ROI Contrast Intensity Graph. The blue, red, green, and pink colored

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curves in the Figure 1B corresponded to the ROI Ref, ROI 3, ROI 4, and ROI 2 in Figure A, respectively. The slopes of the time-density curve of the ROIs in left hind

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limb were decreased significantly as seen in the green-colored and pink-colored

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curves, indicating a significant reduction of blood flow to the limb.

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Statistical analysis

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All statistical analyses were performed using SPSS 23.0. Unless specified, data are shown as mean ± standard deviation. TTP of iliac-femoral arteries, and ROI peak and

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ROI peak time of skeletal muscles were compared before and after embolization using

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the Wilcoxon signed rank test. A p value < 0.05 was considered statistically significant.

Results Hind limb ischemia models involving the left thigh muscle were successfully established in 12 beagles. No significant difference were observed between the TTP values on the left and right sides for either the iliac or femoral arteries (Table 1). 10

ACCEPTED MANUSCRIPT Before embolization, the ROI peak in the proximal thigh was lower than in the distal thigh on the same side, whereas ROI peak time in the proximal thighs was longer than in the distal thighs. There was no significant difference in ROI peak or ROI peak time between the sides. After embolization, ROI peaks in the proximal and distal skeletal

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muscles of the left hind limb were significantly lower than on the contralateral side.

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ROI peak time was significantly longer in the left proximal and left distal thigh

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compared to the contralateral side. There was no significant difference in ROI peak or ROI peak time in the right proximal and right distal thigh compared to

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pre-embolization. The changes in ROI peak and ROI peak time were larger in the left

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proximal thigh compared to the left distal thigh (Tables 2 and 3).

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Table 1 Time to peak (TTP) of the iliac and femoral arteries in both hind limbs before

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embolization

Left limb

Right limb P value TTP(s)

4.393±0.075

4.391±0.079

0.571

Proximal femoral artery

4.972±0.204

4.926±0.251

0.262

Middle femoral artery

5.273±0.187

5.271±0.193

0.522

Distal femoral artery

5.469±0.211

5.467±0.216

0.571

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TTP(s)

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Middle iliac artery

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ACCEPTED MANUSCRIPT Table 2 Region of interest (ROI) peaks in bilateral proximal and distal thighs before and after embolization Pre-embolization

Post-embolization P value

Change

0.503±0.021

ROI peak

Proximal left thigh

1.153±0.057

0.650±0.055

0.002

Proximal right thigh

1.144±0.058

1.146±0.059

0.627

P value

0.077

0.002

Distal left thigh

1.439±0.076

1.059±0.110

0.002

0.381±0.061

Distal right thigh

1.440±0.061

1.447±0.080

0.421

0.007±0.030

P value

1.000

0.002

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ROI peak

0.002

0.002

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0.002±0.012

Note: The P value of change of the ROI peak in the proximal left thigh was 0.003

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compared to the distal thigh of the same side. The P value of change of the ROI peak

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in the proximal right thigh muscles was 0.550 compared to that of the distal thigh of

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the same side.

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Table 3 Region of Interest (ROI) peak times in the bilateral proximal and distal thighs before and after embolization Pre-embolization

Post-embolization

P Change

ROI peak time(s)

ROI peak time (s)

value

Proximal left thigh

10.049±0.190

12.802±0.397

0.002

2.753±0.240

Proximal right thigh

10.040±0.185

10.039±0.182

0.918

0.001±0.020

P value

0.080

0.002 12

0.002

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Distal left thigh

9.908±0.135

12.033±0.247

0.002

2.126±0.142

Distal right thigh

9.916±0.128

9.939±0.174

0.473

0.023±0.069

P value

0.303

0.002

0.002

Note: The P value of change of ROI peak time in the proximal left thigh was 0.002

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compared to the distal thigh of the same side. The P value of change of ROI peak time

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in the proximal right thigh was 0.514 compared to the distal thigh of the same side.

Discussion

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In this study, we devised a hind limb ischemia model by injecting embolization

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material into the left femoral artery via a catheter to block or reduce skeletal muscle perfusion. This hind limb ischemia model could be easily performed and reproduced,

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and resulted in minimal trauma. The ischemic area could be controlled by embolizing

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different blood vessel branches. Studies have shown that animal ischemia models produced by the interventional embolization method have lower mortality rates and

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less postoperative inflammatory response compared to surgical models [20-22].

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Polyvinyl alcohol granules were used as embolic materials in this study. However, there is no standard for the types of embolic materials used for interventional embolization. Other studies have used various types of embolic materials with varying properties, such as autologous thrombus, micro-coil, and n-butyl acrylate, for which efficacy remains to be elucidated [14-16].

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ACCEPTED MANUSCRIPT Currently available methods to assess the severity of arterial ischemia in the lower extremities include clinical examinations such symptomatic evaluation, arterial pulse of the lower extremity, and flat walking distance, Ankle-Brachial Index (ABI), Transcutaneous oximetry (TcPO2), Doppler ultrasound, CT angiogram (CTA), MR

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angiogram (MRA), and DSA. There are limitations in these methods. For example,

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clinical examinations involve some subjective aspects. ABI detection is specific but

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has relatively low sensitivity. TcPO2 measurements are susceptible to various distorting factors including blood oxygen concentration, skin thickness, edema, and

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inflammation. Moreover, Doppler ultrasound, CTA, MRA, and DSA can be limited

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by arterial lumen shape. In addition, evaluation and quantification of skeletal muscle perfusion in the lower extremities cannot be conducted with real-time hemodynamic

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parameters by any of these methods [22].

In our study, CC-DSA was applied to bilateral skeletal muscles in a hind limb

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ischemia model. A single sequence of 2D-DSA data was recalculated in Syngo iFlow

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software, in which the perfusion situation was parameterized to yield a group of time-density, color-coded images for hemodynamics evaluation. In this way, subjective DSA images were transformed into an objective parametric index [6-11, 23]. TTP of the bilateral iliac-femoral arteries as well as ROI peak and ROI peak time in the skeletal muscle of both hind limbs were measured before and after embolization. No significant differences in TTP between sides of the iliac-femoral arteries or ROI peak and ROI peak time between proximal and distal thighs were 14

ACCEPTED MANUSCRIPT found after insertion of the 4F vascular sheath and 4F pigtail catheter.

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indicated that neither the vascular sheath nor catheter significantly affected hemodynamics and skeletal muscle perfusion. After embolization, perfusion of the left thigh was lower compared to the contralateral side, as reflected by the decrease in

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ROI peak and increase in ROI peak time on the left. The changes in ROI peak and

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ROI peak time in the left proximal thigh were larger than in the left distal thigh, when

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compared to the contralateral side. This suggested that there was a difference in the degree of embolization in the proximal and distal thigh. One reason for this difference

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might be due to the fact that the branch of the left deep femoral artery mainly

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supplying blood to the left proximal thigh muscle, where the embolic agent could accumulate. Another explanation could be due to the fact that the position of the

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selected ROI in the distal thigh was closer to the vasculature compared to the ROI in

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the proximal thigh, which may have influenced our measurements. Moreover, CC-DSA was a planar projection of 3D spatial data. Thus, measurements may

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potentially include the tissue or blood vessel partial volume along the projection

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direction [12, 17]. Furthermore, our animal model of hind limb ischemia mimicked acute ischemia, and therefore may not accurately reflect what would be seen in clinical chronic ischemia. Nevertheless, the computational measurements in CC-DSA enabled one-stop acquisition and assessment of embolic effects in real-time without increasing X-ray exposure time/dose or contrast agent doses [23-25].

There were several limitations of the CC-DSA technique. Variables such as catheter location, the dosage and rate of the contrast injection during angiography and cardiac 15

ACCEPTED MANUSCRIPT output could potentially affect the accuracy of the perfusion assessment. The contrast time density curve could be affected if there was alteration in the catheter location or the dose and rate of contrast injection. If the catheter location or the amount of contrast injected were varied, then the TTP would have changed. Nevertheless, the

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angiography in our study were performed strictly according to the standardized

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protocol, which may have helped to alleviate some of the concerns with this technique.

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Additionally, we recognize the limitation of the CC-DSA technique presented in this study as being semi-quantitative for lack of internal control as a reference. Decrease

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in cardiac output could lead to changes in the TTP and the time-density curve.

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Conclusions

In summary, we have established an animal model of hind limb ischemia by using

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interventional embolization through femoral artery puncture. Compared to other models, this model is easier to perform, causing less trauma and with higher

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reproducibility. CC-DSA could provide real-time measurement of changes in vascular hemodynamics and alterations in skeletal muscle perfusion without increasing X-ray

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or contrast agent dose, which in turn may allow for simultaneous monitoring and evaluation of revascularization in interventional therapy.

Conflict of interest The authors declared no conflicts of interest.

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ACCEPTED MANUSCRIPT Funding support This work was supported by the General Program of Medical Research of Health and Family Planning Commission of Jiangsu Province of China (H2017046)

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References

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[1] Leng GC,Lee AJ,Fowkes FG,et a1．Incidence, natural history and cardiovascular

SC

events in symptomatic and asymptomatic peripheral arterial disease in the general population[J]. Int J Epidemiol, 1996, 25(6):1172-1181.

NU

[2] Falluji N, Mukherjee D. Critical and acute limb ischemia: an overview[J].

MA

Angiology, 2014,65(2):137-146. DOI:10.1177/0003319712470966. [3] Valle JA, Waldo SW.Current endovascular management of acute limb ischemia[J].

D

Interv Cardiol Clin, 2017,6(2):189-196. DOI:10.1016/j.iccl. 2016.12.003.

PT E

[4] Watson K,Watson BD,Pater KS.Peripheral arterial disease: a review of disease awareness and management[J].Am J Geriatr Pharmacother, 2006,4(4):365-379.

CE

[5] Gölitz P,Struffert T,Lücking H,et al. Parametric color coding of digital subtraction

AC

angiography in the evaluation of carotid cavernous fistulas[J]. Clin Neuroradiol， 2013，23(2):113-120.DOI: 10.1007/s00062 -012-0184-8. [6] Kondapavulur S,Cooke DL,Kao A,et al. Estimation of intra-arterial chemotherapy distribution to the retina in pediatric retinoblastoma patients using quantitative digital subtraction angiography[J]. Interv Neuroradiol, 2018,24(2): 214-219 . DOI:10.1177/ 1591019917749825.

17

ACCEPTED MANUSCRIPT [7] Burkhardt JK,Chen X,Winkler EA,et al. Delayed Venous Drainage in Ruptured Arteriovenous Malformations Basedon Quantitative Color-Coded Digital Subtraction Angiography[J]. World Neurosurg, 2017,104:619-627.DOI: 10.1016/j. wneu.2017.04. 120.

PT

[8]Yamamoto K, Yamamoto K,Nakai G, et al. Novel Software-Assisted Hemodynamic

RI

Evaluation of Pelvic Flow During Chemoperfusion of Pelvic Arteries for Bladder

SC

Cancer: Double-Versus Single-Balloon Technique[J]. Cardiovasc Intervent Radiol, 2016,39(6): 824-830.DOI: 10.1007/s00270- 016- 1296-3.

NU

[9] Cattaneo GFM,Ding A,Jost T,et al. In vitro, contrast agent-based evaluation of the

MA

influence of flow diverter size and position on intra-aneurysmal flow dynamics using syngo iFlow[J]. Neuroradiology, 2017,59(12):1275-1283. DOI:10.1007 /s00234

D

-017-1903-2.

PT E

[10] Wang J，Cheng JJ，Huang KY，et a1．Quantitative assessment of angiographic perfusion reduction using color-coded digital subtraction angiography during chemoembolization[J].

Abdom

Radio1(NY),2016,41(3):545-552.

CE

transarterial

AC

DOI:10.1007/ s00261- 015-0622 -6 . [11] Zhang Y,Li C,Zhang H,et al. Color-coded Digital Subtraction Angiography for Assessing Acute Skeletal Muscle Ischemia-Reperfusion Injury in a Rabbit Model[J], Acad Radiol,2018 Apr 23.pii: S1076- 6332(18) 30133- 8.DOI: 10.1016/ j.acra. 2018.03.020.

18

ACCEPTED MANUSCRIPT [12] Guang H,Cai C,Zuo S,et al. Multiparametric evaluation of hindlimb ischemia using time-series indocyanine green fluorescence imaging[J]. J Biophotonics, 2017, 10(3):456-464. DOI: 10.1002/jbio. 201600029. [13] Del Giudice C,Ifergan G,Goudot G，et al.Evaluation of a new model of hind limb

PT

ischemia in rabbit[J],JVascSurg,2017Oct 23.pii: S0741- 5214(17)32122 -5. DOI:

RI

10.1016/j.jvs.2017.07.140.

SC

[14] Long CA,Timmins LH,Koutakis P，et al. An endovascular model of ischemic myopathy from peripheral arterial disease[J], J Vasc Surg, 2017, 66(3):891-901.DOI:

NU

10.1016/j.jvs.2016.07.127.

MA

[15] Shin CI,Kim HC,Song YS,et al.Rat model of hindlimb ischemia induced via embolization with polyvinyl alcohol and N-butyl cyanoacrylate[J], Korean J Radiol,

D

2013,14(6):923-930. DOI:10.3348 /kjr.2013.14.6.923.

PT E

[16] Long CA, Timmins LH, Koutakis P,et al.An endovascular model of ischemic myopathy from peripheral arterial disease,J Vasc Surg,2017 66(3):891-901. DOI:

CE

10.1016/j. jvs. 2016.07. 127.

of

Distal

Hemodynamic

AC

[17] Lou WS, Su HB, Huang KY,et al. Evaluation

Changes of Lower Extremity after Endovascular Treatment: Correlation between Measurements of Color-Coded Quantitative Digital Subtraction Angiography and Ankle-Brachial Index[J]. J Vasc Interv Radiol, 2016, 27(6),852-858. DOI: 10.1016 /j.jvir. 2016.02.011. [18] Shakur SF,Brunozzi D,Hussein AE,et al.Validation of cerebral arteriovenous malformation hemodynamics assessed by DSA using quantitative magnetic resonance 19

ACCEPTED MANUSCRIPT angiography: preliminary study[J]. J Neurointerv Surg,2018,10(2):156-161. DOI: 10.1136/

neurintsurg-2017- 012991.

[19] Kostrzewa M, Kara K, Pilz L,et al. Treatment Evaluation of Flow-Limiting Stenoses of the Superficial Femoral and Popliteal Artery by Parametric Color-Coding

PT

Analysis of Digital Subtraction Angiography Series[J]. Cardiovasc Intervent

RI

Radiol,2017,40(8):1147-1154. DOI: 10.1007/s00270 -017- 1670-9.

muscle

ischaemia[J],

Atherosclerosis,

2013,

227(1):1-8.

DOI:10.1016/j.

NU

atherosclerosis. 2012.10.060.

SC

[20] Lotfi S1,Patel AS,Mattock K,et al. Towards a more relevant hind limb model of

MA

[21] Zhuang ZW,Shi J,Rhodes JM,et al. Challenging the surgical rodent hindlimb ischemia model with the miniinterventional technique[J].J Vasc Interv Radiol,

D

2011,22(10): 1437-1446. DOI:10.1016/j. jvir.2010.12.039.

PT E

[22]Liddell RP, Patel TH, Weiss CR, et al. Endovascular model of rabbit hindlimb ischemia:a platform to evaluate therapeutic angiogenesis[J]. J Vasc Interv

CE

Radiol,2005 ,16(7):991-998.

AC

[23] Su H,Lou W,Gu J. Clinical values of hemodynamics assessment by parametric color coding of digital subtraction angiography before and after endovascular therapy for critical limb ischaemia[J],Zhonghua Yi Xue Za Zhi, 2015,95(37):3036-3040. [24] Lin CJ，Hung sc，Guo wY，et a1．Monitoring peri-therapeutic cerebral circulation time: a feasibility study using color-coded quantitative DSA in patients with steno-occlusive arterial disease[J].AJNR Am J Neuroradiol, 2012,33(9):1685-1690. DOI:10.3174/ajnr.A3049. 20

ACCEPTED MANUSCRIPT [25] Lin CJ,Luo CB,Hung SC,et a1. Application of color-coded digital subtraction angiography in treatment of indirect carotid-cavernous fistulas: initial experience[J].J

AC

CE

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D

MA

NU

SC

RI

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Chin Med Assoc,2013,76(4): 218-224．DOI：10.1016/j.jcma.2012.12.009.

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ACCEPTED MANUSCRIPT Highlights 

An animal model of hind limb ischemia was established by using interventional embolization through femoral artery puncture, which is easier to perform, causing less trauma and with higher reproducibility. Color-coded DSA(CC-DSA) was used to provide real-time measurement of

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

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changes in vascular hemodynamics and alterations in skeletal muscle

The canine hind limb ischemia model with perfusion data presented here may

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be useful for future limb ischemia research.

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

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perfusion.

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