Structured Exercise Therapy Builds Muscle Strength in Porcine Model of Peripheral Artery Disease
Carson Hoffmann1, Jarrod Call2, Maiko Sasaki1, Feifei Li1, Dylan McLaughlin1, Ahmed Ismaeel3, Panagiotis Koutakis3, Luke Brewster1
1Atlanta VA Medical Center, Emory University, Atlanta, GA;2University of Georgia, Athens, GA;3Baylor University, Waco, TX
IntroductionStructured exercise therapy (SET) is first line therapy to improve walking distance, gait, and decrease pain during ambulation for patients with peripheral artery disease (PAD). The mechanism by which SET exerts its benefits is unclear but likely involves strengthening or training the ischemic muscle to function better under ischemic conditions. We hypothesized that SET improves muscle strength in ischemic muscles. Our objective was to test this hypothesis using our large animal model of ischemic myopathy to mimic PAD conditions in the hindlimb.
MethodsSeven female, Yorkshire swine who had reached skeletal maturity were included in this study. All underwent treadmill training prior to the hindlimb ischemia (HLI) operation. Three animals were grouped into the sedentary control group. Four animals participated in SET, consisting of a staged treadmill protocol three times weekly. HLI was induced by first excluding collateral flow to the right common femoral and external iliac artery (EIA) with a covered stent extending into the superficial femoral artery. We then placed a vascular plug inside this stent to occlude inline flow to the common femoral artery. Blood flow was quantified with arterial duplex, ankle-ankle pressure indices, and arteriography. Bilateral muscle strength (peak-isometric torque) and blood flow of the hindlimbs were assessed prior to surgery and at week 1-4 post-surgery. Peak-isometric torque was elicited using 120 Hz electrical stimulus to the common peroneal nerve with 0.1 ms pulses over 500 ms with increasing amperage (100-400 mA) to achieve maximal contraction (tetanus) (Aurora Scientific, 890A). Blood flow indices, walking distance, and peak-isometric torque were evaluated with 2-way ANOVA testing for an interaction between time and limb (within-subjects). When appropriate, a Sidak posthoc test was then used to determine differences among groups at each time point. Paired and unpaired Student's t-test with two tails was used for all other analyses. Data are reported as mean ± SD, and the alpha level was set at 0.05.
ResultsHLI was induced in the right hindlimb and average ankle pressure indices remained decreased compared to preoperative measurements in both sedentary and SET groups at all time points (p<0.01) (Figure 1). Postoperatively no arterial signal at the hoof was identified in the right hindlimb, and the right common femoral artery had minimal to no flow via ultrasound. The improvement in blood flow over time was attributed to increased collateral flow through the ipsilateral internal iliac artery , which increased in both the sedentary (58%±28%, p=0.05) and SET (39%±13%, p=0.005) groups.
The four SET animals successfully participated in SET three times weekly with the following average walking times and ranges (in minutes): 7 (4-13), 30.5 (23-44), 36.4 (24-51), and 38.3 (28-49) minutes for weeks 1-4 respectively. SET animals had improved ambulatory function as noted by average increasing walking distance each week (331, 839, 1,654, and 1,972 meters for weeks 1-4 respectively) and increasingly difficult settings (speed increased by 1 km/h weekly).
Immediately after HLI, there was no difference in the ratio of torque between ischemic and normal limbs. The anterior tibialis in sedentary animals had decreased peak-isometric torque over time with a nadir of 3 weeks. In contrast, strength in the anterior tibialis of SET animals demonstrated sustained improvement (figure 2A-B). The control limb in sedentary animals
showed no significant change in peak-isometric torque; however, control limb strength progressively increased over time in the SET pigs. At weeks 3 and 4, peak-isometric torque was greater in SET pigs compared to week one (+28% and +34%, respectively, figure 2C). Additionally, peak-isometric torque at week three was greater in SET pigs compared to sedentary pigs (+34%; figure 2C). In the ischemic limb, peak-isometric torque as a percentage of contralateral torque was greater for SET pigs compared to sedentary, independent of time (Group Effect: 83% vs 56%, respectively; figure 2D).
ConclusionWe have successfully implemented a SET protocol into our large-animal model of ischemic myopathy, which we have previously demonstrated reflects the ischemic myopathy of PAD. We also demonstrate that SET increases muscle strength in this animal model, but we have not yet defined the optimal duration of SET in this model. Future work will investigate: i) the molecular mechanisms of SET-induced adaptations in ischemic limbs; ii) optimization of SET protocols to find ideal training frequency, duration, and intensity; and iii) exploration of combined strategies (e.g., SET with revascularization) to reach the goal of full limb function restoration. 
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