Emily Caldwell

Ischemic post-conditioning and vasodilator therapy during standard cardiopulmonary resuscitation to reduce cardiac and brain injury after prolonged untreated ventricular fibrillation

AIM OF THE STUDY We investigated the effects of ischemic postconditioning (IPC) with and without cardioprotective vasodilatory therapy (CVT) at the initiation of cardiopulmonary resuscitation (CPR) on cardio-cerebral function and 48-h survival. METHODS Prospective randomized animal study. Following 15 min of ventricular fibrillation, 42 Yorkshire farm pigs weighing an average of 34 ± 2 kg were randomized to receive standard CPR (SCPR, n=12), SCPR+IPC (n=10), SCPR+IPC+CVT (n=10), or SCPR+CVT (n=10). IPC was delivered during the first 3 min of CPR with 4 cycles of 20s of chest compressions followed by 20-s pauses. CVT consisted of intravenous sodium nitroprusside (2mg) and adenosine (24 mg) during the first minute of CPR. Epinephrine was given in all groups per standard protocol. A transthoracic echocardiogram was obtained on all survivors 1 and 4h post-ROSC. The brains were extracted after euthanasia at least 24h later to assess ischemic injury in 7 regions. Ischemic injury was graded on a 0-4 scale with (0=no injury to 4 ≥ 50% neural injury). The sum of the regional scores was reported as cerebral histological score (CHS). 48 h survival was reported. RESULTS Post-resuscitation left ventricular ejection (LVEF) fraction improved in SCPR+CVT, SCPR+IPC+CVT and SCPR+IPC groups compared to SCPR (59% ± 9%, 52% ± 14%, 52% ± 14% vs. 35% ± 11%, respectively, p<0.05). Only SCPR+IPC and SCPR+IPC+CVT, but not SCPR+CVT, had lower mean CHS compared to SCPR (5.8 ± 2.6, 2.8 ± 1.8 vs. 10 ± 2.1, respectively, p<0.01). The 48-h survival among SCPR+IPC, SCPR+CVT, SCPR+IPC+CVT and SCPR was 6/10, 3/10, 5/10 and 1/12, respectively (Cox regression p<0.01). CONCLUSIONS IPC and CVT during standard CPR improved post-resuscitation LVEF but only IPC was independently neuroprotective and improved 48-h survival after 15 min of untreated cardiac arrest in pigs.

Sodium nitroprusside enhanced cardiopulmonary resuscitation (SNPeCPR) improves vital organ perfusion pressures and carotid blood flow in a porcine model of cardiac arrest

PURPOSE OF THE STUDY To describe a new method of CPR that optimizes vital organ perfusion pressures and carotid blood flow. We tested the hypothesis that a combination of high dose sodium nitroprusside (SNP) as well as non-invasive devices and techniques known independently to enhance circulation would significantly improve carotid blood flow (CBF) and return of spontaneous circulation (ROSC) rates in a porcine model of cardiac arrest. METHODS 15 isofluorane anesthetized pigs (30±1 kg), after 6 min of untreated ventricular fibrillation, were subsequently randomized to receive either 15 min of standard CPR (S-CPR) (8 animals) or 5 min epochs of S-CPR followed by active compression-decompression (ACD)+inspiratory impedance threshold device (ITD) CPR followed by ACD+ITD+abdominal binding (AB) with 1mg of SNP administered at minutes 2, 7, 12 of CPR (7 animals). Primary endpoints were CBF and ROSC rates. ANOVA and Fishers exact test were used for comparisons. RESULTS/CONCLUSION There was significant improvement in the hemodynamic parameters in the SNP animals. ROSC was achieved in 7/7 animals that received SNP and in 2/8 in the S-CPR (p=0.007). CBF and end tidal CO(2) (ETCO(2)) were significantly higher in the ACD+ITD+AB+SNP (SNPeCPR) animals during CPR. Bolus doses of SNP, when used in conjunction with ACD+ITD+AB CPR, significantly improve CBF and ROSC rates compared to S-CPR.

Early Access to the Cardiac Catheterization Laboratory for Patients Resuscitated From Cardiac Arrest Due to a Shockable Rhythm: The Minnesota Resuscitation Consortium Twin Cities Unified Protocol

Background In 2013 the Minnesota Resuscitation Consortium developed an organized approach for the management of patients resuscitated from shockable rhythms to gain early access to the cardiac catheterization laboratory (CCL) in the metro area of Minneapolis‐St. Paul. Methods and Results Eleven hospitals with 24/7 percutaneous coronary intervention capabilities agreed to provide early (within 6 hours of arrival at the Emergency Department) access to the CCL with the intention to perform coronary revascularization for outpatients who were successfully resuscitated from ventricular fibrillation/ventricular tachycardia arrest. Other inclusion criteria were age >18 and <76 and presumed cardiac etiology. Patients with other rhythms, known do not resuscitate/do not intubate, noncardiac etiology, significant bleeding, and terminal disease were excluded. The primary outcome was survival to hospital discharge with favorable neurological outcome. Patients (315 out of 331) who were resuscitated from VT/VF and transferred alive to the Emergency Department had complete medical records. Of those, 231 (73.3%) were taken to the CCL per the Minnesota Resuscitation Consortium protocol while 84 (26.6%) were not taken to the CCL (protocol deviations). Overall, 197 (63%) patients survived to hospital discharge with good neurological outcome (cerebral performance category of 1 or 2). Of the patients who followed the Minnesota Resuscitation Consortium protocol, 121 (52%) underwent percutaneous coronary intervention, and 15 (7%) underwent coronary artery bypass graft. In this group, 151 (65%) survived with good neurological outcome, whereas in the group that did not follow the Minnesota Resuscitation Consortium protocol, 46 (55%) survived with good neurological outcome (adjusted odds ratio: 1.99; [1.07–3.72], P=0.03). Conclusions Early access to the CCL after cardiac arrest due to a shockable rhythm in a selected group of patients is feasible in a large metropolitan area in the United States and is associated with a 65% survival rate to hospital discharge with a good neurological outcome.

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients with Intermittent Claudication Injected with ALDH Bright Cells)

Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute–sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. Methods: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. Results: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] −0.6 to 2.5; P=0.238), collateral count (0.9±0.6 arteries; 95% CI, −0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, −0.8 to 0.8; P=0.978), and capillary perfusion (−0.2±0.6%; 95% CI, −1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1–2.9; P=0.047) in participants with completely occluded femoral arteries. Conclusions: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute–sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. Methods: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. Results: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] −0.6 to 2.5; P =0.238), collateral count (0.9±0.6 arteries; 95% CI, −0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, −0.8 to 0.8; P =0.978), and capillary perfusion (−0.2±0.6%; 95% CI, −1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1–2.9; P =0.047) in participants with completely occluded femoral arteries. Conclusions: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. Clinical Trial Registration: URL: . Unique identifier: [NCT01774097][1]. # Clinical Perspective {#article-title-36} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01774097&atom=%2Fcirculationaha%2F135%2F15%2F1417.atom

Sodium nitroprusside-enhanced cardiopulmonary resuscitation improves resuscitation rates after prolonged untreated cardiac arrest in two porcine models.

Objective:Sodium nitroprusside-enhanced cardiopulmonary resuscitation consists of active compression-decompression, an impedance threshold device, abdominal binding, and large intravenous doses of sodium nitroprusside. We hypothesize that sodium nitroprusside-enhanced cardiopulmonary resuscitation will significantly increase carotid blood flow and return of spontaneous circulation compared to standard cardiopulmonary resuscitation after prolonged ventricular fibrillation and pulseless electrical activity cardiac arrest. Design:Prospective randomized animal study. Setting:Hennepin County Medical Center Animal Laboratory. Subjects:Forty Yorkshire female farm-bred pigs weighing 32 ± 2 kg. Interventions:In protocol A, 24 isoflurane-anesthetized pigs underwent 15 mins of untreated ventricular fibrillation and were subsequently randomized to receive standard cardiopulmonary resuscitation (n = 6), active compression-decompression cardiopulmonary resuscitation + impedance threshold device (n = 6), or sodium nitroprusside-enhanced cardiopulmonary resuscitation (n = 12) for up to 15 mins. First defibrillation was attempted at minute 6 of cardiopulmonary resuscitation. In protocol B, a separate group of 16 pigs underwent 10 mins of untreated ventricular fibrillation followed by 3 mins of chest compression only cardiopulmonary resuscitation followed by countershock-induced pulseless electrical activity, after which animals were randomized to standard cardiopulmonary resuscitation (n = 8) or sodium nitroprusside-enhanced cardiopulmonary resuscitation (n = 8). Measurements and Main Results:The primary end point was carotid blood flow during cardiopulmonary resuscitation and return of spontaneous circulation. Secondary end points included end-tidal CO2 as well as coronary and cerebral perfusion pressure. After prolonged untreated ventricular fibrillation, sodium nitroprusside-enhanced cardiopulmonary resuscitation demonstrated superior rates of return of spontaneous circulation when compared to standard cardiopulmonary resuscitation and active compression-decompression cardiopulmonary resuscitation + impedance threshold device (12 of 12, 0 of 6, and 0 of 6 respectively, p < .01). In animals with pulseless electrical activity, sodium nitroprusside-enhanced cardiopulmonary resuscitation increased return of spontaneous circulation rates when compared to standard cardiopulmonary resuscitation. In both groups, carotid blood flow, coronary perfusion pressure, cerebral perfusion pressure, and end-tidal CO2 were increased with sodium nitroprusside-enhanced cardiopulmonary resuscitation. Conclusions:In pigs, sodium nitroprusside-enhanced cardiopulmonary resuscitation significantly increased return of spontaneous circulation rates, as well as carotid blood flow and end-tidal CO2, when compared to standard cardiopulmonary resuscitation or active compression-decompression cardiopulmonary resuscitation + impedance threshold device.

Sodium nitroprusside enhanced cardiopulmonary resuscitation prevents post-resuscitation left ventricular dysfunction and improves 24-hour survival and neurological function in a porcine model of prolonged untreated ventricular fibrillation.

AIM OF STUDY Sodium nitroprusside-enhanced CPR, or SNPeCPR, consists of active compression-decompression CPR with an impedance threshold device, abdominal compression, and intravenous sodium nitroprusside (SNP). We hypothesize that SNPeCPR will improve post resuscitation left ventricular function and neurological function compared to standard (S) CPR after 15 min of untreated ventricular fibrillation in a porcine model of cardiac arrest. METHODS Pigs (n = 22) anesthetized with isoflurane underwent 15 min of untreated ventricular fibrillation, were then randomized to 6 min of S-CPR (n = 11) or SNPeCPR (n = 11) followed by defibrillation. The primary endpoints were neurologic function as measured by cerebral performance category (CPC) score and left ventricular ejection fraction. RESULTS SNPeCPR increased 24-hour survival rates compared to S-CPR (10/11 versus 5/11, p = 0.03) and improved neurological function (CPC score 2.5 ± 1, versus 3.8 ± 0.4, respectively, p = 0.004). Left ventricular ejection fractions at 1, 4 and 24 hours after defibrillation were 72 ± 11, 57 ± 11.4 and 64 ± 11 with SNPeCPR versus 29 ± 10, 30 ± 17 and 39 ± 6 with S-CPR, respectively (p < 0.01 for all). CONCLUSIONS In this pig model, after 15 min of untreated ventricular fibrillation, SNPeCPR significantly improved 24-hour survival rates, neurologic function and prevented post-resuscitation left ventricular dysfunction compared to S-CPR.

Early coronary revascularization improves 24h survival and neurological function after ischemic cardiac arrest. A randomized animal study.

BACKGROUND Survival after out-of-hospital cardiac arrest (OHCA) remains poor. Acute coronary obstruction is a major cause of OHCA. We hypothesize that early coronary reperfusion will improve 24h-survival and neurological outcomes. METHODS Total occlusion of the mid LAD was induced by balloon inflation in 27 pigs. After 5min, VF was induced and left untreated for 8min. If return of spontaneous circulation (ROSC) was achieved within 15min (21/27 animals) of cardiopulmonary resuscitation (CPR), animals were randomized to a total of either 45min (group A) or 4h (group B) of LAD occlusion. Animals without ROSC after 15min of CPR were classified as refractory VF (group C). In those pigs, CPR was continued up to 45min of total LAD occlusion at which point reperfusion was achieved. CPR was continued until ROSC or another 10min of CPR had been performed. Primary endpoints for groups A and B were 24-h survival and cerebral performance category (CPC). Primary endpoint for group C was ROSC before or after reperfusion. RESULTS Early compared to late reperfusion improved survival (10/11 versus 4/10, p=0.02), mean CPC (1.4±0.7 versus 2.5±0.6, p=0.017), LVEF (43±13 versus 32±9%, p=0.01), troponin I (37±28 versus 99±12, p=0.005) and CK-MB (11±4 versus 20.1±5, p=0.031) at 24-h after ROSC. ROSC was achieved in 4/6 animals only after reperfusion in group C. CONCLUSIONS Early reperfusion after ischemic cardiac arrest improved 24h survival rate and neurological function. In animals with refractory VF, reperfusion was necessary to achieve ROSC.

Cell therapy and satellite centers: The cardiovascular cell therapy research network experience

Due to the changing population in patients with myocardial infarction, recruiting patients in clinical trials continues to challenge clinical investigators. The Cardiovascular Cell Therapy Research Network (CCTRN) chose to expand the reach and power of its recruitment effort by incorporating both referral and treatment satellite centers. Eight treatment satellites were successfully identified and they screened patients over a two year period. The result of this effort was an increase in recruitment, with these treatment satellites contributing 30% of the patients to two of the three Network studies. The hurdles that these satellite treatment centers faced and how they surmounted them provide instruction to clinical research groups eager to expand to satellite systems and to health care practitioners who are interested in taking part in multicenter clinical trials.

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN Patients with Intermittent Claudication Injected with ALDH Bright Cells (PACE) Trial

Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute–sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. Methods: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. Results: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] −0.6 to 2.5; P=0.238), collateral count (0.9±0.6 arteries; 95% CI, −0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, −0.8 to 0.8; P=0.978), and capillary perfusion (−0.2±0.6%; 95% CI, −1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1–2.9; P=0.047) in participants with completely occluded femoral arteries. Conclusions: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute–sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. Methods: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. Results: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] −0.6 to 2.5; P =0.238), collateral count (0.9±0.6 arteries; 95% CI, −0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, −0.8 to 0.8; P =0.978), and capillary perfusion (−0.2±0.6%; 95% CI, −1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1–2.9; P =0.047) in participants with completely occluded femoral arteries. Conclusions: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. Clinical Trial Registration: URL: . Unique identifier: [NCT01774097][1]. # Clinical Perspective {#article-title-36} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01774097&atom=%2Fcirculationaha%2F135%2F15%2F1417.atom

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery DiseaseClinical Perspective: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells)

Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute–sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. Methods: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. Results: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] −0.6 to 2.5; P=0.238), collateral count (0.9±0.6 arteries; 95% CI, −0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, −0.8 to 0.8; P=0.978), and capillary perfusion (−0.2±0.6%; 95% CI, −1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1–2.9; P=0.047) in participants with completely occluded femoral arteries. Conclusions: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute–sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. Methods: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. Results: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] −0.6 to 2.5; P =0.238), collateral count (0.9±0.6 arteries; 95% CI, −0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, −0.8 to 0.8; P =0.978), and capillary perfusion (−0.2±0.6%; 95% CI, −1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1–2.9; P =0.047) in participants with completely occluded femoral arteries. Conclusions: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. Clinical Trial Registration: URL: . Unique identifier: [NCT01774097][1]. # Clinical Perspective {#article-title-36} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01774097&atom=%2Fcirculationaha%2F135%2F15%2F1417.atom