Dynamic Contrast-Enhanced MRI Assessment of Hyperemic Fractional Microvascular Blood Plasma Volume in Peripheral Arterial Disease: Initial Findings

Versluis, Bas; Dremmen, Marjolein H G; Nelemans, Patty J.; Wildberger, Joachim E.; Schurink, Geert-Willem; Leiner, Tim; Backes, Walter H.

doi:10.1371/journal.pone.0037756

Cited by 11 publications

(8 citation statements)

References 41 publications

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“…(17, 18) These measures showed the ability to discriminate between PAD and normal participants, especially in hyperemic conditions. (7, 12, 19–21) Indeed, similar to previous studies, we found that there was a significant difference between PAD and normal participants in both capillary perfusion measured by calf muscle plasma volume and the transfer constant also showing high reproducibility. Identifcation of a pre-defined plane for acquisition of the arterial input function located proximal to the imaging plane is complicated by the possibility of there being an occlusion or even a partial stenosis of the arterial wall changing flow characteristics.…”

Section: Discussionsupporting

confidence: 89%

“…Tissue spin-lattice relaxation time (T1) maps of 8 transverse slices centered at the thickest portion of the calf was calculated using a multiple flip-angle method with same positioning and imaging parameters for the DCE-MRI sequence but with varying flip angles of 5°, 8°, 12° and 15°. (7) The DCE-MRI data acquisition of the calf was performed with a spoiled fast gradient echo sequence and a flip angle of 15°: slice thickness of 5 mm, slice gap = 1 mm, in-plane acquired spatial resolution of 1 mm × 1mm, TR/TE ~ 2.5 ms/1 ms, and parallel imaging factor of 2. This yielded a temporal resolution of approximately 3–4 s per dynamic, and the continuous acquisition of 100 dynamics results in a scan time of 5–6 minutes.…”

Section: Methodsmentioning

confidence: 99%

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Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study

Ambale-Venkatesh

Nauffal

Noda

et al. 2017

American Heart Journal

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Background Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in MRI techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate endpoints after pro-angiogenic therapies. Methods The “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (PACE) study is a randomized, double-blind, placebo-controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow-derived ALDHbr stem cells. The primary MRI endpoints of the study are; 1) total collateral count, 2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and 3) peak hyperemic popliteal flow by phase contrast MRI. Results The inter- and intra-reader and test-retest results demonstrated good-to-excellent reproducibility (ICC range: 0.61–0.98) for all MR measures. The PAD participants (n=82) had lower capillary perfusion measured by calf muscle plasma volume (3.8 vs 5.6%), and peak hyperemic popliteal flow (4.1 vs 13.5 ml/s) as compared to the normal participants (n=16), with a significant level of collateralization. Conclusions Reproducibility of the MRI primary endpoints in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared to normal participants. The MRI tools utilized in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies.

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study

Ambale-Venkatesh

Nauffal

Noda

et al. 2017

American Heart Journal

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“…Endpoints were selected based on published reproducibility assessments. (21, 22) Lower extremity peripheral artery anatomy and function will be assessed by using time-resolved contrast-enhanced magnetic resonance angiography (CE-MRA) after the injection (0.05 mmol/kg) of an extravascular gadolinium-based contrast agent (GBCA). For upper leg MRA, 3D CE-MRA data acquisition will be triggered when the injected contrast bolus (0.1 mmol/kg) is seen at the target anatomy by using a real-time monitoring scan.…”

Section: Methodsmentioning

confidence: 99%

“…At this sample size, the power for each of the change in number of new vessels (Mann-Whitney U statistic, 90% power), vascular flow (2-tailed t -test, 95% power), and perfusion (2-tailed t -test, 90% power) is adequate based on Verslius. (21, 22) …”

Section: Methodsmentioning

confidence: 99%

Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells

Perin¹,

Murphy

Cooke

et al. 2014

American Heart Journal

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Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in PAD patients, have limitations. Cells identified usingcytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network (CCTRN) to assess the safety and efficacy of autologous bone marrow–derived ALDHbr cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index <0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary endpoints are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance (MR) imaging at 6 months compared to baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based endpoints that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDHbr cells in patients with claudication and provide valuable insight into the utility of advanced MR imaging endpoints.

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“…23 At this sample size, the power for the change in collateral count, peak hyperemic popliteal flow, and capillary perfusion, each using 2-tailed t -tests, was over 90%. 24,25 …”

Section: Methodsmentioning

confidence: 99%

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease

Perin¹,

Murphy²,

March³

et al. 2017

Circulation

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Background Atherosclerotic peripheral artery disease (PAD) affects 8–12% of Americans over 65 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 is an NHLBI-sponsored, randomized, double-blind, placebo-controlled phase 2, exploratory clinical trial designed to assess safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in PAD patients and to explore associated claudication physiologic mechanisms. Methods All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by ten injections into the thigh and calf of the index leg. The co-primary endpoints were: change from baseline to six months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging (MRI); as well as safety. Results A total of 82 patients with claudication and infra-inguinal PAD were randomized at nine sites, of which 78 had analyzable data (57 male, 21 female; mean age 66±9 years). The mean differences in the change over six months between study groups for PWT (mean ± standard error of the mean [SEM]) (0.9±0.8 minutes; 95% 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/sec; 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. Additionally, there were no significant differences for the secondary endpoints, including quality of life measures. There were no adverse safety outcomes. Correlative relationships between MRI 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 to 2.9; p=0.047) in participants with completely occluded femoral arteries. Conclusions ALDHbr cell administration did not improve PWT or MR outcomes, and the changes in PWT were not associated with the anatomic or physiologic MRI endpoints. Future PAD cell therapy investigational trial design may be informed by new anatomic and perfusion insights.

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Dynamic Contrast-Enhanced MRI Assessment of Hyperemic Fractional Microvascular Blood Plasma Volume in Peripheral Arterial Disease: Initial Findings

Cited by 11 publications

References 41 publications

Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study

Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study

Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease

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