Dynamic magnetic resonance measurements of calf muscle oxygenation and energy metabolism in peripheral artery disease

Abstract

Background: Clinical assessments of peripheral artery disease (PAD) severity are insensitive to pathophysiological changes in muscle tissue oxygenation and energy metabolism distal to the affected artery.

Purpose: To quantify the blood oxygenation level-dependent (BOLD) response and phosphocreatine (PCr) recovery kinetics on a clinical MR system during a single exercise-recovery session in PAD patients.

Study type: Case-control study.

Subjects: Fifteen Fontaine stage II patients, and 18 healthy control subjects FIELD STRENGTH/SEQUENCE: Interleaved dynamic multiecho gradient-echo ¹ H T₂ * mapping and adiabatic pulse-acquire ³¹ P-MR spectroscopy at 3T.

Assessment: Blood pressure in the arms and ankles were measured to determine the ankle-brachial index (ABI). Subjects performed a plantar flexion exercise-recovery protocol. The gastrocnemius and soleus muscle BOLD responses were characterized using the T₂ * maps. High-energy phosphate metabolite concentrations were quantified by fitting the series of ³¹ P-MR spectra. The PCr recovery time constant (τ_PCr ) was derived as a measure of in vivo mitochondrial oxidative capacity.

Statistical tests: Comparisons between groups were performed using two-sided Mann-Whitney U-tests. Relations between variables were assessed by Pearson's r correlation coefficients.

Results: The amplitude of the functional hyperemic BOLD response in the gastrocnemius muscle was higher in PAD patients compared with healthy subjects (-3.8 ± 1.4% vs. -1.4 ± 0.3%; P < 0.001), and correlated with the ABI (r = 0.79; P < 0.001). PCr recovery was slower in PAD patients (τ_PCr = 52.0 ± 13.5 vs. 30.3 ± 9.7 sec; P < 0.0001), and correlated with the ABI (r = -0.64; P < 0.001). Moreover, τ_PCr correlated with the hyperemic BOLD response in the gastrocnemius muscle (r = -0.66; P < 0.01).

Data conclusion: MR readouts of calf muscle tissue oxygenation and high-energy phosphate metabolism were acquired essentially simultaneously during a single exercise-recovery session. A pronounced hypoxia-triggered vasodilation in PAD is associated with a reduced mitochondrial oxidative capacity.

Level of evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:98-107.

Keywords: atherosclerosis; exercise stress; interleaved scanning; intermittent claudication; metabolic hyperemia; mitochondrial dysfunction.

Figure 1

Overview of the dynamic scan series for interleaved acquisitions of T₂* maps and ³¹P‐MRS during plantar flexion exercise and subsequent recovery. The effective TR for both readouts was 3 seconds, yielding a temporal resolution of 3 seconds for ³¹P‐MR spectra and ¹H MRI of the BOLD response. Tissue concentrations of ATP, PCr, and P_i as well as the tissue pH are plotted against time, revealing PCr depletion during exercise and subsequent recovery after cessation of exercise. Median normalized gastrocnemius (G) and soleus (S) muscle R₂* values were determined from ROIs in the T₂* maps, and plotted against time to characterize the BOLD response to exercise. Time courses of the PCr and P_i concentrations are included in the graph for a direct comparison of tissue oxygenation dynamics with high‐energy phosphate metabolism during the same exercise‐recovery protocol. T₂* maps acquired during exercise were discarded due to motion artifacts. ATP, adenosine 5′‐triphosphate; BOLD, blood oxygenation level‐dependent; PCr, phosphocreatine; P_i, inorganic phosphate.

Figure 2

Time curves of the normalized R₂* for the gastrocnemius muscle (a) and soleus muscle (b) for PAD patients (shaded circles) and healthy control subjects (open circles) obtained during recovery after plantar flexion exercise. The amplitude of the hyperemic BOLD response in the gastrocnemius muscle correlated (r = 0.79; P < 0.001) with the ABI for PAD severity (c). BOLD, blood oxygenation level‐dependent.

Figure 3

Series of ³¹P‐MR spectra obtained during plantar flexion exercise and subsequent recovery in a healthy control subject (a). The PCr recovery time constant (τ_PCr) showed a strong negative correlation (r = –0.64; P < 0.001) with the ABI for PAD severity (b). ATP, adenosine 5′‐triphosphate; PDE, phosphodiesters; P_i, inorganic phosphate.

Figure 4

Correlations between the relative amplitude of the hyperemic BOLD response in the gastrocnemius muscle and the PCr recovery time constant (τ_PCr) (a) and the end‐exercise inorganic phosphate (P_i) concentration (b), acquired during the same exercise‐recovery session. BOLD, blood oxygenation level‐dependent; P_i, inorganic phosphate.