Dynamic 31P-MRI and 31P-MRS of lower leg muscles in heart failure patients

Abstract

Impaired oxidative metabolism is one of multi-variate factors leading to exercise intolerance in heart failure patients. The purpose of the study was to demonstrate the use of dynamic 31P magnetic resonance spectroscopy (MRS) and 31P magnetic resonance imaging (MRI) techniques to measure PCr resynthesis rate post-exercise as a biomarker for oxidative metabolism in skeletal muscle in HF patients and controls. In this prospective imaging study, we recruited six HF patients and five healthy controls. The imaging protocol included 31P-MRS, spectrally selective 3D turbo spin echo for 31P-MRI, and Dixon multi-echo GRE for fat–water imaging on a 3 T clinical MRI scanner. All the subjects were scanned pre-exercise, during plantar flexion exercise, and post-exercise recovery, with two rounds of exercise for 31P -MRS and 31P-MRI, respectively. Unpaired t-tests were used to compare 31P-MRS and 31P-MRI results between the HF and control cohorts. The results show that PCr resynthesis rate was significantly slower in the HF cohort compared to the controls using 31P-MRS (P = 0.0003) and 31P-MRI (P = 0.0014). 31P-MRI showed significant differences between the cohorts in muscle groups (soleus (P = 0.0018), gastrocnemius lateral (P = 0.0007) and gastrocnemius medial (P = 0.0054)). The results from this study suggest that 31P-MRS/31P-MRI may be used to quantify lower leg muscle oxidative metabolism in HF patients, with 31P-MRI giving an additional advantage of allowing further localization of oxidative metabolism deficits. Upon further validation, these techniques may serve as a potentially useful clinical imaging biomarker for staging and monitoring therapies in HF-patients.

Could SGLT2 Inhibitors Improve Exercise Intolerance in Chronic Heart Failure?

“…HF is associated with impaired oxidative skeletal muscle metabolism as shown by dynamic in vivo measurements with 31 phosphorus (31P) magnetic resonance spectroscopy (MRS) [ 2 , 68 , 69 , 118 ]. This technique, which allows for quantification of high-energy phosphate decline rates during exercise and post-exercise rates of recovery, provides an adequate method for assessing in vivo mitochondrial oxidative metabolism.…”

“…This technique, which allows for quantification of high-energy phosphate decline rates during exercise and post-exercise rates of recovery, provides an adequate method for assessing in vivo mitochondrial oxidative metabolism. Previous studies showed an increased depletion of highly energetic phosphates and a prolonged phosphocreatine (PCr) recovery rate, implying that oxidative mitochondrial function in skeletal muscle is impaired in HF during exercise [ 2 , 69 , 119 , 120 ]. A detected decrease in intramuscular pH during exercise [ 68 , 69 ] and increase in blood lactate levels [ 100 ] in HF compared with healthy subjects furthermore suggest that abnormal skeletal muscle metabolism induces an earlier shift from oxidative metabolism to glycolytic metabolism, as discussed below.…”

“…Previous studies showed an increased depletion of highly energetic phosphates and a prolonged phosphocreatine (PCr) recovery rate, implying that oxidative mitochondrial function in skeletal muscle is impaired in HF during exercise [ 2 , 69 , 119 , 120 ]. A detected decrease in intramuscular pH during exercise [ 68 , 69 ] and increase in blood lactate levels [ 100 ] in HF compared with healthy subjects furthermore suggest that abnormal skeletal muscle metabolism induces an earlier shift from oxidative metabolism to glycolytic metabolism, as discussed below. The 31P MRS in vivo measurements have been shown to correlate well with in vitro measurements of mitochondrial capacity by muscle biopsies [ 121 , 122 ], supporting the conclusion that the rapid decline in high-energy phosphates and prolonged resynthesis rate in HF during exercise reflect impairment of mitochondrial oxidative capacity [ 2 , 121 ].…”

“…However, due to the increase in breakdown products, this energy production system leads to an earlier onset of fatigue as compared with oxidative phosphorylation. HF is characterized by a shift from aerobic FA oxidation to anaerobic glucose oxidation, both in cardiac and skeletal muscle, resulting in all the aforementioned consequences [ 68 , 69 , 100 ].…”

“…In addition, multiple studies have shown HF-induced pathophysiological changes in skeletal muscle. HF is associated with a reduction in maximal muscle mass, a reduction in muscle strength, and impairment of oxidative skeletal muscle metabolism [ 66 , 67 , 68 , 69 ].…”