Myocardial glucose and fatty acid metabolism is altered and associated with lower cardiac function in young adults with Barth syndrome.

BACKGROUND: Barth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function. METHODS/RESULTS: Young adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of 15O-water and 1-11C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and 31P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 µmol·g-1·min-1, P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g-1·min-1, P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS. CONCLUSIONS: Myocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS. Clinical Trials #: NCT01625663.

Skeletal Muscle Regeneration in Advanced Diabetic Peripheral Neuropathy.

BACKGROUND: Decreased lean muscle mass in the lower extremity in diabetic peripheral neuropathy (DPN) is thought to contribute to altered joint loading, immobility, and disability. However, the mechanism behind this loss is unknown and could derive from a reduction in size of myofibers (atrophy), destruction of myofibers (degeneration), or both. Degenerative changes require participation of muscle stem (satellite) cells to regenerate lost myofibers and restore lean mass. Determining the degenerative state and residual regenerative capacity of DPN muscle will inform the utility of regeneration-targeted therapeutic strategies. METHODS: Biopsies were acquired from 2 muscles in 12 individuals with and without diabetic neuropathy undergoing below-knee amputation surgery. Biopsies were subdivided for histological analysis, transcriptional profiling, and satellite cell isolation and culture. RESULTS: Histological analysis revealed evidence of ongoing degeneration and regeneration in DPN muscles. Transcriptional profiling supports these findings, indicating significant upregulation of regeneration-related pathways. However, regeneration appeared to be limited in samples exhibiting the most severe structural pathology as only extremely small, immature regenerated myofibers were found. Immunostaining for satellite cells revealed a significant decrease in their relative frequency only in the subset with severe pathology. Similarly, a reduction in fusion in cultured satellite cells in this group suggests impairment in regenerative capacity in severe DPN pathology. CONCLUSION: DPN muscle exhibited features of degeneration with attempted regeneration. In the most severely pathological muscle samples, regeneration appeared to be stymied and our data suggest that this may be partly due to intrinsic dysfunction of the satellite cell pool in addition to extrinsic structural pathology (eg, nerve damage). CLINICAL RELEVANCE: Restoration of DPN muscle function for improved mobility and physical activity is a goal of surgical and rehabilitation clinicians. Identifying myofiber degeneration and compromised regeneration as contributors to dysfunction suggests that adjuvant cell-based therapies may improve clinical outcomes.

Outcomes of the Bridle Procedure for the Treatment of Foot Drop.

BACKGROUND: The purpose of this study was to determine the clinical outcomes and objective measures of function that can be expected for patients following the Bridle procedure (modification of the posterior tibial tendon transfer) for the treatment of foot drop. METHODS: Nineteen patients treated with a Bridle procedure and 10 matched controls were evaluated. The Bridle group had preoperative and 2-year postoperative radiographic foot alignment measurements and completion of the Foot and Ankle Ability Measure. At follow-up, both groups were tested for standing balance (star excursion test) and for ankle plantarflexion and dorsiflexion isokinetic strength, and the American Orthopaedic Foot & Ankle Society and Stanmore outcome measures were collected only on the Bridle patients. RESULTS: There was no change in radiographic foot alignment from pre- to postoperative measurement. Foot and Ankle Ability Measure subscales of activities of daily living and sport, American Orthopaedic Foot & Ankle Society, and Stanmore scores were all reduced in Bridle patients as compared with controls. Single-limb standing-balance reaching distance in the anterolateral and posterolateral directions were reduced in Bridle participants as compared with controls (P < .03). Isokinetic ankle dorsiflexion and plantarflexion strength was lower in Bridle participants (2 ± 4 ft·lb, 44 ± 16 ft·lb) as compared with controls (18 ± 13 ft·lb, 65 ± 27 ft·lb, P < .02, respectively). All Bridle participants reported excellent to good outcomes and would repeat the operation. No patient wore an ankle-foot orthosis for everyday activities. CONCLUSION: The Bridle procedure was a successful surgery that did not restore normal strength and balance to the foot and ankle but allowed individuals with foot drop and a functional tibialis posterior muscle to have significantly improved outcomes and discontinue the use of an ankle-foot orthosis. In addition, there was no indication that loss of the normal function of the tibialis posterior muscle resulted in change in foot alignment 2 years after surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

Progression of foot deformity in Charcot neuropathic osteoarthropathy.

BACKGROUND: Charcot neuropathic osteoarthropathy associated foot deformity can result in joint instability, ulceration, and even amputation. The purpose of the present study was to follow patients with and without active Charcot osteoarthropathy for as long as two years to examine the magnitude and timing of foot alignment changes. METHODS: We studied fifteen subjects with Charcot osteoarthropathy and nineteen subjects with diabetes mellitus and peripheral neuropathy without Charcot osteoarthropathy for one year; eight of the subjects with osteoarthropathy and five of the subjects with diabetes and peripheral neuropathy were followed for two years. Bilateral weight-bearing radiographs of the foot were made at baseline for all subjects, with repeat radiographs being made at six months for the osteoarthropathy group and at one and two years for both groups. Radiographic measurements included the Meary angle, cuboid height, calcaneal pitch, and hindfoot-forefoot angle. RESULTS: The Meary angle, cuboid height, and calcaneal pitch worsened in feet with Charcot osteoarthropathy over one year as compared with the contralateral, uninvolved feet and feet in patients with diabetes and peripheral neuropathy. Cuboid height continued to worsen over the two-year follow-up in the feet with Charcot osteoarthropathy. These feet also had a greater change in the hindfoot-forefoot angle at one year as compared with the feet in patients with diabetes and peripheral neuropathy and at two years as compared with the contralateral, uninvolved feet. CONCLUSIONS: In patients with Charcot neuropathic osteoarthropathy, radiographic alignment measurements demonstrate the presence of foot deformity at the time of the initial clinical presentation and evidence of progressive changes over the first and second years. The six-month data suggest worsening of medial column alignment prior to lateral column worsening. This radiographic evidence of worsening foot alignment over time supports the need for aggressive intervention (conservative bracing or surgical fixation) to attempt to prevent limb-threatening complications.