Evaluation of muscle microvascular perfusion in primary mitochondrial disease by contrast-enhanced ultrasound: Feasibility study.

BACKGROUND: Primary mitochondrial disease (PMD) are genetic disorders characterized by impaired oxidative metabolism and microvascular abnormalities that contribute to the myopathy. OBJECTIVES: This study evaluates the feasibility and utility of contrast-enhanced ultrasound (CEUS) for quantifying skeletal muscle perfusion in patients with PMD. In addition, we assessed exercise-induced changes following cardiopulmonary exercise testing (CPET) to characterize dynamic vascular responses. DESIGN: Prospective pilot feasibility study. METHODS: We enrolled genetically confirmed PMD and healthy control participants with ability to complete the CPET protocol. CEUS of the vastus lateralis muscle was performed at rest and following CPET. Imaging parameters were standardized across all CEUS scans, with a fixed mechanical index of 0.13. Perfusion parameters, including perfusion index (PI), peak enhancement (PE), and area under the curve (AUC) were quantified using delta projection analysis, and compared between PMD and control participants, and within each group, pre- and post-exercise. RESULTS: A total of 5 PMD and 5 control participants were evaluated. At rest, CEUS demonstrated a trend in higher muscle perfusion in PMD as compared to control participants on comparing PI (13.7 ± 2.7 vs. 10.7 ± 3.2; p = 0.42), PE (24.9 ± 11.5 vs. 14.3 ± 6.8; p = 0.22), and AUC (95,253.4 ± 35,072.8 vs. 73,591.2 ± 32,820.6; p = 0.31), which did not reach statistical significance, likely in part due to the small cohort size. Following CPET, PMD participants demonstrated exaggerated percentage increases in PI (+21.1% vs. +16.0%), PE (+11.2% vs. +7.6%), and AUC (+20.2% vs. +12.5%) as compared to control participants. Within group analysis revealed a significant post-exercise increase in AUC among PMD participants (p = 0.01) but did not reach significance in control participants. CONCLUSION: This is the first study to demonstrate the feasibility and utility of conducting CEUS to assess skeletal muscle perfusion in ambulatory PMD patients. The distinct perfusion patterns and exaggerated exercise-induced responses observed in PMD as compared to control participants suggest that reactive hyperemia occurs in PMD at rest and is further exaggerated by exercise. CEUS may serve as a sensitive tool for detecting microvascular alterations in PMD.