Early Detection Of Autonomic Neuropathy In Diabetic Minipigs By Blood Pressure And Heart Rate Variability: Relationship With Changes In Vagus Nerve Morphometry

Early detection of cardiac autonomic neuropathy (CAN) is imperative for successful therapeutic intervention. The streptozotocin-diabetic minipig is a suitable model to study cardiac function and determine the earliest markers of the condition. Blood Pressure (BP) and Heart Rate (HR) variability, analysed with spectral analysis and performed in control animals exhibited a mostly unique peak synchronized with respiration. The Respiratory Peak (RP) of HR was dramatically reduced by atropine, suggesting a vagal control of this oscillation. A pharmacological baroreflex curve was also constructed, and the gain of this curve was found significantly related (r = 0.70, p < 0.05) with the gain of the cross-spectral analysis between SBP and HR. Diabetes significantly decreased BP at 3 and 6 months and increased HR at 6 months (77.4 ± 3.8 vs 66.6 ± 2.7 bpm). The RP of HR was significantly lowered at 3 months (3.2 ± 0.4 vs 5.6 ± 0.7 bpm) and was still decreased at 6 months (3.7 ± 0.5 vs 4.9 ± 0.7 bpm). The gain of the cross spectral analysis was also reduced at the early stage of the disease (1.1 ± 0.2 vs 1.6 ± 0.4 bpm/mmHg, p < 0.05). Morphometric analysis revealed abnormalities only in the proximal vagus nerve with a significant difference in the axon and fibre size frequency distribution between controls and diabetic animals (p = 0.05), due to a greater proportion of fibers with smaller axon sizes (<3 μm2) in diabetic minipigs. In conclusion this model exhibited CAN at an early stage of diabetes with an impairment of the baroreflex sensitivity associated with structural changes of proximal vagus nerve.