Cardiac autonomic neuropathy (CAN) represents a major cause of morbidity and mortality in diabetes. It is usually seen early in the course of diabetes as an impaired heart rate variability (HRV) and baroreflex sensitivity (BRS), and represents an independent risk predictor of cardiac mortality. CAN development is linked to hyperglycemia; however, current understanding extends cardiovascular risk to pre-diabetic patients with slight glycemic changes. As well, recent evidence suggests that anti-diabetic drugs (metformin and pioglitazone) reduced the risk of cardiovascular complications in pre-diabetic patients. Here, we assessed whether CAN develops independent of hyperglycemia and whether metformin or pioglitazone modify this process. Rats were fed a hypercaloric (HC) diet (4.035 KCal/g vs. 3 KCal/g for control rats) composed of: weight (calories) 18.06 % fat (38.68%), 15.8% protein (15.66%), and 46.13% carbohydrates (45.73%). Stable fasting hyperglycemia developed by 16 weeks of feeding. However, at 12 weeks of feeding, there was no elevation in body weight, fasting or random blood glucose, and no difference in oral glucose tolerance, yet an increase in adipose inflammatory cytokines was observed (4- and 40- fold increase in IL-1β and TGF-β expression). No change in systolic blood pressure was observed over the course of feeding. At 12 weeks, carotid and jugular access were established. Mean arterial pressure (MAP) and heart rate (HR) were recorded, and BRS was assessed using Oxford method. HC-fed rats had a higher pressor response to increasing i.v. doses of phenylephrine vs. control rats. BRS sensitivity was blunted (slope of the ΔMAP vs. ΔHR line, -1.018 ± 0.1217 vs. -0.3379 ± 0.04135) indicating reduced parasympathetic feedback. A 2-week treatment with pioglitazone (2.5 mg/Kg) or metformin (100 mg/Kg) normalized the adipose cytokine profile, yet only pioglitazone improved BRS (-0.7463 ± 0.05775). Parasympathetic dysfunction in HC fed rats was further demonstrated by a decreased high frequency power upon frequency domain analysis of HRV data (3098 ± 233 vs. 89 ± 88 μs
2
). To our knowledge, this is the first report that CAN occurs prior to any glycemic alterations with a potential role for adipose inflammation and modification by antidiabetic drugs.
Heart rate variability evaluation in the assessment of cardiac autonomic neuropathy in patients with type 2 diabetes
