Pulmonary Vein Ganglia Are Remodeled in the Diabetic Heart

BACKGROUND: Cardiac autonomic neuropathy is thought to cause adverse cardiovascular effects in diabetes mellitus. Pulmonary vein ganglia (PVG), which have been implicated in normal and abnormal heart rhythm regulation, have not been fully investigated in type 1 diabetes mellitus (T1D). We examined the functional and anatomical effects of T1D on PVG and studied the details of T1D‐induced remodeling on the PVG structure and function. METHODS AND RESULTS: We used a mouse model of T1D (Akita mouse), immunofluorescence, isolated Langendorff‐perfused hearts, and mathematical simulations to explore the effects of T1D on PVG. Whole‐mount atrial immunofluorescence of choline acetyltransferase and tyrosine hydroxylase labeling showed that sympathetic and parasympathetic somas of the PVG neurons were significantly hypotrophied in T1D hearts versus wild type. Stimulation of PVG in isolated Langendorff‐perfused hearts caused more pronounced P‐P interval prolongation in wild type compared with Akita hearts. Propranolol resulted in a comparable P‐P prolongation in both phenotypes, and atropine led to more pronounced P‐P interval shortening in wild type compared with Akita hearts. Numerical modeling using network simulations revealed that a decrease in the sympathetic and parasympathetic activities of PVG in T1D could explain the experimental results. CONCLUSIONS: T1D leads to PVG remodeling with hypotrophy of sympathetic and parasympathetic cell bodies and a concomitant decrease in the PVG sympathetic and parasympathetic activities.