The co-occurrence of myocardial dysfunction and peripheral insensate neuropathy in a streptozotocin-induced rat model of diabetes

Maria N Marangoni,Mariann R Piano,Scott T Brady,Shamim A Chowdhury

doi:10.1186/1475-2840-13-11

Maria N Marangoni, Mariann R Piano + Show 2 more

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https://doi.org/10.1186/1475-2840-13-11

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Abstract

BackgroundCardiomyopathy and distal symmetrical polyneuropathy (DSPN), including sensory and autonomic dysfunction, often co-occur in diabetic mellitus (DM) patients. However, the temporal relationship and progression between these two complications has not been investigated. Using a streptozotocin DM animal model that develops insensate neuropathy, our aim was to examine in parallel the development of DSPN and DM-associated changes in cardiac structure and function as well as potential mechanisms, such as autonomic dysfunction, evaluated by changes in urinary and myocardial norepinephrine content and myocardial neuronal markers.MethodsSensory neuropathy was measured by behavioral tests using Von Frey filaments and Hargreaves methods. Echocardiography was used to evaluate myocardial structure and function. Autonomic function was evaluated by measuring urinary and myocardial norepinephrine (NE) levels by enzyme-linked immunosorbent assay and high-performance liquid chromatography/mass spectrometry. Quantitative immunohistochemistry was used to measure the myocardial neuronal markers, calcitonin gene-related peptide (CGRP) and general neuronal protein gene product 9.5 (PGP 9.5).ResultsThe DM group developed tactile and thermal insensate neuropathy 4–5 weeks after DM onset. Cardiovascular changes were found between 4 and 12 weeks after DM onset and included bradycardia, diastolic and systolic dysfunction and cardiac dilation. There was a 2.5-fold reduction in myocardial NE levels and a 5-fold increase in urinary NE levels in the DM group. Finally, there was a 2.3-fold increase in myocardial CGRP levels in the DM group and no change in PGP9.5 levels.ConclusionsCardiovascular structural and functional changes developed early in the course of DM and in combination with insensate neuropathy. In parallel, signs of cardiac autonomic dysfunction were also found and included decreased myocardial NE levels and altered CGRP levels. These results may indicate the need for early cardiovascular evaluation in DM patients with insensate neuropathy.

Highlights

Cardiomyopathy and distal symmetrical polyneuropathy (DSPN), including sensory and autonomic dysfunction, often co-occur in diabetic mellitus (DM) patients
Diabetic animal model Glucose levels measured at 4, 8, and 12 weeks were significantly greater in the Streptozotocin-induced diabetes mellitus (STZ-DM) animals compared to CON rats (Table 1)
Data are expressed as mean ± SEM; CON: control; STZ-DM: streptozotocin-induced diabetes mellitus; Heart rate (HR): heart rate; BW: body weight; left ventricular end-diastolic dimension (LVDD): left ventricular enddiastolic dimension; LVSD: left ventricular end-systolic dimension; Interventricular Septum in diastole (IVSD): interventricular septum in diastole, Interventricular septum in systole (IVSS): interventricular septum in systole; LV: left ventricle; RWT: relative wall thickness; Fractional shortening (FS): fractional shortening; Ratio e wave (E/A): E wave to A wave ratio; IVRT: isovolumic relaxation time; DecT: deceleration time

Summary

Introduction

Cardiomyopathy and distal symmetrical polyneuropathy (DSPN), including sensory and autonomic dysfunction, often co-occur in diabetic mellitus (DM) patients. Using a streptozotocin DM animal model that develops insensate neuropathy, our aim was to examine in parallel the development of DSPN and DM-associated changes in cardiac structure and function as well as potential mechanisms, such as autonomic dysfunction, evaluated by changes in urinary and myocardial norepinephrine content and myocardial neuronal markers. Diabetes mellitus (DM) is associated with many disabling complications, including nephropathy, retinopathy, polyneuropathy, and cardiomyopathy. Among these complications, polyneuropathy such as distal symmetrical polyneuropathy (DSPN) and other peripheral neuropathies are the most common long-term complication of DM. Several studies have evaluated myocardial norepinephrine (NE) levels and myocardial sympathetic and parasympathetic density separately, but no study has measured these variables together in the same animal model

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