Effects of exercise training on cardiac autonomic function in patients with subclinical diabetic heart disease

This trial aims to determine the relationship between diabetic myocardial disease and cardiac autonomic neuropathy and the response of cardiac autonomic function to exercise training in patients demonstrating evidence of subclinical myocardial disease. The patient cohort will comprise apparently healthy patients with type 2 diabetes. Subjects with known cardiovascular disease or other significant co-morbidities such as malignancy, psychiatric or renal disease will be excluded. Pregnant or breast-feeding women will also be excluded. 225 patients will be recruited and undergo screening using echocardiography for diabetic heart disease. Based on past research conducted by our group, approximately one-third of patients will demonstrate evidence of subclinical myocardial dysfunction. Previous exercise training interventions have demonstrated significant improvements in maximal oxygen uptake (VO2max) in patient numbers of less than 30, so a proportionate improvement should be detectable from the study group even allowing for a 30% drop-out. There are no previous studies investigating cardiac autonomic function in diabetic patients with myocardial disease on which this study can be powered. Baseline measures on all subjects will include: body mass index, waist and hip circumference and resting haemodynamic parameters. Fasting blood samples will be collected to assess haematological parameters, renal and hepatic function, lipid profile, glucose, insulin, HbA1c, and B-type Natriuretic Peptide (BNP) concentrations. Urine collection for albumin to creatinine ratio for detection of diabetic nephropathy will also be performed. All study subjects will undergo a baseline transthoracic echocardiogram to assess for evidence of systolic or diastolic dysfunction using standard echocardiographic parameters. Tissue Doppler imaging (TDI) including tissue velocity, strain and strain rate will be employed to detect further subclinical abnormalities. All subjects will then undergo a standard treadmill exercise stress test before being re-imaged at peak heart rate for evidence of inducible wall motion abnormalities (indicative of ischaemic heart disease) and with TDI for subtle myocardial dysfunction which is not otherwise apparent at rest. Those with inducible wall motion abnormalities will be excluded based on their likelihood to have ischaemic heart disease. Appropriate clinical follow-up will be arranged. In addition to the echocardiography and exercise testing, patients will be studied for cardiac autonomic function using heart rate variability measured by electrocardiogram during supine rest. A standard 5-minute segment of R-R intervals will be analysed for both time and frequency domain parameters of heart rate variability. Patients will also undergo testing of cardiovascular reflexes (including heart rate responses to deep breathing, valsalva and standing and systolic blood pressure response to standing) to complete the battery of cardiac autonomic function tests. Patients with subclinical myocardial dysfunction or autonomic neuropathy will be allocated to exercise training (based on the current guidelines) or control for 6 months. Throughout the intervention, patients will receive 4-weekly follow-up to monitor for adverse events and compliance. Following the intervention, anthropometric, biochemical, autonomic, and imaging with rest and exercise echocardiograms will be repeated. Projected Outcomes: This trial aims to determine the efficacy of exercise training in diabetic cardiac autonomic neuropathy and subclinical myocardial disease. We hypothesise that exercise training will represent an effective treatment to improve exercise capacity and cardiac autonomic function, and that these improvements may represent mechanisms by which exercise training can improve myocardial function in patients with subclinical myocardial disease.