Glucose fluctuations increase the incidence of atrial fibrillation in diabetic rats
Diabetes mellitus (DM) is a major risk factor for cardiovascular diseases such as ischaemic heart disease, heart failure, and arrhythmias. For decades, risk of cardiovascular complications in DM has been believed to correlate with elevated glycated haemoglobin (HbA1c) and fasting glucose levels.1,2 However, several large-scale clinical trials have recently proposed adverse effects caused by intensive glycaemic control. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial revealed that intensive glycaemic control targeting a level of glycated haemoglobin <6.0% increased all-cause mortality more than standard therapy targeting 7.0–7.9%, and the study was terminated prematurely.3 The Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study also demonstrated that intensive glycaemic control caused high mortality in patients hospitalized in an intensive care unit.4 These results have raised concerns that hypoglycaemic episode could aggravate patient prognosis. Furthermore, a basic research showed that recurrent hypoglycaemic episodes increased mitochondrial free radical release and exacerbated cerebral ischaemic damage.5 In addition, intermittent high glucose exposure exacerbated oxidative stress and apoptosis in endothelial cells.6 On the basis of these observations, we hypothesized that glucose fluctuations may directly affect cardiomyocytes by increasing reactive oxygen species (ROS) levels and predispose to cardiac complications.
Atrial fibrillation (AF) is a common but critical arrhythmia because of the high risk of cerebral thrombosis associated with it. Hypertension, heart failure, hyperthyroidism, and DM are the known major risk factors for AF.7,8 Structural remodelling due to increased cardiac fibrosis by DM was associated with greater atrial arrhythmogenicity in rats.9 Increased fibrosis in myocardium also has been reported in human diabetic hearts.10,11 Because ROS facilitate apoptosis and cardiac fibrosis, glucose fluctuations may aggravate AF in accordance with ROS increase.12,13 In the present study, we investigated whether glucose fluctuations induced by repeated starvation increase the incidence of AF by facilitating atrial fibrosis more than persistent hyperglycaemia. We also explored the mechanisms involved in the observed effects.
Methods
All experimental procedures were performed in accordance with the guidelines of the Physiological Society of Oita University, Japan, for the care and use of laboratory animals, which follow the guidelines established by the U.S. National Institutes of Health.
Haemodynamic parameters and echocardiography
Systolic blood pressure and heart rate were measured using the tail-cuff method. Transthoracic echocardiography (Hitachi Aloka Medical, Ltd, Tokyo, Japan) was then performed at the end of the sequential pattern of glucose fluctuations under anaesthesia by an intraperitoneal injection of a mixture of ketamine (60 mg/kg) and xylazine (10 mg/kg) which was confirmed not to decrease the blood pressure. Measurements included left atrial dimension (LAD), left ventricular (LV) end-diastolic dimension, LV end-systolic dimension, LV fractional shortening (FS), LV ejection fraction (LVEF), and LV end-diastolic posterior wall thickness (LVPWth). We also measured peak early (E) and late (A) transmitral flow velocities. The deceleration time of the mitral E-wave (DcT) was measured from its peak to the time when the descent of the wave intercepted the baseline.
Source: https://academic.oup.com/cardiovascres/article/104/1/5/317328/Glucose-fluctuations-increase-the-incidence-of