Hypoglycaemia and cardiac arrhythmias in diabetes

Abstract

Hypoglycaemia remains an inevitable risk in insulin-treated type 1 diabetes and type 2 diabetes and has been associated with multiple adverse outcomes. Whether hypoglycaemia is a cause of fatal cardiac arrhythmias in diabetes, or merely a marker of vulnerability, is still unknown. Since a pivotal report in 1991, hypoglycaemia has been suspected to induce cardiac arrhythmias in patients with type 1 diabetes, the so-called 'dead-in-bed syndrome'. This suspicion has subsequently been supported by the coexistence of an increased mortality and a three-fold increase in severe hypoglycaemia in patients with type 2 diabetes receiving intensive glucose-lowering treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Studies have investigated the association between hypoglycaemia-induced cardiac arrhythmias. In a rat-model, severe hypoglycaemia resulted in a specific pattern of cardiac arrhythmias including QT-prolongation, ventricular tachycardia, second- and third-degree AV block and ultimately cardiorespiratory arrest. In clinical studies of experimentally induced hypoglycaemia, QTc-prolongation, a risk factor of ventricular arrhythmias, is an almost consistent finding. The extent of QT-prolongation seems to be modified by several factors, including antecedent hypoglycaemia, diabetes duration and cardiac autonomic neuropathy. Observational studies indicate diurnal differences in the pattern of electrocardiographic alterations during hypoglycaemia with larger QTc-prolongations during daytime, whereas the risk of bradyarrhythmias may be increased during sleep. Daytime periods of hypoglycaemia are characterized by shorter duration, increased awareness and a larger increase in catecholamines. The counterregulatory response is reduced during nightly episodes of hypoglycaemia, resulting in prolonged periods of hypoglycaemia with multiple nadirs. An initial sympathetic activity at plasma glucose nadir is replaced by increased vagal activity, which results in bradycardia. Here, we provide an overview of the existing literature exploring potential mechanisms for hypoglycaemia-induced cardiac arrhythmias and studies linking hypoglycaemia to cardiac arrhythmias in patients with diabetes.

Keywords: cardiac arrhythmias; diabetes complications; hypoglycaemia; type 1 diabetes; type 2 diabetes.

Figure 1.

Pattern of electrocardiographic changes during insulin-induced severe hypoglycaemia in a rat model as described by Reno and colleagues. QTc, corrected QT interval.

Figure 2.

Proposed mechanism for hypoglycaemia-induced cardiac arrhythmias. Sympathoadrenal activity and parasympathetic activity is depicted with red arrows and blue arrows, respectively. When awake, a marked increase in catecholamines during episodes of hypoglycaemia results in an increase in heart rate and QTc, which is a well-stablished risk factor of ventricular arrhythmias. At night, the sympathoadrenal response is blunted and QTc prolongations less pronounced. The initial sympathoadrenal response is followed by increased vagal activity resulting in bradycardia. Preclinical studies have indicated that bradycardia may be the initial step leading to high-grade AV-block and cardiac arrest during severe hypoglycaemia. AV block, atrioventricular block; PSNS, parasympathetic nervous system; QTc, corrected QT interval; SNS, sympathetic nervous system.