Severe Hypoglycemia–Induced Fatal Cardiac Arrhythmias Are Augmented by Diabetes and Attenuated by Recurrent Hypoglycemia

Reno, Candace M.; VanderWeele, Jennifer; Bayles, Justin; Litvin, Marina; Skinner, Allie; Jordan, Andrew N.; Daphna-Iken, Dorit; Fisher, Simon J.

doi:10.2337/db17-0306

Cited by 23 publications

(28 citation statements)

References 19 publications

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“…Hence, hypoglycemia was preceded by a relatively small decline in plasma glucose (PG). It has also been suggested that diabetes may aggravate the risk of cardiac rhythm abnormalities ( 11 , 15 ); however, in the only study comparing the electrophysiological response to hypoglycemia in patients with type 2 diabetes with the response in controls without diabetes, only a fraction of the patients with type 2 diabetes were insulin-treated ( 11 ). Consequently, it is uncertain whether the results from this study translate into a risk population of insulin-treated patients.…”

Section: Introductionmentioning

confidence: 99%

Acute hypoglycemia and risk of cardiac arrhythmias in insulin-treated type 2 diabetes and controls

Andersen

Baldassarre

Christensen

et al. 2021

European Journal of Endocrinology

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Objective. Hypoglycemia is associated with increased risk of cardiovascular disease including cardiac arrhythmias. We investigated the effect of hypoglycemia in the setting of acute glycemic fluctuations on cardiac rhythm and cardiac repolarization in insulin-treated patients with type 2 diabetes compared with matched controls without diabetes. Design. A non-randomised, mechanistic intervention study Methods. Insulin-treated patients with type 2 diabetes (n=21, [mean±SD] age 62.8±6.5 years, BMI 29.0±4.2 kg/m2, HbA1c 6.8±0.5% [51.0±5.4 mmol/mol]) and matched controls (n=21, age 62.2±8.3 years, BMI 29.2±3.5 kg/m2, HbA1c 5.3±0.3% [34.3±3.3 mmol/mol]) underwent a sequential hyperglycemic and hypoglycemic clamp with three steady-states of plasma glucose: 1) fasting plasma glucose, 2) hyperglycemia (fasting plasma glucose+10 mmol/L) and 3) hyperinsulinemic hypoglycemia (plasma glucose<3.0 mmol/L). Participants underwent continuous ECG monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained. Results. Both groups experienced progressively increasing heart rate corrected QT (Fridericia’s formula)) interval prolongations during hypoglycemia ([∆mean (95% CI)] 31 ms [16, 45] and 39 ms [24, 53] in the group of patients with type 2 diabetes and controls, respectively) with similar increases from baseline at the end of the hypoglycemic phase (P=0.43). The incidence of ventricular premature beats increased significantly in both groups during hypoglycemia (P=0.033 and P<0.0001, respectively). One patient with type 2 diabetes developed atrial fibrillation during recovery from hypoglycemia. Conclusions. In insulin-treated patients with type 2 diabetes and controls without diabetes, hypoglycemia causes clinically significant and similar increases in cardiac repolarization that might increase vulnerability for serious cardiac arrythmias and sudden cardiac death.

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Section: Introductionmentioning

confidence: 99%

Acute hypoglycemia and risk of cardiac arrhythmias in insulin-treated type 2 diabetes and controls

Andersen

Baldassarre

Christensen

et al. 2021

European Journal of Endocrinology

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“…20 In a diabetic rodent model with streptozotocintreated diabetic rats, insulin-deficiency more than doubled the risk of third-degree AV block and death during severe hypoglycaemia compared with nondiabetic rats. 21 However, exposure of QTc, corrected QT interval.…”

Section: Preclinical Studiesmentioning

confidence: 99%

“…streptozotocin-treated rats to antecedent moderate hypoglycaemia the days before being exposed to hypoglycaemia resulted in reduced sympatoadrenergic response during severe hypoglycaemia and a significant reduction in third-degree AV block and mortality compared with nondiabetic rats. 21 Hence, while diabetes might increase the risk of fatal cardiac arrhythmias during severe hypoglycaemia, antecedent hypoglycaemia blunts the sympatoadrenergic response to hypoglycaemia, which might serve as a mediator of cardiac arrhythmias during severe hypoglycaemia. 21 Although the abovementioned findings point towards a central role for catecholamines and the sympathetic nervous system in cardiac arrhythmias during severe hypoglycaemia, they have recently been contradicted by a study from the same group.…”

Section: Preclinical Studiesmentioning

confidence: 99%

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Hypoglycaemia and cardiac arrhythmias in diabetes

Andersen

Jørgensen

Knop

et al. 2020

Therapeutic Advances in Endocrinology

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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.

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“…Furthermore, it has been reported that the risk of AF in individuals with insulin-deficient (type 1 and advanced type 2) diabetes increased with worsening glycemic control and periods of hypoglycemia ( 11 – 13 ). Similarly, severe hypoglycemia-induced fatal cardiac arrhythmias were enhanced in diabetic rats with insulin deficiency ( 14 ). Recently, we demonstrated that long term high-fat diet-induced insulin resistance enhanced the vulnerability of AF induction in a rodent model ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Insulin Treatment Reduces Susceptibility to Atrial Fibrillation in Type 1 Diabetic Mice

Maria

Campolo

Scherlag

et al. 2020

Front. Cardiovasc. Med.

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Diabetes has been identified as an independent risk factor for atrial fibrillation (AF), the most common chronic cardiac arrhythmia. Whether or not glucose and insulin disturbances observed during diabetes enhance arrhythmogenicity of the atria, potentially leading to AF, is not well-known. We hypothesized that insulin deficiency and impaired glucose transport provide a metabolic substrate for the development and maintenance of AF during diabetes. Transesophageal atrial pacing was used to induce AF in healthy, streptozotocin-induced insulin-deficient type 1 diabetic, and insulin-treated diabetic mice. Translocation of insulin-sensitive glucose transporters (GLUTs) to the atrial cell surface was measured using a biotinylated photolabeling assay in the perfused heart. Fibrosis and glycogen accumulation in the atrium were measured using histological analysis. Diabetic mice displayed mild hyperglycemia, increased duration and frequency of AF episodes vs. age-matched controls (e.g., AF duration: 19.7 ± 6.8 s vs. 1.8 ± 1.1 s, respectively, p = 0.032), whereas insulin-treated diabetic animals did not. The translocation of insulin-sensitive GLUT-4 and-8 to the atrial cell surface was significantly downregulated in the diabetic mice (by 67 and 79%, respectively; p ≤ 0.001), and rescued by insulin treatment. We did not observe fibrosis or glycogen accumulation in the atria of diabetic mice. Therefore, these data suggest that insulin and glucose disturbances were sufficient to induce AF susceptibility during mild diabetes.

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Severe Hypoglycemia–Induced Fatal Cardiac Arrhythmias Are Augmented by Diabetes and Attenuated by Recurrent Hypoglycemia

Cited by 23 publications

References 19 publications

Acute hypoglycemia and risk of cardiac arrhythmias in insulin-treated type 2 diabetes and controls

Acute hypoglycemia and risk of cardiac arrhythmias in insulin-treated type 2 diabetes and controls

Hypoglycaemia and cardiac arrhythmias in diabetes

Insulin Treatment Reduces Susceptibility to Atrial Fibrillation in Type 1 Diabetic Mice

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