Cardiac repolarization during hypoglycaemia in type 1 diabetes: impact of basal renin-angiotensin system activity

Due-Andersen, Rikke; Høi-Hansen, Thomas; Larroudé, Charlotte Ellen; Olsen, Niels Vidiendal; Kanters, Jørgen K.; Boomsma, Frans; Pedersen‐Bjergaard, Ulrik; Thorsteinsson, Birger

doi:10.1093/europace/eun137

Cited by 14 publications

(15 citation statements)

References 42 publications

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“…13 We did not observe any effect of candesartan on counter-regulatory hormone or substrate responses to hypoglycaemia. This is in contrast to a study of healthy men treated with losartan, 27 which reported an attenuated adrenaline response to hypoglycaemia in the treatment arm compared to placebo and in line with a study of healthy men treated with captopril and ACE inhibitor reporting no difference in symptoms and counter-regulation.…”

Section: Discussionmentioning

confidence: 52%

“…[11][12][13] In patients with type 1 diabetes the QT interval was more prolonged in patients with high RAS activity than patients with low activity during controlled hypoglycaemia. 13 QT prolongation is a common finding during hypoglycaemia, 11 and may be involved in sudden death from ventricular tachyarrhythmia, the so-called 'dead-in-bed' syndrome. 14,15 High RAS activity is implicated in ventricular tachyarrhythmia.…”

Section: Introductionmentioning

confidence: 99%

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Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

Færch

Thorsteinsson

Tarnow

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Introduction: High spontaneous activity of the renin–angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function during hypoglycaemia. Methods: Nine patients with type 1 diabetes and high spontaneous RAS activity were included in a double-blind, randomised, cross-over study on the effect of angiotensin II receptor antagonist (candesartan 32 mg) or placebo for one week on cognitive function, cardiovascular parameters, hormonal counter-regulatory response, substrate mobilisation, and symptoms during hypoglycaemia induced by two hyperinsulinaemic, hypoglycaemic clamps. Results: Compared to placebo, candesartan did neither change performance of the cognitive tests nor the EEG at a plasma glucose concentration of 2.6±0.2 mmol/l. During candesartan treatment, the QT interval in the ECG was not affected. No effect of candesartan was observed in the hormonal counter-regulatory responses, in substrate concentrations, or in symptom scores. A 36% reduced glucose infusion rate during hypoglycaemia with candesartan was observed. Conclusion: In conclusion candesartan has no effect on cerebral function during mild experimental hypoglycaemia in subjects with type 1 diabetes and high RAS activity. Candesartan may reduce glucose utilisation or increase endogenous glucose production during hypoglycaemia.

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Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

Færch

Thorsteinsson

Tarnow

et al. 2014

J Renin Angiotensin Aldosterone Syst

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“…The latter is substantiated by a lag time between hypoglycemia and QT aberrations 6 and the fact that the magnitude of adrenaline release was correlated to the QTc changes. 7 The primary objective of the present study was to assess the effect of insulin-induced hypoglycemia on the EEG in T1DM patients. These results have been published.…”

Section: Introductionmentioning

confidence: 99%

Hypoglycemia-Associated Electroencephalogram and Electrocardiogram Changes Appear Simultaneously

Larsen¹,

Højlund

Poulsen

et al. 2013

J Diabetes Sci Technol

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“…This distinction is important because unlike rodents, patients with t1DM do not exhibit heart rate corrected QT-interval prolongation in the absence of confounding factors, such as diabetic ketoacidosis (24) or spontaneous hypoglycemia (11). Clinically, these additional stimuli are required to unmask pathological QT-interval prolongation in patients with t1DM (11,14,17,24).More importantly, most EP studies in t1DM have been performed in animal models that exhibited highly artificial rises (Ͼ300%) in blood glucose levels that are well beyond what is commonly encountered in patients with diabetes (20,33,36,40,46). Such extreme levels of hyperglycemia, which are known to affect ion channels, preclude the direct translation of some of these earlier findings to humans.…”

mentioning

confidence: 99%

Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs

Xie

Biary

Tocchetti

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Chronic hyperglycemia in type-1 diabetes mellitus is associated with oxidative stress (OS) and sudden death. Mechanistic links remain unclear. We investigated changes in electrophysiological (EP) properties in a model of chronic hyperglycemia before and after challenge with OS by GSH oxidation and tested reversibility of EP remodeling by insulin. Guinea pigs survived for 1 mo following streptozotocin (STZ) or saline (sham) injection. A treatment group received daily insulin for 2 wk to reverse STZ-induced hyperglycemia (STZ + Ins). EP properties were measured using high-resolution optical action potential mapping before and after challenge of hearts with diamide. Despite elevation of glucose levels in STZ compared with sham-operated (P = 0.004) and STZ + Ins (P = 0.002) animals, average action potential duration (APD) and arrhythmia propensity were not altered at baseline. Diamide promoted early (<10 min) formation of arrhythmic triggers reflected by a higher arrhythmia scoring index in STZ (P = 0.045) and STZ + Ins (P = 0.033) hearts compared with sham-operated hearts. APD heterogeneity underwent a more pronounced increase in response to diamide in STZ and STZ + Ins hearts compared with sham-operated hearts. Within 30 min, diamide resulted in spontaneous incidence of ventricular tachycardia and ventricular fibrillation (VT/VF) in 3/6, 2/5, 1/5, and 0/4 STZ, STZ + Ins, sham-operated, and normal hearts, respectively. Hearts prone to VT/VF exhibited greater APD heterogeneity (P = 0.010) compared with their VT/VF-free counterparts. Finally, altered EP properties in STZ were not rescued by insulin. In conclusion, GSH oxidation enhances APD heterogeneity and increases arrhythmia scoring index in a guinea pig model of chronic hyperglycemia. Despite normalization of glycemic levels by insulin, these proarrhythmic properties are not reversed, suggesting the importance of targeting antioxidant defenses for arrhythmia suppression.

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Cardiac repolarization during hypoglycaemia in type 1 diabetes: impact of basal renin-angiotensin system activity

Abstract: Low basal RAS activity may be associated with a slightly more pronounced QT prolongation during hypoglycaemia, when compared with high RAS activity. The impact, however, is modest and the clinical consequence is unclear.

Cited by 14 publications

References 42 publications

Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

Hypoglycemia-Associated Electroencephalogram and Electrocardiogram Changes Appear Simultaneously

Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs

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