Hypoglycaemia combined with mild hypokalaemia reduces the heart rate and causes abnormal pacemaker activity in a computational model of a human sinoatrial cell

Low blood glucose, hypoglycaemia, has been implicated as a possible contributing factor to sudden cardiac death (SCD) in people with diabetes but it is challenging to investigate in clinical studies. We hypothesized the effects of hypoglycaemia on the sinoatrial node (SAN) in the heart to be a candidate mechanism and adapted a computational model of the human SAN action potential developed by Fabbri et al., to investigate the effects of hypoglycaemia on the pacemaker rate. Using Latin hypercube sampling, we combined the effects of low glucose (LG) on the human ether-a-go-go-related gene channel with reduced blood potassium, hypokalaemia, and added sympathetic and parasympathetic stimulus. We showed that hypoglycaemia on its own causes a small decrease in heart rate but there was also a marked decrease in heart rate when combined with hypokalaemia. The effect of the sympathetic stimulus was diminished, causing a smaller increase in heart rate, with LG and hypokalaemia compared to normoglycaemia. By contrast, the effect of the parasympathetic stimulus was enhanced, causing a greater decrease in heart rate. We therefore demonstrate a potential mechanistic explanation for hypoglycaemia-induced bradycardia and show that sinus arrest is a plausible mechanism for SCD in people with diabetes

Cardiac autonomic regulation and repolarization during acute experimental hypoglycemia in Type 2 diabetes

Hypoglycemia is associated with increased cardiovascular mortality in trials of intensive therapy in type 2 diabetes (T2DM). We previously observed an increase in arrhythmias during spontaneous prolonged hypoglycemia in T2DM patients. Our aim was to examine changes in cardiac autonomic function and repolarization during sustained experimental hypoglycemia. Twelve adults with T2DM and eleven age, BMI-matched nondiabetic controls underwent paired hyperinsulinemic clamps separated by 4 weeks. Glucose was maintained at euglycemia (6.0mmol/L) or hypoglycemia (2.5mmol/L) for one hour. Heart rate, blood pressure, heart rate variability were assessed every thirty minutes and corrected QT (QTc) and T wave morphology every 60 minutes. Heart rate initially increased in T2DM participants but then fell towards baseline despite maintained hypoglycemia at 1 hour, accompanied by reactivation of vagal tone. In nondiabetic participants, vagal tone remained depressed during sustained hypoglycemia. Diabetic participants exhibited greater heterogeneity of repolarization during hypoglycemia as demonstrated by T wave symmetry and Principal Component Analysis (PCA) ratio compared with the nondiabetic group. Epinephrine levels during hypoglycemia were similar between groups. Cardiac autonomic regulation during hypoglycemia appears time-dependent. T2DM individuals demonstrate greater repolarization abnormalities for a given hypoglycemic stimulus despite comparable sympathoadrenal responses. These mechanisms could contribute to arrhythmias during clinical hypoglycemic episodes

Influence of cardiac autonomic neuropathy on cardiac repolarisation during incremental adrenaline infusion in type 1 diabetes

Aims/hypothesis We examined the effect of a standardised sympathetic stimulus, incremental adrenaline (epinephrine) infusion on cardiac repolarisation in individuals with type 1 diabetes with normal autonomic function, subclinical autonomic neuropathy and established autonomic neuropathy. Methods Ten individuals with normal autonomic function and baroreceptor sensitivity tests (NAF), seven with subclinical autonomic neuropathy (SAN; normal standard autonomic function tests and abnormal baroreceptor sensitivity tests); and five with established cardiac autonomic neuropathy (CAN; abnormal standard autonomic function and baroreceptor tests) underwent an incremental adrenaline infusion. Saline (0.9% NaCl) was infused for the first hour followed by 0.01 μg kg−1 min−1 and 0.03 μg kg−1 min−1 adrenaline for the second and third hours, respectively, and 0.06 μg kg−1 min−1 for the final 30 min. High resolution ECG monitoring for QTc duration, ventricular repolarisation parameters (T wave amplitude, T wave area symmetry ratio) and blood sampling for potassium and catecholamines was performed every 30 min. Results Baseline heart rate was 68 (95% CI 60, 76) bpm for the NAF group, 73 (59, 87) bpm for the SAN group and 84 (78, 91) bpm for the CAN group. During adrenaline infusion the heart rate increased differently across the groups (p = 0.01). The maximum increase from baseline (95% CI) in the CAN group was 22 (13, 32) bpm compared with 11 (7, 15) bpm in the NAF and 10 (3, 18) bpm in the SAN groups. Baseline QTc was 382 (95% CI 374, 390) ms in the NAF, 378 (363, 393) ms in the SAN and 392 (367, 417) ms in the CAN groups (p = 0.31). QTc in all groups lengthened comparably with adrenaline infusion. The longest QTc was 444 (422, 463) ms (NAF), 422 (402, 437) ms (SAN) and 470 (402, 519) ms (CAN) (p = 0.09). T wave amplitude and T wave symmetry ratio decreased and the maximum decrease occurred earlier, at lower infused adrenaline concentrations in the CAN group compared with NAF and SAN groups. AUC for the symmetry ratio was different across the groups and was lowest in the CAN group (p = 0.04). Plasma adrenaline rose and potassium fell comparably in all groups. Conclusions/interpretation Participants with CAN showed abnormal repolarisation in some measures at lower adrenaline concentrations. This may be due to denervation adrenergic hypersensitivity. Such individuals may be at greater risk of cardiac arrhythmias in response to physiological sympathoadrenal challenges such as stress or hypoglycaemia

Diurnal Differences in Risk of Cardiac Arrhythmias during Spontaneous Hypoglycemia in Young People with Type 1 Diabetes

OBJECTIVE Hypoglycemia may exert proarrhythmogenic effects on the heart via sympathoadrenal stimulation and hypokalemia. Hypoglycemia-induced cardiac dysrhythmias are linked to the “dead-in-bed syndrome,” a rare but devastating condition. We examined the effect of nocturnal and daytime clinical hypoglycemia on electrocardiogram (ECG) in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS Thirty-seven individuals with type 1 diabetes underwent 96 h of simultaneous ambulatory ECG and blinded continuous interstitial glucose monitoring (CGM) while symptomatic hypoglycemia was recorded. Frequency of arrhythmias, heart rate variability, and cardiac repolarization were measured during hypoglycemia and compared with time-matched euglycemia during night and day. RESULTS A total of 2,395 h of simultaneous ECG and CGM recordings were obtained; 159 h were designated hypoglycemia and 1,355 h euglycemia. A median duration of nocturnal hypoglycemia of 60 min (interquartile range 40–135) was longer than daytime hypoglycemia of 44 min (30–70) (P = 0.020). Only 24.1% of nocturnal and 51.0% of daytime episodes were symptomatic. Bradycardia was more frequent during nocturnal hypoglycemia compared with matched euglycemia (incident rate ratio [IRR] 6.44 [95% CI 6.26, 6.63], P < 0.001). During daytime hypoglycemia, bradycardia was less frequent (IRR 0.023 [95% CI 0.002, 0.26], P = 0.002) and atrial ectopics more frequent (IRR 2.29 [95% CI 1.19, 4.39], P = 0.013). Prolonged QTc, T-peak to T-end interval duration, and decreased T-wave symmetry were detected during nocturnal and daytime hypoglycemia. CONCLUSIONS Asymptomatic hypoglycemia was common. We identified differences in arrhythmic risk and cardiac repolarization during nocturnal versus daytime hypoglycemia in young adults with type 1 diabetes. Our data provide further evidence that hypoglycemia is proarrhythmogenic

Effect of Hypoglycemia on Inflammatory Responses and the Response to Low Dose Endotoxemia in Humans

Context: Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective: To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting: Single-blinded, prospective study of three independent parallel groups. Participants and Interventions: Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/l), euglycemic (6.0 mmol/l) or sham-saline clamp (n=8 for each group). Forty-eight hours later, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main outcome measures: We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results: Hypoglycemia increased total leucocytes (9.98±1.14 x109/l vs euglycemia: 4.38±0.53 x109/l; P<0.001 vs sham-saline: 4.76±0.36 x109/l; P<0.001) (mean±SEM), mobilized proinflammatory intermediate monocytes (42.20±7.52/μl vs euglycemia: 20.66±3.43/μl; P<0.01 vs sham-saline: 26.20±3.86/μl; P<0.05) and non-classical monocytes (36.16±4.66/μl vs euglycemia: 12.72±2.42/μl; P<0.001 vs sham-saline: 19.05±3.81/μl; P<0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (AUC) increased (73.87±7.30 vs 52.50±4.04; P<0.05) and formation of monocyte-platelet aggregates increased (96.05±14.51/μl vs 49.32±6.41/μl; P<0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51±1.42/μl vs euglycemia: 4.19±1.08/μl; P<0.05 vs sham-saline: 3.81±1.42/μl; P<0.05) and non-classical monocytes (9.53±1.08/μl vs euglycemia: 2.86±0.72/μl; P<0.01 vs sham-saline: 3.08±1.01/μl; P<0.05) with platelets compared to controls. Hypoglycemia led to greater leucocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96±0.97 vs euglycemia: 8.21±0.85 x109/l; P<0.05). Conclusions: Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute towards increased cardiovascular risk observed in people with diabetes

Wavelet analysis of laser-induced changes of the microcirculation - preliminary findings

There is substantial evidence that low level laser irradiation may induce vascular relaxation leading to an improved tissue perfusion in the microvascular network [Maegawa et al. 2000]. This is relevant since adequate blood supply is an important factor in the treatment of pain syndromes in sport medicine. However, the underlying mechanisms have not been studied in depth and the corresponding reports are mainly restricted to animal models. Therefore, continuous wavelet transformation was applied to the laser Doppler signals which were recorded immediately before and after a standardized laser needle stimulation over acupuncture point Neiguan [Pe6] in 6 healthy, nonsmoking males. Five defined frequency intervals were analysed corresponding to cardiac, respiratory, neurogenic, myogenic and endothelial metabolic activity. The mean amplitude of the total spectrum [0.009-2 Hz] and the absolute and normalized amplitude of each particular interval were calculated. Current findings demonstrated insignificant alterations in skin blood flow as well as in calculated amplitudes. It seems that laser needle stimulation has no effect on peripheral blood flow and microvascular control under the conditions of the present study. However, confidence interval estimation alludes to plausible effects. Further research on LDS and wavelet analysis in terms of randomised, controlled trials with adequate sample sizes is required. References Maegawa, Y., Itoh, T., Hosokawa, T., Yaegashi, K., and Nishi, M. [2000]. Effects of Near-Infrared Low-Level Laser Irradiation on Microcirculation. Lasers Surg. Med. 27, 427-437