Spectral analysis of the laser Doppler flow (LDF) signal in the frequency interval from 0.0095–2.0 Hz reveals blood flow oscillations with frequencies around 1.0, 0.3, 0.1, 0.04 and 0.01 Hz. The ...heartbeat, the respiration, the intrinsic myogenic activity of vascular smooth muscle, the neurogenic activity of the vessel wall and the vascular endothelium influence these oscillations, respectively. The first aim of this study was to investigate if a slow oscillatory component could be detected in the frequency area below 0.0095 Hz of the human cutaneous blood perfusion signal. Unstimulated basal blood skin perfusion and enhanced perfusion during iontophoresis with the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were measured in healthy male volunteers and the wavelet transform was computed. A low-frequency oscillation between 0.005 and 0.0095 Hz was found both during basal conditions and during iontophoresis with ACh and SNP. Iontophoresis with ACh increased the normalized amplitude to a greater extent than SNP (
P
=
0.001) indicating modulation by the vascular endothelium. To gain further insight into the mechanisms for this endothelium dependency, we inhibited nitric oxide (NO) synthesis with N
G-monomethyl-
l-arginine (
l-NMMA) and prostaglandin (PG) synthesis by aspirin.
l-NMMA did not affect the increased response to ACh vs. SNP iontophoresis in the 0.005–0.0095-Hz interval (
P
=
0.006) but abolished the difference in the 0.0095–0.021-Hz interval (
P
=
0.97). Aspirin did not affect the difference in response to ACh and SNP in either of the two frequency intervals. Thus, other endothelial mechanisms, such as endothelium-derived hyperpolarizing factor (EDHF), might be involved in the regulation of this sixth frequency interval (0.005–0.0095 Hz).
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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 QT
c
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 QT
c
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). QT
c
in all groups lengthened comparably with adrenaline infusion. The longest QT
c
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.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The complex interactions that give rise to heart rate variability (HRV) involve coupled physiological oscillators operating over a wide range of different frequencies and length-scales. Based on the ...premise that interactions are key to the functioning of complex systems, the time-dependent deterministic coupling parameters underlying cardiac, respiratory and vascular regulation have been investigated at both the central and microvascular levels. Hypertension was considered as an example of a globally altered state of the complex dynamics of the cardiovascular system. Its effects were established through analysis of simultaneous recordings of the electrocardiogram (ECG), respiratory effort, and microvascular blood flow by laser Doppler flowmetry (LDF). The signals were analyzed by methods developed to capture time-dependent dynamics, including the wavelet transform, wavelet-based phase coherence, non-linear mode decomposition, and dynamical Bayesian inference, all of which can encompass the inherent frequency and coupling variability of living systems. Phases of oscillatory modes corresponding to the cardiac (around 1.0 Hz), respiratory (around 0.25 Hz), and vascular myogenic activities (around 0.1 Hz) were extracted and combined into two coupled networks describing the central and peripheral systems, respectively. The corresponding spectral powers and coupling functions were computed. The same measurements and analyses were performed for three groups of subjects: healthy young (Y group, 24.4 ± 3.4 y), healthy aged (A group, 71.1 ± 6.6 y), and aged treated hypertensive patients (ATH group, 70.3 ± 6.7 y). It was established that the degree of coherence between low-frequency oscillations near 0.1 Hz in blood flow and in HRV time series differs markedly between the groups, declining with age and nearly disappearing in treated hypertension. Comparing the two healthy groups it was found that the couplings to the cardiac rhythm from both respiration and vascular myogenic activity decrease significantly in aging. Comparing the data from A and ATH groups it was found that the coupling from the vascular myogenic activity is significantly weaker in treated hypertension subjects, implying that the mechanisms of microcirculation are not completely restored by current anti-hypertension medications.
Non‐technical summary Traffic carried over two branches of the sympathetic nervous system can be recorded in cooperative human subjects, with fine needles inserted directly into leg nerves. We made ...simultaneous recordings of sympathetic activity with two needles inserted into nerve tracts supplying skin and muscles, and used a mathematical method, wavelet phase coherence, to obtain insights into how the brain regulates neural oscillations. Our results document continuously varying and coherently coupled human skin and muscle sympathetic nerve oscillations over time (suggesting that they are driven by other central frequency generators).
Frequency‐domain analyses of simultaneously recorded skin and muscle sympathetic nerve activities may yield unique information on otherwise obscure central processes governing human neural outflows. We used wavelet transform and wavelet phase coherence methods to analyse integrated skin and muscle sympathetic nerve activities and haemodynamic fluctuations, recorded from nine healthy supine young men. We tested two null hypotheses: (1) that human skin and muscle sympathetic nerve activities oscillate congruently; and (2) that whole‐body heating affects these neural outflows and their haemodynamic consequences in similar ways. Measurements included peroneal nerve skin and tibial nerve muscle sympathetic activities; the electrocardiogram; finger photoplethysmographic arterial pressure; respiration (controlled at 0.25 Hz, and registered with a nasal thermistor); and skin temperature, sweating, and laser‐Doppler skin blood flow. We made recordings at ∼27°C, for ∼20 min, and then during room temperature increases to ∼38°C, over 35 min. We analysed data with a wavelet transform, using the Morlet mother wavelet and wavelet phase coherence, to determine the frequencies and coherences of oscillations over time. At 27°C, skin and muscle nerve activities oscillated coherently, at ever‐changing frequencies between 0.01 and the cardiac frequency (∼1 Hz). Heating significantly augmented oscillations of skin sympathetic nerve activity and skin blood flow, arterial pressure, and R‐R intervals, over a wide range of low frequencies, and modestly reduced coordination between skin and muscle sympathetic oscillations. These results suggest that human skin and muscle sympathetic motoneurones are similarly entrained by external influences, including those of arterial baroreceptors, respiration, and other less well‐defined brainstem oscillators. Our study provides strong support for the existence of multiple, time‐varying central sympathetic neural oscillators in human subjects.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Background Increased cardiovascular mortality has been reported in trials of intensive glycaemic control in patients with type 2 diabetes. Evidence that hypoglycaemia predicts subsequent ...mortality in the weeks after a cardiovascular event is strong. Altered fibrin structure characteristics and subclinical inflammation have been implicated in the predisposition to cardiovascular events. We hypothesised that hypoglycaemia creates a thrombotic–inflammatory environment, contributing to increased mortality after the event. Methods Ten patients with type 2 diabetes were recruited (mean age 50 years SD 8, duration of diabetes 9·5 years 4·6, and HbA1c 8·7% 2·1). They all completed paired hyperinsulinaemic clamp studies separated by at least 4 weeks. Glucose was maintained at hypoglycaemia (2·5 mmol/L) or euglycaemia (6 mmol/L) for two 60 min periods. Four timepoints were analysed: baseline, end of clamp, and days 1 and 7 post clamp in both arms. Fibrin network properties and fibrinolysis of plasma samples were assessed with a dynamic turbidimetric assay. Plasma fibrinogen concentrations were measured with the Clauss assay, and high sensitivity CRP (hsCRP) was measured with an immunoturbidimetric assay. We also analysed heart rate variability as an indicator of vagal activity. Findings Clot maximum absorbance, a measure of clot density, increased after hypoglycaemic clamp reaching a peak at day 7, whereas a decrease occurred after euglycaemic clamp (mean change from baseline Δ 0·040 SD 0·093 and −0·035 0·080, respectively; p=0·01). Clot lysis time, an indicator of fibrinolysis potential, increased after hypoglycaemic clamp up to day 7 but decreased after euclycaemic clamp (mean Δ 64 s SD 119 vs −51 64, p=0·02). hsCRP increased on day 7 after hypoglycaemic clamp whereas there was a reduction after euglycaemic clamp (0·80 mg/dL 0·98 vs −0·89 0·80, p<0·0001). Similarly, fibrinogen concentrations were higher at day 7 after hypoglycaemic clamp than after euglycaemic clamp (1·09 mg/mL 2·58 vs 0·17 1·25, p=0·05). There were similar decreases in vagal tone as shown by high frequency heart rate variability after hypoglycaemic clamp in contrast with an increase in vagal tone after euglycaemic clamp (p=0·02) Interpretation Hypoglycaemia induces prothrombotic changes in the fibrin network and aggravates subclinical inflammation, with effects that are sustained for at least 1 week. The mechanism of these changes is unclear but might involve depression of the cholinergic anti-inflammatory pathway. Hypoglycaemia might mitigate the benefits of intensive glucose control by creating a thrombotic and inflammatory milieu. Our data provide a possible explanation for the observed increase in cardiovascular mortality weeks after a hypoglycaemic event. Funding National Institute of Health Research.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Recent trials of intensive glycemic control suggest a possible link between hypoglycemia and excess cardiovascular mortality in patients with type 2 diabetes. Hypoglycemia might cause arrhythmias ...through effects on cardiac repolarization and changes in cardiac autonomic activity. Our aim was to study the risk of arrhythmias during spontaneous hypoglycemia in type 2 diabetic patients with cardiovascular risk. Twenty-five insulin-treated patients with type 2 diabetes and a history of cardiovascular disease or two or more risk factors underwent simultaneous continuous interstitial glucose and ambulatory electrocardiogram monitoring. Frequency of arrhythmias, heart rate variability, and markers of cardiac repolarization were compared between hypoglycemia and euglycemia and between hyperglycemia and euglycemia matched for time of day. There were 134 h of recording at hypoglycemia, 65 h at hyperglycemia, and 1,258 h at euglycemia. Bradycardia and atrial and ventricular ectopic counts were significantly higher during nocturnal hypoglycemia compared with euglycemia. Arrhythmias were more frequent during nocturnal versus daytime hypoglycemia. Excessive compensatory vagal activation after the counterregulatory phase may account for bradycardia and associated arrhythmias. QT intervals, corrected for heart rate, >500 ms and abnormal T-wave morphology were observed during hypoglycemia in some participants. Hypoglycemia, frequently asymptomatic and prolonged, may increase the risk of arrhythmias in patients with type 2 diabetes and high cardiovascular risk. This is a plausible mechanism that could contribute to increased cardiovascular mortality during intensive glycemic therapy.
Impaired awareness of hypoglycaemia (IAH) increases the risk of severe hypoglycaemia in people with type 1 diabetes mellitus (T1DM). IAH can be reversed through meticulous avoidance of hypoglycaemia. ...Diabetic autonomic neuropathy (DAN) has been proposed as an underlying mechanism contributing to IAH; however, data are inconsistent. The aim of this study was to examine the effects of cardiac autonomic neuropathy (CAN) on IAH reversibility inT1DM.
Participants with T1DM and IAH (Gold score ≥4) recruited to the HypoCOMPaSS (24-week 2 × 2 factorial randomised controlled) trial were included. All underwent screening for cardiac autonomic function testing at baseline and received comparable education and support aimed at avoiding hypoglycaemia and improving hypoglycaemia awareness. Definite CAN was defined as the presence of ≥2 abnormal cardiac reflex tests. Participants were grouped according to their CAN status, and changes in Gold score were compared.
Eighty-three participants (52 women 62.7%) were included with mean age (SD) of 48 (12) years and mean HbA1c of 66 (13) mmol/mol (8.2 3.3 %). The mean duration of T1DM was 29 (13) years. The prevalence of CAN was low with 5/83 (6%) participants having definite autonomic neuropathy with 11 (13%) classified with possible/early neuropathy. All participants, regardless of the autonomic function status, showed a mean improvement in Gold score of ≥1 (mean improvement -1.2 95% CI -0.8, -1.6; p < 0.001).
IAH can be improved in people with T1DM, and a long duration of disease, with and without cardiac autonomic dysfunction. These data suggest that CAN is not a prime driver for modulating IAH reversibility.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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.
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.
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) (
= 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,
< 0.001). During daytime hypoglycemia, bradycardia was less frequent (IRR 0.023 95% CI 0.002, 0.26,
= 0.002) and atrial ectopics more frequent (IRR 2.29 95% CI 1.19, 4.39,
= 0.013). Prolonged QTc, T-peak to T-end interval duration, and decreased T-wave symmetry were detected during nocturnal and daytime hypoglycemia.
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.
Hypoglycemia is associated with increased cardiovascular mortality in trials of intensive therapy in type 2 diabetes mellitus (T2DM). We previously observed an increase in arrhythmias during ...spontaneous prolonged hypoglycemia in patients with T2DM. We examined changes in cardiac autonomic function and repolarization during sustained experimental hypoglycemia. Twelve adults with T2DM and 11 age- and BMI-matched control participants without diabetes underwent paired hyperinsulinemic clamps separated by 4 weeks. Glucose was maintained at euglycemia (6.0 mmol/L) or hypoglycemia (2.5 mmol/L) for 1 h. Heart rate, blood pressure, and heart rate variability were assessed every 30 min and corrected QT intervals and T-wave morphology every 60 min. Heart rate initially increased in participants with T2DM but then fell toward baseline despite maintained hypoglycemia at 1 h accompanied by reactivation of vagal tone. In control participants, vagal tone remained depressed during sustained hypoglycemia. Participants with T2DM exhibited greater heterogeneity of repolarization during hypoglycemia as demonstrated by T-wave symmetry and principal component analysis ratio compared with control participants. Epinephrine levels during hypoglycemia were similar between groups. Cardiac autonomic regulation during hypoglycemia appears to be time dependent. Individuals with T2DM demonstrate greater repolarization abnormalities for a given hypoglycemic stimulus despite comparable sympathoadrenal responses. These mechanisms could contribute to arrhythmias during clinical hypoglycemic episodes.
Abstract
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). After 48 hours, 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 leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/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 nonclassic 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 (area under the curve) 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 nonclassic 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 with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/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 to increased cardiovascular risk observed in people with diabetes.
Using an in vivo human experimental model, we show that hypoglycemia primes the innate immune system, leading to a more profound inflammatory response to a subsequent inflammatory stimulus.
PDF
