Association of cardiac autonomic neuropathy with alteration of sympatho-vagal balance through heart rate variability analysis

Early sub-clinical assessment of severity of cardiac autonomic neuropathy (CAN) and intervention are of prime importance for risk stratification and early treatment in preventing sudden death due to silent myocardial infarction. The Ewing battery is currently the diagnostic tool of choice but is unable to detect sub-clinical disease and requires patient cooperation. Time and frequency domain analysis have several shortcomings including sensitivity to recording length, respiratory activity and non-stationarities in the ECG signal. An important step forward is to have a non-invasive method of detecting CAN that is robust against these shortcomings and has a higher sensitivity for the presence of both sub-clinical and overt clinical disease. This study presents a novel parameter, tone–entropy (T–E) that analyses heart rate variability (HRV) of 20 min lead II ECG recordings. Tone (T) represents sympatho-vagal balance and entropy (E) the autonomic regularity activity. Thirteen normal subjects without (CAN?) and 21 with CAN (CAN+) participated in this study. Among 21 CAN+ subjects, 13 are early CAN+ (eCAN+), eight are definite CAN+ (dCAN+) according to autonomic nervous system function tests as described by Ewing. The results showed that tone was higher and the entropy was lower in the dCAN+ group (T = ?0.033 to ?0.010 and E = 1.73–2.24) compared with the eCAN+ (T = ?0.0927 to ?0.0311 and E = 2.0–2.65) and normal (T = ?0.128 to ?0.0635 and E = 2.64–3.15) group. The research verified that T–E is a suitable method to determine the presence of CAN that correctly identifies experimentally induced changes in cardiac function akin to parasympathetic and sympathetic dysfunction and differentiates between stages in CAN disease progression identified using the Ewing battery.     

Influence of sympatho-vagal balance on airway responsiveness in athletes

The increased prevalence of airway hyperresponsiveness (AHR) observed among athletes suggests that high-level training may contribute to the development of AHR. We investigated the possible influence of the sympatho-vagal balance on this phenomenon in 40 athletes and 10 sedentary controls. Each subject filled out a respiratory questionnaire, had a methacholine challenge, and measurements were made of their baseline plasma catecholamines [epinephrine (E), norepinephrine (NE) and dopamine (DA)] as a reflection of sympathetic tone, and their heart rate variability (SDNN: standard deviation of all normal-to-normal intervals) as an indicator of parasympathetic tone. The athletes had a 45% prevalence of AHR (defined as PC20 < 16 mg/ml, where PC20 is the concentration of methacholine inducing a 20% fall in the forced expiratory volume in 1 s, FEV1) with a mean PC20 of 21.2 mg/ml compared with 10% prevalence (mean PC20: 74.4 mg/ml) in sedentary subjects (P < 0.01). Plasma catecholamine values were not significantly different between the two groups (all P > 0.05), but the estimated parasympathetic tone was higher in athletes (P = 0.01). When data from all subjects were analyzed together, plasma E and NE correlated with PC20 (r = 0.39, P = 0.005 and r = 0.29, P < 0.005) but DA and SDNN did not (both P > 0.05). However, the ratios E/SDNN, NE/SDNN and DA/SDNN showed significant correlations with PC20 (r = 0.42, P < 0.01; r = 0.33, P < 0.005 and r = 0.31, P < 0.05, respectively) This study suggests that the sympatho-vagal balance may contribute to the increased AHR in the population studied but this influence alone cannot explain the higher prevalence of AHR in athletes.     

Influence of sympatho-vagal balance on airway responsiveness in athletes

The increased prevalence of airway hyper-responsiveness (AHR) observed among athletes suggests that high-level training may contribute to the development of AHR. We investigated the possible influence of the sympatho-vagal balance on this phenomenon in 40 athletes and 10 sedentary controls. Each subject filled out a respiratory questionnaire, had a methacholine challenge, and measurements were made of their baseline plasma catecholamines [epinephrine (E), norepinephrine (NE) and dopamine (DA)] as a reflection of sympathetic tone, and their heart rate variability (SDNN: standard deviation of all normal-to-normal intervals) as an indicator of parasympathetic tone. The athletes had a 45% prevalence of AHR (defined as PC₂₀ < 16 mg/ml, where PC₂₀ is the concentration of methacholine inducing a 20% fall in the forced expiratory volume in 1 s, FEV₁) with a mean PC₂₀ of 21.2 mg/ml compared with 10% prevalence (mean PC₂₀: 74.4 mg/ml) in sedentary subjects (P < 0.01). Plasma catecholamine values were not significantly different between the two groups (all P > 0.05), but the estimated parasympathetic tone was higher in athletes (P=0.01). When data from all subjects were analyzed together, plasma E and NE correlated with PC₂₀ (r=0.39, P=0.005 and r=0.29, P < 0.005) but DA and SDNN did not (both P > 0.05). However, the ratios E/SDNN, NE/SDNN and DA/SDNN showed significant correlations with PC₂₀ (r=0.42, P < 0.01; r=0.33, P < 0.005 and r=0.31, P < 0.05, respectively). This study suggests that the sympatho-vagal balance may contribute to the increased AHR in the population studied but this influence alone cannot explain the higher prevalence of AHR in athletes. Accepted: 26 July 2000     

Intra-amygdala injection of GABAA agonist, muscimol, reduces tachycardia and modifies cardiac sympatho-vagal balance during restraint stress in rats

At present, little is known about the brain origin of stress-induced cardiac sympathetic drive responsible for stress-induced tachycardia. Our aim was to determine the effect of bilateral microinjections of the GABA(A) receptor agonist, muscimol, into the amygdaloid complex on both the heart rate and cardiac autonomic activity during restraint stress. Experiments were performed in male Sprague-Dawley rats (n=9), with pre-implanted electrocardiographic electrodes. Heart rate increased sharply after the onset of the restraint and reached a peak 1-2 min later (from 344+/-6-440+/-20 BPM). Subsequently, heart rate began to fall, and during the next 10-15 min approached the steady-state level of 384+/-11. After vehicle, mean heart rate during each of three 10-min restraint epochs was significantly higher compared with the pre-restraint level. After muscimol, mean heart rate was significantly elevated only during the first 10 min of restraint. There was no difference in the early peak tachycardia between both conditions. Muscimol substantially accelerated the fall of the HR from the peak to the steady-state level, and thus the area under the curve value for muscimol (503+/-162 BPM x min) was significantly smaller than that for vehicle (1221+/-231 BPM x min); P<0.05. After vehicle, the high-frequency spectral power of the heart rate decreased and the low-frequency power increased during the restraint, resulting in a significant rise of the low frequency/high frequency ratio from 1.2+/-0.2-2.8+/-0.6 (n=9, P<0.05). Muscimol suppressed these stress-induced effects. We conclude that inhibition of the amygdala neurons abolishes the sustained component of tachycardia during the restraint, has no effect on the early tachycardic component, and prevents stress-induced alterations in the heart rate variability indices.     

The effect of change in sympatho-vagal balance on heart rate and blood pressure variability in the foetal lamb

Cardiac and vascular function is mainly under autonomic nervous control within seconds to minutes, although the control is not mature at birth. We studied sympatho-vagal control of heart rate and blood pressure in chronically catheterized foetal lambs in the last trimester of gestation. Power spectral analysis was used to quantitate the frequency-specific heart rate variability (HRV) and blood pressure variability. We performed 15 experiments in seven foetal lambs. These preliminary studies showed that parasympathetic blockade by atropine (eight experiments) had no significant effect on the distribution of HRV to different frequencies. Beta-sympathetic blockade by propranolol (seven experiments) decreased the ratio of low and mid to high frequency (0.025-0.13 to 0.13-1.00 Hz) HRV (P= 0.02). The increased high frequency HRV in the absence of a similar increase in blood pressure variability and tracheal pressure variability suggests enhanced baroreflex responsiveness after propranolol administration. The frequency-specific sympathetic control of HRV in foetal lambs, the change in ratio of low and mid to high frequency HRV, might have clinical implications in estimating the level of foetal sympathetic activation in the follow-up of high-risk pregnancies.     

Cardiac autonomic balance versus cardiac regulatory capacity

The concept of autonomic balance views autonomic states along a bipolar continuum from sympathetic (S) to parasympathetic (P) dominance, whereas regulatory capacity models emphasize overall autonomic flexibility as a marker of the capacity for regulation. These two concepts were evaluated for their utility in characterizing patterns of autonomic control. Measures of P (high frequency heart rate variability, HF) and S (preejection period, PEP) cardiac control were obtained. A measure of cardiac autonomic balance (CAB) was derived as the difference in the normalized P index minus the S index, and a measure of cardiac autonomic regulation (CAR) was derived as the normalized P index plus the S index. Results reveal that CAR, but not CAB, was a significant predictor of the prior occurrence of a myocardial infarction, net of demographic and other variables, whereas CAB, but not CAR, was a significant predictor of concurrent diabetes.     

Regulation of cardiac protein balance by hydrocortisone: interaction with insulin

In fetal mouse hearts in organ culture the rate of protein synthesis was substantially reduced and the rate of protein degradation slightly increased by hydrocortisone in the absence of insulin, but in the presence of insulin the steroid caused a small increase in protein synthesis and a significant reduction in protein degradation. Hydrocortisone promoted the net uptake (or reduced the net release) of branched-chain amino acids independent of insulin and independent of simultaneous changes in protein balance. The specific activities of the lysosomal enzymes cathepsin D and glucosaminidase were reduced by hydrocortisone in all media, whereas the specific activity of creatine kinase increased when the medium contained insulin but decreased in the absence of insulin. It is concluded that hydrocortisone regulates cardiac protein balance via alterations both in synthesis and in degradation. Some of the hormone's myocardial effects are influenced by insulin so that hydrocortisone is anabolic in its presence but catabolic in its absence.     

Antibodies to Dopamine as Neuromodulators of Behavioral Responses of Mice of Different Genotypes

The possibility of long-term changes in the innate characteristics of the behaviour of mice of different genotypes (C57Bl/6 and BALB/c) after active immunization with dopamine-BSA conjugates was studied. These experiments revealed significant differences in the effects of anti-dopamine antibody on behavioral responses in an open field and neurotransmitter contents of brain structures in mice of different lines. Immunization with the dopamine-protein conjugate led to increases in the functional activity of the corresponding brain receptors, to different extents in mice of different lines.     

Effect of direct cardiac massage on peripheral blood erythrocytes

The effect of direct cardiac massage on peripheral blood erythrocytes is examined. A significant increase in the count of transitory reversible forms of erythrocytes is observed after 1 h of direct cardiac massage without no significant changes in the hemoglobin content, hematocrit, and erythrocyte and reticulocyte counts. It is concluded that direct cardiac massage produces less severe damage to erythrocytes than other means of assisted circulation. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 123, No. 3, pp. 353–356, March, 1997     

The effect of cardiac surgery on peripheral blood lymphocyte populations

BACKGROUND: Cardiac surgery using cardiopulmonary bypass (CPB) is associated with some adverse postoperative complications caused by an altered immune response. An alternative approach to cardiac surgery, operating without the use of CPB (i.e. off-pump surgery), seems to display less adverse impacts on the immune response. Patients and METHODS: Peripheral blood lymphocytes in 40 patients undergoing cardiac surgery either with CPB ("on-pump") or without CPB ("off-pump") were followed using flow cytometry. The samples of peripheral blood were taken at five intervals: preoperatively, after termination of the surgery, on the first, on the third and on the seventh postoperative day, respectively. RESULTS: The most substantial changes appeared on the first postoperative day in both subgroups of patients. While the percentage of both total T cells and CD4+ T cells were decreased, the percentage of HLA-DR+ activated lymphocytes was increased. These changes were more profound in the "on-pump" subgroup compared to the "off-pump" subgroup. CONCLUSION: Our results may suggest that the "off-pump" surgical approach reveals less adverse impact on adaptive immune responses.     

Disturbance of pro-oxidative/antioxidative balance in allogeneic peripheral blood stem cell transplantation

High dose chemotherapy causes increased free radical formation and depletion of tissue antioxidants. Whether allogeneic hematopoietic stem cell transplantation (HSCT) has an effect on oxidative stress is uncertain. The aims of the study were to determine the effect of allogeneic HSCT on plasma concentrations of antioxidants and oxidative stress biomarkers, and to investigate their relationships with graft-versus-host disease (GVHD), conditioning regimens, and transplant-related mortality (TRM) in patients with hematological malignancies. Patients (n=25) undergoing allogeneic HSCT from HLA-matched sibling donors were enrolled in the study. Plasma oxidant and antioxidant status were measured at day -1 before transplantation and 30 days after HSCT. In both myeloablative (n=14) and non-myeloablative (n=11) transplant groups, the mean levels of plasma malondialdehyde (MDA) and nitric oxide (NO) increased after allogeneic HSCT (p <0.01), whereas superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities decreased compared with baseline values (p <0.01). No significant relationships were found between either the pretransplant or post-transplant mean levels of the oxidative stress parameters and the existence of graft-versus-host disease (GVHD), the type of conditioning regimen, or transplant related mortality (TRM). This study documents a significant disturbance of pro-oxidative/antioxidative balance in the plasma of patients undergoing allogeneic HSCT regardless of the intensity of the conditioning regimen.     

Determination of cardiac risk by dipyridamole-thallium imaging before peripheral vascular surgery

To evaluate the severity of coronary artery disease in patients with severe peripheral vascular disease requiring operation, we performed preoperative dipyridamole-thallium imaging in 54 stable patients with suspected coronary artery disease. Of the 54 patients, 48 had peripheral vascular surgery as scheduled without coronary angiography, of whom 8 (17 per cent) had postoperative cardiac ischemic events. The occurrence of these eight cardiac events could not have been predicted preoperatively by any clinical factors but did correlate with the presence of thallium redistribution. Eight of 16 patients with thallium redistribution had cardiac events, whereas there were no such events in 32 patients whose thallium scan either was normal or showed only persistent defects (P less than 0.0001). Six other patients also had thallium redistribution but underwent coronary angiography before vascular surgery. All had severe multivessel coronary artery disease, and four underwent coronary bypass surgery followed by uncomplicated peripheral vascular surgery. These data suggest that patients without thallium redistribution are at a low risk for postoperative ischemic events and may proceed to have vascular surgery. Patients with redistribution have a high incidence of postoperative ischemic events and should be considered for preoperative coronary angiography and myocardial revascularization in an effort to avoid postoperative myocardial ischemia and to improve survival. Dipyridamole-thallium imaging is superior to clinical assessment and is safer and less expensive than coronary angiography for the determination of cardiac risk.     

Lower resting cardiac autonomic balance in young adults with current major depression

Research on cardiac autonomic function in major depressive disorder (MDD) has predominantly examined cardiac vagal control and adopted a model of reciprocal autonomic balance. A proposed bivariate autonomic continuum uses cardiac autonomic balance (CAB) and cardiac autonomic regulation (CAR) models, derived from normalized values of respiratory sinus arrhythmia and pre‐ejection period, to more adequately index patterns of autonomic control. The purpose of this study was to assess resting levels of CAB and CAR among young adults with and without a current diagnosis of major depression. One hundred forty‐two young adults (n = 65 MDD, n = 77 healthy controls; 20.8 ± 2.6 years) completed a structured diagnostic interview, cardiovascular assessment, and a maximal aerobic fitness test. The findings revealed that CAB, but not CAR, significantly predicted current MDD status (OR = 0.70, 95% CI [0.53, 0.93]), an effect that remained after controlling for aerobic fitness and body mass index. Although CAB was found to be a significant predictor of current MDD status among a sample of young adults, there remained substantial variation in autonomic control that was not captured by the traditional model of reciprocal autonomic balance.     

Normal T-helper 1/T-helper 2 balance in peripheral blood of coeliac disease patients

Activated T cells, with their secretion of cytokines, probably play an important role in the pathogenesis of mucosal lesions in coeliac disease (COD) and the prominence of a T-helper (Th)1-type cytokine pattern has been reported. As the process of immunological activation in the jejunal mucosa in active CoD has been shown to also cause some differences in peripheral blood lymphocyte populations, we sought to establish any changes in the Th 1/Th2 balance in peripheral blood of patients, at different stages of CoD, relative to healthy individuals. Twenty-two CoD patients and 10 healthy controls were included in the study. The Th1/Th2 balance was examined both in resting cells and after polyclonal stimulation using two different methods: intracytoplasmic cytokine contents were measured using an intracellular staining method and three-colour flow cytometry and cytokine contents of cell culture supernatants were measured using traditional enzyme-linked immunosorbent assays (ELISAs). Interferon-gamma (IFN-gamma)-producing cells (Thl) were as prominent in untreated CoD patients and treated CoD patients as in healthy controls, while cells fitting a Th2 or ThO-type cytokine pattern were few in all groups. In ELISA assays, Th1 type (IFN-gamma or interleukin (IL)-2) cytokines were again prominent in all study groups but no statistically significant differences were found in IFN-gamma, IL-4 or IL-2 levels among the three groups. These results suggest that the increased shift towards a Th1 response is mainly restricted to the actual site of inflammation and that circulating T cells do not show a similar response, presumably because activated cells in peripheral blood are too few. Further research on cytokine profiles measuring T-cell activation in CoD should be focused on the actual tissue of inflammation.     

Coronary arterial predominance or balance on the surface of the human cardiac ventricles.

Normal hearts obtained from suicide victims were studied after injection of gelatin containing red or blue pigment and a radiopaque substance into each coronary artery. Schlesinger's types of coronary artery unilateral predominance or bilateral balance were identified and their incidence determined. The relation to general factors of anatomical variation was also pointed out. Physiologic and clinical features were discussed on the basis of the morphologic pattern, diverse results recorded in the literature were pointed out, and some discrepancies explained. Hearts with right coronary artery predominance (73.5%) prevailed over left predominance (19.4%) and over the balanced hearts (7.1%). An evaluation of both the blood supply and drainage of the heart as a whole, not restricted to the superficial parietal arteries of the ventricles, would better meet the requirements of clinical cardiology.