Ruy S. Moraes

Sympathetic nervous system representation in time and frequency domain indices of heart rate variability

Abstract This study evaluated the contributions of sympathetic and parasympathetic modulation to heart rate variability during situations in which vagal and sympathetic tone predominated. In a placebo-controlled, randomized, double blind blockade study, six young healthy male individuals received propranolol (0.2 mg · kg−1), atropine (0.04 mg · kg−1), propranolol plus atropine, or placebo infusions over 4 days. Time-domain indices were calculated during 40 min of rest and 20 min of exercise at 70% of maximal exercise intensity. Spectrum analysis, using fast Fourier transformation, was also performed at rest and during the exercise. The time-domain indices standard deviation of R-R intervals, mean of the standard deviations of all R-R intervals for all 5-min segments, percentage of number of pairs of adjacent R-R intervals differing by more than 50 ms, and square root of the mean of the sum of squares of differences between adjacent R-R intervals were reduced after atropine and propranolol plus atropine. Propranolol alone caused no appreciable change in any of the time-domain indices. At rest, all spectrum components were similar after placebo and propranolol infusions, but following parasympathetic and double autonomic blockade there was a reduction in all components of the spectrum analysis, except for the low:high ratio. During exercise, partial and double blockade did not change significantly any of the spectrum components. Thus, time and frequency-domain indices of heart rate variability were able to detect vagal activity, but could not detect sympathetic activity. During exercise, spectrum analysis is not capable of evaluating autonomic modulation of heart rate.

Cholinergic stimulation with pyridostigmine reduces ventricular arrhythmia and enhances heart rate variability in heart failure.

BACKGROUND Increased ventricular arrhythmia density and reduced heart rate variability are associated with risk of death in patients with heart failure. Cholinesterase inhibition with pyridostigmine bromide increases heart rate variability in normal subjects, but its effect on patients with heart failure is unknown. In this study, we tested the hypothesis that short-term administration of pyridostigmine bromide, a cholinesterase inhibitor, reduces ventricular arrhythmia density and increases heart rate variability in patients with congestive heart failure. METHODS Patients with heart failure and in sinus rhythm participated in a double-blind, cross-over protocol, randomized for placebo and pyridostigmine (30 mg orally 3 times daily for 2 days). Twenty-four hour electrocardiographic recordings were performed for arrhythmia analysis and for the measurement of time domain indices of heart rate variability. Patients were separated into 2 groups, according to their ventricular arrhythmia density. The arrhythmia group (n = 11) included patients with >10 ventricular premature beats (VPBs) per hour (VPBs/h), and the heart rate variability group (n = 12) included patients with a number of VPBs in 24 hours not exceeding 1% of the total number of R-R intervals. RESULTS For the arrhythmia group, pyridostigmine resulted in a 65% reduction of ventricular ectopic activity (placebo 266 +/- 56 VPBs/h vs pyridostigmine 173 +/- 49 VPBs/h, P =.03). For the heart rate variability group, pyridostigmine administration increased mean R-R interval (placebo 733 +/- 22 ms vs pyridostigmine 790 +/- 33 ms, P =.01), and in the time domain indices of heart rate variability root-mean-square of successive differences (placebo 21 +/- 2 ms vs pyridostigmine 27 +/- 3 ms, P =.01) and percentage of pairs of adjacent R-R intervals differing by >50 ms (placebo 3% +/- 1% vs pyridostigmine 6% +/- 2%, P =.03). CONCLUSION In patients with heart failure, pyridostigmine reduced ventricular arrhythmia density and increased heart rate variability, most likely due to its cholinomimetic effect. Long-term trials with pyridostigmine in heart failure should be conducted.

Enhancement of heart rate variability by cholinergic stimulation with pyridostigmine in healthy subjects

The purpose of this study was to determine the effect of the oral administration of pyridostigmine bromide on indices of heart rate variability (HRV) in healthy young volunteers. Seventeen healthy participants (11 men, 6 women; aged 27±8 y) submitted to a randomized, crossover, double-blind protocol, in which they received 30 mg pyridostigmine bromide (PYR) or placebo orally at 8-hour intervals for 24 hours, on two separate days. Venous blood samples were collected 2 and 24 hours after the first dose for determination of serum cholinesterase activity. Holter tapes were recorded during the 24-hour period and analyzed using a semiautomatic technique to evaluate time- and frequency-domain indices of HRV and to build three-dimensional return maps for later quantification. Symptoms were mild and occurred similarly during administration of PYR and placebo (p=0.140). Serum cholinesterase activity was reduced by 15% at 2 hours (p=0.013) and by 14% at 24 hours (p=0.010) after the first dose of PYR, but not after administration of placebo. Pyridostigmine administration caused a significant increase in the mean 24-hour R-R interval (placebo: 814±20 msec; PYR: 844±18 msec; p=0.003) and in time-domain indices of HRV, such as the standard deviation of all R-R intervals (SDNN; placebo: 151±9 msec; PYR: 164 ±9 msec; p=0.017), and the percentage of pairs of adjacent R-R intervals differing by more than 50 msec (pNN50; placebo: 12.8±1.8%; PYR: 13.9±1.5%; p=0.029). Pyridostigmine had no significant effect on frequency-domain indices of HRV, but resulted in significant increase in P2, a parasympathetic index derived from the three-dimensional return map (placebo: 93±13 msec; PYR: 98±13 ms; p=0.029). In conclusion, low-dose pyridostigmine reduced mean heart rate and increased HRV during a 24-hour period in healthy young subjects.

Three-dimensional return map : a new tool for quantification of heart rate variability

BACKGROUND Several methods are used to study heart rate variability, but they have limitations, which might be overcome by the use of a three-dimensional return map. OBJECTIVES To evaluate the performance of three-dimensional return map-derived indices to detect (1) sympathetic and parasympathetic modulation to the sinus node and (2) autonomic dysfunction in diabetic patients. METHODS Six healthy subjects underwent partial and total pharmacological autonomic blockade in a protocol that incorporated vagal and sympathetic predominance. Twenty-two patients with type 2 diabetes mellitus and 12 normal controls participated in the subsequent validation experiment. Three-dimensional return maps were constructed by plotting RRn intervals versus the difference between adjacent RR intervals [(RRn+1)-(RRn)] versus the number of counts, and four derived indices (P1, P2, P3, MN) were created for quantification. RESULTS Both indices P1 and MN were significantly increased after sympathetic blockade with propranolol, while all indices except P1 were modified after parasympathetic blockade (P < 0.05). During the validation experiments, P1 and MN detected differences between normal controls, and diabetic patients with and without autonomic neuropathy. The overall accuracy of most three-dimensional indices to detect autonomic dysfunction, estimated by the area under the ROC curve, was significantly better than traditional time domain indices. Three-dimensional return map-derived indices also showed adequate reproducibility on two different recording days (intra-class correlation coefficients of 0.69 to 0.82; P < 0.001). CONCLUSIONS Three-dimensional return map-derived indices are reproducible, quantify parasympathetic as well as sympathetic modulation to the sinus node, and are capable of detecting autonomic dysfunction in diabetic patients.

Hormone replacement therapy does not affect the 24-hour heart rate variability in postmenopausal women : Results of a randomized, placebo-controlled trial with two regimens

Postmenopausal women are at greater risk of coronary heart disease. The results of previous studies of the effects of hormone replacement therapy (HRT) on cardiac autonomic modulation in postmenopausal women have been contradictory. This study examined whether continuous treatment for 3 months with estradiol alone (ERT) or with estradiol plus norethisterone (HRT), increases 24‐hour heart rate variability (HRV) in postmenopausal women. In this double‐blind, placebo‐controlled trial, 40 healthy postmenopausal women, 46–63 years of age, were randomly assigned to (1) continuous 2 mg of estradiol plus 1 mg of norethisterone acetate daily (HRT, n = 13), or (2) 2 mg of estradiol daily (ERT, n = 14), or (3) placebo (n = 13). Before and after 3 months of therapy, blood estradiol concentrations were measured and 24‐hour electrocardiograms recorded for evaluation of 24‐hour time‐domain indices of HRV, and indices derived from the three‐dimensional return map. Both hormone replacement regimens significantly increased blood estradiol concentrations, while no change occurred in the placebo group. In the three treatment groups, multiple 24‐hour time‐domain indices of HRV and indices derived from the three‐dimensional return map remained unchanged. In healthy postmenopausal women, HRT with estradiol or estradiol and norethisterone for 3 months did not modify cardiac autonomic activity evaluated by 24‐hour indices of HRV. These findings are consistent with a lack of protective cardiovascular effect of HRT described in recent large randomized trials.

Atrial automaticity and atrioventricular conduction in athletes: contribution of autonomic regulation

Abstract Little is known about the sinoatrial automatism and atrioventricular conduction of trained individuals who present a normal resting electrocardiogram. We used transesophageal atrial stimulation, a minimally invasive technique, to evaluate aerobically trained athletes (n=10) and sedentary individuals (n=10) with normal resting electrocardiograms, to test the hypothesis that parasympathetic tone, as detected by heart rate variability, could be associated with changes in sinoatrial automatism and atrioventricular conduction. Corrected sinus node recovery time tended to be longer in athletes than in sedentary individuals, but this difference did not reach statistical significance. The Wenckebach point occurred at a lower rate in athletes than in the controls. Over a 24-h period of measurement, the mean RR interval was longer in the athletes than in the sedentary individuals. The mean square root of successive differences (rMSSD) tended to be higher in athletes than in controls, but this difference did not reach statistical significance. There was a moderate correlation (r=0.48, P < 0.05) between the index of atrioventricular conduction, the rate at the Wenckebach point, and the logarithmically transformed rMSSD. Thus, as a corollary to its effects on the sinus node, where increased parasympathetic tone, decreased sympathetic tone, and non-autonomic components may contribute to sinus bradycardia, it is possible that athletic training may also induce intrinsic adaptations in the conduction system, which could contribute to the higher prevalence of atrioventricular conduction abnormalities observed in athletes.

Inspiratory Muscle Training in Type 2 Diabetes with Inspiratory Muscle Weakness

PURPOSE Patients with type 2 diabetes mellitus may present weakness of the inspiratory muscles. We tested the hypothesis that inspiratory muscle training (IMT) could improve inspiratory muscle strength, pulmonary function, functional capacity, and autonomic modulation in patients with type 2 diabetes and weakness of the inspiratory muscles. METHODS Maximal inspiratory muscle pressure (PImax) was evaluated in a sample of 148 patients with type 2 diabetes. Of these, 25 patients with PImax<70% of predicted were randomized to an 8-wk program of IMT (n=12) or placebo-IMT (n=13). PImax, inspiratory muscle endurance time, pulmonary function, peak oxygen uptake, and HR variability were evaluated before and after intervention. RESULTS The prevalence of inspiratory muscle weakness was 29%. IMT significantly increased the PImax (118%) and the inspiratory muscle endurance time (495%), with no changes in pulmonary function, functional capacity, or autonomic modulation. There were no significant changes with placebo-IMT. CONCLUSIONS Patients with type 2 diabetes may frequently present inspiratory muscle weakness. In these patients, IMT improves inspiratory muscle function with no consequences in functional capacity or autonomic modulation.

Acute ingestion of alcohol and cardiac autonomic modulation in healthy volunteers

Arrhythmogenic effects of alcohol may be intermediated by its effects over heart rate variability (HRV). Most studies about the effects of alcohol over HRV were observational and did not explore the temporal influence of alcohol ingestion over autonomic modulation. The aim of this study was to verify if an acute ingestion of alcohol has a time-dependent influence over time-domain indices of HRV. The effect of the ingestion of 60 g of ethanol or placebo over autonomic modulation was compared in healthy men (35 per group), with 18-25 years of age, before and during 17 h after ingestion. Alcohol promoted a fall in the standard deviation of all normal R-R intervals, root mean square of successive differences, and percentage of pairs of adjacent R-R intervals differing by more than 50 ms and in two indices of the three-dimensional return map, by a period up to 10 h after the ingestion of alcohol, accompanied by an increase in heart rate. The indices returned to values similar of the control group 10 h after ingestion. The effects over HRV indices were attenuated by adjustment for heart rate. The ingestion of alcohol induces a broad cardiovascular adaptation secondary to vagal withdrawal and sympathetic activation that may be responsible for arrhythmogenic effects of alcohol ingestion.

Short-term folinic acid supplementation improves vascular reactivity in HIV-infected individuals: A randomized trial

OBJECTIVE HIV-infected individuals present a cluster of conditions that activate or injure the vascular endothelium. The administration of folates may exert beneficial effects on endothelial function in different populations at risk for cardiovascular disease. The aim of this study was to determine the effects of 4 wk of folinic acid supplementation on forearm vascular responses during reactive hyperemia in HIV-infected patients under highly active antiretroviral therapy. METHODS This was a prospective, randomized, double-blind, placebo-controlled trial to compare the effects of 4 wk of daily ingestion of 5 mg of folinic acid (n = 15) or placebo (n = 15). Participants had to have been on antiretroviral therapy (ART) for at least 6 mo before enrollment, with undetectable viral load, and CD4 cell count >200 cells/mm(3). Vascular function was evaluated with venous occlusion plethysmography at baseline and after 4 wk, for the determination of brachial artery reactive hyperemia, and after isosorbide dinitrate administration. RESULTS The groups were comparable. The mean age of patients was 45 y; there were eight women in each group. There was no difference regarding ART regimen. The supplementation of folinic acid produced a significant improvement in reactive hyperemia (from 14.9 to 21.2 mL•min•100 mL). The same was not observed in placebo group (from 15.3 to 14.6 mL•min•100 mL; group P, 0.017; time P < 0.001; interaction P < 0.001). Endothelium-independent responses remained unchanged. CONCLUSIONS Short-term folinic acid supplementation improved vascular reactivity in HIV-infected individuals enrolled in the studied. As folate supplementation is safe and relatively inexpensive, long-term clinical trials should be conducted.

Autonomic modulation in patients with congenital generalized lipodystrophy (Berardinelli-Seip syndrome)

AIMS This study was designed to assess cardiac autonomic regulation in congenital generalized lipodystrophy (CGL) patients using 24 h heart rate variability (HRV). METHODS AND RESULTS A cross-sectional study was carried out to evaluate 18 patients with CGL and 19 healthy controls matched by sex and age. We measured blood pressure, plasma concentrations of glucose, triglycerides, cholesterol, high-density lipoprotein-cholesterol, insulin resistance by the homeostatic model assessment (HOMA-R), left ventricular mass (LVM) (by two-dimensional echocardiography), and 24 h HRV (by the time domain indices MeanRR, SDNN, and rMSSD). Compared with controls, CGL patients had higher blood pressure (systolic, 131.1 vs. 106.3 mmHg, P < 0.05; diastolic, 85.0 vs. 68.2 mmHg, P < 0.05) and 10 patients met criteria for arterial hypertension and concentric left ventricular hypertrophy (LVM index > or =115 g/m(2)and relative left ventricular wall thickness > or =0.42). Patients with CGL had higher levels of glucose, triglycerides, cholesterol, and HOMA-R and 12 met criteria for type 2 diabetes mellitus. Compared with controls, CGL patients had lower MeanRR (639.8 vs. 780.5 ms, P < 0.001), SDNN (79.2 vs. 168.5 ms, P < 0.001), and rMSSD (15.8 vs. 59.6 ms, P < 0.001). In CGL patients, the reduction in HRV was independent of the metabolic and haemodynamic disturbances. CONCLUSION Congenital generalized lipodystrophy patients have abnormal autonomic modulation, reflected by increased heart rate and pronounced reduction in HRV, independent of the metabolic and haemodynamic disturbances observed in this disorder.