Elton L. Ferlin

Inspiratory muscle training improves blood flow to resting and exercising limbs in patients with chronic heart failure.

OBJECTIVES We tested the hypothesis that inspiratory muscle loading could result in exaggerated peripheral vasoconstriction in resting and exercising limbs and that inspiratory muscle training (IMT) could attenuate this effect in patients with chronic heart failure (CHF) and inspiratory muscle weakness. BACKGROUND Inspiratory muscle training improves functional capacity of patients with CHF, but the mechanisms of this effect are unknown. METHODS Eighteen patients with CHF and inspiratory muscle weakness (maximal inspiratory pressure <70% of predicted) and 10 healthy volunteers participated in the study. Inspiratory muscle loading was induced by the addition of inspiratory resistance of 60% of maximal inspiratory pressure, while blood flow to the resting calf (CBF) and exercising forearm (FBF) were measured by venous occlusion plethysmography. For the patients with CHF, blood flow measurements as well as ultrasound determination of diaphragm thickness were made before and after a 4-week program of IMT. RESULTS With inspiratory muscle loading, CHF patients demonstrated a more marked reduction in resting CBF and showed an attenuated rise in exercising FBF when compared with control subjects. After 4 weeks of IMT, CHF patients presented hypertrophy of the diaphragm and improved resting CBF and exercise FBF with inspiratory muscle loading. CONCLUSIONS In patients with CHF and inspiratory muscle weakness, inspiratory muscle loading results in marked reduction of blood flow to resting and exercising limbs. Inspiratory muscle training improves limb blood flow under inspiratory loading in these patients.

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.

Relationship between cardiovascular dysfunction and hyperglycemia in streptozotocin-induced diabetes in rats

Streptozotocin (STZ)-induced diabetes in rats is characterized by cardiovascular dysfunction beginning 5 days after STZ injection, which may reflect functional or structural autonomic nervous system damage. We investigated cardiovascular and autonomic function, in rats weighing 166 +/- 4 g, 5-7, 14, 30, 45, and 90 days after STZ injection (N = 24, 33, 27, 14, and 13, respectively). Arterial pressure (AP), mean AP (MAP) variability (standard deviation of the mean of MAP, SDMMAP), heart rate (HR), HR variability (standard deviation of the normal pulse intervals, SDNN), and root mean square of successive difference of pulse intervals (RMSSD) were measured. STZ induced increased glycemia in diabetic rats vs control rats. Diabetes reduced resting HR from 363 +/- 12 to 332 +/- 5 bpm (P < 0.05) 5 to 7 days after STZ and reduced MAP from 121 +/- 2 to 104 +/- 5 mmHg (P = 0.007) 14 days after STZ. HR and MAP variability were lower in diabetic vs control rats 30-45 days after STZ injection (RMSSD decreased from 5.6 +/- 0.9 to 3.4 +/- 0.4 ms, P = 0.04 and SDMMAP from 6.6 +/- 0.6 to 4.2 +/- 0.6 mmHg, P = 0.005). Glycemia was negatively correlated with resting AP and HR (r = -0.41 and -0.40, P < 0.001) and with SDNN and SDMMAP indices (r = -0.34 and -0.49, P < 0.01). Even though STZ-diabetic rats presented bradycardia and hypotension early in the course of diabetes, their autonomic function was reduced only 30-45 days after STZ injection and these changes were negatively correlated with plasma glucose, suggesting a metabolic origin.

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.

Time course of changes in heart rate and blood pressure variability in streptozotocin-induced diabetic rats treated with insulin

Autonomic neuropathy is a frequent complication of diabetes associated with higher morbidity and mortality in symptomatic patients, possibly because it affects autonomic regulation of the sinus node, reducing heart rate (HR) variability which predisposes to fatal arrhythmias. We evaluated the time course of arterial pressure and HR and indirectly of autonomic function (by evaluation of mean arterial pressure (MAP) variability) in rats (164.5 +/- 1.7 g) 7, 14, 30 and 120 days after streptozotocin (STZ) injection, treated with insulin, using measurements of arterial pressure, HR and MAP variability. HR variability was evaluated by the standard deviation of RR intervals (SDNN) and root mean square of successive difference of RR intervals (RMSSD). MAP variability was evaluated by the standard deviation of the mean of MAP and by 4 indices (P1, P2, P3 and MN) derived from the three-dimensional return map constructed by plotting MAPn x [(MAPn + 1)-(MAPn)] x density. The indices represent the maximum concentration of points (P1), the longitudinal axis (P2), and the transversal axis (P3) and MN represents P1 x P2 x P3 x 10(-3). STZ induced increased urinary glucose in diabetic (D) rats compared to controls (C). Seven days after STZ, diabetes reduced resting HR from 380.6 +/- 12.9 to 319.2 +/- 19.8 bpm, increased HR variability, as demonstrated by increased SDNN, from 11.77 +/- 1.67 to 19.87 +/- 2.60 ms, did not change MAP, and reduced P1 from 61.0 +/- 5.3 to 51.5 +/- 1.8 arbitrary units (AU), P2 from 41.3 +/- 0.3 to 29.0 +/- 1.8 AU, and MN from 171.1 +/- 30.2 to 77.2 +/- 9.6 AU of MAP. These indices, as well as HR and MAP, were similar for D and C animals 14, 30 and 120 days after STZ. Seven-day rats showed a negative correlation of urinary glucose with resting HR (r = -0.76, P = 0.03) as well as the MN index (r = -0.83, P = 0.01). We conclude that rats with short-term diabetes mellitus induced by STZ presented modified autonomic control of HR and MAP which was reversible. The metabolic control may influence these results, suggesting that insulin treatment and a better metabolic control in this model may modify arterial pressure, HR and MAP variability.

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.