Pedro Paulo Soares

Coronary artery bypass surgery and longitudinal evaluation of the autonomic cardiovascular function

IntroductionImbalance in autonomic cardiovascular function increases the risk for sudden death in patients with coronary artery disease (CAD), but the time course of the impact of coronary artery bypass grafting (CABG) on autonomic function has been little studied. Thus, the purpose of the present study was to determine the effects of the CABG on the cardiovascular autonomic function.MethodsPatients undergoing CABG (n = 13) and two matched control groups (patients with CAD who refused surgical treatment [n = 9], and healthy volunteers [n = 9]) underwent a prospective longitudinal study consisting of autonomic evaluation before and after (3, 6, 15, 30, 60, and 90 days) surgery, including measurement of heart rate variability (HRV), respiratory sinus arrhythmia (RSA), and Valsalva maneuver.ResultsAfter CABG there was a decrease in, and a later recovery of, (1) the HRV in the time domain and in the frequency domain, (2) RSA, and (3) Valsalva maneuver.ConclusionsCABG caused an impairment, reversible after 60 days, of cardiovascular autonomic function, with a maximal decrease on about the sixth day after surgery.

Transcranial direct current stimulation influences the cardiac autonomic nervous control

To investigate whether the manipulation of brain excitability by transcranial direct current stimulation (tDCS) modulates the heart rate variability (HRV), the effect of tDCS applied at rest on the left temporal lobe in athletes (AG) and non-athletes (NAG) was evaluated. The HRV parameters (natural logarithms of LF, HF, and LF/HF) was assessed in 20 healthy men before, and immediately after tDCS and sham stimulation. After anodal tDCS in AG the parasympathetic activity (HF(log)) increased (P<0.01) and the sympathetic activity (LF(log)) and sympatho-vagal balance (LF/HF(log)) decreased (P<0.01), whereas no significant effects were detected in NAG (P>0.05). No significant changes in HRV indexes were provoked by sham stimulation in both AG and NAG (P>0.05). In conclusion, tDCS applied on the left temporal lobe significantly increased the overall HRV in AG, enhancing the parasympathetic and decreasing the sympathetic modulation of heart rate. Consequently the sympatho-vagal balance decreased at rest in AG but not in NAG. Releasing a weak electric current to stimulate selected brain areas may induce favorable effects on the autonomic control to the heart in highly fit subjects.

Time-dependent effects of training on cardiovascular control in spontaneously hypertensive rats: role for brain oxidative stress and inflammation and baroreflex sensitivity.

Baroreflex dysfunction, oxidative stress and inflammation, important hallmarks of hypertension, are attenuated by exercise training. In this study, we investigated the relationships and time-course changes of cardiovascular parameters, pro-inflammatory cytokines and pro-oxidant profiles within the hypothalamic paraventricular nucleus of the spontaneously hypertensive rats (SHR). Basal values and variability of arterial pressure and heart rate and baroreflex sensitivity were measured in trained (T, low-intensity treadmill training) and sedentary (S) SHR at weeks 0, 1, 2, 4 and 8. Paraventricular nucleus was used to determine reactive oxygen species (dihydroethidium oxidation products, HPLC), NADPH oxidase subunits and pro-inflammatory cytokines expression (Real time PCR), p38 MAPK and ERK1/2 expression (Western blotting), NF-κB content (electrophoretic mobility shift assay) and cytokines immunofluorescence. SHR-S vs. WKY-S (Wistar Kyoto rats as time control) showed increased mean arterial pressure (172±3 mmHg), pressure variability and heart rate (358±7 b/min), decreased baroreflex sensitivity and heart rate variability, increased p47phox and reactive oxygen species production, elevated NF-κB activity and increased TNF-α and IL-6 expression within the paraventricular nucleus of hypothalamus. Two weeks of training reversed all hypothalamic changes, reduced ERK1/2 phosphorylation and normalized baroreflex sensitivity (4.04±0.31 vs. 2.31±0.19 b/min/mmHg in SHR-S). These responses were followed by increased vagal component of heart rate variability (1.9-fold) and resting bradycardia (−13%) at the 4th week, and, by reduced vasomotor component of pressure variability (−28%) and decreased mean arterial pressure (−7%) only at the 8th week of training. Our findings indicate that independent of the high pressure levels in SHR, training promptly restores baroreflex function by disrupting the positive feedback between high oxidative stress and increased pro-inflammatory cytokines secretion within the hypothalamic paraventricular nucleus. These early adaptive responses precede the occurrence of training-induced resting bradycardia and blood pressure fall.

Parasympathetic dysfunction is associated with baroreflex and chemoreflex impairment in streptozotocin-induced diabetes in rats

This study explored physiological mechanisms of diabetic dysfunction in baroreceptors and chemoreceptors-mediated hemodynamic responses, and cholinergic neurotransmission in 30-day diabetic rats (n = 14) and controls (n = 14). Basal hemodynamic data and vagal response to electrical stimulation and methacholine injection were also evaluated. Muscarinic receptors were characterized using a radioligand receptor binding assay ([3H]N methylscopolamine). Experimental diabetes (50 mg/kg of STZ, i.v.) decreased systolic, diastolic, and mean arterial pressure and basal heart rate. Heart rate (HR) responses to vagal electrical stimulation (16, 32, and 64 Hz) were 15%, 11%, and 14% higher in diabetics vs non-diabetics, as were HR responses to methacholine injection (-130+/-24, -172+/-18, -206+/-15 bpm vs. -48+/-15, -116+/-12, -151+/-18 bpm, P < 0.05). Muscarinic receptor density was higher (267.4+/-11 vs 193.5+/-22 fmol/mg/prot, P < 0.05) in the atria of diabetic rats than in those of controls; the affinity was similar between groups. Diabetes-induced reduction of reflex responses to baro- (reflex bradycardia: -3.4+/-0.3 and -2.7+/-0.2 bpm/mm Hg; reflex tachycardia: -1.6+/-0.1 and -1.4+/-0.07 bpm/mm Hg, in control and diabetics, P < 0.05) and chemoreceptor stimulation, enhancement of HR responsiveness to cardiac vagal electrical stimulation and methacholine stimulation, plus an increase in the number of atrial muscarinic receptors indicates reduced parasympathetic activity, which is probably derived from central nervous system derangement.

Cholinergic stimulation with pyridostigmine blunts the cardiac responses to mental stress

Mental stress may induce myocardial ischemia and ventricular arrhythmia in patients with coronary artery disease, and cholinergic stimulation is a potential protective mechanism. The purpose of this study was to determine the effect of pyridostigmine bromide (PYR), a reversible cholinesterase inhibitor, on the cardiac responses to a mental stress challenge. Twelve healthy young volunteers were submitted to a mental stress test (arithmetic test) 2 hours after the oral administration of either placebo or PYR (45 mg) on two separate days, following a randomized crossover double-blind protocol. Heart rate was reduced after both placebo and PYR (p<0.05), but the cardiac responses to the mental stress were lower with PYR (p<0.05): mean RR interval (mean±SE)—placebo: 730±19 msec; PYR: 769±21 msec; Peak systolic pressure-placebo: 129±4 mmHg; PYR: 124±3 mmHg; Peak diastolic pressure-placebo: 92±3 mmHg; PYR: 89±4 mmHg; Mean ratepressure product-placebo: 10,496±412 bpm×mmHg; PYR: 9,746±383 bpm×mmHg. In conclusion, 45 mg of pyridostigmine blunted the pressor and chronotropic responses to mental stress in healthy young subjects.

Cholinergic stimulation with pyridostigmine improves autonomic function in infarcted rats

In the present study we evaluated the effects of short‐term pyridostigmine bromide (0.14 mg/mL) treatment started early after myocardial infarction (MI) on left ventricular (LV) and autonomic functions in rats. Male Wistar rats were divided into control, pyridostigmine, infarcted and infarcted + pyridostigmine‐treated groups. Pyridostigmine was administered in the drinking water, starting immediately after MI or sham operation, for 11 days. Left ventricular function was evaluated indirectly by echocardiography and directly by LV catheterization. Cardiovascular autonomic control was evaluated by baroreflex sensitivity (BRS), heart rate variability (HRV) and pharmacological blockade. All evaluations started after 7 days pyridostigmine treatment and were finalized after 11 days treatment. Pyridostigmine prevented the impairment of +dP/dT and reduced the MI area in infarcted + pyridostigmine compared with infarcted rats (7 ± 3% vs 17 ± 4%, respectively). Mean blood pressure was restored in infarcted + pyridostigmine compared with infarcted rats (103 ± 3 vs 94 ± 3 mmHg, respectively). In addition, compared with the infarcted group, pyridostigmine improved BRS, as evaluated by tachycardic (1.6 ± 0.2 vs 2.5 ± 0.2 b.p.m./mmHg, respectively) and bradycardic (−0.42 ± 0.01 vs −1.9 ± 0.1 b.p.m./mmHg) responses, and reduced the low frequency/high frequency ratio of HRV (0.81 ± 0.11 vs 0.24 ± 0.14, respectively). These improvements are probably associated with increased vagal tone and reduced sympathetic tone in infarcted + pyridostigmine compared with infarcted rats. In conclusion, the data suggest that short‐term pyridostigmine treatment started early after MI can improve BRS, HRV and parasympathetic and sympathetic tone in experimental rats. These data may have potential clinical implications because autonomic markers have prognostic significance after MI.

Subacute effects of a maximal exercise bout on endothelium-mediated vasodilation in healthy subjects

We evaluated vascular reactivity after a maximal exercise test in order to determine whether the effect of exercise on the circulation persists even after interruption of the exercise. Eleven healthy sedentary volunteers (six women, age 28 +/- 5 years) were evaluated before and after (10, 60, and 120 min) a maximal exercise test on a treadmill. Forearm blood flow (FBF) was measured by venous occlusion plethysmography before and during reactive hyperemia (RH). Baseline FBF, analyzed by the area under the curve, increased only at 10 min after exercise (P = 0.01). FBF in response to RH increased both at 10 and 60 min vs baseline (P = 0.004). Total excess flow for RH above baseline showed that vascular reactivity was increased up to 60 min after exercise (mean +/- SEM, before: 526.4 +/- 48.8; 10 min: 1053.0 +/- 168.2; 60 min: 659.4 +/- 44.1 ml 100 ml(-1) min(-1) . s; P = 0.01 and 0.02, respectively, vs before exercise). The changes in FBF were due to increased vascular conductance since mean arterial blood pressure did not change. In a time control group (N = 5, 34 +/- 3 years, three women) that did not exercise, FBF and RH did not change significantly (P = 0.07 and 0.7, respectively). These results suggest that the increased vascular reactivity caused by chronic exercise may result, at least in part, from a summation of the subacute effects of successive exercise bouts.

Electrocardiographic criteria for vagotonia—validation with pharmacological parasympathetic blockade in healthy subjects

BACKGROUND The importance of vagal tone on cardiac function and cardiovascular mortality is well established. Although the presence of an enhanced cardiac vagal tone (CVT) is frequently diagnosed using the 12-lead resting electrocardiogram (ECG) in daily practice, most of the proposed criteria have been determined on an empirical basis. Our objective was to evaluate the effects of pharmacological blockade of the parasympathetic component of the autonomic nervous system on resting ECG tracings. METHODS Nine healthy young adults (24+/-5 year-old) underwent parasympathetic blockade with atropine sulfate i.v. (0.04 mg kg(-1)) and resting ECGs were obtained before and 15 min thereafter. CVT was assessed by a dimensionless index, which measures the RR interval reduction caused by the vagal withdrawal induced by a 4-s exercise test performed on a cycle ergometer where the subjects pedal as fast as possible with no added resistance. RESULTS This index was 1.63+/-0.24 and 1.03+/-0.03, before and after atropine, respectively (P<0.0001). Atropine reduced the R-R intervals (P<0.0001), and the amplitude of T-waves in several leads (DII: P=0.03; V4: P=0.04; V5: P=0.03; V6: P=0.01), and abolished the appiculation of T-waves, J-point and ST-segment elevations (P<0.05), and U-waves (P<0.05), which were present in baseline ECG in all subjects in at least two leads. The R-wave amplitude in leads V4, V5, and V6 (all P>/=0.10) was not modified by atropine infusion. CONCLUSION The duration of the R-R intervals and the amplitude of T-waves in leads DII, V4, V5, and V6, and the presence of T-wave appiculation, U-waves, and elevation of J-point and ST-segment should be used to detect enhanced cardiac vagal tone in healthy subjects.

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

Exercise training (ExT) is recommended to treat hypertension along with pharmaceutical antihypertensive therapies. Effects of ExT in hypothalamic content of high mobility box 1 (HMGB1) and microglial activation remain unknown. We examined whether ExT would decrease autonomic and cardiovascular abnormalities in spontaneously hypertensive rats (SHR), and whether these effects were associated with decreased HMGB1 content, microglial activation, and inflammation in the hypothalamic paraventricular nucleus (PVN). Normotensive Wistar-Kyoto (WKY) rats and SHR underwent moderate-intensity ExT for 2 wk. After ExT, cardiovascular (heart rate and arterial pressure) and autonomic parameters (arterial pressure and heart rate variability, peripheral sympathetic activity, cardiac vagal activity, and baroreflex function) were measured in conscious and freely-moving rats through chronic arterial and venous catheterization. Cerebrospinal fluid, plasma, and brain were collected for molecular and immunohistochemistry analyses of the PVN. In addition to reduced heart rate variability, decreased vagal cardiac activity and increased mean arterial pressure, heart rate, arterial pressure variability, cardiac, and vasomotor sympathetic activity, SHR had higher HMGB1 protein expression, IκB-α phosphorylation, TNF-α and IL-6 protein expression, and microglia activation in the PVN. These changes were accompanied by higher plasma and cerebrospinal fluid levels of HMGB1. The ExT + SHR group had decreased expression of HMGB1, CXCR4, SDF-1, and phosphorylation of p42/44 and IκB-α. ExT reduced microglial activation and proinflammatory cytokines content in the PVN, and improved autonomic control as well. Data suggest that training-induced downregulation of activated HMGB1/CXCR4/microglia/proinflammatory cytokines axis in the PVN of SHR is a prompt neural adaptation to counterbalance the deleterious effects of inflammation on autonomic control.

Cardiovascular responses to passive static flexibility exercises are influenced by the stretched muscle mass and the Valsalva maneuver

BACKGROUND: The respiratory pattern is often modified or even blocked during flexibility exercises, but little is known about the cardiovascular response to concomitant stretching and the Valsalva maneuver (VM) in healthy subjects. OBJECTIVES: This study evaluated the heart rate (HR), systolic blood pressure (SBP), and rate-pressure product (RPP) during and after large and small muscle group flexibility exercises performed simultaneously with the VM. METHODS: Asymptomatic volunteers (N  =  22) with the following characteristics were recruited: age, 22 ± 3 years; weight, 73 ± 6 kg; height, 175 ± 5 cm; HR at rest, 66 ± 9 BPM; and SBP at rest, 113 ± 10 mmHg. They performed two exercises: four sets of passive static stretching for 30 s of the dorsi-flexion (DF) of the gastrocnemius and the hip flexion (HF) of the ischio-tibialis. The exercises were performed with (V+) or without (V-) the VM in a counterbalanced order. The SBP and HR were measured, and the RPP was calculated before the exercise session, at the end of each set, and during a 30-min post-exercise recovery period. RESULTS: The within-group comparisons showed that only the SBP and RPP increased throughout the sets (p<0.05), but no post-exercise hypotension was detected. The between-group comparisons showed that greater SBP increases were related to the VM and to a larger stretched muscle mass. Differences for a given set were identified for the HR (the HFV+ and HFV- values were higher than the DFV+ and DFV- values by approximately 12 BPM), SBP (the HFV+ value was higher than the DFV+ and DFV- values by approximately 12 to 15 mmHg), and RPP (the HFV+ value was higher than the HFV- value by approximately 2000 mmHGxBPM, and the HFV+ value was higher than the DFV+ and DFV- values by approximately 4000 mmHGxBPM). CONCLUSION: Both the stretched muscle mass and the VM influence acute cardiovascular responses to multiple-set passive stretching exercise sessions.