Carlos Eduardo Negrão

State-of-the-Art Lecture Influence of Exercise Training on Neurogenic Control of Blood Pressure in Spontaneously Hypertensive Rats

Exercise training plays an important role in the reduction of high blood pressure. In this review, we discuss the effect of distinct intensities of exercise training on the reduction of high blood pressure in spontaneously hypertensive rats (SHR). In addition, we present some hemodynamic mechanisms and associated neural controls by which exercise training attenuates hypertension in SHR. Low-intensity exercise training is more effective in reducing high blood pressure than is high-intensity exercise training in SHR. The decrease in blood pressure is due to resting bradycardia, and in consequence, lower cardiac output. Sympathetic attenuation to the heart is the major explanation for the resting bradycardia. Recovery of the sensitivity of baroreflex control of heart rate, which is usually impaired in SHR, is an important neurogenic component involved in the benefits elicited by exercise training.

The effects of exercise training on sympathetic neural activation in advanced heart failure ☆: A randomized controlled trial

OBJECTIVES The goal of this study was to test the hypothesis that exercise training reduces resting sympathetic neural activation in patients with chronic advanced heart failure. BACKGROUND Exercise training in heart failure has been shown to be beneficial, but its mechanisms of benefit remain unknown. METHODS Sixteen New York Heart Association class II to III heart failure patients, age 35 to 60 years, ejection fraction < or =40% were divided into two groups: 1) exercise-trained (n = 7), and 2) sedentary control (n = 9). A normal control exercise-trained group was also studied (n = 8). The four-month supervised exercise training program consisted of three 60 min exercise sessions per week, at heart rate levels that corresponded up to 10% below the respiratory compensation point. Muscle sympathetic nerve activity (MSNA) was recorded directly from peroneal nerve using the technique of microneurography. Forearm blood flow was measured by venous plethysmography. RESULTS Baseline MSNA was greater in heart failure patients compared with normal controls; MSNA was uniformly decreased after exercise training in heart failure patients (60 +/- 3 vs. 38 +/- 3 bursts/100 heart beats), and the mean difference in the change was significantly (p < 0.05) greater than the mean difference in the change in sedentary heart failure or trained normal controls. In fact, resting MSNA in trained heart failure patients was no longer significantly greater than in trained normal controls. In heart failure patients, peak VO(2) and forearm blood flow, but not left ventricular ejection fraction, increased after training. CONCLUSIONS These findings demonstrate that exercise training in heart failure patients results in dramatic reductions in directly recorded resting sympathetic nerve activity. In fact, MSNA was no longer greater than in trained, healthy controls.

Selective Atrial Vagal Denervation Guided by Evoked Vagal Reflex to Treat Patients With Paroxysmal Atrial Fibrillation

Background— The aim of this study was to evaluate whether selective radiofrequency (RF) catheter ablation of the atrial sites in which high-frequency stimulation induces vagal reflexes prevents paroxysmal atrial fibrillation (AF). Methods and Results— Ten patients with episodes suggestive of vagal-induced paroxysmal AF and no heart disease were selected for percutaneous epicardial and endocardial mapping of the atria to search for sites in which high-frequency transcatheter stimulation (20 Hz,) induced vagal reflexes. A vagal response defined as AV block of >2 seconds was elicited in 7 of 10 patients (70%) with an average of 5±2.4 (range, 2 to 9) sites per patient, and RF pulses (21.0±12.0 per patient) were applied at those sites to eliminate all evoked vagal reflexes. The 3 patients in whom evoked vagal reflexes were not obtained underwent circumferential pulmonary vein ablation with an average of 58.0±13.9 RF pulses per patient (P=0.022). Autonomic evaluation was performed before and 48 hours and 3 months after the procedure and was consistent with vagal withdrawal in all patients. Two of the 7 patients who underwent denervation remained asymptomatic without the use of antiarrhythmic medication at a mean follow-up of 8.3±2.8 months (range, 5 to 15 months); 4 had frequent recurrences and were referred for circumferential pulmonary vein ablation; and 1 had few AF episodes without antiarrhythmic medication. The 3 patients without evoked vagal reflexes who underwent circumferential pulmonary vein ablation remained asymptomatic without antiarrhythmic medication. One patient had acute delayed gastric emptying after atrial vagal denervation. Conclusions— RF catheter ablation of selected atrial sites in which high-frequency stimulation induced vagal reflexes may prevent AF recurrences in selected patients with apparently vagal-induced paroxysmal AF.

Postexercise blood pressure reduction in elderly hypertensive patients.

OBJECTIVES We sought to study: 1) the impact of hemodynamic and left ventricular function on short-term postexercise blood pressure reduction in elderly hypertensive patients; and 2) the 22-h postexercise effects on ambulatory blood pressure in elderly hypertensive patients. BACKGROUND Although early exercise provokes postexercise blood pressure reduction, the mechanisms underlying this response are not completely understood. Besides, it is unclear whether the reduction in blood pressure after exercise lasts long enough to have clinical relevance in elderly hypertensive patients. METHODS We studied 24 elderly hypertensive patients (age 68.9 +/- 1.5 years) and 18 age-matched normotensive control subjects (age 68.1 +/- 1.2 years). Cardiac output (carbon dioxide rebreathing) and blood pressure (auscultatory) were measured at rest and after a 45-min period of low-intensity bicycle exercise (50% maximal oxygen uptake) and at 15, 30, 60 and 90 min after exercise. Left ventricular function (by Doppler echocardiography) was also evaluated. Ambulatory blood pressure monitoring was evaluated after 45 min of exercise or 45 min of rest, in a randomized order. RESULTS In the hypertensive patients, exercise provoked a significant reduction in blood pressure, cardiac output, stroke volume and left ventricular end-diastolic volume. It also provoked a significant reduction in systolic, mean and diastolic blood pressure during a 22-h period, at daytime and nighttime. CONCLUSIONS The short-term reduction in blood pressure after exercise in elderly hypertensive patients is associated with a decrease in stroke volume and left ventricular end-diastolic volume. The 22-h postexercise reduction in blood pressure demonstrates the clinical relevance of low-intensity exercise in elderly hypertensive patients.

Exercise Training Increases Baroreceptor Gain Sensitivity in Normal and Hypertensive Rats

Exercise training attenuates arterial hypertension and increases baroreflex sensitivity in spontaneous hypertension. However, no information exists regarding the portion of the baroreflex arch in which this attenuation takes place. We tested the hypothesis that exercise training increases the afferent pathway sensitivity of baroreflex control in both normotensive and spontaneously hypertensive rats (SHR). Arterial pressure and whole-nerve activity of the aortic baroreceptor (multifiber preparation) were evaluated in 30 male rats assigned to 4 groups: sedentary and exercise-trained normotensive rats and sedentary and exercise-trained SHR. Exercise training was performed on a motor treadmill, 5 d/wk for 60 minutes, gradually progressing toward a speed of 26.8 m/min. Exercise training reduced mean arterial pressure in conscious exercise-trained SHR (183±4 versus 165±7 mm Hg). The relation between changes in aortic baroreceptor discharge and changes in systolic arterial pressure increased significantly in exercise-trained normotensive rats (2.09±0.1 versus 1.44±0.1%/mm Hg) and exercise-trained SHR (0.92±0.1 versus 0.71±0.1%/mm Hg) compared with their respective sedentary rats. Likewise, the average aortic baroreceptor gain sensitivity (calculated by logistic equation) was significantly higher in exercise-trained normotensive rats (2.25±0.19 versus 1.77±0.03%/mm Hg) and exercise-trained SHR (1.07±0.04 versus 0.82±0.05%/mm Hg) compared with their respective sedentary control rats. In conclusion, exercise training increases aortic baroreceptor gain sensitivity in normotensive and SHR, thus improving baroreceptor sensitivity, which may result in a more efficient arterial pressure regulation by the baroreflexes.

Low-intensity exercise training decreases cardiac output and hypertension in spontaneously hypertensive rats

The decrease in cardiac sympathetic tone and heart rate after low-intensity exercise training may have hemodynamic consequences in spontaneously hypertensive rats (SHR). The effects of exercise training of low and high intensity on resting blood pressure, cardiac output, and total peripheral resistance were studied in sedentary (n = 17), low- (n = 17), and high-intensity exercise-trained (n = 17) SHR. Exercise training was performed on a treadmill for 60 min, 5 times per week for 18 weeks, at 55% or 85% maximum oxygen uptake. Blood pressure was evaluated by a cannula inserted into the carotid artery, and cardiac output was evaluated by a microprobe placed around the ascending aorta. Low-intensity exercise-trained rats had a significantly lower mean blood pressure than sedentary and high-intensity exercise-trained rats (160 +/- 4 vs. 175 +/- 3 and 173 +/- 2 mmHg, respectively). Cardiac index (20 +/- 1 vs. 24 +/- 1 and 24 +/- 1 ml.min-1 x 100 g-1, respectively) and heart rate (332 +/- 6 vs. 372 +/- 14 and 345 +/- 9 beats/min, respectively) were significantly lower in low-intensity exercise-trained rats than in sedentary and high-intensity exercise-trained rats. No significant difference was observed in stroke volume index and total peripheral resistance index in all groups studied. In conclusion, low-intensity, but not high-intensity, exercise training decreases heart rate and cardiac output and, consequently, attenuates hypertension in SHR.The decrease in cardiac sympathetic tone and heart rate after low-intensity exercise training may have hemodynamic consequences in spontaneously hypertensive rats (SHR). The effects of exercise training of low and high intensity on resting blood pressure, cardiac output, and total peripheral resistance were studied in sedentary ( n = 17), low- ( n = 17), and high-intensity exercise-trained ( n = 17) SHR. Exercise training was performed on a treadmill for 60 min, 5 times per week for 18 weeks, at 55% or 85% maximum oxygen uptake. Blood pressure was evaluated by a cannula inserted into the carotid artery, and cardiac output was evaluated by a microprobe placed around the ascending aorta. Low-intensity exercise-trained rats had a significantly lower mean blood pressure than sedentary and high-intensity exercise-trained rats (160 ± 4 vs. 175 ± 3 and 173 ± 2 mmHg, respectively). Cardiac index (20 ± 1 vs. 24 ± 1 and 24 ± 1 ml ⋅ min-1 ⋅ 100 g-1, respectively) and heart rate (332 ± 6 vs. 372 ± 14 and 345 ± 9 beats/min, respectively) were significantly lower in low-intensity exercise-trained rats than in sedentary and high-intensity exercise-trained rats. No significant difference was observed in stroke volume index and total peripheral resistance index in all groups studied. In conclusion, low-intensity, but not high-intensity, exercise training decreases heart rate and cardiac output and, consequently, attenuates hypertension in SHR.

The impact of obstructive sleep apnea on metabolic and inflammatory markers in consecutive patients with metabolic syndrome.

Background Obstructive Sleep Apnea (OSA) is tightly linked to some components of Metabolic Syndrome (MetS). However, most of the evidence evaluated individual components of the MetS or patients with a diagnosis of OSA that were referred for sleep studies due to sleep complaints. Therefore, it is not clear whether OSA exacerbates the metabolic abnormalities in a representative sample of patients with MetS. Methodology/Principal Findings We studied 152 consecutive patients (age 48±9 years, body mass index 32.3±3.4 Kg/m2) newly diagnosed with MetS (Adult Treatment Panel III). All participants underwent standard polysomnography irrespective of sleep complaints, and laboratory measurements (glucose, lipid profile, uric acid and C-reactive protein). The prevalence of OSA (apnea-hypopnea index ≥15 events per hour of sleep) was 60.5%. Patients with OSA exhibited significantly higher levels of blood pressure, glucose, triglycerides, cholesterol, LDL, cholesterol/HDL ratio, triglycerides/HDL ratio, uric acid and C-reactive protein than patients without OSA. OSA was independently associated with 2 MetS criteria: triglycerides: OR: 3.26 (1.47–7.21) and glucose: OR: 2.31 (1.12–4.80). OSA was also independently associated with increased cholesterol/HDL ratio: OR: 2.38 (1.08–5.24), uric acid: OR: 4.19 (1.70–10.35) and C-reactive protein: OR: 6.10 (2.64–14.11). Indices of sleep apnea severity, apnea-hypopnea index and minimum oxygen saturation, were independently associated with increased levels of triglycerides, glucose as well as cholesterol/HDL ratio, uric acid and C-reactive protein. Excessive daytime sleepiness had no effect on the metabolic and inflammatory parameters. Conclusions/Significance Unrecognized OSA is common in consecutive patients with MetS. OSA may contribute to metabolic dysregulation and systemic inflammation in patients with MetS, regardless of symptoms of daytime sleepiness.

Increased muscle sympathetic nerve activity predicts mortality in heart failure patients

BACKGROUND Previous studies have associated neurohumoral excitation, as estimated by plasma norepinephrine levels, with increased mortality in heart failure. However, the prognostic value of neurovascular interplay in heart failure (HF) is unknown. We tested the hypothesis that the muscle sympathetic nerve activity (MSNA) and forearm blood flow would predict mortality in chronic heart failure patients. METHODS One hundred and twenty two heart failure patients, NYHA II-IV, age 50+/-1 ys, LVEF 33+/-1%, and LVDD 7.1+/-0.2 mm, were followed up for one year. MSNA was directly measured from the peroneal nerve by microneurography. Forearm blood flow was obtained by venous occlusion plethysmography. The variables were analyzed by using univariate, stepwise multivariate Cox proportional hazards analysis, and Kaplan-Meier analysis. RESULTS After one year, 34 pts died from cardiac death. The univariate analysis showed that MSNA, forearm blood flow, LVDD, LVEF, and heart rate were significant predictors of mortality. The multivariate analysis showed that only MSNA (P=0.001) and forearm blood flow (P=0.003) were significant independent predictors of mortality. On the basis of median levels of MSNA, survival rate was significantly lower in pts with >49 bursts/min. Similarly, survival rate was significantly lower in pts with forearm blood flow <1.87 ml/min/100 ml (P=0.002). CONCLUSION MSNA and forearm blood flow predict mortality rate in patients with heart failure. It remains unknown whether therapies that specifically target these abnormalities will improve survival in heart failure.

Exercise Training Restores Baroreflex Sensitivity in Never-Treated Hypertensive Patients

The effects of exercise training on baroreflex control of sympathetic nerve activity in human hypertension are unknown. We hypothesized that exercise training would improve baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate (HR) in patients with hypertension and that exercise training would reduce MSNA and blood pressure (BP) in hypertensive patients. Twenty never-treated hypertensive patients were randomly divided into 2 groups: exercise-trained (n=11; age: 46±2 years) and untrained (n=9; age: 42±2 years) patients. An age-matched normotensive exercise-trained group (n=12; age: 42±2 years) was also studied. Baroreflex control of MSNA (microneurography) and HR (ECG) was assessed by stepwise intravenous infusions of phenylephrine and sodium nitroprusside and analyzed by linear regression. BP was monitored on a beat-to-beat basis. Exercise training consisted of three 60-minute exercise sessions per week for 4 months. Under baseline conditions (before training), BP and MSNA were similar between hypertensive groups but significantly increased when compared with the normotensive group. Baroreflex control of MSNA and HR was similar between hypertensive groups but significantly decreased when compared with the normotensive group. In hypertensive patients, exercise training significantly reduced BP (P<0.01) and MSNA (P<0.01) levels and significantly increased baroreflex control of MSNA and HR during increases (P<0.01 and P<0.03, respectively) and decreases (P<0.01 and P<0.03, respectively) in BP. The baseline (preintervention) difference in baroreflex sensitivity between hypertensive patients and normotensive individuals was no longer observed after exercise training. No significant changes were found in untrained hypertensive patients. In conclusion, exercise training restores the baroreflex control of MSNA and HR in hypertensive patients. In addition, exercise training normalizes MSNA and decreases BP levels in these patients.

Post-exercise changes in blood pressure, heart rate and rate pressure product at different exercise intensities in normotensive humans

To evaluate the effect of exercise intensity on post-exercise cardiovascular responses, 12 young normotensive subjects performed in a randomized order three cycle ergometer exercise bouts of 45 min at 30, 50 and 80% of VO2peak, and 12 subjects rested for 45 min in a non-exercise control trial. Blood pressure (BP) and heart rate (HR) were measured for 20 min prior to exercise (baseline) and at intervals of 5 to 30 (R5-30), 35 to 60 (R35-60) and 65 to 90 (R65-90) min after exercise. Systolic, mean, and diastolic BP after exercise were significantly lower than baseline, and there was no difference between the three exercise intensities. After exercise at 30% of VO2peak, HR was significantly decreased at R35-60 and R65-90. In contrast, after exercise at 50 and 80% of VO2peak, HR was significantly increased at R5-30 and R35-60, respectively. Exercise at 30% of VO2peak significantly decreased rate pressure (RP) product (RP = HR x systolic BP) during the entire recovery period (baseline = 7930 +/- 314 vs R5-30 = 7150 +/- 326, R35-60 = 6794 +/- 349, and R65-90 = 6628 +/- 311, P < 0.05), while exercise at 50% of VO2peak caused no change, and exercise at 80% of VO2peak produced a significant increase at R5-30 (7468 +/- 267 vs 9818 +/- 366, P < 0.05) and no change at R35-60 or R65-90. Cardiovascular responses were not altered during the control trial. In conclusion, varying exercise intensity from 30 to 80% of VO2peak in young normotensive humans did not influence the magnitude of post-exercise hypotension. However, in contrast to exercise at 50 and 80% of VO2peak, exercise at 30% of VO2peak decreased post-exercise HR and RP.