Abstract 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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 groupsexercise-trained (n=11; age46±2 years) and untrained (n=9; age42±2 years) patients. An age-matched normotensive exercise-trained group (n=12; age42±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.
Autonomic dysfunction, including baroreceptor attenuation and sympathetic activation, has been reported in patients with myocardial infarction (MI) and has been associated with increased mortality. ...We tested the hypotheses that exercise training (ET) in post-MI patients would normalize arterial baroreflex sensitivity (BRS) and muscle sympathetic nerve activity (MSNA), and long-term ET would maintain the benefits in BRS and MSNA. Twenty-eight patients after 1 month of uncomplicated MI were randomly assigned to 2 groups, ET (MI-ET) and untrained. A normal control group was also studied. ET consisted of three 60-minute exercise sessions per week for 6 months. We evaluated MSNA (microneurography), blood pressure (automatic oscillometric method), heart rate (ECG), and spectral analysis of RR interval, systolic arterial pressure (SAP), and MSNA. Baroreflex gain of SAP-RR interval and SAP-MSNA were calculated using the α-index. At 3 to 5 days and 1 month after MI, MSNA and low-frequency SAP were significantly higher and BRS significantly lower in MI patients when compared with the normal control group. ET significantly decreased MSNA (bursts per 100 heartbeats) and the low-frequency component of SAP and significantly increased the low-frequency component of MSNA and BRS of the RR interval and MSNA. These changes were so marked that the differences between patients with MI and the normal control group were no longer observed after ET. MSNA and BRS in the MI-untrained group did not change from baseline over the same time period. ET normalizes BRS, low-frequency SAP, and MSNA in patients with MI. These improvements in autonomic control are maintained by long-term ET. These findings highlight the clinical importance of this nonpharmacological therapy based on ET in the long-term treatment of patients with MI.
The blood pressure‐lowering effect of aerobic training is preceded by improving cardiovascular autonomic control. We previously demonstrated that aerobic training conducted in the evening (ET) ...induces a greater decrease in blood pressure than morning training (MT). To study whether the greater blood pressure decrease after ET occurs through better cardiovascular autonomic regulation, this study aimed to compare MT versus ET on muscle sympathetic nerve activity (MSNA) and baroreflex sensitivity (BRS) in treated patients with hypertension. Elderly patients treated for hypertension were randomly allocated into MT (n = 12, 07.00–10.00 h) or ET (n = 11, 17.00–20.00 h) groups. Both groups trained for 10 weeks, 3 times/week, cycling for 45 min at moderate intensity. Beat‐to‐beat blood pressure (finger photoplethysmography), heart rate (electrocardiography) and MSNA (microneurography) were assessed at the initial and final phases of the study at baseline and during sequential bolus infusions of sodium nitroprusside and phenylephrine (modified‐Oxford technique) to evaluate cardiac and sympathetic BRS. Mean blood pressure decreased significantly after ET but not after MT (−9 ± 11 vs. −1 ± 8 mmHg, P = 0.042). MSNA decreased significantly only after ET with no change after MT (−12 ± 5 vs. −3 ± 7 bursts/100 heart beats, P = 0.013). Sympathetic BRS improved after ET but not after MT (−0.8 ± 0.7 vs. 0.0 ± 0.8 bursts/100 heart beats/mmHg, P = 0.052). Cardiac BRS improved similarly in both groups (ET: +1.7 ± 1.8 vs. MT: +1.4 ± 1.9 ms/mmHg, Pphase ≤ 0.001). In elderly patients treated for hypertension, only ET decreased mean blood pressure and MSNA and improved sympathetic BRS. These findings revealed that the sympathetic nervous system has a key role in ET's superiority to MT in blood pressure‐lowering effect.
Key points
Reducing muscle nerve sympathetic activity and increasing sympathetic baroreflex sensitivity plays a key role in promoting the greater blood pressure reduction observed with evening training.
These findings indicated that simply changing the timing of exercise training may offer additional benefits beyond antihypertensive medications, such as protection against sympathetic overdrive and loss of baroreflex sensitivity, independent markers of mortality.
Our new findings also suggest new avenues of investigation, such as the possibility that evening aerobic training may be beneficial in other clinical conditions with sympathetic overdrive, such as congestive heart failure and hypertrophic cardiomyopathy.
figure legend Ten weeks of aerobic training in the evening but not in the morning decreased muscle sympathetic nerve activity and increased sympathetic baroreflex sensitivity in elderly patients with hypertension already receiving antihypertensive medication. Arrows indicate directions of a variable change after aerobic training: → (maintenance); ↑ (increase); ↓ (decrease). Created with Biorender.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
COVID-19 has become a dramatic health problem during this century. In addition to high mortality rate, COVID-19 survivors are at increased risk for cardiovascular diseases 1-year after infection. ...Explanations for these manifestations are still unclear but can involve a constellation of biological alterations. We hypothesized that COVID-19 survivors compared with controls exhibit sympathetic overdrive, vascular dysfunction, cardiac morpho-functional changes, impaired exercise capacity, and increased oxidative stress.
Nineteen severe COVID-19 survivors and 19 well-matched controls completed the study. Muscle sympathetic nerve activity (microneurography), brachial artery flow-mediated dilation and blood flow (Doppler-Ultrasound), carotid-femoral pulse wave velocity (Complior), cardiac morpho-functional parameters (echocardiography), peak oxygen uptake (cardiopulmonary exercise testing), and oxidative stress were measured ~3 months after hospital discharge. Complementary experiments were conducted on human umbilical vein endothelial cells cultured with plasma samples from subjects.
Muscle sympathetic nerve activity and carotid-femoral pulse wave velocity were greater and brachial artery flow-mediated dilation, brachial artery blood flow, E/e' ratio, and peak oxygen uptake were lower in COVID-19 survivors than in controls. COVID-19 survivors had lower circulating antioxidant markers compared with controls, but there were no differences in plasma-treated human umbilical vein endothelial cells nitric oxide production and reactive oxygen species bioactivity. Diminished peak oxygen uptake was associated with sympathetic overdrive, vascular dysfunction, and reduced diastolic function in COVID-19 survivors.
Our study revealed that COVID-19 survivors have sympathetic overactivation, vascular dysfunction, cardiac morpho-functional changes, and reduced exercise capacity. These findings indicate the need for further investigation to determine whether these manifestations are persistent longer-term and their impact on the cardiovascular health of COVID-19 survivors.
Purpose
Patients with chronic chagasic cardiomyopathy with preserved ventricular function present with autonomic imbalance. This study evaluated the effects of exercise training (ET) in restoring ...peripheral and cardiac autonomic control and skeletal muscle phenotype in patients with subclinical chronic chagasic cardiomyopathy.
Methods
This controlled trial (NCT02295215) included 24 chronic chagasic cardiomyopathy patients who were randomized
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into two groups: those who underwent exercise training (
n
= 12) and those who continued their usual activities (
n
= 12). Eight patients completed the exercise training protocol, and 10 patients were clinically followed up for 4 months. Muscular sympathetic nerve activity was measured by microneurography and muscle blood flow (MBF) using venous occlusion plethysmography. The low-frequency component of heart rate variability in normalized units (LFnuHR) reflects sympathetic activity in the heart, and the low-frequency component of systolic blood pressure variability in normalized units reflects sympathetic activity in the vessels. The infusion of vasoactive drugs (phenylephrine and sodium nitroprusside) was used to evaluate cardiac baroreflex sensitivity, and a vastus lateralis muscle biopsy was performed to evaluate atrogin-1 and MuRF-1 gene expression.
Results
The baroreflex sensitivity for increases (
p
= 0.002) and decreases (
p
= 0.02) in systolic blood pressure increased in the ET group. Muscle blood flow also increased only in the ET group (
p
= 0.004). Only the ET group had reduced resting muscular sympathetic nerve activity levels (
p
= 0.008) and sympathetic activity in the heart (LFnu;
p
= 0.004) and vessels (
p
= 0.04) after 4 months. Regarding skeletal muscle, after 4 months, participants in the exercise training group presented with lower atrogin-1 gene expression than participants who continued their activities as usual (
p
= 0.001). The reduction in muscular sympathetic nerve activity was positively associated with reduced atrogin-1 (
r
= 0.86;
p
= 0.02) and MuRF-1 gene expression (
r
= 0.64;
p
= 0.06); it was negatively associated with improved baroreflex sensitivity both for increases (
r
= –0.72;
p
= 0.020) and decreases (
r
= –0.82;
p
= 0.001) in blood pressure.
Conclusions
ET improved cardiac and peripheral autonomic function in patients with subclinical chagasic cardiomyopathy. ET reduced MSNA and sympathetic activity in the heart and vessels and increased cardiac parasympathetic tone and baroreflex sensitivity. Regarding peripheral muscle, after 4 months, patients who underwent exercise training had an increased cross-sectional area of type I fibers and oxidative metabolism of muscle fibers, and decreased atrogin-1 gene expression, compared to participants who continued their activities as usual. In addition, the reduction in MSNA was associated with improved cardiac baroreflex sensitivity, reduced sympathetic cardiovascular tone, and reduced atrogin-1 and MuRF-1 gene expression.
Trial registration
ID: NCT02295215. Registered in June 2013.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To test the effects of exercise training on sleep and neurovascular control in patients with systolic heart failure with and without sleep disordered breathing.
Prospective interventional study.
...Cardiac rehabilitation and exercise physiology unit and sleep laboratory.
Twenty-five patients with heart failure, aged 42 to 70 years, and New York Heart Association Functional Class I-III were divided into 1 of 3 groups: obstructive sleep apnea (n=8), central sleep apnea (n=9) and no sleep apnea (n=7). INTERVENTIONS Four months of no-training (control) followed by 4 months of an exercise training program (three 60-minute, supervised, exercise sessions per week).
Sleep (polysomnography), microneurography, forearm blood flow (plethysmography), peak VO2, and quality of life were evaluated at baseline and at the end of the control and trained periods. No significant changes occurred in the control period. Exercise training reduced muscle sympathetic nerve activity (P < 0.001) and increased forearm blood flow (P < 0.01), peak VO2( P < 0.01), and quality of life (P < 0.01) in all groups, independent of the presence of sleep apnea. Exercise training improved the apnea-hypopnea index, minimum 0O saturation, and amount stage 3-4 sleep (P < 0.05) in patients with obstructive sleep apnea but had no significant effects in patients with central sleep apnea.
The beneficial effects of exercise training on neurovascular function, functional capacity, and quality of life in patients with systolic dysfunction and heart failure occurs independently of sleep disordered breathing. Exercise training lessens the severity of obstructive sleep apnea but does not affect central sleep apnea in patients with heart failure and sleep disordered breathing.
1 Heart Institute (Instituto do Coração), Medical School, and 2 School of Physical Education and Sports, University of São Paulo, São Paulo, Brazil; and 3 Medical School, Department of Cardiology, ...University of California, Los Angeles, California
Submitted 21 December 2005
; accepted in final form 16 June 2006
Exercise training improves arterial baroreflex control in heart failure (HF) rabbits. However, the mechanisms involved in the amelioration of baroreflex control are unknown. We tested the hypothesis that exercise training would increase the afferent aortic depressor nerve activity (AODN) sensitivity in ischemic-induced HF rats. Twenty ischemic-induced HF rats were divided into trained ( n = 11) and untrained ( n = 9) groups. Nine normal control rats were also studied. Power spectral analysis of pulse interval, systolic blood pressure, renal sympathetic nerve activity (RSNA), and AODN were analyzed by means of autoregressive parametric spectral and cross-spectral algorithms. Spontaneous baroreflex sensitivity of heart rate (HR) and RSNA were analyzed during spontaneous variation of systolic blood pressure. Left ventricular end-diastolic pressure was higher in HF rats compared with that in the normal control group ( P = 0.0001). Trained HF rats had a peak oxygen uptake higher than untrained rats and similar to normal controls ( P = 0.01). Trained HF rats had lower low-frequency 1.8 ± 0.2 vs. 14.6 ± 3 normalized units (nu), P = 0.0003 and higher high-frequency (97.9 ± 0.2 vs. 85.0 ± 3 nu, P = 0.0005) components of pulse interval than untrained rats. Trained HF rats had higher spontaneous baroreceptor sensitivity of HR (1.19 ± 0.2 vs. 0.51 ± 0.1 ms/mmHg, P = 0.003) and RSNA 2.69 ± 0.4 vs. 1.29 ± 0.3 arbitrary units (au)/mmHg, P = 0.04 than untrained rats. In HF rats, exercise training increased spontaneous AODN sensitivity toward normal levels (trained HF rats, 1,791 ± 215; untrained HF rats, 1,150 ± 158; and normal control rats, 2,064 ± 327 au/mmHg, P = 0.05). In conclusion, exercise training improves AODN sensitivity in HF rats.
baroreflex control; autonomic nervous system
Address for reprint requests and other correspondence: C. E. Negrão, Instituto do Coração, Unidade de Reabilitação Cardiovascular e Fisiologia do Exercício, Av. Dr. Enéas de Carvalho Aguiar, 44Cerqueira César, São PauloSP, CEP 05403-000 Brazil (e-mail: cndnegrao{at}incor.usp.br )
Previous studies have shown that both sympathetic hyperactivity and enhanced inflammatory responses are associated with poor outcomes in patients with acute coronary syndrome (ACS). Whether there is ...a correlation between these two characteristics remains unclear. Thirty-four patients with uncomplicated ACS were evaluated; their mean age was 51.7±7.0 years, 79.4% were male, and 94.1% had myocardial infarction (MI). On the fourth day of hospitalization, they underwent muscle sympathetic nerve activity (MSNA) analysis (microneurography), as well as ultrasensitive C-reactive protein (usCRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A
(Lp-PLA
) activity measurements. These evaluations were repeated at 1, 3, and 6 months after hospitalization. Both MSNA and inflammatory biomarkers were elevated during the acute phase of ACS and then decreased over time. At hospitalization, the median usCRP level was 17.75 (IQR 8.57; 40.15) mg/l, the median IL-6 level was 6.65 (IQR 4.45; 8.20), the mean Lp-PLA
activity level was 185.8 ±52.2 nmol/min per ml, and mean MSNA was 64.2±19.3 bursts/100 heart beats. All of these variables decreased significantly over 6 months compared with the in-hospital levels. MSNA was independently associated with the peak level of creatine kinase isoenzyme MB (CKMB) in the acute phase (
=0.027) and with left ventricular ejection fraction (LVEF) at 6 months (
=0.026). Despite the increased levels of inflammatory biomarkers and sympathetic hyperactivity in the initial phase of ACS, no significant correlations between them were observed in any of the analyzed phases. Our data suggest that although both sympathetic hyperactivity and inflammation are concomitantly present during the early phase of ACS, these characteristics manifest via distinct pathological pathways.
Aims The clinical effects of different modalities of treatment for neurally mediated syncope have been studied for years; however, their influences on its pathophysiological mechanisms still have not ...been determined. This research aimed to observe the effects of physical training, tilt training, and pharmacological therapy on the arterial baroreflex sensitivity and muscle sympathetic nerve activity in neurally mediated syncope patients. Methods and results Seventy patients with recurrent neurally mediated syncope were included in this study. Patients were divided into the following four groups, depending on the treatment proposed: (i) physical training, (ii) tilt training, (iii) pharmacological therapy, and (iv) control group. All patients underwent an autonomic evaluation with microneurography, when the vagal and sympathetic arterial baroreflex gain were tested, using graded infusions of phenylephrine or sodium nitroprusside, before and 4 months after the interventions. The vagal and sympathetic arterial baroreflex gain significantly increased after a 4-month protocol of physical training. Tilt training, pharmacological therapy, and the control group had no significant change in the arterial baroreceptor responses. Conclusion Physical training improves arterial baroreflex sensitivity in neurally mediated syncope patients and could be applied as a non-pharmacological therapeutic alternative for these patients.
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