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Our data reveal for the first time that associations between aerobic fitness and resting muscle sympathetic nerve activity are sex and age specific; inverse relationships are evident in younger males (

During 1-leg cycling, contralateral muscle sympathetic nerve activity (MSNA) falls in healthy adults but increases in most with reduced ejection fraction heart failure (HFrEF). We hypothesized that their peak oxygen uptake (V̇O2peak) relates inversely to their MSNA response to exercise. Twenty-nine patients (6 women; 63 ± 9 years; left ventricular ejection fraction: 30 ± 7%; V̇O2peak: 78 ± 23 percent age-predicted (%V̇O2peak); mean ± SD) and 21 healthy adults (9 women; 58 ± 7 years; 115 ± 29%V̇O2peak) performed 2 min of mild- (“loadless”) and moderate-intensity (“loaded”) 1-leg cycling. Heart rate, blood pressure (BP), contralateral leg MSNA and perceived exertion rate (RPE) were recorded. Resting MSNA burst frequency (BF) was higher (p < 0.01) in HFrEF (51 ± 11 vs 44 ± 7 bursts·min−1). Exercise heart rate, BP and RPE responses at either intensity were similar between groups. In minute 2 of “loadless” and “loaded” cycling, group mean BF fell from baseline values in controls (−5 ± 6 and −7 ± 7 bursts·min−1, respectively) but rose in HFrEF (+5 ± 7 and +5 ± 10 bursts·min−1). However, in 10 of the latter cohort, BF fell, similarly to controls. An inverse relationship between ΔBF from baseline to “loaded” cycling and %V̇O2peak was present in patients (r = −0.43, p < 0.05) but absent in controls (r = 0.07, p = 0.77). In HFrEF, ∼18% of variance in %V̇O2peak can be attributed to the change in BF elicited by exercise. Novelty: Unlike healthy individuals, in the majority of heart failure patients with reduced ejection fraction (HFrEF), 1-leg cycling increases muscle sympathetic nerve activity (MSNA). In HFrEF, ∼18% of age-predicted peak oxygen uptake (V̇O2peak) can be attributed to changes in MSNA elicited by low-intensity exercise. This relationship is absent in healthy adults.

Patients with sympathetic excess are those most likely to benefit from novel interventions targeting the autonomic nervous system. To inform such personalized therapy, we identified determinants of augmented muscle sympathetic nerve activity (MSNA) in heart failure, versus healthy controls.We compared data acquired in 177 conventionally-treated, stable non-diabetic patients in sinus rhythm, aged 18-79 years (149 males; 28 females; LVEF: 25±11% [mean±SD]; range 5-60%), and, concurrently, under similar conditions, in 658 healthy, normotensive volunteers (398 males; 260 females; aged 18-81 years). In heart failure, MSNA ranged between 7 and 90 bursts·minBurst frequency and incidence exceeded normative values in only ~53% and ~33% of patients. Such diversity encourages selective deployment of sympatho-modulatory therapies. Clinical characteristics can highlight individuals who may benefit from future personalized interventions targeting pathological sympathetic activation.

Background: Heart failure with reduced ejection fraction (HFrEF) is associated with reduced cardiac β-adrenergic signal transduction in response to chronic elevations in neurally released and circulating norepinephrine. Whether elevations in muscle sympathetic nerve activity (MSNA) are accompanied by attenuated α-adrenoceptor–mediated vasoconstriction remains unclear. Therefore, the objective of the current work was to compare transduction of sympathetic firing into blood pressure (BP) in treated patients with HFrEF and healthy controls. Methods: Twenty-three treated patients with HFrEF (4 females, left ventricular ejection fraction: 28±2%) and 22 healthy controls (6 females) underwent a 7-minute resting measurement of continuous beat-to-beat BP (finger photoplethysmography), heart rate (electrocardiography), and MSNA (microneurography). Sympathetic-BP transduction was quantified using both signal averaging, whereby the BP response to each MSNA burst was serially tracked over 15 cardiac cycles and averaged to derive the peak change in BP, and cross-spectral analysis of low-frequency (0.04–0.15 Hz) MSNA and BP oscillations. Results: Compared with controls, patients with HFrEF had less sympathetic-BP transduction (0.7±0.3 versus 0.2±0.3 mm Hg; P 2 ; P 2 ; P P =0.01) and further attenuated (0.1±0.1 mm Hg; P =0.03) in patients with HFrEF with elevated resting MSNA. Conclusions: Treated HFrEF is associated with lower sympathetic-BP transduction, even when MSNA is not elevated, and diminishes further with disease progression. These adaptations may serve to limit the adverse consequences of oscillatory surges in sympathetic vasoconstrictor discharge on stroke volume.

Background Reflected arterial waves contribute to left ventricular (LV) afterload. Heart failure patients with reduced ejection fraction (HFrEF) are afterload sensitive and sympathetically activated. We tested the hypothesis that HFrEF patients exhibit a positive relationship between sympathetic vasoconstrictor discharge and aortic wave reflection. Methods Sixteen treated patients with HFrEF (61 ± 9 years of age, left ventricular ejection fraction 30 ± 7%, 3 women) and 16 similar-aged healthy control subjects (57 ± 7 years of age, 4 women) underwent noninvasive measurements of radial pulse waveforms (applanation tonometry) to calculate central blood pressures and aortic wave reflection characteristics: augmentation pressure (AP), augmentation index (AIx), and AIx corrected to a heart rate of 75 beats/min (AIx@75). Muscle sympathetic nerve activity (MSNA) burst frequency was recorded from the fibular nerve (microneurography). Results HFrEF patients had higher AIx (26 ± 9 vs 17 ± 15%; P .05), AP (11 ± 5 vs 7 ± 8 mm Hg; P = 0.11), or AIx@75 (19 ± 9 vs 13 ± 11%,-P = 0.14). MSNA correlated positively with AP (r = 0.50; P 0.49). Conclusions In patients with HFrEF, but not similarly aged healthy subjects, indices of aortic wave reflection correlate positively with MSNA. By increasing LV afterload, such neurovascular coupling could impair LV performance and worsen heart failure symptoms. Therapies that attenuate neurogenic vasoconstriction may benefit HFrEF patients by diminishing arterial wave reflection.

During 1-leg cycling, contralateral muscle sympathetic nerve activity (MSNA) falls in healthy adults but increases in most with reduced ejection fraction heart failure (HFrEF). We hypothesized that their peak oxygen uptake (

Introduction: Elevated muscle sympathetic nerve activity (MSNA) both at rest and during dynamic cycling relates inversely to peak oxygen uptake (VO 2peak ) in patients with heart failure due to a reduced ejection fraction (HFrEF). We observed a drop in MSNA both rest (-6±2 bursts/min) and mild exercise (-4±2) in HFrEF patients after 6 months of cardiac rehabilitation. Hypothesis: We hypothesized that after training those HFrEF patients with LOW VO2peak (less than median 74% of age predicted) would have a larger decrease in MSNA during dynamic exercise than those with HIGH VO2peak (over 74%). Methods: In 21 optimally treated HFrEF patients (5 Female) (13 HIGH: mean VO 2peak =26 ml·kg/min; 98% of predicted; 8 LOW VO 2peak =12; 50%) we assessed VO 2peak (open-circuit spirometry), heart rate variability (HRV) and fibular MSNA (microneurography) at rest, during 1-leg cycling (2 min each of mild and moderate intensity upright 1-leg cycling, n=19) and recovery before and after 6 months of exercise training (45 min aerobic exercise, 5 days/ wk at 60-70 % of VO 2peak; and resistance training 2 days/wk). Results: HIGH and LOW groups had similar age (63±3 vs 63±4 years) , LVEF (30±2 vs 28±3%), BMI, resting heart rate (HR), blood pressure and MSNA (52±3 vs 50±3 bursts/min). Training increased VO 2peak in both groups (main effect P=0.009), with no group difference in HR response or ratings of perceived exertion. MSNA at rest tended to decrease after training in the HIGH but not LOW group (interaction P=0.08). MSNA during cycling increased in both HIGH (P=0.04) and LOW (P Conclusions: Contrary to our hypothesis, the sympatho-inhibitory effect of 6 months of exercise-based cardiac rehabilitation favours HFrEF patients with an already normal VO 2peak . This suggests that increasing initially low VO 2peak may be insufficient to trigger beneficial exercise and recovery autonomic modulation and altered training paradigms may be required in such patients. Funded by Canadian Institutes for Health Research (CIHR)

The sympathetic nervous system coordinates the cardiovascular response to exercise. This regulation is impaired in both experimental and human heart failure with reduced ejection fraction (HFrEF), resulting in a state of sympathoexcitation which limits exercise capacity and contributes to adverse outcome. Exercise training can moderate sympathetic excess at rest. Recording sympathetic nerve firing during exercise is more challenging. Hence, data acquired during exercise are scant and results vary according to exercise modality. In this review we will: (1) describe sympathetic activity during various exercise modes in both experimental and human HFrEF and consider factors which influence these responses; and (2) summarise the effect of exercise training on sympathetic outflow both at rest and during exercise in both animal models and human HFrEF. We will particularly highlight studies in humans which report direct measurements of efferent sympathetic nerve traffic using intraneural recordings. Future research is required to clarify the neural afferent mechanisms which contribute to efferent sympathetic activation during exercise in HFrEF, how this may be altered by exercise training, and the impact of such attenuation on cardiac and renal function.

As with blood pressure, age-related changes in muscle sympathetic nerve activity (MSNA) may differ nonlinearly between sexes. Data acquired from 398 male (age: 39±17; range: 18–78 years [mean±SD]) and 260 female (age: 37±18; range: 18–81 years) normotensive healthy nonmedicated volunteers were analyzed using linear regression models with resting MSNA burst frequency as the outcome and the predictors sex, age, MSNA, blood pressure, and body mass index modelled with natural cubic splines. Age and body mass index contributed 41% and 11%, respectively, of MSNA variance in females and 23% and 1% in males. Overall, changes in MSNA with age were sigmoidal. At age 20, mean MSNA of males and females were similar, then diverged significantly, reaching in women a nadir at age 30. After 30, MSNA increased nonlinearly in both sexes. Both MSNA discharge and blood pressure were lower in females until age 50 (17±9 versus 25±10 bursts·min −1 ; P −19 ; 106±11/66±8 versus 116±7/68±9 mm Hg; P −1 ; P =0.17; 119±15/71±13 versus 120±13/72±9 mm Hg; P >0.56). Compared with age 30, MSNA burst frequency at age 70 was 57% higher in males but 3-fold greater in females; corresponding increases in systolic blood pressure were 1 (95% CI, −4 to 5) and 12 (95% CI, 6–16) mm Hg. Except for concordance in females beyond age 40, there was no systematic change with age in any resting MSNA-blood pressure relationship. In normotensive adults, MSNA increases after age 30, with ascendance steeper in women.

Muscle sympathetic nerve activity (MSNA) decreases during low-intensity dynamic one-leg exercise in healthy subjects but increases in patients with heart failure with reduced ejection fraction (HFrEF). We hypothesized that increased peak oxygen uptake (V̇o2peak) after aerobic training would be accompanied by less sympathoexcitation during both mild and moderate one-leg dynamic cycling, an attenuated muscle metaboreflex, and greater skin vasodilation. We studied 27 stable, treated HFrEF patients (6 women; mean age: 65 ± 2 SE yr; mean left ventricular ejection fraction: 30 ± 1%) and 18 healthy age-matched volunteers (6 women; mean age: 57 ± 2 yr). We assessed V̇o2peak (open-circuit spirometry) and the skin microcirculatory response to reactive hyperemia (laser flowmetry). Fibular MSNA (microneurography) was recorded before and during one-leg cycling (2 min unloaded and 2 min at 50% of V̇o2peak) and, to assess the muscle metaboreflex, during posthandgrip ischemia (PHGI). HFrEF patients were evaluated before and after 6 mo of exercise-based cardiac rehabilitation. Pretraining V̇o2peak and skin vasodilatation were lower ( P < 0.001) and resting MSNA higher ( P = 0.01) in HFrEF than control subjects. Training improved V̇o2peak (+3.0 ± 1.0 mL·kg−1·min−1; P < 0.001) and cutaneous vasodilation and diminished resting MSNA (−6.0 ± 2.0, P = 0.01) plus exercise MSNA during unloaded (−4.0 ± 2.5, P = 0.04) but not loaded cycling (−1.0 ± 4.0 bursts/min, P = 0.34) and MSNA during PHGI ( P < 0.05). In HFrEF patients, exercise training lowers MSNA at rest, desensitizes the sympathoexcitatory metaboreflex, and diminishes MSNA elicited by mild but not moderate cycling. Training-induced downregulation of resting MSNA and attenuated reflex sympathetic excitation may improve exercise capacity and survival.

OBJECTIVE Delayed heart rate (HR) recovery in the immediate postexercise period has been linked to adverse cardiovascular prognosis. The after effects of an acute bout of exercise on HR modulation in postmenopausal women (PMW) and the influence of estrogen therapy are unknown. METHODS In 13 sedentary PMW (54 ± 2 y, mean ± SEM), we assessed HR variability (HRV)--an index of HR modulation--and the influence of estrogen therapy on HRV. HRV in the frequency domain was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes, at 60% VO2peak. PMW were studied before and after 4 weeks of oral estradiol. To obtain reference values for the after effects of exercise on HRV in healthy young women, 14 premenopausal women (PreM) completed the identical exercise protocol. RESULTS Compared with PreM, PMW demonstrated lower high frequency (vagal modulation) and total HRV (P < 0.05) at rest. In PreM, all HRV values were similar before and after exercise. In contrast, in PMW after exercise, despite having identical HR to PreM, high frequency and total HRV were all lower (all P ≤ 0.01) compared with pre-exercise HRV values. Estrogen therapy had no effect on pre or postexercise values for HRV. CONCLUSIONS When compared with PreM, PMW have identical HR, but lower vagal HR modulation at rest and delayed HRV recovery after exercise. Estrogen does not restore baseline HRV or accelerate HRV recovery postexercise, suggesting aging rather than estrogen deficiency per se may lower HRV in PMW.

Muscle sympathetic nerve activity (MSNA) at rest increases with age. However, the influence of age on MSNA recorded during dynamic leg exercise is unknown. We tested the hypothesis that aging attenuates the sympatho-inhibitory response observed in young subjects performing mild to moderate 1-leg cycling. After predetermining peak oxygen uptake, we compared contra-lateral fibular nerve MSNA during 2 min each of mild (unloaded) and moderate (30%–40% of the work rate at peak oxygen uptake, halved for single leg) 1-leg cycling in 18 young (age, 23 ± 1 years (mean ± SE)) and 18 middle-aged (age, 57 ± 2 years) sex-matched healthy subjects. Mean height, weight, resting heart rate, systolic blood pressure, and percent predicted peak oxygen uptake were similar between groups. Middle-aged subjects had higher resting MSNA burst frequency and incidence (P < 0.001) and diastolic blood pressure (P = 0.04). During moderate 1-leg cycling, older subjects’ systolic blood pressure increased more (+21 ± 5 vs. +10 ± 1 mm Hg; P = 0.02) and their fall in MSNA burst incidence was amplified (−19 ± 2 vs. −11 ± 2 bursts/100 heart beats; P = 0.01) but because heart rate rose less (+15 ± 3 vs. +19 ± 2 bpm; P = 0.03), exercise induced similar reductions in burst frequency (P = 0.25). Contrary to our initial hypothesis, with advancing age, mild- to moderate-intensity dynamic leg exercise elicits a greater rise in systolic blood pressure and a larger fall in MSNA.

© 2018, Canadian Science Publishing. All rights reserved. This perspective document summarizes discussions held at the Canadian Society for Exercise Physiology Annual Meeting in Winnipeg on October 27, 2017, when an expert panel was assembled to discuss the key questions and challenges for future research in cardiovascular exercise physiology. We were inspired by the example of the late Dr. Mike Sharratt, an accomplished and impactful Professor in the Faculty of Kinesiology at the University of Waterloo. Dr. Sharratt had a unique ability to bring experts together and translate theory into action, with a central goal of optimizing the health benefits of exercise, particularly in the fields of cardiac rehabilitation and aging (University of Waterloo Applied Health Science Department 2016; University of Waterloo Health Science Newsletter, 10-1-2017 (http://uwaterloo.ca/applied-health-sciences/news/rememberingmike-sharratt)).

OBJECTIVE Untrained individuals with exaggerated blood pressure (EBP) responses to graded exercise testing are characterized as having resting dysfunction of the sympathetic and cardiovascular systems. The purpose of this study was to determine the resting cardiovascular state of endurance-trained individuals with EBP through a comparison of normotensive athletes with and without EBP. METHODS EBP was defined as a maximal systolic blood pressure (SBP) at least 190 mmHg and at least 210 mmHg for women and men respectively, in response to a graded exercise test. Twenty-two life-long endurance-trained athletes (56 ± 5 years, 16 men) with EBP (EBP+) and 11 age and sex-matched athletes (55 ± 5 years, eight men) without EBP (EBP-) participated in the study. Sympathetic reactivity was assessed using BP responses to a cold pressor test, isometric handgrip exercise, and postexercise muscle ischemia. Resting left ventricular structure and function was assessed using two-dimensional echocardiography, whereas central arterial stiffness was assessed using carotid-to-femoral pulse wave velocity. Calf vascular conductance was measured at rest and peak postexercise using strain-gauge plethysmography. RESULTS All sympathetic reactivity, left ventricular, and arterial stiffness indices were similar between groups. There was no between-group difference in resting vascular conductance, whereas peak vascular conductance was higher in EBP+ relative to EBP- (1.81 ± 0.65 vs. 1.45 ± 0.32 ml/100 ml/min/mmHg, P

The reflex fibular muscle sympathetic nerve (MSNA) response to dynamic handgrip exercise is elicited at a lower threshold in heart failure with reduced ejection fraction (HFrEF). The present aim was to test the hypothesis that the contralateral MSNA response to mild to moderate dynamic one-legged exercise is augmented in HFrEF relative to age- and sex-matched controls. Heart rate (HR), blood pressure and MSNA were recorded in 16 patients with HFrEF (left ventricular ejection fraction = 31 ± 2%; age 62 ± 3 years, mean ± SE) and 13 healthy control subjects (56 ± 2 years) before and during 2 min of upright one-legged unloaded cycling followed by 2 min at 50% of peak oxygen uptake (). Resting HR and blood pressure were similar between groups whereas MSNA burst frequency was higher (50.0 ± 2.0 vs. 42.3 ± 2.7 bursts min−1, P = 0.03) and lower (18.0 ± 2.0 vs. 32.6 ± 2.8 ml kg−1 min−1, P

In chronic heart failure (CHF) due to left ventricular dysfunction, diminished heart rate variability (HRV) is an independent predictor of poor prognosis. Caffeine has been shown to increase HRV in young healthy subjects. Such an increase may be of potential benefit to patients with CHF.We hypothesized that intravenous infusion of caffeine would increase HRV in CHF, and in age-matched healthy control subjects.On two separate days, 11 patients (1F) with CHF (age=51.3±4.6 years; left ventricular ejection fraction=18.6±2.7%; mean±standard error) and 10 healthy control subjects (age=48.0±4.0) according to a double-blind randomization design, received either saline or caffeine (4 mg/kg) infusion. We assessed HRV over 7 minutes of supine rest (fast Fourier Transform analysis) to determine total spectral power as well as its high-frequency (HF) (0.15-0.50 Hz) and low-frequency (LF) (0.05-0.15 Hz) components, and recorded muscle sympathetic nerve activity (MSNA) directly from the peroneal nerve (microneurography).In healthy control subjects, compared with saline, caffeine reduced both heart rate and sympathetic nerve traffic (Caffeine increases cardiac vagal heart rate modulation and reduces MSNA in middle-aged healthy subjects, but not in those with CHF.

Purpose: Muscle sympathetic nerve activity (MSNA) is increased in older endurance-trained men, yet the reflex sympathetic forearm vasoconstrictor response to graded lower body negative pressure (LBNP) diminishes with age. The aim of this study was to assess the influence of aerobic exercise capacity on this altered neurovascular coupling. We hypothesized that during graded LBNP, the forearm vascular resistance (FVR)�MSNA relationship would be steeper in sedentary versus fit men. Methods: We therefore studied 20 healthy middle-age men (age = 52 ± 2 yr, mean ± SE), 10 physically active (FIT) and 10 sedentary (SED) (129% ± 4% vs 85% ± 3% of predicted peak oxygen uptake) during 4 min each of LBNP at -5, -10, -20, and -40 mm Hg, applied in a random order. We determined HR, plasma norepinephrine, and MSNA (microneurography) and derived FVR from blood pressure and forearm blood flow (plethysmography). The FVR�MSNA relationship was determined by linear regression in each group separately, and groups were compared using multiple linear regression. Results: MSNA burst frequency and FVR at rest and during LBNP (P < 0.003) were similar in the two groups, whereas HR was significantly lower (P < 0.002) both at rest and during LBNP in FIT men (P < 0.05). FVR during LBNP correlated positively with MSNA in the SED group (r = 0.44, P < 0.001) but not in the FIT group (r = 0.19, P = 0.10). Multiple linear regression confirmed that both MSNA (P < 0.001) and fitness level (P = 0.04) contribute to the forearm vascular response. Conclusions: Thus, during simulated orthostasis, middle-age SED men exhibit a significant FVR�MSNA relationship, which is not evident in age-matched FIT men. This alteration in neurovascular coupling may potentially affect cardiovascular risk in middle-age men.

Many heart failure (HF) patients exhibit paradoxical forearm vasodilation when central blood volume is reduced by lower body negative pressure (LBNP). We tested the hypothesis that this response results from reflex sympathetic withdrawal. We recorded simultaneously forearm blood flow, muscle sympathetic nerve activity (MSNA), and plasma norepinephrine (PNE) during four random applications of LBNP, −5, −10, −20, and −40 mmHg, in 12 men with HF (mean left ventricular ejection fraction = 24 ± 2%) and 10 healthy, normal, age-matched men (N). Compared with N, MSNA burst frequency ( P = 0.001) and PNE ( P = 0.005) were significantly higher in the HF group, both at rest and during LBNP. As anticipated in N, LBNP −40 mmHg significantly increased MSNA (+14.2 ± 2.5 bursts/min; P < 0.05) and PNE (+0.83 ± 0.22 nmol/l; P < 0.05) and decreased forearm vascular conductance (FVC) (−11.7 ± 3.2 ml·min−1·mmHg−1; P < 0.05). In the HF group, LBNP elicited similar increases in MSNA (+11.5 ± 2.0; P < 0.05) and PNE (+0.85 ± 0.12; P < 0.05), without affecting FVC significantly (−4.1 ± 2.4; P = 0.01 vs. N, interaction P = 0.03). However, within the HF group, responses were bimodal: LBNP −40 mmHg increased MSNA in all subjects ( P < 0.001), yet the six patients with nonischemic or dilated cardiomyopathy (DCM) exhibited significant vasoconstriction (decrease in FVC; P = 0.001), whereas the six patients with ischemic cardiomyopathy (ICM) exhibited significant vasodilation (increase in FVC; P < 0.02 vs. DCM and N; interaction P = 0.02). Cold pressor testing increased MSNA and decreased FVC in ICM ( n = 4). Thus paradoxical forearm vasodilator responses to LBNP in HF are not mediated by reflex sympathetic withdrawal. ICM and DCM patients differ qualitatively in their vascular responses to hypotensive LBNP.

To determine, in patients with pulmonary arterial hypertension (PAH), whether there is a relationship: (1) between sympathetic nerve firing rate and spectral indices of sympathetic neural heart rate modulation; and (2) between heart rate variability (HRV) and right atrial pressure, a stimulus to sinoatrial node stretch.Characterisation of patients and healthy controls.Teaching hospital-based study.9 PAH patients without elevated pulmonary capillary wedge pressure and nine age-matched control subjects.Heart rate (HR) and muscle sympathetic nerve activity (MSNA) were recorded during 10 min of supine rest in both PAH patients studied after right heart catheterisation, and healthy volunteers. Coarse-graining spectral analysis determined HR spectral power.(1) Low-frequency (PL) spectral component of HRV; (2) MSNA burst frequency; and in PAH patients: (3) right atrial pressure.MSNA burst frequency was higher in PAH patients (48 (24) and 29 (11) bursts/min, respectively; mean (SD); p = 0.05), whereas total power (p = 0.01), its fractal (p0.01) and harmonic (p = 0.04) components, and PL (p = 0.01) were all reduced. PL related inversely to both MSNA burst frequency (r = -0.86, p = 0.005) and right atrial systolic pressure (r = -0.77, p = 0.04).Thus, in PAH (as in patients with left ventricular systolic dysfunction) loss of PL relates inversely to gain in MSNA burst frequency. Diminished sympathetic neural heart rate modulation and increased right atrial stretch may combine to attenuate HRV, an adverse prognostic marker.

The cardiovascular benefits of light to moderate red wine consumption often have been attributed to its polyphenol constituents. However, the acute dose-related hemodynamic, vasodilator, and sympathetic neural effects of ethanol and red wine have not been characterized and compared in the same individual. We sought to test the hypotheses that responses to one and two alcoholic drinks differ and that red wine with high polyphenol content elicits a greater effect than ethanol alone. Thirteen volunteers (24–47 yr; 7 men, 6 women) drank wine, ethanol, and water in a randomized, single-blind trial on three occasions 2 wk apart. One drink of wine and ethanol increased blood alcohol to 38 ± 2 and 39 ± 2 mg/dl, respectively, and two drinks to 72 ± 4 and 83 ± 3 mg/dl, respectively. Wine quadrupled plasma resveratrol ( P < 0.001) and increased catechin ( P < 0.03). No intervention affected blood pressure. One drink had no heart rate effect, but two drinks of wine increased heart rate by 5.7 ± 1.6 beats/min; P < 0.001). Cardiac output fell 0.8 ± 0.3 l/min after one drink of ethanol and wine (both P < 0.02) but increased after two drinks of ethanol (+0.8 ± 0.3 l/min) and wine (+1.2 ± 0.3 l/min) ( P < 0.01). One alcoholic drink did not alter muscle sympathetic nerve activity (MSNA), while two drinks increased MSNA by 9–10 bursts/min ( P < 0.001). Brachial artery diameter increased after both one and two alcoholic drinks ( P < 0.001). No beverage augmented, and the second wine dose attenuated ( P = 0.02), flow-mediated vasodilation. One drink of ethanol dilates the brachial artery without activating sympathetic outflow, whereas two drinks increase MSNA, heart rate, and cardiac output. These acute effects, which exhibit a narrow dose response, are not modified by red wine polyphenols.

The sympathetic nervous system is critical for coordinating the cardiovascular response to various types of physical exercise. In a number of disease states, including human heart failure with reduced ejection fraction (HFrEF), this regulation can be disturbed and adversely affect outcome. The purpose of this review is to describe sympathetic activity at rest and during exercise in both healthy humans and those with HFrEF and outline factors, which influence these responses. We focus predominately on studies that report direct measurements of efferent sympathetic nerve traffic to skeletal muscle (muscle sympathetic nerve activity; MSNA) using intraneural microneurographic recordings. Differences in MSNA discharge between subjects with and without HFrEF both at rest and during exercise and the influence of exercise training on the sympathetic response to exercise will be discussed. In contrast to healthy controls, MSNA increases during mild to moderate dynamic exercise in the presence of HFrEF. This increase may contribute to the exercise intolerance characteristic of HFrEF by limiting muscle blood flow and may be attenuated by exercise training. Future investigations are needed to clarify the neural afferent mechanisms that contribute to efferent sympathetic activation at rest and during exercise in HFrEF.

Caffeine increases submaximal exercise performance in healthy young subjects; its effects on exercise tolerance in heart failure (HF) have not been characterized.To determine whether caffeine increases exercise tolerance in HF, caffeine (4 mg/kg intravenously, equivalent to 2 cups of coffee) or vehicle were infused into 10 treated HF patients (left ventricular ejection fraction 25 +/- 2 %), and 10 age-matched normal subjects (N) on 2 separate days in a double-blind, randomized, crossover design. We measured heart rate, blood pressure, and ventilation at rest and during graded cycling (15 W/minute) to peak effort. Peak oxygen consumption was unaffected in either group. Mean exercise time was unchanged in N (1,013 +/- 87 versus 988 +/- 107 seconds; P = .86) but was significantly increased by caffeine in HF (from 511 +/- 28 to 560 +/- 37 seconds; P = .004) despite an increase in peak minute ventilation (P.05). Resting and peak blood pressures were higher after caffeine (P.05) in HF, not N.Caffeine allows HF patients to exercise longer at peak effort.

Sustained hypotension after an acute dynamic exercise bout is due primarily to peripheral vasodilation. We tested the hypothesis that adenosine-mediated vasodilation contributes to hypotension after exercise, by determining the effect of blocking its actions with caffeine.Fourteen healthy middle-aged subjects (mean age = 51 +/- 3 years), cycled to peak effort on 2 study days, after a randomized double-blind intravenous infusion of caffeine (4 mg/kg) selective for adenosine receptor blockade, or vehicle. Both studies were performed after 72 h of caffeine abstinence.Infusion achieved 52.0 +/- 6.1 mumol/L caffeine in plasma. Significant reductions in mean and diastolic blood pressure (BP) were elicited by prior exercise on the vehicle day (from 93 +/- 2 to 85 +/- 2 mm Hg v from 79 +/- 2 to 73 +/- 3 mm Hg, respectively; both P.05), but not after caffeine infusion. Systolic and mean BP, 10 min after exercise, were higher on the caffeine than on the vehicle day (by 9 +/- 3 and 6 +/- 2 mm Hg, respectively; P.05), as was heart rate (HR) (100 +/- 5 v 93 +/- 4 beats/min; P.05).These data suggest that endogenous adenosine contributes to early hypotension after exercise in healthy middle-aged subjects and underscore the importance of caffeine abstinence if BP or HR immediately after exercise is used to infer cardiovascular risk.

Both exercise and postmenopausal estrogen therapy augment endothelial function. We hypothesized that their interaction would be additive. The study objectives were to determine in postmenopausal women (1) the effects of an acute bout of exercise on brachial artery endothelium-dependent flow-mediated vasodilation (FMD), (2) whether these responses to exercise are augmented by concurrent estrogen treatment, and (3) whether these 2 interventions, independently or together, achieve FMD values observed in premenopausal women.In postmenopausal women (n = 13; age 54 +/- 2 [mean +/- SE] years), FMD was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes at 60% V* O2max. Subjects were studied twice: before and after 4 weeks of oral estradiol. To obtain reference normal values, FMD was determined concurrently in 14 premenopausal (28 +/- 1 years) women under identical basal conditions.Flow-mediated vasodilation in postmenopausal women, markedly impaired when compared with premenopausal women (5.3% +/- 0.5% vs 12.1% +/- 1.5%, P.01), was significantly increased by exercise (to 9.9% +/- 0.6%, P.01). In contrast, after estrogen, FMD was augmented at rest (P.01) but was not further enhanced after exercise (11.5% +/- 0.6% vs 9.9% +/- 0.5%, P = .3). Both interventions increased, independently, FMD to values in premenopausal women (P.05).In postmenopausal women, both acute exercise and estrogen therapy normalize FMD. However, their effects are not additive, possibly because of redundancy of nitric oxide signaling pathways activated by these 2 interventions. When considered in the context of recent trials with adverse cardiovascular outcomes, these results reinforce the therapeutic potential of exercise as an alternative nonpharmacological intervention to estrogen in postmenopausal women with endothelial dysfunction.

To determine, in sedentary normotensive postmenopausal women, the after-effects of exercise on systemic and regional hemodynamics, and whether changes in total peripheral conductance after exercise relate to changes in brachial artery flow-mediated vasodilation (FMD).In 13 sedentary postmenopausal women, the blood pressure (BP), cardiac output, total peripheral resistance and total peripheral conductance, calf vascular resistance and FMD were measured during baseline rest, and again commencing 45 min after treadmill exercise. Fourteen premenopausal women completed the identical protocol to obtain reference values for the after-effects of exercise in healthy females.In postmenopausal women, exercise was followed by falls in systolic BP (P0.01) and diastolic BP (P0.001). BP did not fall after exercise in premenopausal women. In both groups the cardiac output (P0.01) increased and the calf vascular resistance (P0.01) and total peripheral resistance (P0.05) decreased after exercise, but resistance fell more (P0.05) in postmenopausal women. Baseline FMD was greater in premenopausal women (12.1 +/- 1.5 versus 5.3 +/- 1.3%, P0.01), and similar before and after exercise, whereas prior exercise nearly doubled the FMD of postmenopausal women (to 9.9 +/- 1.4%, P0.01). These increases in FMD correlated with baseline values (r = -0.75, P0.01) and with relative changes in total peripheral conductance (r = 0.72, P0.02). The latter relationship was absent in premenopausal women (r = -0.29).In postmenopausal women, acute dynamic exercise elicits sustained increases in FMD that could facilitate post-exercise hypotension in this population. These observations reinforce the concept of exercise as an important non-pharmacological intervention to modify cardiovascular risk in postmenopausal women.

People with diminished ventricular contraction who develop heart failure have higher sympathetic nerve firing rates at rest compared with healthy individuals of a similar age and this is associated with less exercise capacity. During handgrip exercise, sympathetic nerve activity to muscle is higher in patients with heart failure but the response to leg exercise is unknown because its recording requires stillness. We measured sympathetic activity from one leg while the other leg cycled at a moderate level and observed a decrease in nerve firing rate in healthy subjects but an increase in subjects with heart failure. Because these nerves release noradrenaline, which can restrict muscle blood flow, this observation helps explain the limited exercise capacity of patients with heart failure. Lower nerve traffic during exercise was associated with greater peak oxygen uptake, suggesting that if exercise training attenuated sympathetic outflow functional capacity in heart failure would improve.The reflex fibular muscle sympathetic nerve (MSNA) response to dynamic handgrip exercise is elicited at a lower threshold in heart failure with reduced ejection fraction (HFrEF). The present aim was to test the hypothesis that the contralateral MSNA response to mild to moderate dynamic one-legged exercise is augmented in HFrEF relative to age- and sex-matched controls. Heart rate (HR), blood pressure and MSNA were recorded in 16 patients with HFrEF (left ventricular ejection fraction = 31 ± 2%; age 62 ± 3 years, mean ± SE) and 13 healthy control subjects (56 ± 2 years) before and during 2 min of upright one-legged unloaded cycling followed by 2 min at 50% of peak oxygen uptake (V̇O2,peak). Resting HR and blood pressure were similar between groups whereas MSNA burst frequency was higher (50.0 ± 2.0 vs. 42.3 ± 2.7 bursts min(-1), P = 0.03) and V̇O2,peak lower (18.0 ± 2.0 vs. 32.6 ± 2.8 ml kg(-1) min(-1), P0.001) in HFrEF. Exercise increased HR (P0.001) with no group difference (P = 0.1). MSNA burst frequency decreased during mild to moderate dynamic exercise in the healthy controls but increased in HFrEF (-5.5 ± 2.0 vs. 6.9 ± 1.8 bursts min(-1), P0.001). Exercise capacity correlated inversely with MSNA burst frequency at 50% V̇O2,peak (n = 29; r = -0.64; P0.001). At the same relative workload, one-legged dynamic exercise elicited a fall in MSNA burst frequency in healthy subjects but sympathoexcitation in HFrEF, a divergence probably reflecting between-group differences in reflexes engaged by cycling. This finding, coupled with an inverse relationship between MSNA burst frequency during loaded cycling and subjects' V̇O2,peak, is consistent with a neurogenic determinant of exercise capacity in HFrEF.

Background —The purpose of this study was to determine if atrial natriuretic peptide (ANP) exerts a relative inhibitory effect on muscle sympathetic nerve activity (MSNA) at rest and during nonhypotensive lower body negative pressure (LBNP) in heart failure, as in healthy subjects. Methods and Results —Fifteen men (age 39±2 years [mean±SE]) with dilated cardiomyopathy (ejection fraction 18±3%) received intravenous ANP (50 μg bolus, then 50 ng · kg −1 · min −1 ) and nitroglycerin (NTG, 8 mg/min) as a hemodynamic control. During each infusion MSNA, blood pressure (BP), central venous pressure (CVP), and heart rate (HR) were recorded before and during LBNP at −6 and −12 mm Hg. NTG and ANP caused similar and significant reductions in CVP and diastolic BP, but resting MSNA did not increase with either infusion. LBNP at −6 mm Hg lowered CVP ( P P P P =NS). Conclusions —These observations are consistent with the concept that ANP exerts a sympathoinhibitory action in heart failure. This is most evident in response to reductions in atrial pressures that do not affect systemic BP.

Blood pressure and heart rate responses to adenosine infusion (35, 70, and 140 microg/kg/min, intravenously) were studied in 7 healthy men after 6, 30, 78, 150, and 318 hours of abstinence from regular caffeine use. The finding that caffeine abstinence augmented the systolic pressor response (from -1 +/- 2 mm Hg at 6 hours to +9 +/- 2 mm Hg at 318 hours; p = 0.01) but not the tachycardic response to adenosine has implications for current clinical and research applications of this purine.

L'adenosine augmente la frequence cardiaque et l'activite nerveuse sympathique de maniere reflexe chez les humains conscients et ce, par l'intermediaire de divers mecanismes. Le but de la presente etude a ete d'evaluer l'influence sur ces reponses d'une decharge des barorecepteurs arteriels, d'une stimulation des chemorecepteurs carotidiens, ainsi que d'autres nerfs afferents sensibles a l'adenosine. Chez 12 hommes sains, on a compare l'effet d'une pression negative des membres inferieurs (PNMI; -15 mmHg (1 mmHg = 133,3 Pa)) avec celui de l'adenosine intraveineuse (35, 70 et 140 μg.kg-1.min -1 ) sur la pression arterielle, la frequence cardiaque (FC) et l'activite nerveuse sympathique musculaire (ANSM; nerf perionnier). Chez huit sujets, on a reinjecte la plus forte dose d'adenosine en presence de 100% d'oxygene afin de supprimer les chemorecepteurs arteriels. Les reductions de pression arterielle durant la PNMI et l'adenosine (140 μg-kg -1 .min -1 ) ont ete similaires. La frequence cardiaque n'a pas change significativement durant la PNMI (+2 ± 2 battements/min; moyenne ± ET), mais elle a augmente a la plus forte dose d'adenosine (+25 ± 3 battements/min; p 0,1). L'oxygene a inhibe les augmentations de FC et d'ANSM induites par l'adenosine (de +305 ± 99 a 198 ± 75 unites/100 battements et de +26 ± 4 a +18 ± 3 battements/min; p < 0,05 dans les deux cas). La reponse de l'ANSM a ces deux stimuli combines a ete similaire a celle observee durant la PNMI. A l'oppose, la reponse FC residuelle (+18 ± 3 battements/min) a ete significativement plus forte que la reponse a la PNMI (+2 ± 2 battements/min; p < 0,05). Ces resultats indiquent que la decharge des barorecepteurs arteriels ne peut justifier l'augmentation de FC marquee induite par l'adenosine, mais elle pourrait etre suffisante pour expliquer son effet sur l'ANSM. L'effet obtenu en presence de 100% d'oxygene confirme que la stimulation des chemorecepteurs carotidiens contribue a environ un tiers de la reponse de l'ANSM et de la FC a l'adenosine. Toutefois, d'autres mecanismes, tels que la stimulation des nerfs afferents sensibles a l'adenosine dans d'autres lits vasculaires, participent a la reponse de la frequence cardiaque et possiblement de l'ANSM.

Previous reports, involving hypercholesterolaemic hypertensive subjects, that statins reduce muscle sympathetic nerve activity (MSNA) did not investigate potential neural sites of such sympathoinhibition or determine its consequences for endothelial function or insulin resistance. This study of hypertensive subjects with lower plasma cholesterol tested the hypotheses that lipophilic simvastatin would attenuate resting sympathoexcitation and augment baroreflex modulation of MSNA and heart rate (HR), flow-mediated vasodilation and insulin sensitivity.Prospective, randomised, double-blind, placebo-controlled crossover study.Academic hospital-based study.Fourteen non-hyperlipidaemic primary hypertensive subjects (10 men; overall mean±SD age 58±12 years).Four weeks of simvastatin (80 mg/day) or placebo.Resting blood pressure (BP), HR, MSNA, spontaneous arterial baroreflex MSNA and HR modulation, endothelium-dependent and endothelium-independent vasodilation, and the homoeostatic model assessment of insulin resistance (HOMA-IR).Simvastatin lowered MSNA burst frequency (from 32±12 to 25±9 bursts/min) and MSNA burst incidence (from 55±23% to 43±17%; all p0.01) without affecting BP, HR, baroreflex modulation of either MSNA or HR, or HR variability (all p0.05). Plasma glucose, insulin, HOMA-IR and endothelium-dependent vasodilation (all p0.05) were unchanged, whereas endothelium-independent vasodilation increased (7.1±3.8% to 9.7±3.9%, n=13; p0.01). The fall in MSNA was unrelated to the decrease in low-density lipoprotein cholesterol (r=0.41, p=0.14).These findings are consistent with the concept that, in non-hyperlipidaemic subjects with primary hypertension, simvastatin causes a cholesterol-independent reduction in an elevated central set-point for MSNA, without affecting arterial baroreflex modulation of either MSNA or HR. There may be less neurogenic constraint on endothelium-independent vasodilation as a consequence.

BACKGROUND To determine whether angiotensin II (ANG II) contributes to the reflex skeletal muscle sympathoexcitation elicited by isometric and isotonic exercise, we tested the hypothesis that angiotensin AT 1 receptor blockade (ARB) would attenuate reflex sympathoneural responses to handgrip (HG) and to post-handgrip ischemia (PHGI). METHODS Seventeen healthy men were studied before and 1 week after random double-blind crossover allocation to oral losartan (100 mg daily) and placebo. Heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were recorded at rest, and during 2 min bouts of isotonic HG at 50% maximum voluntary contraction (MVC) and isometric HG at 30% MVC, performed randomly, each followed by 2 min of PHGI. RESULTS At rest, losartan doubled plasma renin (P= 0. 01 ) and ANG II (P = 0.03) concentrations, and lowered BP (P < 0.01) yet had no effect on MSNA burst frequency or incidence. HR trended higher (P = 0.060). Losartan's hypotensive effect persisted throughout each exercise bout (P < 0.045). MSNA and HR responses to isotonic exercise and postexercise ischemia were not affected by losartan. Isometric exercise and postexercise ischemia increased MSNA on both sessions (all P < 0.01). Losartan augmented the HR response (P ≤ 0.03), and after losartan MSNA burst frequency (P < 0.01) and incidence (P < 0.04) were significantly higher at all time points, but the magnitude of the MSNA response to isometric exercise and postexercise ischemia was unchanged. CONCLUSION In healthy men, short-term ARB does not attenuate reflex sympathoneural responses to HG or PHGI.

In healthy subjects a standard drink of either red wine (RW) or ethanol (EtOH) has no effect on muscle sympathetic nerve activity or on heart rate (HR), whereas two drinks increase both. Using time- and frequency-domain indexes of HR variability (HRV), we now tested in 12 subjects (24–47 yr, 6 men) the hypotheses that 1) this HR increase reflects concurrent dose-related augmented sympathetic HR modulation and 2) RW with high-polyphenol content differs from EtOH in its acute HRV effects. RW, EtOH, and water were provided on 3 days, 2 wk apart according to a randomized, single-blind design. Eight-minute segments were analyzed. One alcoholic drink increased blood concentrations to 36 ± 2 mg/dl (mean ± SE), and 2 drinks to 72 ± 4 (RW) and 80 ± 2 mg/dl (EtOH). RW quadrupled plasma resveratrol ( P < 0.001). HR fell after both water drinks. When compared with respective baselines, one alcoholic drink had no effect on HR or HRV, whereas two glasses of both increased HR (RW, +5.4 ± 1.2; and EtOH, +5.7 ± 1.2 min−1; P < 0.001), decreased total HRV by 28–33% ( P < 0.05) and high-frequency spectral power by 32–42% (vagal HR modulation), and increased low-frequency power by 28–34% and the ratio of low frequency to high frequency by 98–119% (sympathetic HR modulation) (all, P ≤ 0.01). In summary, when compared with water, one standard drink lowered time- and frequency-domain markers of vagal HR modulation. When compared with respective baselines, two alcoholic drinks increased HR by diminished vagal and augmented sympathetic HR modulation. Thus alcohol exerts dose-dependent HRV responses, with RW and EtOH having a similar effect.

Background. Patients with end-stage renal disease (ESRD) have a reduced exercise capacity as assessed by peak oxygen uptake (VO2peak). Nocturnal haemo- dialysis (NHD) augments uraemic clearance and vascular responsiveness to nitric oxide and lowers blood pressure (BP) and peripheral resistance. Methods. To assess the impact of NHD on exercise duration and capacity, 13 consecutive ESRD patients (age: 41 � 3; (meanSEM)) and healthy normal subjects (n ¼ 14) matched for age and body mass index exercised to peak effort (VO2peak) as determined by open-circuit spirometry during a graded cycle ergometer test with a ramp increase in work rate (by 17 watts/min). Results. Exercise was performed before, 2 and 3-6 months after conversion from conventional haemodia- lysis (CHD) (3 sessions per week; 4 h per session) to NHD (5-6 sessions per week; 6-8 h per session). Exercise duration increased progressively (from 617 � 50 (CHD) to 634 � 47 (NHD 2 months) to 682 � 55 (NHD 3-6 months), P ¼ 0.03) as did exercise capacity, expressed as percent of predicted (based on age, sex and body size) VO2peak, (from 66 � 8 (CHD) to 72 � 6 (NHD 2 months) to 75 � 6% (NHD 3-6 months), P < 0.05). Conclusion. Enhanced uraemia control by NHD improved both exercise duration and capacity. When coupled with augmented uraemia management, an increase in physical activity, perhaps due to more effective oxygen delivery or improved muscle metabo- lism, has the potential to improve the quality of life of patients with ESRD.

The magnitude of sympathetic activation in chronic heart failure is assumed to be independent of its cause. However, because a higher sympathetic component of heart rate variability (HRV) in patients with ischemic cardiomyopathy (ICM) has been reported, we hypothesized that patients with ICM would have a higher resting muscle sympathetic nerve activity (MSNA) than patients with nonischemic dilated cardiomyopathy (DCM).Resting MSNA was assessed by microneurography and HRV concurrently by coarse-graining spectral analysis in 30 treated normotensive patients with chronic heart failure (12 with ICM and 18 with DCM), matched for age and left ventricular ejection fraction, and 23 healthy normal control subjects, matched for age and blood pressure. Peak oxygen uptake was determined during graded cycling (17 W/min) to maximum effort. MSNA was significantly different between groups (P.001; ICM 60 +/- 3; DCM 47 +/- 3; control subjects 35 +/- 3 bursts/min). Compared with control subjects, the total spectral power and the high-frequency component of HRV were lower in both ICM and DCM groups, but fractal and low-frequency power were lower only in the ICM group (P.05). Peak oxygen uptake (milliliters per kilogram of body weight per minute) was significantly less in the ICM group than in the DCM group (P = .04) and lower in both groups than in the control subjects (P.001).These observations suggest an additional ischemic stimulus to sympathetic activation in heart failure, which may impair exercise capacity reflexively.

To the Editor: Muscle sympathetic nerve activity (MSNA), as measured during supine rest, is similar between patients with chronic heart failure (HF) due to left ventricular systolic function with relatively preserved capacity for exercise (percentage of peak oxygen uptake [VO2peak] predicted by

Adenosine (Ado) increases muscle sympathetic nerve activity (MSNA) reflexively. Plasma Ado and MSNA are elevated in heart failure (HF). We tested the hypothesis that Ado receptor blockade by caffeine would attenuate reflex MSNA responses to handgrip (HG) and posthandgrip ischemia (PHGI) and that this action would be more prominent in HF subjects than in normal subjects. We studied 12 HF subjects and 10 age-matched normal subjects after either saline or caffeine (4 mg/kg) infusion during isometric [30% of maximal voluntary contraction (MVC)] and isotonic (10%, 30%, and 50%) HG exercise, followed by 2 min of PHGI. In normal subjects, caffeine did not block increases in MSNA during PHGI after 50% HG. In HF subjects, caffeine abolished MSNA responses to PHGI after both isometric and 50% isotonic exercise ( P < 0.05) but MSNA responses during HG were unaffected. These findings are consistent with muscle metaboreflex stimulation by endogenous Ado during ischemic or intense nonischemic HG in HF and suggest an important sympathoexcitatory role for endogenous Ado during exercise in this condition.

Objectives Activation of the sympathetic nervous system, decreased heart rate variability (HRV), and loss of modulation of muscle sympathetic nerve activity (MSNA) within the low frequency (LF, 0.05-0.15 Hz) range are three adverse features of advanced congestive heart failure (CHF). In healthy men, atrial natriuretic peptide (ANP) infusion attenuates reflex increases in MSNA and reduces LF components of HRV spectral power. Sympathoinhibitory actions have also been documented in CHF, but effects on the variability of MSNA and HRV have not been described. Design and methods Heart rate and MSNA were recorded in 10 men (aged 39 ± 3 years, mean ± SE) with dilated cardiomyopathy (mean EF 20 ± 4%) treated with angiotensin converting enzyme (ACE) inhibitors. Subjects received i.v. ANP (50 μg bolus then 50 ng/kg/min) and nitroglycerin (NTG, 8 mg/min) as a hemodynamic control. Signals at baseline, and 13-20 min into each infusion were submitted to spectral analysis. Results ANP had no effect on HRV, but increased MSNA LF (from 7.9 ± 1.5 to 12.1 ± 2.6 U 2 ; P< 0.02) and total spectral power (from 47.9 ± 5.4 to 61.9 ± 6.8 U 2 ; P< 0.05). NTG had no effect on the variability of MSNA or HRV. Conclusions In CHF patients receiving ACE inhibitors, ANP (i) does not suppress HRV and (ii) enhances the modulation of MSNA, particularly within the LF range. This latter action is not observed with NTG. These findings suggest beneficial actions of exogenous ANP on neurogenic circulatory control.

Peak oxygen uptake (V˙o 2 peak) in patients with heart failure (HF) is inversely related to muscle sympathetic nerve activity (MSNA) at rest. We hypothesized that the MSNA response to handgrip exercise is augmented in HF patients and is greatest in those with lowV˙o 2 peak. We studied 14 HF patients and 10 age-matched normal subjects during isometric [30% of maximal voluntary contraction (MVC)] and isotonic (10%, 30%, and 50% MVC) handgrip exercise that was followed by 2 min of posthandgrip ischemia (PHGI). MSNA was significantly increased during exercise in HF but not normal subjects. Both MSNA and HF levels remained significantly elevated during PHGI after 30% isometric and 50% isotonic handgrip in HF but not normal subjects. HF patients with lower V˙o 2 peak (2 peak > 56% predicted ( n = 6) and normal subjects. The muscle metaboreflex contributes to the greater reflex increase in MSNA during ischemic or intense nonischemic exercise in HF. This occurs at a lower threshold than normal and is a function ofV˙o 2 peak.