Catherine F. Notarius

Hemodynamic after-effects of acute dynamic exercise in sedentary normotensive postmenopausal women.

Objectives 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). Methods 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. Results In postmenopausal women, exercise was followed by falls in systolic BP (P < 0.01) and diastolic BP (P < 0.001). BP did not fall after exercise in premenopausal women. In both groups the cardiac output (P < 0.01) increased and the calf vascular resistance (P < 0.01) and total peripheral resistance (P < 0.05) decreased after exercise, but resistance fell more (P < 0.05) in postmenopausal women. Baseline FMD was greater in premenopausal women (12.1 ± 1.5 versus 5.3 ± 1.3%, P < 0.01), and similar before and after exercise, whereas prior exercise nearly doubled the FMD of postmenopausal women (to 9.9 ± 1.4%, P < 0.01). These increases in FMD correlated with baseline values (r = −0.75, P < 0.01) and with relative changes in total peripheral conductance (r = 0.72, P < 0.02). The latter relationship was absent in premenopausal women (r = −0.29). Conclusions 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.

Effect of Atrial Natriuretic Peptide on Muscle Sympathetic Activity and Its Reflex Control in Human Heart Failure

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 microgram 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<0.05), whereas LBNP at -12 mm Hg caused significant reductions in CVP, systolic BP, and diastolic BP. These effects of nonhypotensive and hypotensive LBNP on CVP and BP were similar during ANP and NTG infusions, yet MSNA was lower both before and with LBNP during ANP (P<0.02). Nonhypotensive LBNP increased MSNA during NTG (+133+/-68 Units; P<0.001) but not during ANP infusion (+24+/-23 Units; 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.

Dose-related effects of red wine and alcohol on heart rate variability

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 + or - 2 mg/dl (mean + or - SE), and 2 drinks to 72 + or - 4 (RW) and 80 + or - 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 + or - 1.2; and EtOH, +5.7 + or - 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 < or = 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.

Discordance between microneurographic and heart rate spectral indices of sympathetic activity in pulmonary arterial hypertension

Objectives: 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. Design: Characterisation of patients and healthy controls. Setting: Teaching hospital-based study. Patients: 9 PAH patients without elevated pulmonary capillary wedge pressure and nine age-matched control subjects. Interventions: 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. Main outcome measures: (1) Low-frequency (PL) spectral component of HRV; (2) MSNA burst frequency; and in PAH patients: (3) right atrial pressure. Results: 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 (p<0.01) 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). Conclusions: 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.

Simvastatin reduces sympathetic outflow and augments endothelium-independent dilation in non-hyperlipidaemic primary hypertension

Abstract Objectives 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. Design Prospective, randomised, double-blind, placebo-controlled crossover study. Setting Academic hospital-based study. Patients Fourteen non-hyperlipidaemic primary hypertensive subjects (10 men; overall mean±SD age 58±12 years). Interventions Four weeks of simvastatin (80 mg/day) or placebo. Main outcome measures 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). Results Simvastatin lowered MSNA burst frequency (from 32±12 to 25±9 bursts/min) and MSNA burst incidence (from 55±23% to 43±17%; all p<0.01) without affecting BP, HR, baroreflex modulation of either MSNA or HR, or HR variability (all p>0.05). Plasma glucose, insulin, HOMA-IR and endothelium-dependent vasodilation (all p>0.05) were unchanged, whereas endothelium-independent vasodilation increased (7.1±3.8% to 9.7±3.9%, n=13; p<0.01). The fall in MSNA was unrelated to the decrease in low-density lipoprotein cholesterol (r=0.41, p=0.14). Conclusions 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.

Caffeine abstinence augments the systolic blood pressure response to adenosine in humans

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.

Divergent muscle sympathetic responses to dynamic leg exercise in heart failure and age-matched healthy subjects.

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.

Muscle sympathetic activity in resting and exercising humans with and without heart failure.

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.

Effect of Fitness on Reflex Sympathetic Neurovascular Transduction in Middle-Age Men

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.

Atrial natriuretic peptide augments the variability of sympathetic nerve activity in human heart failure.

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 μ g 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 U2;P < 0.02) and total spectral power (from 47.9 ± 5.4 to 61.9 ± 6.8 U2;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.