Hisayoshi Murai

Paradoxical muscle sympathetic reflex activation in human heart failure.

Background— Muscle sympathetic activation in heart failure with reduced ejection fraction (HFrEF) has been attributed, on the basis of multiunit recordings, to attenuated inhibitory feedback from stretch-sensitive cardiopulmonary mechanoreceptors. However, such preparations integrate 2 populations of single units exhibiting directionally opposite firing when atrial pressure is perturbed. We tested the hypothesis that the proportion of single units firing paradoxically when filling pressure increases is augmented in HFrEF. Methods and Results— Muscle sympathetic nerve activity and estimated central venous pressure were recorded during nonhypotensive lower body negative pressure (LBNP; -10 mm Hg) and nonhypertensive positive pressure (LBPP; +10 mm Hg) in 11 treated HFrEF (left ventricular ejection fraction 25±6% [mean±standard deviation]) patients and 14 similarly aged controls. Single-unit muscle sympathetic nerve activity discharge was termed either anticipated, if firing frequency exhibited classic negative-feedback responses, or paradoxical. LBNP and LBPP had no heart rate, stroke volume, or blood pressure effects (P>0.05). Estimated central venous pressure decreased with LBNP (P<0.05), increased with LBPP (P<0.05), and was consistently higher in HFrEF (P<0.05). During LBNP, the ratio of single units with anticipated and paradoxical discharge was similar in HFrEF (18:7) and controls (27:5), whereas LBPP elicited paradoxical reflex excitation in a greater proportion of HFrEF single units (7:18 versus 24:6; P=0.0001). Consequently, LBPP increased mean single-unit firing frequency (P<0.05) and did not inhibit multiunit muscle sympathetic nerve activity of HFrEF subjects (P<0.05 versus controls). Firing of 12/18 HFrEF (but no control) single units increased during both LBPP and LBNP. Conclusion— These findings provide the first evidence in human HFrEF for an augmented excitatory cardiopulmonary–muscle sympathetic nerve activity reflex response to increased preload, incorporating 2 distinct single-unit populations with differing firing properties.

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.

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.

Microneurographic evidence in healthy middle-aged humans for a sympathoexcitatory reflex activated by atrial pressure

Atrial mechanoreceptors, stimulated by increased pressure or volume, elicit in healthy humans a net sympathoinhibitory response. The co-existence of an atrial reflex eliciting muscle sympathoexcitation has been postulated but undetected by conventional multi-unit muscle sympathetic nerve activity (MSNA). We hypothesized that in response to a selective increase in atrial pressure, single-unit MSNA would reveal a subpopulation of efferent sympathetic neurons with firing patterns opposite to the integrated multi-unit MSNA envelope. Multi- and single-unit MSNA recordings were acquired in eight healthy middle-aged subjects (age, 57 ± 8 years; body mass index, 25 ± 2 kg/m(2)) submitted to selective decreases or increases in atrial pressure by nonhypotensive lower body negative pressure (LBNP; -10 mmHg) or nonhypertensive lower body positive pressure (LBPP; +10 mmHg), respectively. Single-unit MSNA firing responses were classified as anticipated if spike frequency and incidence increased with LBNP or decreased with LBPP and paradoxical if they decreased with LBNP or increased with LBPP. LBNP decreased (3.2 ± 2.8 to 1.4 ± 3.1 mmHg, P < 0.01) and LBPP increased (3.3 ± 2.7 to 4.9 ± 2.8 mmHg, P < 0.01) estimated central venous pressure without affecting stroke volume, systemic pressure, or resistance. Multi-unit MSNA increased with LBNP (31 ± 17 to 38 ± 19 bursts/min, P < 0.01) and diminished with LBPP (33 ± 15 to 28 ± 15 bursts/min, P < 0.01). Of 21 single-units identified, 76% exhibited firing responses to both LBNP and LBPP concordant with multi-unit MSNA, whereas 24% demonstrated discordant or paradoxical responses. The detection of two subpopulations of single-units within the multi-unit MSNA recording, exhibiting opposite firing characteristics, establishes the first evidence in humans for the existence of an excitatory cardiac-muscle sympathetic reflex activated by increasing atrial pressure.

Arousal From Sleep and Sympathetic Excitation During Wakefulness

Obstructive apnea during sleep elevates the set point for efferent sympathetic outflow during wakefulness. Such resetting is attributed to hypoxia-induced upregulation of peripheral chemoreceptor and brain stem sympathetic function. Whether recurrent arousal from sleep also influences daytime muscle sympathetic nerve activity is unknown. We therefore tested, in a cohort of 48 primarily nonsleepy, middle-aged, male (30) and female (18) volunteers (age: 59±1 years, mean±SE), the hypothesis that the frequency of arousals from sleep (arousal index) would relate to daytime muscle sympathetic burst incidence, independently of the frequency of apnea or its severity. Polysomnography identified 24 as having either no or mild obstructive sleep apnea (apnea–hypopnea index <15 events/h) and 24 with moderate-to-severe obstructive sleep apnea (apnea–hypopnea index >15 events/h). Burst incidence correlated significantly with arousal index (r=0.53; P<0.001), minimum oxygen saturation (r=−0.43; P=0.002), apnea–hypopnea index (r=0.41; P=0.004), age (r=0.36; P=0.013), and body mass index (r=0.33; P=0.022) but not with oxygen desaturation index (r=0.28; P=0.056). Arousal index was the single strongest predictor of muscle sympathetic nerve activity burst incidence, present in all best subsets regression models. The model with the highest adjusted R2 (0.456) incorporated arousal index, minimum oxygen saturation, age, body mass index, and oxygen desaturation index but not apnea–hypopnea index. An apnea- and hypoxia-independent effect of sleep fragmentation on sympathetic discharge during wakefulness could contribute to intersubject variability, age-related increases in muscle sympathetic nerve activity, associations between sleep deprivation and insulin resistance or insomnia and future cardiovascular events, and residual adrenergic risk with persistence of hypertension should therapy eliminate obstructive apneas but not arousals.

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.

Neurogenic Retrograde Arterial Flow During Obstructive Sleep Apnea: A Novel Mechanism for Endothelial Dysfunction?

To the Editor: Patients with obstructive sleep apnea (OSA) exhibit impaired brachial artery flow-mediated dilation during wakefulness, a phenomenon that has been attributed to a carryover into the awake state of the consequences of recurrent cycles of hypoxia and reperfusion during sleep, resulting in decreased NO bioavailability and vascular inflammation.1 However, recent prospective studies have failed to identify clearly an independent predictive relationship between markers of oxidative stress and endothelial function.2 Our unanticipated detection of retrograde arterial flow during spontaneous obstructive apnea in an experimental subject who fell asleep when studied during the daytime leads us to propose a novel, additional mechanism for the development of this marker of endothelial dysfunction. A 67-year–old man (blood pressure: 142/84 mm Hg; heart rate: 49 bpm) with known severe untreated OSA (apnea-hypopnea index: 63 events per hour) and treated hypertension (40 mg of fosinopril), whose apneas precipitated …

Association between Resting State Brain Functional Connectivity and Muscle Sympathetic Burst Incidence

The insula (IC) and cingulate are key components of the central autonomic network and central nodes of the salience network (SN), a set of spatially distinct but temporally correlated brain regions identified with resting-state (task free) functional MRI (rsMRI). To examine the SNs involvement in sympathetic outflow, we tested the hypothesis that individual differences in intrinsic connectivity of the SN correlate positively with resting postganglionic muscle sympathetic nerve activity (MSNA) burst incidence (BI) in subjects without and with obstructive sleep apnea (OSA). Overnight polysomnography, 5-min rsMRI, and fibular MSNA recording were performed in 36 subjects (mean age 57 yr; 10 women, 26 men). Independent component analysis (ICA) of the entire cohort identified the SN as including bilateral IC, pregenual anterior cingulate cortex (pgACC), midcingulate cortex (MCC), and the temporoparietal junction (TPJ). There was a positive correlation between BI and the apnea-hypopnea index (AHI) (P < 0.001), but dual-regression analysis identified no differences in SN functional connectivity between subjects with no or mild OSA (n = 17) and moderate or severe (n = 19) OSA. Correlation analysis relating BI to the strength of connectivity within the SN revealed large (i.e., spatial extent) and strong correlations for the left IC (P < 0.001), right pgACC/MCC (P < 0.006), left TPJ (P < 0.004), thalamus (P < 0.035), and cerebellum (P < 0.013). Indexes of sleep apnea were unrelated to BI and the strength of SN connectivity. There were no relationships between BI and default or sensorimotor network connectivity. This study links connectivity within the SN to MSNA, demonstrating several of its nodes to be key sympathoexcitatory regions.

Discordant Orthostatic Reflex Renin–Angiotensin and Sympathoneural Responses in Premenopausal Exercising-Hypoestrogenic Women

Our prior observations in normotensive postmenopausal women stimulated the hypotheses that compared with eumenorrheic women, active hypoestrogenic premenopausal women with functional hypothalamic amenorrhea would demonstrate attenuated reflex renin–angiotensin–aldosterone system responses to an orthostatic challenge, whereas to defend blood pressure reflex increases in muscle, sympathetic nerve activity would be augmented. To test these hypotheses, we assessed, in recreationally active women, 12 with amenorrhea (ExFHA; aged 25±1 years; body mass index 20.7±0.7 kg/m2; mean±SEM) and 17 with eumenorrhea (ExOv; 24±1 years; 20.9±0.5 kg/m2), blood pressure, heart rate, plasma renin, angiotensin II, aldosterone, and muscle sympathetic nerve activity at supine rest and during graded lower body negative pressure (−10, −20, and −40 mm Hg). At baseline, heart rate and systolic blood pressure were lower (P<0.05) in ExFHA (47±2 beats/min and 94±2 mm Hg) compared with ExOv (56±2 beats/min and 105±2 mm Hg), but muscle sympathetic nerve activity and renin–angiotensin–aldosterone system constituents were similar (P>0.05). In response to graded lower body negative pressure, heart rate increased (P<0.05) and systolic blood pressure decreased (P<0.05) in both groups, but these remained consistently lower in ExFHA (P<0.05). Lower body negative pressure elicited increases (P<0.05) in renin, angiotensin II, and aldosterone in ExOv, but not in ExFHA (P>0.05). Muscle sympathetic nerve activity burst incidence increased reflexively in both groups, but more so in ExFHA (P<0.05). Otherwise, healthy hypoestrogenic ExFHA women demonstrate low blood pressure and disruption of the normal circulatory response to an orthostatic challenge: plasma renin, angiotensin II, and aldosterone fail to increase and blood pressure is defended by an augmented sympathetic vasoconstrictor response.

Cortical autonomic network gray matter and sympathetic nerve activity in obstructive sleep apnea

The sympathetic excitation elicited acutely by obstructive apnea during sleep (OSA) carries over into wakefulness. We hypothesized that OSA induces structural changes in the insula and cingulate, key central autonomic network (CAN) elements with projections to brainstem sympathetic premotor regions. The aims of this study were to: 1) apply two distinct but complementary methods (cortical thickness analysis [CTA] and voxel based morphometry [VBM]) to compare insula and cingulate grey matter thickness in subjects without and with OSA; 2) determine if oxygen desaturation index (ODI) relates to cortical thickness; and 3) determine if cortical thickness or volume in these regions predicts muscle sympathetic nerve (MSNA) burst incidence (BI). Overnight polysomnography, anatomical MRI and MSNA data were acquired in 41 subjects with no or mild OSA (n=19; 59±2 yrs [Mean±SE]; 6 female; apnea-hypopnea index [AHI] 7±1 events/hour) or moderate to severe OSA (n=22; 59±2 yrs; 5 female; AHI 31±4 events/hour). Between group CTA analyses identified cortical thinning within the left dorsal posterior insula (LdpIC) and thickening within the left mid-cingulate (LMCC) cortex, while VBM identified thickening within bilateral thalami (all, (P<0.05)). CTA revealed inverse relationships between ODI and bilateral dpIC and left posterior cingulate (LPCC)/precuneus thickness. Positive correlations between BI and LMCC grey matter thickness/volume were evident with both methods and between BI and left posterior thalamus volume using VBM. In OSA the magnitude of insular thinning, although a function of hypoxia severity, does not influence MSNA whereas cingulate and thalamic thickening relate directly to the intensity of sympathetic discharge during wakefulness.