Shoemaker, J. Kevin

Discrete physiological stressors differentially affect sympathetic postganglionic neuronal rate-, population-, and temporal-coding strategies. When performing end-expiratory apnea (APN) during graded baroreflex unloading via lower body negative pressure (LBNP): 1) augmented sympathetic neuronal firing probability, 2) recruited larger and previously silent sympathetic postganglionic neurons at ambient and −10 mmHg, but not −40 mmHg LBNP, and 3) reduced neuronal discharge latency similarly across all conditions, independent of the level of baroreflex unloading.

Background Muscle sympathetic nerve activity (MSNA) is augmented in patients with sleep apnea. This increase in activity is due to increases in firing probability and mean firing rates of individual vasoconstrictor neurons, in addition to multiple within‐burst firing; however, contributing mechanisms and the impact of such firing patterns on peripheral vascular tone are less clear. We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing and recruitment strategies and the relationship between changes in MSNA and neurovascular transduction following acute IH. We hypothesized exposure to acute IH would increase MSNA via an increase in action potential (AP) discharge rates and within‐burst firing. We further hypothesized any change in discharge patterns following acute IH would be positively related to a change in neurovascular transduction. Methods Blood pressure (brachial arterial catheter) and MSNA (microneurography of the peroneal nerve) were assessed in 17 healthy adults (11M/6F; 31 ± 1 yrs) during quiet normoxic rest prior to and following 30‐min of experimental IH [30‐s hypoxic (0.05 F i O 2 ) exposures alternating with 90‐s room air breathing]. AP patterns were studied from the filtered raw MSNA signal using wavelet‐based methodology. The slope of the relationship between diastolic blood pressure (DBP) and the preceding MSNA burst area at a fixed cardiac cycle lag was used to quantify neurovascular transduction. Results IH resulted in 15 events where oxygen saturation was reduced (S p O 2 : 99 ± 1% vs 92 ± 1%, P <0.01). Compared to baseline, multi‐unit MSNA burst incidence (33 ± 4 to 43 ± 5 bursts/100 heart beats), AP incidence (272 ± 50 to 501 ± 112 AP/100 heart beats) and AP content per integrated burst (7 ± 1 to 10 ± 1 AP/burst; 4 ± 1 to 5 ± 1 clusters/burst) were increased following IH (all P< 0.05). Neurovascular transduction was not altered following IH ( P =0.34); however, there was a positive relationship between the change (Δ) in neurovascular transduction (mmHg/%/s) and changes in AP discharge rate (AP/100 heart beats; R=0.52, P= 0.03) and within‐burst firing (AP/burst; R=0.38, P= 0.14) following IH. Conclusions Acute IH increases sympathetic neuronal discharge by increasing within‐burst firing of low‐threshold axons. A positive relationship exists between increases in the neural discharge rates and neurovascular transduction following acute IH, such that those individuals with the greatest increase in AP firing exhibited the greatest increase in transduction of sympathetic activity into blood pressure. These data may have important implications for mechanistic understanding of sympathetic activation in sleep apnea and its down‐stream effects, including the development of hypertension and cardiovascular disease. Support or Funding Information Funding: NIH HL130339, Mayo Clinic Center for Biomedical Discovery, Mizzou HES PURE, APS UGSRF. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

PURPOSE Sympathetic nervous system responses to voluntary apnea are increased by hypoxia and attenuated by hyperoxia. However, whether neural firing and recruitment strategies in response to apnea can be modified by hypoxia and/or hyperoxia were previously unknown. We examined the influence of chemoreceptor stimuli on sympathetic neural firing and recruitment strategies during voluntary end‐expiratory apnea. We hypothesized increases in the firing frequency and probability of low‐threshold axons during apnea would be exaggerated during hypoxia and attenuated during hyperoxia. METHODS Multi‐unit muscle sympathetic nerve activity (MSNA, microneurography) was measured in 10 young, healthy men (31±2 yrs, 25±1 kg/m 2 ). Data were collected at baseline and during maximal voluntary end‐expiratory apnea under normoxic (S p O 2 : 98±1%), hypoxic (F i O 2 : 0.17±0.01; S p O 2 : 82±1%), and hyperoxic (F i O 2 : 0.92±0.03; S p O 2 : 100±0%) conditions. Condition order was randomized and trials were separated by a minimum of 15‐min quiet normoxic rest. Action potential (AP) patterns were studied from the filtered raw signal using wavelet‐based methodology. Data are reported from the last 2‐min of baseline and during the second half of apnea, reflecting the time of highest MSNA. RESULTS There was an increase in multi‐unit MSNA (24±3 to 35±3 bursts/min, p=0.04) during normoxic apnea, which was due to an increase in the frequency and incidence of AP spikes (243±75 to 519±134 AP/min, p=0.048; 412±133 to 773±185 AP/100 heart beats, p=0.04). An increase in the probability of AP firing more than once per burst was also observed (p=0.01). There was an increase in multi‐unit MSNA (20±4 to 46±7 bursts/min, p<0.01) during hypoxic apnea that was due to an increase in the frequency and incidence of AP spikes (192±59 to 952±266 AP/min, p<0.01; 326±89 to 1212±327 AP/100 heart beats, p<0.01). Hypoxic apnea also resulted in an increase in the probability of AP firing more than once per burst (p<0.01). Hyperoxia attenuated any increase in MSNA with apnea, such that no changes in multi‐unit MSNA (24±4 to 28±5 bursts/min, p=0.14) nor frequency or incidence of AP spikes (155±35 to 253±71 AP/min, p=0.12; 249±61 to 502±188 AP/100 heart beats, p=0.28) were observed. Hyperoxia also attenuated any increase in the probability of AP firing more than once per burst (p=0.47). CONCLUSION These data are the first to show neural firing and recruitment strategies in response to voluntary end‐expiratory apnea are modified by hypoxia and hyperoxia. Our results demonstrate that hypoxic apnea increases the frequency and incidence of action potential spikes, as well as the probability of multiple within‐burst firing; whereas this response was suppressed when individuals were hyperoxic. These data may have important implications for neural control of the circulation in recreational activities (i.e. diving) and/or clinical conditions prone to apnea (i.e. sleep apnea). Support or Funding Information FUNDING: AHA #15SDG25080095, NIH HL130339, Natural Sciences and Engineering Research Council of Canada Discovery Grant program. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Objective We examined the contribution of the arterial baroreflex to sympathetic discharge patterns in humans by systematically manipulating the reflex using intravenous nitroprusside and phenylephrine. We hypothesized nitroprusside would increase firing of low‐threshold axons, with no effect on recruitment of latent axons and/or synaptic delays. We further hypothesized phenylephrine would decrease firing of low‐threshold axons, with no effect on synaptic delays. Methods Heart rate (HR, ECG), arterial blood pressure (BP, brachial arterial catheter), and multi‐unit muscle sympathetic nerve activity (MSNA, microneurography of the peroneal nerve) were measured in 13 male subjects (30±2 yrs, 25±1 kg/m 2 ) at baseline and during systemic intravenous infusion of nitroprusside (0.4–1.7 μg/kg/min) and phenylephrine (0.2–1.0 μg/kg/min), administered separately. Action potential (AP) patterns were studied from the filtered raw signal using wavelet‐based methodology. Results Compared to baseline, BP decreased and HR and multi‐unit MSNA (41±5 to 53±4 bursts/100 heart beats) increased with nitroprusside (all P <0.01). Nitroprusside increased AP incidence (326±66 to 579±129 AP/100 heart beats) and AP content per integrated burst (8±1 to 11±2 AP/burst) (all P <0.01). The firing probability of low‐threshold axons increased with nitroprusside, and recruitment of previously latent, high‐threshold axons was observed (22±3 to 24±3 max clusters, 9±1 to 11±1 clusters/burst; all P <0.05). Compared to baseline, BP increased and HR and multi‐unit MSNA (41±3 to 21±3 bursts/100 heart beats) decreased with phenylephrine (all P <0.01). Phenylephrine decreased AP discharge rate (406±128 to 166±42 AP/100 heart beats) and resulted in fewer unique clusters (15±2 to 9±1 max clusters, all P <0.05); however, components of an integrated burst were not altered (9±2 vs 8±1 AP/burst; 5±1 vs 4±1 clusters/burst, P >0.05). AP cluster latency decreased with cluster size under both conditions ( P <0.01), but this relationship was not altered with nitroprusside ( P =0.42) or phenylephrine ( P =0.39). Conclusions Baroreflex unloading with systemic nitroprusside increases sympathetic neuronal discharge rate by increasing the firing probability of low‐threshold axons, in addition to recruitment of previously latent, high‐threshold axons. In contrast, baroreflex loading with systemic phenylephrine decreases neuronal discharge rate, including decreased firing probability of high‐threshold axons; however, the components of an integrated burst (AP and clusters per burst) and synaptic delays are unaffected. These data support a hierarchical pattern of sympathetic neural recruitment/de‐recruitment and suggest acute modification of synaptic delays are not influenced by the baroreflex. Support or Funding Information NIH HL083947, NIH HL130339 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Action potentials (APs) of varying sizes and firing probabilities, that are synchronized into bursts of efferent traffic, characterize recordings of muscle sympathetic nerve activity (MSNA). Recent evidence points to ordered recruitment of these APs but the sites of this control remain unknown. This study investigated the role of the paravertebral ganglia in sympathetic AP emission patterns using pharmacological blockade of ganglionic N N ‐nicotinic receptors via trimethaphan camsylate (TM; n = 7 females, 37 ±5 years, 112 ±2/70 ±3 mmHg, 22 ±1 kg/m 2 ). Heart rate (HR; ECG), blood pressure (BP; arterial catheter) and MSNA (microneurography) were recorded during baseline, TM infusion (1–7 mg/min) and Valsalva's manoeuvre. MSNA APs were detected from the filtered raw signal using a wavelet deconstruction approach and were binned in clusters (Scott's rule) based on peak‐to‐peak amplitude (K‐means). In the final minute of MSNA burst detection during TM, HR increased (57 ±11 to 66 ±12 bpm) and mean BP decreased (97 ±7 to 90 ±7 mmHg) (both P < 0.01 compared to baseline). Relative to baseline, TM elicited a progressive reduction in total sympathetic outflow (833 ±458 to 157 ±120 AU/min), characterized by fewer integrated bursts (30 ±14 to 9 ±8 bursts/100 beats) with decaying amplitude (49 ±3 to 31 ±3 AU) (all P < 0.01). Underlying TM‐mediated attenuations in integrated MSNA were reductions in AP incidence (186 ±101 to 29 ±31 AP/100beats) and AP content per integrated burst (7 ±2 to 3 ±1 APs/burst) (all P < 0.01). Compared to baseline, the total number of active AP clusters was reduced with TM (14 ±3 to 9 ±3 AP clusters), resulting in fewer unique clusters per burst (4 ±1 to 3 ±1 AP clusters/burst) (both P < 0.01). Relative to baseline, most participants demonstrated a reduction in the within‐burst firing probability of all AP clusters, with the largest two to six AP clusters ceasing to fire in the last minute before integrated bursting activity was abolished. Following cessation of integrated MSNA bursts, the smallest 6 ±2 sympathetic AP clusters (range: 4 – 8 AP clusters) persisted to fire in an asynchronous pattern (49 ±41 AP/100beats) in all participants. Valsalva's Maneuver did not increase the incidence of these persistent small APs (60 ±42 AP/100beats, P = 0.52), or instigate any larger APs (previously active at baseline) in six of seven participants (6 ±1 total AP clusters, P = 0.30). These data suggest: 1) the paravertebral ganglia may contribute to the heterogeneity in the firing probabilities of varying sized postganglionic sympathetic APs active under baseline conditions, and 2) the presence of non‐synchronized sympathetic APs that express resistance to blockade with trimethaphan. Support or Funding Information Supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada, Discovery Grant #217916‐2013. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Currently, the effect of aging on sympathetic baroreflex control is equivocal, with some studies finding that integrated sympathetic baroreflex threshold gain is not affected by age, and others finding that it is blunted in older compared to young adults. While these studies evaluated the effect of aging on baroreflex control of integrated sympathetic burst frequency, it remains unclear how aging modulates the baroreflex control of postganglionic action potentials (AP). In young adults, the arterial baroreflex exerts non‐uniform control over varying‐sized APs spontaneously firing within bursts of muscle sympathetic nerve activity (MSNA), with the strongest control over medium sized AP clusters, and less control over the smallest and largest APs. Therefore, we tested the hypothesis that resting baroreflex control of AP subpopulations and integrated sympathetic bursts would be blunted in older compared to young adults. Baroreflex threshold relationships for integrated MSNA bursts and the underlying subpopulations of AP clusters (obtained using microneurography and a continuous wavelet transform) were assessed during 5 minutes of supine rest in eleven older (45‐75 years, 5 females) and eleven young (21‐30 years, 5 females) adults. Baroreflex threshold was quantified as the slope of the linear regression between AP probability (%) and MSNA burst probability (%) versus diastolic blood pressure (DBP, mmHg; Finger plethysmography). AP discharge was greater in older compared to young adults (Older: 614 ± 327 spikes/100 beats vs. Young: 211 ± 107 spikes/100 beats, P < 0.001), and the baroreflex control of AP subpopulations was reset towards greater firing probabilities in older adults (group‐by‐cluster effect: P < 0.001). Specifically, the arterial baroreflex threshold gain of medium AP clusters was greater in older compared to young adults (e.g. Cluster 4, Older: ‐7.8 ± 3.1 %/mmHg vs. Young: ‐4.1 ± 2.9 %/mmHg, P = 0.010), whereas the baroreflex threshold gains for the smallest (e.g. Cluster 1, Older: ‐1.2 ± 1.1 %/mmHg vs. Young: ‐0.7 ± 0.4 %/mmHg, P = 0.197) and largest (e.g. Cluster 10, Older: ‐0.5 ± 0.4 %/mmHg vs. Young: ‐0.6 ± 0.6 %/mmHg, P = 0.673) AP clusters were not modified by aging. Additionally, integrated sympathetic burst threshold gain was greater in older compared to young adults (Older: ‐7.9 ± 3.8 %/mmHg vs. Young: ‐3.9 ± 1.8 %/mmHg, P = 0.005), and the operating point was shifted rightward towards a higher DBP (Older: 76 ± 8 mmHg vs. Young: 68 ± 7 mmHg, P = 0.021). Contrary to our hypothesis, the strength of baroreflex control over medium sized AP clusters as well as integrated sympathetic baroreflex threshold gain was greater in this group of older adults compared to young adults.

Our understanding of altered neuro‐cardiovascular control following long‐duration inactivity via head‐down bed rest (HDBR) is incomplete. Here, we retrospectively analyzed two long‐duration HDBR studies, including female (n=17; 32±5 years) and male (n=16; 29±7 years) cohorts, to determine whether HDBR 1) alters spontaneous cardiovagal baroreflex sensitivity (cBRS) similarly between males and females and 2) alters spontaneous baroreflex control of muscle sympathetic action potentials (AP) in males. Heart rate (HR; electrocardiogram) and arterial blood pressure (BP; finger‐plethysmography) were continuously measured during 5‐minutes of supine rest prior to and following 60‐days bed rest in a ‐6° head‐down position. Spontaneous cBRS was assessed by the relationship between R‐R interval and systolic BP analyzed using the linear regression sequence method. Recordings of multi‐unit muscle sympathetic nerve activity (peroneal microneurography) were obtained and a continuous wavelet transform detected APs which were grouped into AP clusters with similar morphology (n=10, all males). Baroreflex threshold for AP cluster discharge was assessed by linear regression analysis of the relationship between AP cluster discharge probability and diastolic BP. No change in resting HR (64±9 versus 66±9 /min, P=0.12) or mean BP (91.2±9.0 versus 90.6±9.2 mmHg, P=0.73) occurred after HDBR. Reductions in cBRS after HDBR (‐4.1±9.4 ms/mmHg, Time effect: P<0.01) were similar between males and females (Time‐by‐Sex effect: P=0.51) and not related to changes in total blood volume (r 2 =0.045, P=0.24). Grouped AP clusters demonstrated heterogenous arterial baroreflex threshold gain according to AP cluster morphology (Cluster effect: P<0.01) which was unaltered following HDBR (Time‐by‐Cluster effect: P=0.43). In summary, males and females similarly attenuate cBRS following 60‐days of HDBR and novel evidence indicates HDBR does not alter spontaneous baroreflex control of muscle sympathetic APs in males.

Background: Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. Methods: We assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry. Results: Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P =0.3), equally likely to be female (44% versus 48%, P =0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P =0.0004), prior antiarrhythmic drug use (52% versus 40%, P =0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P =0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P =0.003; cardioversion: 12.2% versus 5.9%, P =0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P =0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P =0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve ( P <0.05 for each). Conclusions: In this national registry of patients with AF, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient-reported outcomes in AF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.

We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing patterns and the role of the carotid chemoreceptors. We hypothesized exposure to acute IH would increase muscle sympathetic nerve activity (MSNA) via an increase in action potential (AP) discharge rates and within-burst firing. We further hypothesized any change in discharge patterns would be attenuated during acute chemoreceptor deactivation (hyperoxia). MSNA (microneurography) was assessed in 17 healthy adults (11 male/6 female; 31 ± 1 yr) during normoxic rest before and after 30 min of experimental IH. Prior to and following IH, participants were exposed to 2 min of 100% oxygen (hyperoxia). AP patterns were studied from the filtered raw MSNA signal using wavelet-based methodology. Compared with baseline, multiunit MSNA burst incidence ( P < 0.01), AP incidence ( P = 0.01), and AP content per burst ( P = 0.01) were increased following IH. There was an increase in the probability of a particular AP cluster firing once ( P < 0.01) and more than once ( P = 0.03) per burst following IH. There was no effect of hyperoxia on multiunit MSNA at baseline or following IH ( P > 0.05); however, hyperoxia following IH attenuated the probability of particular AP clusters firing more than once per burst ( P < 0.01). Acute IH increases MSNA by increasing AP discharge rates and within-burst firing. A portion of the increase in within-burst firing following IH can be attributed to the carotid chemoreceptors. These data advance the mechanistic understanding of sympathetic activation following acute IH in humans.

We sought to examine the effect of varying chemoreflex stress on sympathetic neural recruitment strategies during end-expiratory apnea. We hypothesized that increases in the firing frequency and probability of low-threshold axons at the asphyxic “break point” would be exaggerated during hypoxia and attenuated during hyperoxia. Multiunit muscle sympathetic nervous system activity (MSNA) (peroneal nerve microneurography) was measured in 10 healthy male subjects (31 ± 2 yr, 25 ± 1 kg/m2). Individuals completed maximal voluntary end-expiratory apnea under normoxic, hypoxic (inspired O2 fraction: 0.17 ± 0.01), and hyperoxic (inspired O2 fraction: 0.92 ± 0.03) conditions. Action potential (AP) patterns were examined from the filtered raw signal with wavelet-based methodology. Multiunit MSNA was increased ( P ≤ 0.05) during normoxic apnea, because of an increase in the frequency and incidence of AP spikes (243 ± 75 to 519 ± 134 APs/min, P = 0.048; 412 ± 133 to 733 ± 185 APs/100 heartbeats, P = 0.02). Multiunit MSNA increased from baseline ( P < 0.01) during hypoxic apnea, which was due to an increase in the frequency and incidence of APs (192 ± 59 to 952 ± 266 APs/min, P < 0.01; 326 ± 89 to 1,212 ± 327 APs/100 heartbeats, P < 0.01). Hypoxic apnea also resulted in an increase in the probability of a particular AP cluster firing more than once per burst ( P < 0.01). Hyperoxia attenuated any increase in MSNA with apnea, such that no changes in multiunit MSNA or frequency or incidence of AP spikes were observed ( P > 0.05). We conclude that increases in frequency and incidence of APs during apnea are potentiated during hypoxia and suppressed when individuals are hyperoxic, highlighting the important impact of chemoreflex stress in AP discharge patterns. The results may have implications for neural control of the circulation in recreational activities and/or clinical conditions prone to apnea. NEW & NOTEWORTHY Our results demonstrate that, compared with normoxic end-expiratory apnea, hypoxic apnea increases the frequency and incidence of action potential spikes as well as the probability of multiple firing. We further show that this response is suppressed when individuals are hyperoxic. These data highlight the potentially important role of chemoreflex stress in neural firing and recruitment and may have implications for neural control of the circulation in recreational and/or clinical conditions prone to apnea.