Wehrwein, Erica A.

Previous studies have indicated that acute slow‐paced breathing (6 breaths/min) significantly decreases arterial blood pressure (BP) in both normotensive and hypertensive individuals. More recent work suggested that muscle sympathetic nerve activity (MSNA) was unchanged during acute slow‐paced breathing, however, the pattern of MSNA firing was altered in that more periods of MSNA quiescence were present. Herein, we examined the ability of MSNA to modulate BP on a beat‐to‐beat basis. We hypothesized that the magnitude of the increase in BP following a burst of MSNA is attenuated during acute slow‐paced breathing contributing to the reduction in BP previously reported. BP (brachial catheter) and MSNA (peroneal microneurography) were continuously measured in 10 young (27 ± 1 years), healthy men during 10 minutes of normal spontaneous breathing (baseline) or paced breathing at six breaths per minute. Signal averaging was used to characterize changes in mean BP for 15 cardiac cycles following heartbeats associated with and without MSNA bursts. MSNA bursts were segregated as either single bursts (directly bordered by ≥1 heartbeat lacking MSNA) or multiple bursts (any burst positioned directly adjacent to another MSNA burst). Respiratory rate was 12 ± 1.1 breaths/min during baseline and 6 ± 0.7 breaths/min during slow‐paced breathing. Compared to baseline, mean BP was decreased during slow‐paced breathing (88±2 vs. 85±2 mmHg, P<0.05), whereas MSNA burst frequency was unchanged (13±2.2 vs. 13±2.4 bursts/min, P>0.05). At baseline, mean BP significantly increased following MSNA bursts (+3.2± 0.2 mmHg, P<0.05) and this increase was augmented during slow‐paced breathing (+5.0± 0.5 mmHg, P<0.05). There was a greater increase in mean BP following single as well as multiple MSNA bursts during slow‐paced breathing. In contrast, cardiac cycles without MSNA bursts (non‐bursts) were associated with a significant decrease in mean BP (−0.7± 0.1 mmHg, P<0.05), which was also augmented during slow‐paced breathing (−1.3± 0.3 mmHg, P<0.05). In summary, the pressor and depressor responses coupled to spontaneous oscillations in MSNA are augmented during slow paced breathing with a net effect of reduced BP. Thus, changes in MSNA firing pattern, without changes in burst frequency, can modulate resting BP. Support or Funding Information Funding: NIH HL‐083947 (MJJ)

Slow, deep breathing (SDB) is thought to lead to reductions in blood pressure by decreasing vascular‐sympathetic coupling. Venous Occlusion Plethysmography (VOP) is used to assess forearm blood flow (FBF) (ml/min/100 dl tissue). We used this technique to determine the vasodilatory effect of device‐guided (DG) vs self‐paced (SP) slow, deep breathing. We hypothesized that SP would lead to a larger vasodilation response than DG due to a more profound reduction in vascular‐sympathetic coupling, and that this would be correlated with psychological evaluations. Young, healthy male subjects (Mean age: 20 yr; DG: n=10; SP: n=11) rested supine for 20 minutes (baseline), followed by 20 minutes of SP or DG slow, deep breathing, then completed 20 minutes of endogenous breathing (recovery). At baseline, there was no difference in breathing rate between SP and DG (14.36±1.03 vs 15.39±1.29 breaths per minute, p=0.27) and respiratory rate was reduced to 8.36±0.74 breaths per minute (BPM) in the SP group (p<0.01 compared to baseline) and to 6.37±0.10 BPM in the DG group (p<0.01 compared to baseline). Respiratory rates between the two groups differed significantly during SDB (p<0.01 between groups). There was a significant increase in SP FBF compared to baseline at the end of the 20 minute intervention (p<0.05),while the DG group saw no significant increases. In DG, there was a strong negative correlation with the cognitive interference scores to VOP responsiveness (−0.77; R2=0.591), as well as between the cognitive failure score and VOP responsiveness (−0.61; R2=0.3693). In contrast, the SP groups had positive correlations when comparing VOP responsiveness to cognitive interference (0.1; R2=0.093) or cognitive failure (0.30; R2=0.011). For subjects in either breathing group, those who had an increase in FBF in response to SDB also had reductions in STAI anxiety score after the intervention whereas those with a decrease in FBF to SDB had an increase in anxiety score during the slow breathing (p=0.04). Overall, male subjects have a variable vasodilator responses to two types of SDB practices related to underlying psychological metrics. Our data underscores the importance of psychological metrics in physiological outcomes related to SDB practices.

Sympathetic neural control has a central role in the regulation of blood pressure. In humans, muscle sympathetic nerve activity (MSNA) is strongly controlled by the arterial baroreflex. Our goal was to evaluate a calculation of blood pressure "error signal" for MSNA burst occurrence and test if there was a gender difference in the relationship between this signal and resting blood pressure. Baseline MSNA was measured in healthy young men (n=49) and women (n=23). T50 (the DBP at which there is a 50% likelihood of an MSNA burst) was calculated. Mean DBP was subtracted from the T50 as an approximate "error signal" for burst activation. We found a positive relationship between this "error signal" and MSNA (bursts/100 heartbeats; BI) in both young men (slope=0.19, r 2 =0.67, p<0.001) and women (slope=0.32, r 2 =0.78, p<0.001). Thus, if DBP was lower than T50, there was an increased likelihood of MSNA bursts and vice versa. Women had a greater average "error signal" (i.e., mean T50 ‐ DBP = ‐5 ± 1 in women and ‐2 ± 0.4 in men), a 59 % steeper slope of the error signal:MSNA relationship, and lower mean BI (31 ± 2 vs 42 ± 4, p<0.05), suggesting that mechanisms exist in women to counteract the larger "driving force" for generation of a MSNA burst. These apparent gender differences in control of MSNA may contribute to differences in prevalence of cardiovascular diseases such as hypertension. NIH HL83947, UL1‐RR24150, Swedish Research Council 12170.

The complex forearm vasodilator response during mental stress (MS) is mediated in part by unchanged or decreased forearm muscle sympathetic nerve activity. However, immediately after MS, nerve activity is increased. To determine the effect of chronic sympathetic denervation on forearm blood flow (FBF, [ml/100ml forearm volume/min]) response to MS, we studied patients pre and post sympathotomy (ETS) for palmar hyperhidrosis. 15 healthy subjects (11 F; 19‐32 yr) with a mean BMI of 23 ± 5 kg/m2 were studied 1 day‐6 mo before ETS and 1‐6 mo after ETS. FBF (plethysmography) was recorded during baseline, 3 min Stroop test, and 2 min post‐MS recovery. ETS did not affect resting HR, BP or FBF. However, resting forearm vascular resistance (FVR, [MAP/FBF]) was reduced after ETS (50 ± 20 vs 33 ± 14, p < 0.01) and forearm vascular conductance (FVC, [(FBF/MAP)*100]) was increased (3 ± 2 vs 4 ± 2, p < 0.05). MS caused significant increases in FBF and FVC, and a decrease in FVR, and these responses were unaffected by ETS. However during post‐MS recovery, ETS caused a significant increase in FBF (2 ± 1 vs 3 ± 1), FVC (3 ± 1 vs 4 ± 2), and a decrease in FVR (52 ± 22 vs 32 ± 16) (p < 0.01). Chronic sympathetic denervation influences post‐MS forearm vasoconstriction, which likely has minor hemodynamic consequences but confirms a greater role for sympathetic control of FBF in the post‐MS period as opposed to during MS. NIH HL‐089331, NS‐32352

Background Hypoglycemia results in a reduction in spontaneous cardiac baroreflex sensitivity (scBRS) and a shift in the baroreflex working range to higher heart rates; this effect may be mediated by the carotid chemoreceptors. We hypothesized changes in baroreflex control of heart rate with hypoglycemia would be blunted in carotid body resected patients when compared with healthy controls. Methods Five patients (3M/2F) with bilateral carotid body resection for glomus tumors and ten healthy controls (7M/3F) completed a 180‐min hyperinsulinemic, hypoglycemic (~3.3 µmol/mL) clamp. Changes in heart rate, blood pressure, and scBRS were assessed. Results scBRS was reduced from baseline during hypoglycemia (p<0.01) and was lower in carotid body resected patients when compared with controls (p=0.01). Hypoglycemia‐mediated reductions in systolic and mean blood pressure were significantly greater in patients when compared with controls (p<0.05). Despite lower blood pressures, increases in heart rate with hypoglycemia were blunted in patients (p<0.01). Conclusion Reductions in scBRS with hypoglycemia cannot be exclusively attributed to the carotid chemoreceptors; however, the chemoreceptors play a role in resetting the baroreflex working range to higher heart rates during hypoglycemia such that a rise in heart rate is not observed in carotid body resected patients. These data support a contribution of the carotid chemoreceptors to baroreflex control of blood pressure during hypoglycemia and highlight potential widespread effects of carotid body resection in humans. Funding DK090541, HL120570

Yoga is thought to reduce stress; however, few studies have quantified plasma levels of stress hormones. Yoga includes physical postures, meditation, and pranayama (controlled breathing) therefore it is difficult to determine which dose and combination of these components is most beneficial. We hypothesized that a single 15 min bout of 6 breaths per minute would be sufficient to cause a reduction in stress hormones. Ten young healthy males (age 18–35, n=10) were instrumented with brachial arterial catheter for blood draws and respiration was monitored continuously using a double pneumobelt. Blood draws were taken after 15 min of supine rest with baseline ventilation and again after 15 min of slow paced breathing. Average baseline supine respiratory rate was 12.1 ± 0.5 breaths/min and during slow breathing it was 5.5 ± 0.4 breaths/min (p<0.05). After 15 min of slow breathing in the supine position there was a significant reduction in arterial norepinephrine (173.9 ± 15.5 vs 135.6 ± 42.9, p=0.002), cortisol (8.2 ± 0.7 vs 7.3 ± 0.59, p=0.002), and adrenocorticotrophic hormone (ACTH, 15.5 ± 2.4 vs 13.4 ± 2.2, p=0.009). As well, there was a trend for reduction in arterial epinephrine (82 ±28.2 vs 42.7 ± 9.7, p=0.15). These changes are consistent with a reduction in sympathetic nerve activity and a blunting of cortisol. In summary, acute yogic breathing significantly reduces stress hormones.

Cardio‐vagal tone (CVT) and heart rate variability (HRV) are reduced during hypoglycemia. Carotid body (CB) peripheral chemoreceptors are multi‐modal; therefore we hypothesized a correlation between CB activity and CVT during hypoglycemia. Seven healthy adults (4M/3F) underwent two 180 min hyperinsulemic (2mU/kg FFM/min), hypoglycemic (3.33 mmol/L) clamps one week apart, randomized to normoxia (arterial P O2 (P a O 2 ) 111 ± 6.3 mmHg) or hyperoxia (P a O 2 345 ± 80.6 mmHg) to desensitize the CB. CVT was assessed via the high frequency (HF) component of HRV from 5 min periods of 5‐lead ECG recording under baseline (euglycemia) and hypoglycemia. HF values decreased significantly from baseline during hypoglycemia, however this reduction was attenuated under hyperoxia (Normoxia (N): −69% vs. Hyperoxia (H): −41%, p=0.04). Heart rate increased significantly during hypoglycemia (N: 59.7 bpm ± 2.4 vs. 71.9 ± 4.0; H: 60.6 bpm ± 1.9 vs. 68.5 ± 3, p<0.001), however, this increase was not different between normoxia and hyperoxia, despite differences in CVT and HRV. These data indicate that the CB chemoreceptors may be partially responsible for the reduction in CVT associated with hypoglycemia, and they provide evidence for a role of the CB chemoreceptors in parasympathetic tone to the heart. Future studies are required to determine whether inhibition of the CB may serve to improve CVT function during hypoglycemia. T32 DK07352, F32 DK84624‐01 A1, CTSA 1 UL 1 RR024150 , R01DK 29953

Slow‐paced breathing is a simple strategy to reduce psychological stress. We tested the hypothesis that slow paced breathing would decrease muscle sympathetic nerve activity (MSNA). Ten young, healthy males were studied. The subjects were instructed to rest supine and breathe normally (baseline) or at six breaths per minute, each for 20 minutes. MSNA was measured (peroneal microneurography) and analyzed 5 minutes into each stage for a steady state measurement. Statistical analysis was completed using one way RM ANOVA and Tukey’s posthoc analysis (reported mean±SEM). Average respiratory rate was 11.9 ± 1.1 breaths/min during baseline and 5.8 ± 0.7 breaths/min during slow‐paced breathing. There was no significant difference from baseline compared to slow paced breathing in MSNA burst frequency (18±2.0 vs 18±2.40 bursts/min), burst incidence (31.2±4.01 vs. 30.4±3.80 bursts/100 heartbeats) or burst area (12.70±2.18 vs 13.02±1.98%). However, there was a change in the pattern of burst firing with a significant increase in quiescent periods between burst clusters during slow paced breathing compared to baseline (6.50±0.61 vs. 3.59±0.41 seconds), which was accompanied by a significant decrease in the number of bursts/cluster (2.9±0.38 vs. 5.6±0.8 bursts). This has physiological relevance since there was a significant decrease in plasma norepinephrine, increase in blood flow, and a reduction in mean arterial pressure during these same periods. These findings indicate that despite no change in burst incidence, slow paced breathing alters the pattern of MSNA firing, which may contribute to favorable cardiovascular changes. Grant Funding Source : Supported by NIH HL‐083947

Young men display a positive association between breathing rate and muscle sympathetic nerve activity (MSNA). We compared breathing rate, peroneal MSNA and cardiovascular variables at rest in 17 men (age 27 ± 2 yrs) and 15 women (age 25 ± 1 yrs). Breathing rates and MSNA were similar in men and women but women had significantly lower systolic and mean blood pressures, cardiac output and stroke volume. In men breathing rate correlated positively to MSNA (r = 0.58, p<0.05) but not in women (r = 0.12, p> 0.05).. In men respiratory rate correlated positively to total peripheral resistance (r = 0.65, p<0.05) and inversely to cardiac output (r = − 0.84, p<0.05) and heart rate (r = − 0.60, p<0.05) but there were no such relationships in women (p> 0.05 for all). In another group of subjects, linear regression was performed on respiratory rate and brachial arterial plasma norepinephrine. There was no relationship in men (r=0.0847, n=38) or women (r=0.0367, n=74). Importantly, MSNA does not always predict plasma NE levels at rest. The positive relationship between breathing and MSNA in men, and the inverse coupling of breathing to cardiac output and heart rate suggest that influences of respiration may be important, not only for dynamic, but also for “tonic” cardiovascular function. The lack of relationships among these variables in women shows that there are fundamental differences in basic blood pressure regulation between the sexes.