Curry, Timothy B.

Background Lower body negative pressure (LBNP) increases carotid body chemosensitivity. Whether the increase in chemosensitivity is functionally significant in the hemodynamic response to LBNP was previously unknown. We tested the hypothesis that desensitization of the carotid body chemoreceptors would improve the hemodynamic response to LBNP. Methods Ten healthy, non‐obese male subjects (35 ± 3 years, BMI: 25 ± 1 kg/m 2 ) completed 2 study visits (Saline, Dopamine), separated by a minimum of 4 weeks. Intravenous dopamine was infused at an individualized dose (1–2 mg/kg/min) shown to maximally blunt the hypoxic ventilatory response (a measure of carotid body chemosensitivity). Arterial blood pressure (brachial catheter) and heart rate (ECG) were continuously recorded. On each study day subjects underwent step‐wise exposures of LBNP (−15, −30, and −45 mmHg) to simulate hemorrhage. Cumulative stress index (CSI) was calculated by summating the product of negative pressure (mmHg) by the time (min) during each LBNP level (−15, −30, and −45 mmHg). Results Dopamine tended to reduce CSI (Saline: 503 ± 52; Dopamine: 408 ± 45 mmHg*min; p=0.07). Changes in heart rate from baseline during graded LBNP were not statistically distinguishable between Saline and Dopamine conditions (− 15 mmHg: +4 ± 1 vs +3 ± 2 BPM, p=0.99; − 30 mmHg: +12 ± 1 vs +12 ± 3 BPM, p=0.99; − 45 mmHg: HR +21 ± 2 vs +19 ± 5 BPM, p=0.99). Similarly, change in systolic blood pressure from baseline during graded LBNP was not different between Saline and Dopamine conditions (− 15 mmHg: +1 ± 1 vs −1 ± 2 mmHg p=0.99; − 30 mmHg: −7 ± 3 vs −6 ± 4 mmHg, p=0.99; − 45 mmHg: −12 ± 4 vs −22 ± 6 mmHg, p=0.19). However, change in diastolic blood pressure from baseline during graded LBNP was higher at −45 mmHg between Saline and Dopamine conditions (− 15 mmHg: +2 ± 1 vs −0 ± 1 mmHg p=0.47; − 30 mmHg: −1 ± 2 vs −2 ± 2 mmHg p=0.26; − 45 mmHg: −2 ± 2 vs −12 ±3 mmHg, p=0.0004). Conclusions Desensitization of the carotid body chemoreceptors reduced diastolic blood pressure responses to LBNP at −45 mmHg only, with minimal effect at lower levels. These data suggest chemoreflex activity during LBNP may be functionally significant in the blood pressure responses only during higher levels of simulated hemorrhage. Support or Funding Information Funding: W81XWH‐13‐2‐0038 (DOD)

Hypovolemia‐induced sympathoexcitation might initiate an immune response through an increase in circulating epinephrine and splenic demargination. We tested the hypothesis that lower body negative pressure (LBNP) and blood loss (BL) result in comparable increases in white blood cell counts (WBCs). We determined WBCs and epinephrine levels in 12 men who performed a LBNP and BL protocol in a randomized order. LBNP consisted of 5‐minute stages at 0, ‐15, ‐30, and ‐45 mmHg of suction. BL included 5 minutes at baseline and following three stages of 333 mL of blood removal (up to 1000 mL total). Blood draws were performed at baseline and after the last stage of each protocol. LBNP to −45mmHg was a greater central hypovolemic stimulus vs. BL, therefore WBCs and epinephrine concentrations were plotted against central venous pressure (CVP) to obtain stimulus‐response relationships using the linear regression line slopes for both protocols. Paired tests were used to determine if the slopes of these regression lines fell on similar trajectories for each protocol. Mean regression line slopes fell on similar trajectories for total WBC (LBNP 183±46 vs. BL 155±109 mcL −1 *mmHg −1 , p=0.15), neutrophils (LBNP 110±29 vs. BL 96±72 mcL −1 *mmHg −1 , p=0.15) and lymphocytes (LBNP 65±21 vs. BL 59±38 mcL −1 *mmHg −1 , p=0.90). Mean regression line slopes for epinephrine were similar as well (LBNP 15±5 vs. BL 16±4 pg *mL −1 *mmHg −1 , p=0.84). Our results indicate that LBNP models the stimulus‐response relationship between CVP and WBCs observed during BL. Central hypovolemia, induced by LBNP or BL, elicits a relative leukocytosis with a predominantly neutrophil‐based response. Support or Funding Information US Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823

Key points Heart failure patients with reduced ejection fraction (HFrEF) exhibit severe limitations in exercise capacity ( peak). One of the primary peripheral mechanisms suggested to underlie exercise intolerance in HFrEF is excessive locomotor muscle group III/IV afferent feedback; however, this has never been investigated in human heart failure. HFrEF patients and controls performed an incremental exercise test to volitional exhaustion to determine peak with lumbar intrathecal fentanyl or placebo. During exercise, cardiac output, leg blood flow and radial artery and femoral venous blood gases were measured. With fentanyl, compared with placebo, patients with HFrEF achieved a higher peak workload, peak, cardiac output, stroke volume and leg blood flow. These findings suggest that locomotor muscle group III/IV afferent feedback in HFrEF leads to increased systemic vascular resistance, which constrains stroke volume, cardiac output and O2 delivery thereby impairing peak and thus exercise capacity. AbstractTo better understand the underlying mechanisms contributing to exercise limitation in heart failure with reduced ejection fraction (HFrEF), we investigated the influence of locomotor muscle group III/IV afferent inhibition via lumbar intrathecal fentanyl on peak exercise capacity ( peak) and the contributory mechanisms. Eleven HFrEF patients and eight healthy matched controls were recruited. The participants performed an incremental exercise test to volitional exhaustion to determine peak with lumbar intrathecal fentanyl or placebo. During exercise, cardiac output and leg blood flow () were measured via open‐circuit acetylene wash‐in technique and constant infusion thermodilution, respectively. Radial artery and femoral venous blood gases were measured. peak was 15% greater with fentanyl compared with placebo for HFrEF (P < 0.01), while no different in the controls. During peak exercise with fentanyl, cardiac output was 12% greater in HFrEF secondary to significant decreases in systemic vascular resistance and increases in stroke volume compared with placebo (all, P < 0.01). From placebo to fentanyl, leg , and O2 delivery were greater for HFrEF during peak exercise (all, P < 0.01), but not control. These findings indicate that locomotor muscle group III/IV afferent feedback in patients with HFrEF leads to increased systemic vascular resistance, which constrains stroke volume, cardiac output and O2 delivery, thereby impairing peak and thus exercise capacity. These findings have important clinical implications as peak is highly predictive of morbidity and mortality in HF.

We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.

Aging increases autonomic support of blood pressure; however, the impact of aerobic fitness on autonomic support of blood pressure has not been addressed in women. As such, we hypothesized that aerobic fitness would be related to the change in blood pressure during ganglionic blockade such that women with greater aerobic fitness would have a blunted fall in blood pressure during ganglionic blockade due to increased vagal tone. Thirteen young premenopausal and 13 older postmenopausal women completed a screening visit where aerobic fitness (maximal oxygen consumption, VO 2max ) was measured. On a separate study day, participants were instrumented for assessment of muscle sympathetic nerve activity, heart rate (electrocardiography), and beat by beat blood pressure (arterial catheter and pressure transducer) and underwent pharmacological blockade of the autonomic ganglia using trimethaphan camyslate. Heart rate, blood pressure, and muscle sympathetic nerve activity were analyzed before and during ganglionic blockade. In young women, there was a significant relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =0.761, P =0.003). In older women, there was no relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =−0.106, P =0.73). Measures of heart rate variability were related to fitness in young women, but not older women (root mean square of successive differences between normal heartbeats, r =0.713, P =0.006 versus r =−0.172, P =0.575). Our data suggest that in young women, autonomic support of blood pressure is attenuated in those that are highly fit; however, this relationship is not significant in older women.

In humans, a novel allosteric hemoglobin-oxygen affinity modulator was administered to comprehensively examine the cardiopulmonary consequences of stabilizing a portion of the available hemoglobin in a high-oxygen affinity state during submaximal exercise in normoxia and hypoxia. Oral administration of voxelotor enhanced arterial oxygen saturation during submaximal exercise without altering oxygen consumption and central hemodynamics; however, the partial pressure of arterial carbon dioxide was reduced and the partial pressure of arterial oxygen was increased implying that hyperventilation also contributed to the increase in oxygen saturation. The preservation of arterial oxygen saturation and content was particularly evident during hypoxic submaximal exercise, when arterial desaturation typically occurs, but this did not influence arterial-venous oxygen difference.

Background Lower body negative pressure (LBNP) simulates hemorrhage, evoking compensatory cardiovascular mechanisms of increased heart rate (HR) while stroke volume (SV) and cardiac output (CO) progressively decline, ultimately leading to presyncope. Previous work has shown that circulating levels of plasma epinephrine are elevated during LBNP; however, the role of early administration of epinephrine in compensatory cardiovascular mechanisms to simulated hemorrhage is not well understood. Purpose We hypothesized that during simulated hemorrhage, a low‐dose exogenous infusion of epinephrine in humans would: 1) augment HR response, 2) attenuate the decline of SV and CO, and 3) prolong time to tolerance. Methods Nine healthy subjects (5M/4F, 35±9yrs, BMI 25±1 kg·m −2 ) participated in LBNP on two separate study days. Protocols on each day consisted of a 10‐minute pre‐infusion baseline, 15‐minute infusion period (randomized to saline or epinephrine, dose = 0.1 μg·kg −1 ·min −1 , delivered through a peripherally inserted central catheter), 10‐minute post‐infusion baseline, and 5 minute stages of progressive LBNP with stepwise increases of 10–15 mmHg negative pressure until tolerance (systolic blood pressure less than 80 mmHg, bradycardia, or voluntary termination due to presyncopal symptoms). Heart rate (HR; electrocardiogram) and blood pressure (BP; radial arterial catheter) were recorded continuously. Cardiovascular function (HR, SV, CO, and systemic vascular resistance (SVR)) was determined using arterial waveform analysis. Data were analyzed via percent tolerance using repeated measures ANOVA with student method for pairwise comparisons. Results Infusion of exogenous epinephrine lowered MAP (p<0.01) and diastolic blood pressure (DBP; p<0.001), but raised systolic blood pressure (SBP; p=0.019) throughout all stages of LBNP. Epinephrine compared to saline augmented mean HR, SV and CO to the penultimate stage of LBNP (p≤0.01 for all cardiac measures) and concurrently reduced SVR (p=0.002). However, time to tolerance was not significantly different between epinephrine and saline conditions (1415 ± 79 vs. 1475 ± 150s, respectively; p=0.69). Discussion Our findings suggest that during simulated hemorrhage exogenous epinephrine can augment cardiac function without increasing tolerance to progressive central hypovolemia. During the epinephrine infusion, benefits to cardiac function may have been limited by reduced vascular resistance. Support or Funding Information The United States Department of Defense W81XWH‐13‐2‐0038