Postexercise Circulatory Arrest Research Articles

Normal sympathetic neural but blunted cardiovascular responses during static handgrip exercise in heart failure with preserved ejection fraction

Background: Exercise intolerance is a hallmark of heart failure, which significantly impacts activities of daily living and quality of life. In heart failure with reduced ejection fraction, exercise intolerance is associated with sympathetic nervous system hyperactivity during exercise. Whether this is also true in heart failure with preserved ejection fraction (HFpEF) is unknown. Therefore, we hypothesized that patients with HFpEF would have augmented sympathetic neural responses to exercise. Methods: Thirty-four patients with HFpEF (19 women, 70±7 [SD] yrs) and 24 age-matched healthy controls (14 women, 70±6 yrs) were studied. Mean arterial pressure (MAP; finger photoplethysmography calibrated with brachial blood pressure [BP]), heart rate (HR; lead II electrocardiogram), cardiac output (CO; derived from the Windkessel model), total peripheral resistance (TPR=MAP/CO), and muscle sympathetic nerve activity (MSNA, microneurography) were measured during 3 min of supine baseline, static handgrip (SHG) exercise at 40% of maximal voluntary contraction (MVC) force until fatigue, and 2 min of post-exercise circulatory arrest (PECA). Sympathetic transduction was estimated using diastolic BP divided by MSNA burst incidence. Results: Patients with HFpEF had a smaller MVC (24±8 vs. 30±9 kg, P=0.020) and a shorter time to fatigue during SHG (162±67 vs. 210±80 sec, P=0.012) than controls. However, there were consistent results across subgroups analyzed according to matched MVC or time to fatigue during SHG. Baseline MSNA burst frequency was higher in HFpEF patients compared with controls (36±16 vs. 24±13 bursts/min, P=0.005); however, there were no differences in MSNA responses (Δ) to SHG and PECA between the groups (SHG peak: 19±14 in HFpEF vs. 19±12 bursts/min in controls, P=0.984; PECA: 8±13 vs. 6±7 bursts/minute, P=0.596). Increases in MAP, HR, and TPR from baseline to peak SHG were smaller in patients with HFpEF than in controls (all P<0.05), while the increase in CO was not different between the groups ( P=0.101). In contrast, ΔMAP, ΔHR and ΔCO from baseline to PECA were not different between the groups (all P>0.05), but ΔTPR remained lower in patients with HFpEF than controls ( P=0.023). The transduction of MSNA burst incidence into diastolic BP was lower in patients with HFpEF compared with controls throughout data collection ( P=0.010). Conclusions: Contrary to our hypothesis, patients with HFpEF have normal sympathetic neural reactivity during SHG exercise despite a higher baseline. The blunted pressor response may be attributed to impaired sympathetic transduction to stress rather than a change in sympathetic neural responsiveness during exercise in HFpEF. Supported by the National Institutes of Health (P01HL137630 and R01HL091078) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Twelve weeks of occlusal splint treatment reduces blood pressure responses to hypertensive stimuli in those with sleep bruxism

Sleep bruxism (SB) is associated with increased sympathetic tone, a risk for the future development of hypertension. It is unclear whether those with SB would demonstrate exaggerated responses to hypertensive stimuli and whether treatment with an occlusal splint could mitigate these responses. Objectives: This study compared hemodynamic responses to the cold pressor test (CPT) and static handgrip (SHG) to fatigue between controls (CON) and those with SB to determine whether those with SB have exaggerated responses. Methods: Nineteen subjects (9 CON, 10 SB) had heart rate (HR) and blood pressure (BP) responses measured during a CPT and SHG with post-exercise circulatory arrest (PECA). SB subjects underwent a 12-wk occlusal splint intervention followed by a repeat of the experimental protocol. Results: No BP differences existed with pre- (PRE) vs. post-intervention (POST) in the SB subjects. CPT induced larger ΔSBP (10±10 vs. 19±7 mmHg; p < 0.05) and ΔDBP (8±8 vs. 17±9 mmHg; p < 0.05) in SB subjects compared to CON. POST had attenuated ∆SBP (15±9 vs. 8±5 mmHg; p < 0.03) and ∆DBP (18±10 vs. 8±6 mmHg; p < 0.05) during CPT. SB subjects experienced greater ∆DBP (21±11 vs. 31±8; p < 0.05) during SHG which was not different during POST. Conclusions: SB individuals may be at increased risk for the development of hypertension based on exaggerated BP responses to hypertensive stimuli. Twelve weeks of occlusal splint treatment attenuated some of these responses.

Comparison of haemodynamic response to muscle reflex in heart failure with reduced vs. preserved ejection fraction.

AimsIsometric handgrip (IHG) training reduces the blood pressure in patients with hypertension. It is unclear how IHG exercise affects the haemodynamics and cardiovascular function through the muscle reflex in patients with heart failure (HF) with reduced (HFrEF) and preserved ejection fraction (HFpEF).Methods and resultsTwenty patients (HFrEF: n = 10, HFpEF: n = 10) underwent left ventricular (LV) pressure–volume assessments using a conductance catheter and microtip manometer to evaluate haemodynamics, LV and arterial function, and LV‐arterial coupling during 3 min of IHG at 30% of maximal voluntary contraction (MVC), followed by 3 min of post‐exercise circulatory arrest (PECA). Three minutes of IHG exercise produced significant and modest increases in the heart rate (HR) and LV end‐systolic pressure (LVESP), respectively, in both HFpEF and HFrEF groups. In HFrEF, the increase in LVESP was caused by the variable increase in effective arterial elastance (Ea), which was counterbalanced by the increase in LV end‐systolic elastance (Ees), resulting in a maintained Ees/Ea. In HFpEF, the increase in LVESP was not accompanied by changes in Ea, Ees, Ees/Ea, or LV end‐diastolic pressure. LVESP during PECA was not maintained in HFpEF, suggesting smaller metabo‐reflex activity in HFpEF.ConclusionsThe IHG exercise used in this study may increase the LVESP and LVEDP without detrimental effects on cardiac function or ventricular‐arterial coupling, especially in HFpEF patients. The effects of IHG exercise on haemodynamics and ventricular‐arterial coupling may be affected by the patient background and the type and intensity of the exercise.

Differential effects of eplerenone versus amlodipine on muscle metaboreflex function in hypertensive humans.

Numerous studies have demonstrated that sympathetic nervous system overactivation during exercise in hypertensive rodents and humans is due, in part, to an exaggerated reflex response known as the exercise pressor reflex. Our prior studies have implicated a key role of mineralocorticoid receptor activation in mediating an augmented exercise pressor reflex in spontaneously hypertensive rats, which is mitigated by blockade with eplerenone. However, the effect of eplerenone on exercise pressor reflex has not been assessed in human hypertension. Accordingly, the authors performed a randomized crossover study to compare the effects of eplerenone to another antihypertensive drug from a different class amlodipine on sympathetic nerve activity (SNA) in 14 patients with uncomplicated hypertension. The authors found that amlodipine unexpectedly augmented the increase in SNA during the second minute of isometric handgrip, which persisted into the post‐exercise circulatory arrest period (∆ SNA, from rest of 15 ± 2 vs. 9 ± 2 vs. 10 ± 2 bursts/min, amlodipine vs. baseline vs. eplerenone, respectively, p < .01), suggesting an exaggerated muscle metaboreflex function. Eplerenone did not alter sympathetic responses to exercise or post‐exercise circulatory arrest in the same hypertensive individuals. In conclusions, our studies provide the first direct evidence for a potentially unfavorable potentiation of muscle metaboreflex by amlodipine during isometric handgrip exercise in hypertensive patients whereas eplerenone has no significant effect. Our study may have clinical implications in terms of selection of antihypertensive agents that have the least detrimental effects on sympathetic neural responses to isometric exercise.

Central Command and the Regulation of Exercise Heart Rate Response in Heart Failure With Preserved Ejection Fraction.

Chronotropic incompetence is common in heart failure with preserved ejection fraction (HFpEF) and is linked to impaired aerobic capacity. Whether upstream autonomic signaling pathways responsible for raising exercise heart rate are impaired in HFpEF is unknown. We investigated the integrity of central command and muscle metaboreceptor function, 2 predominant mechanisms responsible for exertional increases in heart rate, in patients with HFpEF and senior controls. Fourteen healthy senior controls (7 men, 7 women) and 20 carefully screened patients with HFpEF (8 men, 12 women) underwent cardiopulmonary exercise testing (peak Vo2) and static handgrip exercise at 40% of maximal voluntary contraction to fatigue with postexercise circulatory arrest for 2 minutes to assess central command and metaboreceptor function, respectively. Peak Vo2 (13.1±3.4 versus 22.7±4.0 mL/kg/min; P<0.001) and heart rate (122±20 versus 155±14 bpm; P<0.001) were lower in patients with HFpEF than senior controls. There were no significant differences in peak heart rate response during static handgrip between groups (patients with HFpEF versus controls: 90±13 versus 93±10 bpm; P=0.49). Metaboreceptor function, defined as mean arterial blood pressure at the end of postexercise circulatory arrest, was not significantly different between groups. Central command (vagally mediated) and metaboreceptor function (sympathetically mediated) in patients with HFpEF were not different from those in healthy senior controls despite significantly lower peak whole-body exercise heart rates. These results demonstrate key reflex autonomic pathways regulating exercise heart rate responsiveness are intact in HFpEF.

Abstract 13421: Ventricular and Arterial Elastance During Isometric Handgrip Exercise and Post-exercise Circulatory Arrest in Heart Failure With and Without Preserved Ejection Fraction

Introduction: Isometric handgrip (IHG) training at 30% maximal voluntary contraction (MVC) lowers blood pressure in hypertensive patients. Impacts of IHG exercise and post-exercise circulatory arrest (PECA), which isolates metaboreflex control, have been unclear in heart failure (HF). Purpose: To investigate the impacts of IHG exercise and PECA on ventricular-arterial stiffness and left ventricular (LV) relaxation in HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods: We invasively obtained LV pressure-volume (PV) loops in 20 patients (10 HFpEF, 10 HFrEF) using conductance catheter with microtip-manometer during 3 minutes of IHG at 30%MVC and 3 minutes of PECA. Hemodynamics and LV-arterial function including LV end-systolic elastance (Ees) by the single-beat method, effective arterial elastance (Ea), and time constant of LV relaxation (Tau) were evaluated every minute. Results: At rest, HFpEF had higher LV end-systolic pressure (ESP) and lower heart rate than HFrEF with similar LV end-diastolic pressure (EDP). The coupling ratio (Ees/Ea) was greater in HFpEF than HFrEF (1.0±0.3 vs. 0.6±0.3, p&lt;0.01). IHG for 3minutes similarly increased heart rate in HFpEF (by 10±8 bpm) and HFrEF (by 14±6 bpm). IHG also increased end-diastolic and LVESP (134±21 vs. 158±30 mmHg and 113±25 vs. 139±25 mmHg) in both groups (groupхtime effect p≥0.25). In HFpEF, Ees, Ea and Ees/Ea (1.0±0.3 vs. 1.1±0.4) were unaffected during IHG. In HFrEF, IHG induced variable increases in Ea. LV end-systolic volume and the ESPV volume-axis intercept were larger, and Ees at IHG 3 rd min was greater (1.30±0.7 vs. 3.1±2.1 mmHg/ml, p&lt;0.01) than baseline, resulting in unchanged Ees/Ea at IHG 3 rd min (0.6±0.3 vs. 0.8±0.4, p≥0.37). Tau was prolonged only in HFrEF during IHG and was returned to the baseline value during PECA. During the first 2 minutes of PECA, LVESP was lower than that at IHG 3 rd min only in HFpEF, suggesting less metaboreflex control of blood pressure in HFpEF during IHG. Conclusions: IHG exercise at 30%MVC induced modest increases in LV end-systolic and end-diastolic pressures in HFpEF and HFrEF. Although the prolongation of LV relaxation was observed only in HFrEF, the ventricular and arterial coupling was maintained throughout the IHG exercise in both groups.

Augmented Sympathetic Neural Activation in response to Static Handgrip during Early Pregnancy in Humans

Pregnancy is a dynamic process with systemic neuro‐vascular adaptations. Normal pregnancy is associated with sympathetic activation and attenuated vasoconstrictor responsiveness to alpha‐adrenergic stimulation, which starts as early as 4 weeks of gestation. However, little is known about changes in the exercise pressor reflex in pregnancy, a robust sympathetic stimulus originating from contracting skeletal muscle. We hypothesized that the muscle sympathetic nerve activity (MSNA) response to isometric muscle contraction would be greater in early pregnant women compared with non‐pregnant women.We measured heart rate (HR), blood pressure (BP), and MSNA in 21 early pregnant women (6–10 weeks of gestation) and 22 age‐matched healthy non‐pregnant women (controls; mid‐luteal phase) during static handgrip (SHG) exercise to fatigue at 40% of maximal voluntary contraction (MVC) force followed by 2 min of postexercise circulatory arrest (PECA). The total SHG time was divided evenly into five stages. We further utilized matched wavelet‐based methodology to extract sympathetic action potential (AP) discharge patterns.Baseline characteristics were comparable between groups. MVC was not different but the time to fatigue was shorter in pregnant women than non‐pregnant women (109±56 vs. 188±76 secs; P=0.003, mean±SD). Supine resting MSNA was greater in pregnant women (burst frequency (BF): 23±10 vs. 14±11 bursts/min; P=0.01) and sympathetic neural discharge was augmented (AP firing frequency: 235±108 vs. 142±87 spikes/min, P=0.04). Mean arterial pressure was not different between groups (80±9 vs. 83±7 mmHg; P=0.3). In response to SHG and PECA, pregnant women exhibited greater increases in MSNA than controls (time × group interaction P=0.03, group P=0.02). At peak exercise and last min of PECA, changes in MSNA BF were greater in pregnant women compared to controls (Δ MSNA at peak exercise: 34±7 vs.19±7 bursts/min; P=0.01, PECA: 25±6 vs.17±7 bursts/min; P=0.03). Similarly, the augmented sympathetic neural response was concomitant with exaggerated AP recruitment (AP firing frequency: group × time interaction P=0.004, group P=0.02 and Δ AP firing frequency at peak exercise: 365±129 vs.193±116 spikes/min; P=0.006, PECA: 241±88 vs.126±55 spikes/min; P=0.03). BP and HR responses to SHG and PECA were not different between groups.In conclusion, early pregnancy is associated with augmented sympathetic neural responses to isometric muscle contraction, which may be attributed to enhanced metabo‐reflex activation. Despite the heightened neural response, vasoconstriction is blunted in early pregnant women. Our findings provide unique mechanistic insight into blood pressure regulation during early pregnancy.Support or Funding InformationSupported by R01HL142605Changes in muscle sympathetic nerve activity (MSNA) burst frequency (BF) in response to static handgrip (SHG), postexercise circulatory arrest (PECA) and recovery.Figure 1Changes in action potential (AP) recruitment in response to static handgrip (SHG), postexercise circulatory arrest (PECA) and recovery.Figure 2

Early onset neurocirculatory response to static handgrip is associated with greater blood pressure variability in women with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric illness that is more prevalent in women, and accumulating evidence suggests a link between PTSD and future development of cardiovascular disease. The underlying mechanisms are unclear, but augmented sympathetic reactivity to daily stressors may be involved. We measured muscle sympathetic nerve activity (MSNA), blood pressure (BP), and heart rate responses in 14 women with PTSD and 14 healthy women (controls) during static handgrip (SHG) exercise to fatigue at 40% of maximal voluntary contraction (MVC). Two minutes of postexercise circulatory arrest (PECA) was followed immediately after SHG to fatigue. MVC and the time to fatigue during SHG did not differ between groups (both P > 0.05). At the first 30 s of SHG, women with PTSD showed augmented sympathetic neural [mean ± SD, ∆MSNA burst frequency (BF): 5 ± 4 vs. 2 ± 3 bursts/30 s, P = 0.02 and ∆MSNA total activity (TA): 82 ± 58 vs. 25 ± 38 arbitrary units/30 s, P = 0.004] and pressor (∆systolic BP: 10 ± 5 vs. 4 ± 3 mmHg, P = 0.003) responses compared with controls. However, MSNA and BP responses at fatigue and during PECA were not different between groups. More interestingly, the augmented initial neural and pressor responses to SHG were associated with greater awake systolic BP variability during ambulation in women with PTSD (MSNA BF: r = 0.55, MSNA TA: r = 0.62, and SBP: r = 0.69, all P < 0.05). These results suggest that early onset exercise pressor response in women with PTSD may be attributed to enhanced mechano- rather than metaboreflexes, which might contribute to the mechanisms underlying the link between PTSD and cardiovascular risk.NEW & NOTEWORTHY The novel findings of the current study are that women with posttraumatic stress disorder (PTSD) exhibited augmented sympathetic neural and pressor responses at the first 30 s of submaximal isometric muscle contraction. More interestingly, exaggerated neurocirculatory responses at the onset of muscle contraction were associated with greater ambulatory awake systolic blood pressure fluctuations in women with PTSD. Our findings expand the knowledge on the physiological mechanisms that perhaps contribute to increased risk of cardiovascular disease in such a population.

Abstract 17249: Impacts of Isometric Handgrip Exercise and Post-Exercise Circulatory Arrest on Hemodynamics and Left Ventricular Function in Heart Failure With Preserved Ejection Fraction

Introduction: Isometric handgrip (IHG) training at 30% maximal voluntary contraction (MVC) lowers blood pressure (BP) in patients with hypertension and healthy individuals. However, impacts of IHG and post-exercise circulatory arrest (PECA), which isolates the metaboreflex control, on left ventricular (LV) function and hemodynamics have been unclear in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Methods: Sixteen patients with HF (age 63±13 years, 5M:11F, 10HFpEF:6HFrEF) underwent invasive LV pressure-volume assessments using conductance catheter with microtip-manometer during 3min of IHG exercise at 30% MVC, followed by 3 min of PECA. Impacts of IHG and PECA on LV function and hemodynamics were evaluated and compared between HFpEF and HFrEF. Results: During 3 min of IHG at 30% MCV, heart rate increased by 10±8 bpm in HFpEF and by 14±6 bpm in HFrEF. IHG elevated LV end-systolic BP in both HFpEF (134±21 vs. 158±30 mmHg, p&lt;0.01) and HFrEF (119±30 vs. 142±31 mmHg, p&lt;0.01) with no change in stroke volume. There was a trend towards an increase in LV end-diastolic pressure in both groups (HFpEF:14±5 vs. 19±10 mmHg, HFrEF: 15±12 vs. 23±11 mmHg). Time constant of LV relaxation was unchanged by 3 min of IHG in HFpEF (52±14 vs. 54±15 ms), while it was prolonged in HFrEF (48±7 vs. 60±9 ms, p&lt;0.01, groupхtime interaction effect p=0.08). During PECA, LV end-systolic BP decreased in both groups and was maintained higher than baseline throughout PECA only in HFpEF. Conclusions: Although IHG exercise at 30% MVC for 3 min would elevate LV end-systolic and end-diastolic pressures, this IHG exercise has no detrimental effect on LV systolic and diastolic function, especially in HFpEF patients. Chronic effect of IHG training on BP and hemodynamics will need to be evaluated in HFpEF patients who often suffer from arterial hypertension.

Novel Gene Variant Associated with Exercise Pressor Reflex Responsiveness

PURPOSE: Activation of thinly myelinated and unmyelinated afferents innervating contracting skeletal muscle elicits the exercise pressor reflex. We hypothesized that single nucleotide polymorphisms (SNPs) of genes encoding ionotropic and metabotropic receptors commonly found on skeletal muscle afferents might account for part of the typical variation in blood pressure responses to exercise. METHODS: 101 healthy, college age, men and women of European ancestry participated. Multivariate modeling of the mean arterial pressure response to post-exercise circulatory arrest following 3-min of static handgrip exercise (30% of maximum) was used to stratify subjects into quartiles. Subjects from the highest (N=33) and lowest (N=25) quartiles provided buccal mucosa cells. DNA was extracted, amplified, and analyzed for common (minor allele frequency >20%), non-synonymous SNPs of genes with functional associations to autonomic disorders. We evaluated selected variants of the TRP (N=18), ASIC (N=3) and P2X (N=4) receptor families (real-time PCR, custom OpenArray™) and used contingency table analysis to compare the frequency of homozygotes and trait allele carriers between the two groups. RESULTS: Trait allele carriers of rs8065080, a T-to-C missense mutation of TRPV1, were more frequent in the high response group (73% vs 48%, P<0.1). Frequencies of all other SNPs did not differ between groups. CONCLUSIONS: Data from this pilot investigation suggest that intra-subject variation in mean arterial pressure during post-exercise circulatory arrest may associate with SNPs of genes putatively linked to the metabolic component of the exercise pressor reflex. Additional work is warranted to confirm these observations and explore the mechanistic role of TRP channels in exercise pressor reflex responsiveness. Supported in part by the Huck Institutes of the Life Sciences and the College of Health and Human Development.

Augmented exercise pressor response during static handgrip in women with PTSD

Post‐traumatic stress disorder (PTSD) is a psychiatric illness that is more prevalent in women than men, and there is growing evidence suggesting a clear link between PTSD and future development of cardiovascular disease. The underlying mechanisms are unclear, but enhanced sympatheticreactivity to daily stressors may be involved. We hypothesized that PTSD women would have an augmented vasomotor sympathetic response to static exercise. We measured heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) in 12 female patients with PTSD and 8 healthy women (controls) during static handgrip (SHG) exercise to fatigue at 40% of maximal voluntary contraction (MVC) force followed by 2 min of postexercise circulatory arrest (PECA) and 3 min of recovery. The total SHG time was divided evenly into five stages. Age, body mass index, and body surface area were not different between groups. MVC and the time to fatigue during SHG did not differ between patients and controls (P&gt;0.05). MSNA burst frequency (BF) in response to SHG was greater in patients than controls (timexgroup interaction P=0.03, time P=0.0001, group P=0.04), but not during PECA. During the early stages of SHG, PTSD patients showed greater MSNA BF compared to controls [stage 1: 40±5 (SE) vs.19±7 bursts/min; P=0.02, stage 2: 45±6 vs.25±7; P=0.03, stage 3: 55±6 vs.30±7; P=0.02). MSNA BF responses during stage 4 and 5 were not different between groups (P=0.09 and P=0.1, respectively). Similarly, PTSD patients showed greater systolic blood pressure (SBP) compared to controls during early stages of SHG (stage 1: 144±4 vs.129±5 mmHg; P=0.02, stage 2: 149±4 vs.132±5; P=0.03, stage 3: 159±6 vs.138±7; P=0.03, stage 4: 166±6 vs.143±7; P=0.04) but not in the last stage (at fatigue; P=0.2). SBP was not different between groups during PECA and recovery. Diastolic BP and HR were progressively increased during SHG, reached peak at the last stage, and were comparable between groups. These results suggest that women with PTSD have an augmented exercise pressor response, which may be attributed to enhanced mechano‐ rather than metabo‐reflexes. However, the actual role of the muscle reflex in cardiovascular risk in PTSD remains to be elucidated.Support or Funding InformationThis study is supported by Harry S. Moss Heart Trust research funding STU 082016‐057This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Blunted Cardiovascular Responses to Exercise in Parkinson Disease Patients: Role of the Muscle Metaboreflex

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by motor dysfunctions, and non‐motor symptoms, such as autonomic and cardiovascular dysfunctions. Importantly, these impairments have a significant impact on patient's quality of life. Several studies have shown that PD patients exhibit attenuated cardiovascular responses to exercise. Unfortunately, the underlying mechanisms that are potentially contributing to these impairments are not fully understood. The isolation of muscle metaboreflex by post‐exercise circulatory arrest of active limb, called post‐exercise ischemia (PEI), is a well‐known mechanism related to the increase in sympathetic nerve activity and partially maintains exercise‐induced increases in blood pressure in healthy populations. Due its predominant role in mediating sympathetic and pressor response, we reasoned that blunted cardiovascular responses during isolated muscle metaboreflex activation could be one of underling mechanisms related to the impaired cardiovascular responses to exercise in PD patients. Herein, the purpose of the present study was to test the hypothesis that patients with PD would have blunted cardiovascular responses to isolated muscle metaboreflex activation during PEI when compared with age‐matched controls. Mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR) were measured in a beat‐to‐beat basis by using finger photoplethysmography and modelflow method, respectively in 11 PD patients [66 ± 2 yrs; (H&amp;Y: 2 ± 1 a.u. and diagnose time: 7 ± 1 yrs] and eight age‐matched controls (66 ± 3 yrs). Measurements were made at baseline (5 min), during 90‐s of isometric handgrip exercise (IHG) performed at 40% maximal voluntary contraction and during isolated muscle metaboreflex activation by PEI (3 min). In addition, a non‐exercise sympathoexcitatory stimulus (cold pressor test, CPT) was performed to determine if the hypothesized attenuated responses in PD patients were specific to exercise and/or metaboreflex activation and not representative of a blunted overall reactivity to cardiovascular stressors. Changes in MAP from baseline were attenuated in PD patients during IHG (PD patients: Δ25 ± 2 mmHg vs. controls: Δ30 ± 3 mmHg; P &lt; 0.05), and these group differences were maintained during PEI (Δ18 ± 1 mmHg vs. Δ24 ± 1 mmHg, respectively; P &lt; 0.01). Additionally, changes in TPR from baseline were attenuated in PD patients during PEI (PD patients: Δ3 ± 1 mmHg−1 L min−1 vs. controls: Δ6 ± 1 mmHg−1 L min−1, respectively; P &lt; 0.05), indicating blunted reflex vasoconstriction. CO responses to both exercise and PEI were similar between groups. In addition, cardiovascular responses to CPT were not different between groups, suggesting no group differences in generalized sympathetic responsiveness. In summary, compared with control subjects, patients with PD exhibit attenuated blood pressure and vasoconstrictory responses to PEI but preserved cardiovascular responses to CPT. Collectively, these data are consistent with the concept that the attenuated cardiovascular responses to exercise in PD patients are, in part, mediated by the skeletal muscle metaboreflex.Support or Funding InformationBrazilian National Council of Scientific and Technological Development (CNPq), Foundation for Research Support of Federal District (FAPDF), Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sympathetic neural and cardiovascular responses during static handgrip exercise in women with a history of hypertensive pregnancy.

Women with a history of hypertensive pregnancy are at greater risk for future cardiovascular events; however, the mechanisms for this increased risk are unknown. Evidence suggests that an exercise stimulus unmasks latent hypertensive tendencies, identifying individuals at the greatest risk for developing cardiovascular disease. The current study examined the hypothesis that women with a hypertensive pregnancy history exhibit an augmented exercise pressor response. Normotensive women with a history of healthy pregnancy (CON; n=9) and hypertensive pregnancy (HP+; n=12) were studied during the mid-luteal phase of the menstrual cycle. Heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), and muscle sympathetic nerve activity (MSNA) were measured during a cold pressor test (CPT), and, following a sufficient period of recovery, during static handgrip to fatigue (SHG) and post-exercise circulatory arrest (PECA). The BP, HR, and MSNA responses to the CPT were similar between groups. The SBP response to SHG and PECA was similar between groups, but DBP and HR were significantly greater in HP+ women (both p<0.05). MSNA burst frequency, but not burst incidence or total activity, tended to be elevated in HP+ women during the stressor (peak Δ from baseline 31±13 vs. 23±13 bursts/min; p for group=0.06). Despite no clinical signs of cardiovascular disease or hypertension, women with a history of hypertensive pregnancy display an enhanced cardiovascular reactivity to an exercise stimulus compared to women with a healthy pregnancy history. This response may be indicative of impaired cardiovascular control that precedes the clinical manifestation of hypertension or cardiovascular events.

Generalized Response of the Exercise Pressor Reflex

Autonomic responsiveness to reflex stimuli varies considerably between individuals, with implications for predicting cardiovascular disease. PURPOSE: To standardize blood pressures to activation of the exercise pressor reflex using isometric handgrip exercise followed by post-exercise circulatory arrest (PECA). METHODS: Using specific search terms including “metaboreflex”, “ergoreflex”, “handgrip”, “reflex”, “static”, and “isometric”, we identified 151 studies that quantified the pressor response to handgrip exercise followed by PECA in healthy humans aged 19-44 years. We characterized these studies by exercise mode (static vs. dynamic), percentage of maximum voluntary contraction, blood pressure measurement technique, duration of exercise, duration of PECA, and method of data presentation (absolute values vs. changes from baseline). Preliminary analysis revealed distinct effects of exercise intensity and duration. We constrained further analysis to studies including healthy adults completing isometric handgrip exercise at 30-33% of maximum for 3 minutes and 2 or more minutes of PECA, with blood pressure measured from the wrist or finger of the resting arm (total of 4 studies). RESULTS: Using the reported means and variation we employed bootstrapping with weighted re-sampling (n=10,000) to create a statistically comparable normal distribution of responses. Based on these criteria, the average population mean arterial pressure response for the second minute of PECA is 19 mmHg. The first quartile response is 13 mmHg, and the third quartile is 26 mmHg. CONCLUSIONS: The autonomic response following ischemic handgrip varies considerably between individuals, even when experimental conditions are standardized. The possible foundation for these differences may be neural (e.g., afferent, central, or efferent) or extra-neural (e.g., genetic, muscle fiber type, or vascular).

Handgrip Training with Chronic Concomitant Exposure to Moderate Altitude Improves Blood Pressure Responses and Delays the Onset of Fatigue

Exposure to moderate altitude (~2500 m) elicits a sympathoexcitatory response. There may also be long term changes such as a reduction in muscular strength and a quicker onset of muscular fatigue. The purpose of this study was to determine whether a training program with concomitant hypoxic exposure could blunt cardiovascular and neural responses, as well as delay the onset of fatigue. Twelve healthy males had heart rate (HR) and blood pressure (systolic, SBP; diastolic, DBP) measured during baseline (BL), static handgrip to fatigue, and post‐exercise circulatory arrest (PECA). A subset of subjects (n=5) had measurements of muscle sympathetic nerve activity (MSNA). Assessments were done before (PRE) and after (POST) a 6‐week rhythmic handgrip training program (5 days/week, 30% of maximal voluntary contraction, 2 sets of 30 repetitions/min until fatigue). HR was higher at fatigue compared to BL (PRE BL: 65±8 vs 96±20 beats/min, p&lt;0.01) but was not different PRE vs POST (POST BL: 61±7 beats/min). SBP was higher at fatigue and during PECA than during BL (PRE BL: 126±11 vs 168±13 vs 154±12 mmHg, both p&lt;0.01) and was lower POST (main effect, p&lt;0.05). DBP was also higher at fatigue and during PECA (PRE BL: 64±5 vs 90±17 vs 78±8 mmHg, both p&lt;0.05) and tended to be lower POST (main effect, p=0.075). Indices of MSNA were higher during fatigue compared to BL (burst frequency, PRE BL: 11±9 vs 42±29 bursts/min, p&lt;0.01; burst incidence, PRE BL: 17±13 vs 45±23 bursts/100 heart beats, p&lt;0.05) but were no different from PRE to POST (burst frequency, POST BL: 12±10 bursts/min; burst incidence, POST BL: 18±15 bursts/100 heart beats). Maximal voluntary contraction was unchanged after training (52±6 vs 50±5 kg, p=NS); however, time to fatigue was delayed POST training (141.4±32.6 vs 176.4±42.3 sec, p&lt;0.05). After 6 weeks of rhythmic handgrip training we found improvements in cardiovascular parameters and a delay in the onset of fatigue but no change in MSNA indices or strength.Support or Funding InformationSupported by the Faculty Grant Program at Northern Arizona University

Vasomotor sympathetic outflow in the muscle metaboreflex in low birth weight young adults.

A growing body of evidence suggests that low birth weight (LBW) offspring are associated with long-term structural and functional changes in cardiovascular and neuroendocrine systems. We tested the hypothesis that muscle metaboreflex activation produces exaggerated responses in cardiac autonomic tone (represented by heart rate variability ratio) and cutaneous vascular sympathetic tone (represented by plethysmography pulse wave amplitude) in LBW compared to normal birth weight (NBW) young adults. We recruited 23 LBW (18 females and five males) and 23 NBW (14 females and nine males) University of Zimbabwe students with neonatal clinical cards as proof of birth weight at term. Resting electrocardiogram, pulse waves, and blood pressures were recorded. Participants then underwent a static/isometric handgrip exercise until fatigue and a post-exercise circulatory arrest period of 2 minutes. We observed (results mean ± standard deviation) a greater mean increase in heart rate variability ratio from baseline to exercise for LBW compared to NBW individuals (1.015±1.034 versus [vs] 0.119±0.789, respectively; P<0.05). We also observed a greater mean decrease in plethysmography pulse wave amplitude from baseline to exercise (−1.32±1.064 vs −0.735±0.63; P<0.05) and from baseline to post-exercise circulatory arrest (−0.932±0.998 vs −0.389±0.563; P<0.05) for LBW compared to NBW individuals. We conclude that LBW may be associated with an exaggerated sympathetic discharge in response to muscle metaboreflex.

Molecular basis for the improvement in muscle metaboreflex and mechanoreflex control in exercise-trained humans with chronic heart failure.

Previous studies have demonstrated that muscle mechanoreflex and metaboreflex controls are altered in heart failure (HF), which seems to be due to changes in cyclooxygenase (COX) pathway and changes in receptors on afferent neurons, including transient receptor potential vanilloid type-1 (TRPV1) and cannabinoid receptor type-1 (CB1). The purpose of the present study was to test the hypotheses: 1) exercise training (ET) alters the muscle metaboreflex and mechanoreflex control of muscle sympathetic nerve activity (MSNA) in HF patients. 2) The alteration in metaboreflex control is accompanied by increased expression of TRPV1 and CB1 receptors in skeletal muscle. 3) The alteration in mechanoreflex control is accompanied by COX-2 pathway in skeletal muscle. Thirty-four consecutive HF patients with ejection fractions <40% were randomized to untrained (n = 17; 54 ± 2 yr) or exercise-trained (n = 17; 56 ± 2 yr) groups. MSNA was recorded by microneurography. Mechanoreceptors were activated by passive exercise and metaboreceptors by postexercise circulatory arrest (PECA). COX-2 pathway, TRPV1, and CB1 receptors were measured in muscle biopsies. Following ET, resting MSNA was decreased compared with untrained group. During PECA (metaboreflex), MSNA responses were increased, which was accompanied by the expression of TRPV1 and CB1 receptors. During passive exercise (mechanoreflex), MSNA responses were decreased, which was accompanied by decreased expression of COX-2, prostaglandin-E2 receptor-4, and thromboxane-A2 receptor and by decreased in muscle inflammation, as indicated by increased miRNA-146 levels and the stable NF-κB/IκB-α ratio. In conclusion, ET alters muscle metaboreflex and mechanoreflex control of MSNA in HF patients. This alteration with ET is accompanied by alteration in TRPV1 and CB1 expression and COX-2 pathway and inflammation in skeletal muscle.

Sex differences in the modulation of vasomotor sympathetic outflow during static handgrip exercise in healthy young humans

Sex differences in sympathetic neural control during static exercise in humans are few and the findings are inconsistent. We hypothesized women would have an attenuated vasomotor sympathetic response to static exercise, which would be further reduced during the high sex hormone [midluteal (ML)] vs. the low hormone phase [early follicular (EF)]. We measured heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) in 11 women and 10 men during a cold pressor test (CPT) and static handgrip to fatigue with 2 min of postexercise circulatory arrest (PECA). HR increased during handgrip, reached its peak at fatigue, and was comparable between sexes. BP increased during handgrip and PECA where men had larger increases from baseline. Mean ± SD MSNA burst frequency (BF) during handgrip and PECA was lower in women (EF, P < 0.05), as was ΔMSNA-BF smaller (main effect, both P < 0.01). ΔTotal activity was higher in men at fatigue (EF: 632 ± 418 vs. ML: 598 ± 342 vs. men: 1,025 ± 416 a.u./min, P < 0.001 for EF and ML vs. men) and during PECA (EF: 354 ± 321 vs. ML: 341 ± 199 vs. men: 599 ± 327 a.u./min, P < 0.05 for EF and ML vs. men). During CPT, HR and MSNA responses were similar between sexes and hormone phases, confirming that central integration and the sympathetic efferent pathway was comparable between the sexes and across hormone phases. Women demonstrated a blunted metaboreflex, unaffected by sex hormones, which may be due to differences in muscle mass or fiber type and, therefore, metabolic stimulation of group IV afferents.

Abnormal Muscle Metaboreflex Control of Sympathetic Activity in Never-Treated Hypertensive Subjects

Muscle metaboreflex control in hypertensive subjects has not been described yet. We investigated the integrity of muscle metaboreflex control of muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in never-treated hypertensive subjects. Eighteen hypertensive (42+/-1 years) and 22 normotensive subjects (38+/-1 years) were studied. The MSNA was measured by microneurography and forearm blood flow (FBF) by venous occlusion plethysmography. The BP was noninvasively monitored. Baseline MSNA was significantly increased in hypertensive subjects when compared with normal subjects (34+/-2 v 22+/-2 bursts/min, P<.001). Baseline FBF was significantly decreased in hypertensive subjects (2.66+/-0.2 v 2.05+/-0.1 mL/min/100 mL, P=.04). During moderate handgrip exercise (30% maximal voluntary contraction), MSNA levels were significantly higher in hypertensive subjects. However, MSNA responses were significantly lower in hypertensive subjects (1+/-3 v 10+/-2 bursts/100 heart beats, P = .001). Similarly, FBF responses were significantly lower in hypertensive subjects when compared with normotensive subjects (0.70+/-0.19 v 1.60+/-0.36 mL/min/100 mL, P=.04). During the postexercise circulatory arrest, when the metaboreflex control is isolated, MSNA levels returned toward baseline in hypertensive subjects (58+/-4 v 55+/-3 bursts/100 heart beats, P=.98). In contrast, in normotensive subjects, MSNA levels remained significantly elevated when compared with baseline (48+/-3 v 35+/-1 bursts/100 heart beats, P<.001). These findings suggest an association between hypertension and decreased muscle metaboreflex control of MSNA.

Hyperoxia enhances metaboreflex sensitivity during static exercise in humans

Peripheral chemoreflex inhibition with hyperoxia decreases sympathetic nerve traffic to muscle circulation [muscle sympathetic nerve activity (MSNA)]. Hyperoxia also decreases lactate production during exercise. However, hyperoxia markedly increases the activation of sensory endings in skeletal muscle in animal studies. We tested the hypothesis that hyperoxia increases the MSNA and mean blood pressure (MBP) responses to isometric exercise. The effects of breathing 21% and 100% oxygen at rest and during isometric handgrip at 30% of maximal voluntary contraction on MSNA, heart rate (HR), MBP, blood lactate (BL), and arterial O2 saturation (SaO2) were determined in 12 healthy men. The isometric handgrips were followed by 3 min of postexercise circulatory arrest (PE-CA) to allow metaboreflex activation in the absence of other reflex mechanisms. Hyperoxia lowered resting MSNA, HR, MBP, and BL but increased Sa(O2) compared with normoxia (all P < 0.05). MSNA and MBP increased more when exercise was performed in hyperoxia than in normoxia (MSNA: hyperoxic exercise, 255 +/- 100% vs. normoxic exercise, 211 +/- 80%, P = 0.04; and MBP: hyperoxic exercise, 33 +/- 9 mmHg vs. normoxic exercise, 26 +/- 10 mmHg, P = 0.03). During PE-CA, MSNA and MBP remained elevated (both P < 0.05) and to a larger extent during hyperoxia than normoxia (P < 0.05). Hyperoxia enhances the sympathetic and blood pressure (BP) reactivity to metaboreflex activation. This is due to an increase in metaboreflex sensitivity by hyperoxia that overrules the sympathoinhibitory and BP lowering effects of chemoreflex inhibition. This occurs despite a reduced lactic acid production.