Attenuated peripheral oxygen extraction and greater cardiac output in women with posttraumatic stress disorder during exercise.

Posttraumatic stress disorder (PTSD) is associated with an increased risk of developing cardiovascular disease, especially in women. Evidence indicates that men with PTSD exhibit lower maximal oxygen uptake (V̇o2max) relative to controls; however, whether V̇o2max is blunted in women with PTSD remains unknown. Furthermore, it is unclear what determinants (i.e., central and/or peripheral) of V̇o2max are impacted by PTSD. Therefore, we evaluated the central (i.e., cardiac output; Q̇c) and peripheral (i.e., arteriovenous oxygen difference) determinants of V̇o2max in women with PTSD; hypothesizing that V̇o2max would be lower in women with PTSD compared with women without PTSD (controls), primarily due to smaller increases in stroke volume (SV), and therefore Q̇c. Oxygen uptake (V̇o2), heart rate (HR), Q̇c, SV, and arteriovenous oxygen difference were measured in women with PTSD (n = 14; mean [SD]: 43 [11] yr,) and controls (n = 17; 45 [11] yr) at rest, and during an incremental maximal treadmill exercise test, and the Q̇c/V̇o2 slope was calculated. V̇o2max was not different between women with and without PTSD (24.3 [5.6] vs. 26.4 [5.0] mL/kg/min; P = 0.265). However, women with PTSD had higher Q̇c [P = 0.002; primarily due to greater SV (P = 0.069), not HR (P = 0.285)], and lower arteriovenous oxygen difference (P = 0.002) throughout exercise compared with controls. Furthermore, the Q̇c/V̇o2 slope was steeper in women with PTSD relative to controls (6.6 [1.4] vs. 5.7 [1.0] AU; P = 0.033). Following maximal exercise, women with PTSD exhibited slower HR recovery than controls (P = 0.046). Thus, despite attenuated peripheral oxygen extraction, V̇o2max is not reduced in women with PTSD, likely due to larger increases in Q̇c.NEW & NOTEWORTHY The current study indicates that V̇o2max is not different between women with and without PTSD; however, women with PTSD exhibit blunted peripheral extraction of oxygen, thus requiring an increase in Q̇c to meet metabolic demand during exercise. Furthermore, following exercise, women with PTSD demonstrate impaired autonomic cardiovascular control relative to sedentary controls. We interpret these data to indicate that women with PTSD demonstrate aberrant cardiovascular responses during and immediately following fatiguing exercise.

Sympathetic Action Potential Firing and Recruitment Patterns Are Abnormal in Gestational Hypertension.

BACKGROUND: We tested the hypothesis that women who develop gestational hypertension (GH) display abnormal sympathetic action potential (AP) discharge patterns during late pregnancy (32-36 weeks), both at supine rest and during postural stress. METHODS: Thirteen nonpregnant, female controls (nonpregnant controls [CTRL]) and 32 pregnant women participated; 14 had low-risk (no personal history of GH) normal pregnancies (LR-NP), 10 had high-risk (personal history of GH) normal pregnancies (HR-NP), and 8 developed GH. We measured heart rate, blood pressure, and muscle sympathetic nerve activity (microneurography) at supine rest and 60° head-up tilt. Sympathetic AP patterns were studied using wavelet-based methodology. RESULTS: At rest, muscle sympathetic nerve activity burst frequency was elevated in LR-NP, HR-NP, and GH versus CTRL (all P≤0.01); however, the AP content per integrated burst was augmented only in GH (20±5 spikes/burst), compared with CTRL (8±3 spikes/burst), LR-NP (9±2 spikes/burst) and HR-NP (11±4 spikes/burst; all P<0.0001). Thus, total AP firing frequency was greater in GH versus each of CTRL, LR-NP, and HR-NP (all P<0.0001). In pregnancy, AP frequency is related directly to systolic (R2=46%) and diastolic (R2=20%) blood pressure (both P≤0.01). Unlike CTRL (both P<0.01), women who developed GH were unable to increase within-burst AP firing (P=0.71) or recruit latent subpopulations of larger-sized APs (P=0.72) in response to head-up tilt, perhaps related to a ceiling-effect; however, total AP firing frequency in the upright posture was elevated in the GH cohort versus CTRL, LR-NP, and HR-NP (all P<0.05). CONCLUSIONS: Women who develop GH display aberrant sympathetic AP firing patterns in both the supine and upright postures.

Posture-related changes in sympathetic baroreflex sensitivity during normal pregnancy.

Normal pregnancy is associated with vast adjustments in cardiovascular autonomic control. Sympathetic baroreflex sensitivity has been reported to be attenuated during pregnancy in animal models, but most studies in humans are cross-sectional and findings from longitudinal case studies are inconclusive. It remains unclear how sympathetic baroreflex sensitivity is altered longitudinally during pregnancy within an individual in different body postures. Therefore, this study examined the impact of posture on sympathetic baroreflex sensitivity in 24 normal-weight normotensive pregnant women. Spontaneous sympathetic baroreflex sensitivity was assessed during early (6-11 weeks) and late (32-36 weeks) pregnancy and 6-10 weeks postpartum in the supine posture and graded head-up tilt (30° and 60°). In addition, data from the postpartum period were compared with (and no different to) 18 age-matched non-pregnant women to confirm that the postpartum period was reflective of a non-pregnant condition (online supplement). When compared with postpartum (-3.8 ± 0.4 bursts/100 heartbeats/mmHg), supine sympathetic baroreflex sensitivity was augmented during early pregnancy (-5.9 ± 0.4 bursts/100 heartbeats/mmHg, P < 0.001). However, sympathetic baroreflex sensitivity at 30° or 60° head-up tilt was not different between any phase of gestation (P > 0.05). When compared to supine, sympathetic baroreflex sensitivity at 60° head-up tilt was significantly blunted during early (Δ2.0 ± 0.7 bursts/100 heartbeats/mmHg, P = 0.024) and late (Δ1.5 ± 0.6 bursts/100 heartbeats/mmHg, P = 0.049) pregnancy but did not change postpartum (Δ0.4 ± 0.6 bursts/100 heartbeats/mmHg, P = 1.0). These data show that time-course changes in sympathetic baroreflex sensitivity are dependent on the posture it is examined in and provides a foundation of normal blood pressure regulation during pregnancy for future studies in women at risk for adverse pregnancy outcomes.

Impaired sympathetic neural recruitment during exercise pressor reflex activation in women with post-traumatic stress disorder.

Muscle sympathetic nerve activity (MSNA) increases during isometric exercise via increased firing of low-threshold action potentials (AP), recruitment of larger, higher-threshold APs, and synaptic delay modifications. Recent work found that women with post-traumatic stress disorder (PTSD) demonstrate exaggerated early-onset MSNA responses to exercise; however, it is unclear how PTSD affects AP recruitment patterns during fatiguing exercise. We hypothesized that women with PTSD (n = 11, 43 [11] [SD] years) would exhibit exaggerated sympathetic neural recruitment compared to women without PTSD (controls; n = 13, 40 [8] years). MSNA and AP discharge patterns (via microneurography and a continuous wavelet transform) were measured during 1 min of baseline, isometric handgrip exercise (IHG) to fatigue, 2 min of post-exercise circulatory occlusion (PECO), and 3 min of recovery. Women with PTSD were unable to increase AP content per burst compared to controls throughout IHG and PECO (main effect of group: P = 0.026). Furthermore, relative to controls, women with PTSD recruited fewer AP clusters per burst during the first (controls: ∆1.3 [1.2] vs. PTSD: ∆-0.2 [0.8]; P = 0.016) and second minute (controls: ∆1.2 [1.1] vs. PTSD: ∆-0.1 [0.8]; P = 0.022) of PECO, and fewer subpopulations of larger, previously silent axons during the first (controls: ∆5 [4] vs. PTSD: ∆1 [2]; P = 0.020) and second minute (controls: ∆4 [2] vs. PTSD: ∆1 [2]; P = 0.021) of PECO. Conversely, PTSD did not modify the AP cluster size-latency relationship during baseline, the end of IHG, or PECO (all P = 0.658-0.745). Collectively, these data indicate that women with PTSD demonstrate inherent impairments in the fundamental neural coding patterns elicited by the sympathetic nervous system during IHG and exercise pressor reflex activation.

Impact of high-salt versus low-salt intake on the response of sympathetic baroreflex sensitivity to orthostasis in women with a history of normal pregnancy.

Previous studies have demonstrated that sympathetic baroreflex sensitivity (BRS) increases during orthostatic stress in humans. We recently showed that dietary salt intake affects sympathetic neural control in healthy premenopausal women. This study aimed to determine whether salt loading versus salt reduction would impact sympathetic BRS during orthostasis in premenopausal women with a history of normal pregnancy. Nine healthy women [42 ± 3 (SD) yr] were given a standardized isocaloric high-salt (250 mEq sodium/day) or low-salt (50 mEq sodium/day) diet for 1 wk each (∼2 mo apart with the order randomized), whereas water intake was ad libitum. Laboratory testing was performed following each high- and low-salt period in the midluteal phase of the menstrual cycle. Hemodynamics and muscle sympathetic nerve activity (MSNA) were measured at baseline (supine; 2 min) and during a graded head-up tilt (30° for 5 min and 60° for 20 min). Sympathetic BRS was assessed during baseline and head-up tilt. Hemodynamics were not different between salt conditions during baseline or tilt. Both supine and upright MSNA indices were lower in high salt than low salt (all P < 0.05), however, there was no interaction effect (P = 0.507-0.996). On moving from supine to upright, sympathetic BRS remained unchanged in high salt but increased in low salt (P = 0.028 for interaction). Thus, salt loading diminishes the responsiveness of sympathetic BRS during orthostasis compared with salt reduction in healthy premenopausal women with prior normal pregnancy. Whether this is one underlying mechanism for salt-induced development of hypertension during ambulation remains to be determined.

Evidence of Reduced Efferent Renal Sympathetic Innervation After Chemical Renal Denervation in Humans.

BACKGROUND: Renal denervation (RDN) is effective at lowering blood pressure. However, it is unknown if ablative procedures elicit sympathetic denervation of the kidneys in humans. The aim of this investigation was to assess sympathetic innervation of the renal cortex following perivascular chemical RDN, which may be particularly effective at ablating perivascular efferent and afferent nerves. METHODS: Seven hypertensive patients (4F:3M; 50-65 years) completed PET-CT sympathetic neuroimaging of the renal cortex using 11C-methylreboxetine (11C-MRB, norepinephrine transporter ligand) and 6-[18F]-fluorodopamine (18F-FDA; substrate for the cell membrane norepinephrine transporter) before and 8 weeks after chemical RDN (Peregrine System Infusion Catheter, Ablative Solutions; n = 4; 2F:2M) or control renal angiography (n = 3; 2F:1M). Patients completed physiological phenotyping including 24-hour ambulatory blood pressure, hemodynamics, muscle sympathetic nerve activity, and 24-hour urine collection. RESULTS: RDN decreased 11C-MRB-derived radioactivity by ~30% (Δ  11C-MRB/chamber: -0.95 a.u. confidence interval (CI): -1.36 to -0.54, P = 0.0002), indicative of efferent RDN. In contrast, 18F-FDA-derived radioactivity increased (Δ  18F-FDA/chamber: 2.72 a.u. CI: 0.73-4.71, P = 0.009), consistent with reduced vesicular turnover. Controls showed no change in either marker. Ambulatory systolic pressure decreased in 3 of 4 patients (-9 mm Hg CI: -27 to 9, P = 0.058), and central systolic pressure decreased in all patients (-23 mm Hg CI: -51 to 5, P = 0.095). CONCLUSIONS: These results are the first to show efferent sympathetic denervation of the renal cortex following RDN in humans. Further studies of mechanisms underlying variable blood pressure lowering in the setting of documented RDN may provide insights into inconsistencies in clinical trial outcomes. CLINICAL TRIALS REGISTRATION: Trial Number NCT03465917.

Effects of salt intake on sympathetic neural and pressor responses to cold pressor test in premenopausal women with a history of normal pregnancy.

Excessive salt intake is considered a risk factor for the development of hypertension. Additionally, aberrant neurocirculatory responses to a cold stimulus are associated with an increased risk of hypertension. This study aimed to determine whether salt loading versus salt reduction would impact hemodynamic and sympathetic neural responses during the cold pressor test (CPT) in premenopausal women with a history of normal pregnancy. Nine healthy premenopausal women [42 ± 3 (SD) yr] were given a standardized isocaloric high-salt (HS; 250 mEq sodium/day) or low-salt (LS; 50 mEq sodium/day) diet for 1-wk each (∼2 mo apart with the order randomized), while water intake was ad libitum. Laboratory testing was performed following each HS and LS period in the mid-luteal phase of the menstrual cycle. Subjects were in the supine position and beat-by-beat blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were continuously measured during 1-min baseline followed by 2-min CPT, and 3-min recovery. BP and HR increased during the CPT (both P < 0.001); the responses were similar between HS and LS. MSNA increased during the CPT, but the increment (Δ) was greater during HS than LS (29 ± 6 vs. 15 ± 4 bursts/min; P < 0.001). The transduction of MSNA for vasoconstriction during the CPT was lower in HS (P < 0.05). Thus, salt loading augments sympathetic neural reactivity to the cold stimulus with similar pressor responses compared with salt reduction, which may be attributed to the blunted neurovascular transduction-a compensatory mechanism for hemodynamic homeostasis in premenopausal women with a history of normal pregnancy.

Early sympathetic neural responses during a cold pressor test linked to pain perception.

PURPOSE: There is considerable interindividual variability in the perception of pain. Given that pain management is a major public health problem, gaining insight into the underlying physiology of these perceptual differences is important. We tested the hypothesis that when interindividual variability in initial muscle sympathetic nerve activity (MSNA) responses to a cold pressor test (CPT) is identified, the divergent responses will be linked to differences in pain perception in healthy young men and women. METHODS: In the supine position, blood pressure (BP) and MSNA were measured at baseline and during a 2-min CPT. Immediately following the CPT, pain was rated (range 0-10). RESULTS: Two groups were established: positive responders (Pos, n = 12) and negative responders (Neg, n = 12) based on the initial (first 30 s) MSNA response profiles (Pos: 12 ± 9, Neg: -3 ± 3 bursts/min, P < 0.0001). MSNA response profiles throughout the CPT were different between groups (P < 0.0001). Peak MSNA increases were different (Pos: 27 ± 11, Neg: 9 ± 5 bursts/min, P < 0.0001) and corresponded with initial MSNA responses (R2 = 0.6881, P < 0.0001). Blood pressure responses were also different throughout the CPT (P < 0.0001). Most importantly, the perception of pain induced by the CPT was different between the two groups (Pos: 8 ± 1, Neg: 4 ± 1, P < 0.0001). CONCLUSIONS: The results indicate that in healthy young men and women, there are divergent initial sympathetic neural responses to a given painful stimulus that are linked to the magnitude of pain perception. These findings highlight the distinctive sympathetic patterns that may contribute to the considerable interindividual variability in the perception of pain.

Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition.

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague-Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5-ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness.

Cancer cachexia is a syndrome characterized by profound cardiac and diaphragm muscle wasting, which increase the risk of morbidity in cancer patients due to failure of the cardiorespiratory system. In this regard, muscle relies greatly on mitochondria to meet energy requirements for contraction and mitochondrial dysfunction can result in muscle weakness and fatigue. In addition, mitochondria are a major source of reactive oxygen species (ROS) production, which can stimulate increased rates of muscle protein degradation. Therefore, it has been suggested that mitochondrial dysfunction may be an underlying factor that contributes to the pathology of cancer cachexia. To determine if pharmacologically targeting mitochondrial dysfunction via treatment with the mitochondria-targeting peptide SS-31 would prevent cardiorespiratory muscle dysfunction, colon 26 (C26) adenocarcinoma tumor-bearing mice were administered either saline or SS-31 daily (3 mg/kg/day) following inoculation. C26 mice treated with saline demonstrated greater ROS production and mitochondrial uncoupling compared to C26 mice receiving SS-31 in both the heart and diaphragm muscle. In addition, saline-treated C26 mice exhibited a decline in left ventricular function which was significantly rescued in C26 mice treated with SS-31. In the diaphragm, muscle fiber cross-sectional area of C26 mice treated with saline was significantly reduced and force production was impaired compared to C26, SS-31-treated animals. Finally, ventilatory deficits were also attenuated in C26 mice treated with SS-31, compared to saline treatment. These data demonstrate that C26 tumors promote severe cardiac and respiratory myopathy, and that prevention of mitochondrial dysfunction is sufficient to preclude cancer cachexia-induced cardiorespiratory dysfunction.

Low-dose ketamine affects blood pressure, but not muscle sympathetic nerve activity, during progressive central hypovolemia without altering tolerance.

KEY POINTS: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult. Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low-dose ketamine, one of three analgesics employed in the pre-hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown. For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult. Increases in muscle sympathetic nerve activity during progressive lower-body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. ABSTRACT: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. For a haemorrhaging soldier, there are several pain medications (e.g. ketamine) recommended for use in the prehospital, field setting. However, the data to support these recommendations are primarily limited to studies in animals. Therefore, it is unknown whether ketamine adversely affects physiological mechanisms responsible for maintenance of arterial blood pressure (BP) during haemorrhage in humans. In humans, ketamine has been demonstrated to raise resting BP, although it has not been studied with the concomitant central hypovolemia that occurs during haemorrhage. Thus, the present study aimed to test the hypothesis that ketamine does not impair haemorrhagic tolerance in humans. Thirty volunteers (15 females) participated in this double-blinded, randomized, placebo-controlled trial. A pre-syncopal limited progressive lower-body negative pressure (LBNP; a validated model for simulating haemorrhage) test was conducted following the administration of ketamine (20 mg) or placebo (saline). Tolerance was quantified as a cumulative stress index and compared between trials using a paired, two-tailed t test. We compared muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat BP (photoplethysmography) and heart rate (electrocardiogram) responses during the LBNP test using a mixed effects model (time [LBNP stage] × drug). Tolerance to the LBNP test was not different between trials (Ketamine: 635 ± 391 vs. Placebo: 652 ± 360 mmHg‧min, p = 0.77). Increases in MSNA burst frequency (time: P < 0.01, trial: p = 0.27, interaction: p = 0.39) during LBNP stages were no different between trials. Despite the lack of differences for MSNA responses, mean BP (time: P < 0.01, trial: P < 0.01, interaction: p = 0.01) and heart rate (time: P < 0.01, trial: P < 0.01, interaction: P < 0.01) were higher during moderate hypovolemia after ketamine vs. placebo administration (P < 0.05 for all, post hoc), but not at the end of LBNP. These data, which are the first to be obtained in conscious humans, demonstrate that the administration of low-dose ketamine does not impair tolerance to simulated haemorrhage or mechanisms responsible for maintenance of BP.

Impact of sex and age on metabolism, sympathetic activity, and hypertension.

In this brief review, we summarize the current knowledge on the complex interplay between metabolism, sympathetic activity and hypertension with a focus on sex differences and changes with age in humans. Evidence suggests that in premenopausal women, sex hormones, particularly estrogen exerts a profound cardioprotective effect which may be associated with favorable metabolic profiles, as well as lower sympathetic activity and blood pressure at rest and any given physiological and environmental stimuli compared with men of a similar age. Along this line, premenopausal women seem to be generally protected from obesity-induced metabolic and cardiovascular complications. However, postmenopausal estrogen deprivation during midlife and older age has a detrimental impact on metabolism, may lead to adipose tissue redistribution from the subcutaneous to abdominal area, and augments sympathetic activity. All these changes could contribute significantly to the higher prevalence of hypertension and greater cardiometabolic risk in older women than older men. It is proposed that obesity-related hypertension has a neurogenic component which is characterized by sympathetic overactivity, but the impact of sex and age remains largely unknown. Understanding sex and age-specific differences in obesity and sympathetic neural control of blood pressure is important in the prevention and/or risk reduction of cardiometabolic disorders for both men and women.

Salt intake impacts sympathetic neural control but not morning blood pressure surge in premenopausal women with a history of normal pregnancy.

Salt intake may alter blood pressure (BP) regulation, but no study has investigated the impact of salt reduction versus salt loading on morning blood pressure surge (MBPS) and sympathetic neural control in premenopausal women with a history of normal pregnancy. Nine healthy women (42 ± 3 yr; mean ± SD) were given a low-salt diet (LS; 50 mEq sodium/day) and high-salt diet (HS; 250 mEq sodium/day) for 1 wk each (~2 mo apart with the order randomized), while water intake was ad libitum. Ambulatory BP at 24 h was measured, and the percent change in blood volume (BV) was calculated following LS and HS. MBPS was defined as the morning systolic BP (averaged for 2 h after wake-up) minus the lowest nocturnal systolic BP. Beat-by-beat BP, heart rate, and muscle sympathetic nerve activity (MSNA) were measured during supine rest. Signal averaging was used to characterize changes in beat-by-beat mean arterial pressure and total vascular conductance following spontaneous MSNA bursts to assess sympathetic vascular transduction. Ambulatory BP and MBPS (32 ± 7 vs. 26 ± 12 mmHg, P = 0.208) did not differ between LS and HS. From LS to HS, BV increased by 4.3 ± 3.7% (P = 0.008). MSNA (30 ± 20 vs. 18 ± 13 bursts/100 heartbeats, P = 0.005) was higher, whereas sympathetic vascular transduction was lower in LS than HS (both, P < 0.01). Changes in MSNA from LS to HS were correlated to percent changes in BV (r = -0.673; P = 0.047). Thus, salt intake affects sympathetic neural control but not MBPS in premenopausal women with a history of normal pregnancy. The underlying mechanisms remain unknown; however, alterations in sympathetic vascular transduction may, in part, contribute.NEW & NOTEWORTHY This is the first study to demonstrate that MBPS and ambulatory BP were not affected by salt intake despite a significant change in sympathetic outflow in healthy premenopausal women with a history of normal pregnancy. This may be due to compensatory adaptations in MSNA and sympathetic vascular transduction during salt reduction versus salt loading.

Abnormal sympathetic neural recruitment patterns and hemodynamic responses to cold pressor test in women with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is more prevalent in women and associated with greater risk of major forms of cardiovascular disease, but physiological mechanisms underlying this association remain unknown. We hypothesized that abnormal sympathetic responses to sympathoexcitatory stimuli might predispose PTSD patients to a greater risk of cardiovascular disease. We examined changes in integrated muscle sympathetic nerve activity (MSNA) burst and multiunit action potential (AP) recruitment patterns as well as hemodynamic responses during cold pressor test (CPT) in 14 women with PTSD and 14 healthy control subjects. Data were collected during 1-min baseline, 2-min CPT, and 3-min recovery. At baseline, blood pressure (BP) was not different between groups; however, heart rate and sympathetic neural activity were greater in women with PTSD [MSNA burst frequency (BF): 27 ± 13 vs. 18 ± 14 bursts/min (P = 0.04); AP frequency: 272 ± 152 vs. 174 ± 146 spikes/min (P = 0.03)]. In response to CPT, BP responses exhibited a significant group × time interaction (P = 0.01) highlighted by a significant diastolic BP main group effect (P = 0.048) despite the finding that increases in integrated MSNA burst responses were not different between groups (P > 0.05). However, compared with control subjects, AP firing frequency (group × time interaction P = 0.0001, group P = 0.02) and AP per burst (group × time interaction P = 0.03, group P = 0.03) were augmented in women with PTSD. Collectively, women with PTSD exhibited a greater pressor response and an exaggerated sympathetic neural recruitment pattern during sympathoexcitatory stimuli that may, in part, explain the propensity toward developing hypertension and cardiovascular disease later in life.NEW & NOTEWORTHY The novel findings of the present study are that women with posttraumatic stress disorder (PTSD) have an augmented pressor response to the sympathoexcitatory stimulus of a cold pressor test (CPT) compared with healthy control subjects. Although integrated muscle sympathetic nerve activity burst responses were not significantly different between groups, total sympathetic action potential discharge in response to the CPT was markedly elevated in women with PTSD exhibiting increased firing of low-threshold axons as well as the recruitment of latent subpopulations of larger-sized axons that are otherwise silent at baseline. Aberrant autonomic circulatory control in response to sympathoexcitatory stimulus may in part explain the propensity toward developing hypertension and cardiovascular disease in this population.

Influence of multiparity on sympathetic nerve activity during normal pregnancy.

Recent evidence suggests an elevated risk of cardiovascular disease development in multiparous women. Therefore, we investigated the effects of multiparity on within-pregnancy sympathetic neural regulation in normotensive, pregnant women. We retrospectively analyzed heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA; n = 8) data from 10 women whom participated in microneurographic research studies during two sequential pregnancies (i.e., PREG1 and PREG2). There was no difference in resting BP between pregnancies (P > 0.05), whereas HR trended higher in PREG2 versus PREG1 (P = 0.06). MSNA burst frequency was greater in PREG2 versus PREG1 after adjusting for age (32 ± 12 vs. 22 ± 12 bursts/min; P = 0.049), whereas burst incidence did not differ (40 ± 16 vs. 34 ± 17 bursts/100 heartbeats; P = 0.21). Sympathetic baroreflex sensitivity was not different between PREG1 and PREG2 (P > 0.05). Our results may highlight a possible role of altered within-pregnancy sympathetic neural regulation in the observed relationship in women between parity and future cardiovascular disease risk.NEW & NOTEWORTHY To our knowledge, this is the first study to investigate the effects of multiparity on within-pregnancy sympathetic neural regulation. We observed augmented muscle sympathetic nerve activity in women's second studied pregnancy versus their first. Conversely, blood pressure and sympathetic baroreflex sensitivity did not differ, whereas a trend for increased heart rate was observed. Our results highlight a possible role of altered within-pregnancy sympathetic neural regulation in the relationship between increased parity and cardiovascular disease development.

Sex Differences in the Sympathetic Neural Recruitment and Hemodynamic Response to Head-Up Tilt in Older Hypertensives.

This study tested the hypothesis that older hypertensive women display augmented pressor responses and aberrant sympathetic neural discharge patterning in response to orthostatic stress versus older hypertensive men. We evaluated, in older hypertensive and normotensive men and women (n=12 each group), blood pressure, heart rate, cardiac index (acetylene rebreathing), total peripheral resistance, and muscle sympathetic nerve activity (microneurography) at baseline (supine; 3 minutes) and during graded head-up tilt (30° for 5 minutes and 60° for 20 minutes). Sympathetic action potential discharge patterns were studied using wavelet-based methodology. In the upright posture, systolic and diastolic blood pressure responses were greater in hypertensive women versus hypertensive men and normotensive women (P<0.05). No differences existed in the heart rate, stroke index, or cardiac index response between groups; however, the total peripheral resistance response throughout graded head-up tilt was markedly greater in hypertensive women (P<0.01). Yet, the increase in integrated muscle sympathetic nerve activity burst frequency and burst incidence were similar between hypertensive women and men in the supine and upright postures. However, the increase in the mean action potential content per integrated burst and recruitment of previously dormant, larger-sized action potentials during 60° head-up tilt was greater in hypertensive women versus hypertensive men and normotensive women (P<0.001). Therefore, total sympathetic action potential firing frequency was markedly greater in hypertensive women throughout 60° head-up tilt (P<0.001). In conclusion, older hypertensive women displayed exaggerated pressor and peripheral vasoconstrictor responses to orthostasis versus hypertensive men, under conditions of augmented and aberrant sympathetic neural recruitment, rather than increased burst frequency, in the upright posture.

Would a right shift of the oxy-hemoglobin dissociation curve improve exercise capacity in patients with heart failure?

Exercise intolerance is a hallmark of symptoms in patients with heart failure. In addition to reduced cardiac output, a series of impairments in pulmonary and vascular systems leads to decreases in oxygen delivery and availability in locomotor muscles. This contributes to exercise intolerance in heart failure. The oxy-hemoglobin dissociation curve is essentially a graph illustrating the relationship between the partial pressure of oxygen (PO2, X-axis) and oxygen saturation (SaO2, Y-axis) of hemoglobin. The rightward shift of the curve indicates that hemoglobin's affinity for oxygen decreases and in turn, it may allow the release of more oxygen to tissues. In the present study, we discuss the pathophysiological impairment, which causes exercise intolerance in heart failure patients and suggest a strategy to improve exercise capacity without altering cardiac output via modulating the oxy-hemoglobin dissociation curve.

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.