Autonomic Modulation with Mindfulness-Based Stress Reduction in Chronic Kidney Disease: A Randomized Controlled Trial.

Background: Chronic kidney disease (CKD) is characterized by overactivation of the sympathetic nervous system (SNS) that leads to increased cardiovascular disease risk. Despite the deleterious consequences of SNS overactivity, there are very few therapeutic options available to combat sympathetic overactivity. Aim: To evaluate the effects of Mindfulness-Based Stress Reduction (MBSR) on SNS activity in CKD patients. Method: Participants with CKD stages III-IV were randomized to an 8-week MBSR program or Health Education Program (HEP; a structurally parallel, active control group). Primary outcomes were direct intraneural measures of SNS activity directed to muscle (MSNA) via microneurography at rest and during stress maneuvers. Results: 28 participants (63 ±9 years; 86% males) completed the intervention with 16 in MBSR and 12 in HEP. There was a significant Group (MBSR vs. HEP) by Time (baseline vs. post-intervention) interaction in the change in MSNA reactivity to mental stress (p=0.026), with a significant reduction in the mean change in MSNA over 3 minutes of mental arithmetic at post-intervention (10.6 ± 7.1 to 5.0 ± 5.7 bursts/min, p<0.001), while no change was observed within the HEP group (p=0.773). Conclusions: In this randomized controlled trial, patients with CKD had an amelioration of sympathetic reactivity during mental stress following 8-weeks of MBSR but not after HEP. Our findings demonstrate that mindfulness training is feasible and may have clinically beneficial effects on autonomic function in CKD.

Cerebrovascular carbon dioxide reactivity is intact in chronic kidney disease.

Chronic kidney disease (CKD) is characterized by an elevated risk for cerebrovascular disease including stroke. One mechanism that may contribute to this heightened risk is an impairment in cerebrovascular carbon dioxide reactivity (CVR). We compared CVR between CKD patients stages III-IV and controls (CON) without CKD but matched for hypertension and diabetes status. CVR was measured via 5% CO2 inhalation followed by voluntary hyperventilation in 14 CKD and 11 CON participants while mean arterial pressure, end-tidal carbon dioxide, and middle cerebral artery blood velocity (MCAv) were measured continuously. CVR was quantified as the linear relationship between etCO2 and MCAv. We observed no difference in CVR between groups. Hypercapnic CVR: CKD = 1.2 ± 0.9 cm/s/mm Hg, CON = 1.3 ± 0.8 cm/s/mm Hg, hypocapnic CVR: CKD = 1.3 ± 0.9 cm/s/mm Hg, CON = 1.5 ± 0.7 cm/s/mm Hg, integrated CVR: CKD = 1.5 ± 1.1 cm/s/mm Hg, CON = 1.7 ± 0.8 cm/s/mm Hg, p ≥ 0.48. Unexpectedly, CVR was inversely related to estimated glomerular filtration rate in CKD (R2 = 0.37, p = 0.02). We report that CVR remains intact in CKD and is inversely related to eGFR. These findings suggest that other mechanisms beyond CVR contribute to the elevated stroke risk observed in CKD.

Sex differences in sympathetic activity and pulse wave velocity in adults with chronic kidney disease.

Chronic kidney disease (CKD) is characterized by sympathetic nervous system (SNS) overactivity that contributes to increased vascular stiffness and cardiovascular risk. Although it is well established that SNS activity and vascular stiffness are substantially elevated in CKD, whether sex differences in autonomic and vascular function exist in CKD remains unknown. We tested the hypothesis that compared with females, males with CKD have higher baseline sympathetic activity that is related to increased arterial stiffness. One hundred twenty-nine participants (96 males and 33 females) with CKD stages III and IV were recruited and enrolled. During two separate study visits, vascular stiffness was assessed by measuring carotid-to-femoral pulse wave velocity (cfPWV), and resting muscle sympathetic nerve activity (MSNA) was measured by microneurography. Males with CKD had higher resting MSNA compared with females with CKD (68 ± 16 vs. 55 ± 14 bursts/100 heart beats, P = 0.005), whereas there was no difference in cfPWV between the groups (P = 0.248). Resting MSNA was not associated with cfPWV in both males and females. In conclusion, males with CKD have higher resting sympathetic activity compared with females with CKD. However, there was no difference in vascular stiffness between the sexes. There was no correlation between resting MSNA and cfPWV, suggesting that non-neural mechanisms may play a greater role in the progression of vascular stiffness in CKD, particularly in females.NEW & NOTEWORTHY Males with chronic kidney disease (CKD) have higher resting muscle sympathetic nerve activity (MSNA) compared with females. There was no correlation between MSNA and carotid-to-femoral pulse wave velocity (cfPWV), suggesting that non-neural mechanisms may play a greater role in the progression of vascular stiffness in CKD. Sex differences in SNS activity may play a mechanistic role in observations from epidemiological studies suggesting greater cardiovascular risk in males compared with females with CKD.

Differences in peripheral microcirculatory blood flow regulation in chronic kidney disease based on wavelet analysis of resting near-infrared spectroscopy.

Vascular impairment is closely related to increased mortality in chronic kidney disease (CKD). The objective of this study was to assess impairments in the regulation of peripheral microvascular perfusion in patients with CKD based on time-frequency spectral analysis of resting near-infrared spectroscopy (NIRS) signals. Total hemoglobin (tHb) concentration and tissue saturation index (TSI) signals were collected using NIRS for a continuous 5 mins at 10 Hz from the forearm of 55 participants (34 CKD including 5 with end-stage renal disease, and 21 age-matched control). Continuous wavelet transform-based spectral analysis was used to quantify the spectral amplitude within five pre-defined frequency intervals (I, 0.0095-0.021 Hz; II, 0.021-0.052 Hz; III, 0.052-0.145 Hz; IV, 0.145-0.6 Hz and V, 0.6-2.0 Hz), representing endothelial, neurogenic, myogenic, respiratory and heartbeat activity, respectively. CKD patients showed lower tHb average spectral amplitude within the neurogenic frequency interval compared with controls (p = 0.014), consistent with an increased sympathetic outflow observed in CKD. CKD patients also showed lower TSI average spectral amplitude within the endothelial frequency interval compared with controls (p = 0.046), consistent with a reduced endothelial function in CKD. These findings demonstrate the potential of wavelet analysis of NIRS to provide complementary information on peripheral microvascular regulation in CKD.

Sex differences in Black Veterans with PTSD: women versus men have higher sympathetic activity, inflammation, and blunted cardiovagal baroreflex sensitivity.

PURPOSE: Post-traumatic stress disorder (PTSD) is associated with greater risk of incident hypertension and cardiovascular disease (CVD). Inflammation and autonomic derangements are suggested as contributing mechanisms. Women and Black adults have higher CVD risk associated with stress; however, whether there is a sex difference in autonomic and inflammatory mechanisms among Black individuals with PTSD is not known. We hypothesized that Black women with PTSD have higher inflammation, sympathetic nervous system (SNS) activity and impaired baroreflex sensitivity (BRS). METHODS: In 42 Black Veterans with PTSD (Women, N = 18 and Men, N = 24), we measured inflammatory biomarkers, continuous blood pressure (BP), heart rate (HR) and muscle sympathetic nerve activity (MSNA) at rest and during arterial BRS testing via the modified Oxford technique. RESULTS: Groups were matched for age and body mass index (BMI). Resting BP was similar between groups, but HR was higher (76 ± 12 vs. 68 ± 9 beats/min, p = 0.021) in women compared to men. Although women had lower PTSD symptoms severity (57 ± 17 vs. 68 ± 12 a.u.), resting MSNA (27 ± 13 vs. 16 ± 5 bursts/min, p = 0.003) was higher in women compared to men, respectively. Likewise, cardiovagal BRS was blunted (p = 0.002) in women (7.6 ± 4.3 ms/mmHg) compared to men (15.5 ± 8.4 ms/mmHg) while sympathetic BRS was not different between groups (p = 0.381). Black women also had higher (p = 0.020) plasma levels of interleukin-2 (IL-2). CONCLUSION: Black women with PTSD have higher resting HR and MSNA, greater impairment of cardiovagal BRS and possibly higher inflammation. These findings suggest a higher burden of autonomic and inflammatory derangements in Black women compared to Black men with PTSD.

Augmented resting beat-to-beat blood pressure variability in patients with chronic kidney disease.

PURPOSE: Our aim was to test the hypothesis that patients with chronic kidney disease (CKD) would exhibit augmented resting beat-to-beat blood pressure variability (BPV) that is associated with poor clinical outcomes independent of mean blood pressure (BP). In addition, since the arterial baroreflex plays a critical role in beat-to-beat BP regulation, we further hypothesized that an impaired baroreflex control would be associated with an augmented resting beat-to-beat BPV. METHODS: In 25 sedentary patients with CKD stages III-IV (62 ± 9 years) and 20 controls (57 ± 10 years), resting beat-to-beat BP (finger photoplethysmography) and heart rate (electrocardiography) were continuously measured for 10 min. We calculated the standard deviation (SD), average real variability (ARV) and other indices of BPV. The sequence technique was used to estimate spontaneous cardiac baroreflex sensitivity. RESULTS: Compared with controls (CON), the CKD group had significantly increased resting BPV. The ARV (2.2 ± 0.6 versus 1.6 ± 0.5 mmHg, P < 0.001; 1.6 ± 0.7 versus 1.3 ± 0.3 mmHg, P = 0.039; 1.4 ± 0.5 versus 1.0 ± 0.2 mmHg, P < 0.001) of systolic, diastolic and mean BP, respectively, was increased in CKD versus controls. Other traditional measures of variability showed similar results. The cardiac baroreflex sensitivity was lower in CKD compared with controls (CKD: 8.4 ± 4.5 ms/mmHg versus CON: 14.0 ± 8.2 ms/mmHg, P = 0.008). In addition, cardiac baroreflex sensitivity was negatively associated with BPV [systolic blood pressure (SBP) ARV; r = -0.44, P = 0.003]. CONCLUSION: In summary, our data demonstrate that patients with CKD have augmented beat-to-beat BPV and lower cardiac baroreflex sensitivity. BPV and cardiac baroreflex sensitivity were negatively correlated in this cohort. These findings may further our understanding about cardiovascular dysregulation observed in patients with CKD.

Sleep efficiency and PTSD symptom severity predict microvascular endothelial function and arterial stiffness in young, trauma-exposed women.

Posttraumatic stress disorder (PTSD) is linked to sleep disturbances and significantly higher risk of developing cardiovascular disease (CVD). Furthermore, vascular dysfunction and sleep are independently associated with CVD. Uncovering the link between PTSD symptom severity, sleep disturbances, and vascular function could shine a light on mechanisms of CVD risk in trauma-exposed young women. The purpose of the present study was to investigate the individual and combined effects of sleep efficiency and PTSD symptom severity on vascular function. We recruited 60 otherwise healthy women [age, 26 ± 7 yr and body mass index (BMI), 27.7 ± 6.5 kg/m2] who had been exposed to trauma. We objectively quantified sleep efficiency (SE) using actigraphy, microvascular endothelial function via Framingham reactive hyperemia index (fRHI), and arterial stiffness via pulse-wave velocity (PWV). PTSD symptom severity was assessed using the PTSD checklist for fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (PCL5). PWV was correlated with age (r = 0.490, P < 0.001) and BMI (r = 0.484, P < 0.001). In addition, fRHI was positively correlated with SE (r = 0.409, P = 0.001) and negatively correlated with PTSD symptoms (r = -0.382, P = 0.002). To explore the predictive value of SE and PTSD symptoms on PWV and fRHI, we conducted two multivariate linear regression models. The model predicting PWV was significant (R2 = 0.584, P < 0.001) with age, BMI, blood pressure, and SE emerging as predictors. Likewise, the model predicting fRHI was significant (R2 = 0.360, P < 0.001) with both PTSD symptoms and SE as significant predictors. Our results suggest that although PTSD symptoms mainly impact microvascular endothelial function, sleep efficiency is additionally associated with arterial stiffness in young trauma-exposed women, after controlling for age and BMI.NEW & NOTEWORTHY This is the first study to investigate the individual and combined impacts of objective sleep and PTSD symptoms severity on arterial stiffness and microvascular endothelial function in young premenopausal women. We report that in young trauma-exposed women, although low sleep efficiency is associated with overall vascular function (i.e., microvascular endothelial function and arterial stiffness), the severity of PTSD symptoms is specifically associated with microvascular endothelial function, after accounting for age and body mass index.

Neurocirculatory regulation and adaptations to exercise in chronic kidney disease.

Chronic kidney disease (CKD) is characterized by pronounced exercise intolerance and exaggerated blood pressure reactivity during exercise. Classic mechanisms of exercise intolerance in CKD have been extensively described previously and include uremic myopathy, chronic inflammation, malnutrition, and anemia. We contend that these classic mechanisms only partially explain the exercise intolerance experienced in CKD and that alterations in cardiovascular and autonomic regulation also play a key contributing role. The purpose of this review is to examine the physiological factors that contribute to neurocirculatory dysregulation during exercise and discuss the adaptations that result from regular exercise training in CKD. Key neurocirculatory mechanisms contributing to exercise intolerance in CKD include augmentation of the exercise pressor reflex, aberrations in neurocirculatory control, and increased neurovascular transduction. In addition, we highlight how some contributing factors may be improved through exercise training, with a specific focus on the sympathetic nervous system. Important areas for future work include understanding how the exercise prescription may best be optimized in CKD and how the beneficial effects of exercise training may extend to the brain.

Exercise modulates sympathetic and vascular function in chronic kidney disease.

BACKGROUNDChronic kidney disease (CKD) is characterized by chronic overactivation of the sympathetic nervous system (SNS), which increases the risk of cardiovascular (CV) disease and mortality. SNS overactivity increases CV risk by multiple mechanisms, including vascular stiffness. We tested the hypothesis that aerobic exercise training would reduce resting SNS activity and vascular stiffness in patients with CKD.METHODSIn this randomized controlled trial, sedentary older adults with CKD underwent 12 weeks of exercise (cycling, n = 32) or stretching (an active control group, n = 26). Exercise and stretching interventions were performed 20-45 minutes/session at 3 days/week and were matched for duration. Primary endpoints include resting muscle sympathetic nerve activity (MSNA) via microneurography, arterial stiffness by central pulse wave velocity (PWV), and aortic wave reflection by augmentation index (AIx).RESULTSThere was a significant group × time interaction in MSNA and AIx with no change in the exercise group but with an increase in the stretching group after 12 weeks. The magnitude of change in MSNA was inversely associated with baseline MSNA in the exercise group. There was no change in PWV in either group over the study period.CONCLUSIONOur data demonstrate that 12 weeks of cycling exercise has beneficial neurovascular effects in patients with CKD. Specifically, exercise training safely and effectively ameliorated the increase in MSNA and AIx observed over time in the control group. This sympathoinhibitory effect of exercise training showed greater magnitude in patients with CKD with higher resting MSNA.TRIAL REGISTRATIONClinicalTrials.gov, NCT02947750.FUNDINGNIH R01HL135183; NIH R61AT10457; NIH NCATS KL2TR002381; and NIH T32 DK00756; NIH F32HL147547; and VA Merit I01CX001065.

The impact of senescence on muscle wasting in chronic kidney disease.

BACKGROUND: Muscle wasting is a common complication of chronic kidney disease (CKD) that is associated with higher mortality. Although the mechanisms of myofibre loss in CKD has been widely studied, the contribution of muscle precursor cell (MPC) senescence remains poorly understood. Senescent MPCs no longer proliferate and can produce proinflammatory factors or cytokines. In this study, we tested the hypothesis that the senescence associated secretory phenotype (SASP) of MPCs contributes to CKD-induced muscle atrophy and weakness. METHODS: CKD was induced in mice by 5/6th nephrectomy. Kidney function, muscle size, and function were measured, and markers of atrophy, inflammation, and senescence were evaluated using immunohistochemistry, immunoblots, or qPCR. To study the impact of senescence, a senolytics cocktail of dasatinib + quercetin (D&Q) was given orally to mice for 8 weeks. To investigate CKD-induced senescence at the cellular level, primary MPCs were incubated with serum from CKD or control subjects. The roles of specific proteins in MPC senescence were studied using adenoviral transduction, siRNA, and plasmid transfection. RESULTS: In the hindlimb muscles of CKD mice, (i) the senescence biomarker SA-ß-gal was sharply increased (~30-fold); (ii) the DNA damage response marker γ-H2AX was increased 1.9-fold; and (iii) the senescence pathway markers p21 and p16INK4a were increased 1.99-fold and 2.82-fold, respectively (all values, P < 0.05), whereas p53 was unchanged. γ-H2AX, p21, and p16INK4A were negatively correlated at P < 0.05 with gastrocnemius weight, suggesting a causal relationship with muscle atrophy. Administration of the senolytics cocktail to CKD mice for 8 weeks eliminated the disease-related elevation of p21, p16INK4a , and γ-H2AX, abolished positive SA-ß-gal, and depressed the high levels of the SASP cytokines, TNF-α, IL-6, IL-1ß, and IFN (all values, P < 0.05). Skeletal muscle weight, myofibre cross-sectional area, and grip function were improved in CKD mice receiving D&Q. Markers of protein degradation, inflammation, and MPCs dysfunction were also attenuated by D&Q treatment compared with the vehicle treatment in 5/6th nephrectomy mice (all values, P < 0.05). Uraemic serum induced senescence in cultured MPCs. Overexpression of FoxO1a in MPCs increased the number of p21+ senescent cells, and p21 siRNA prevented uraemic serum-induced senescence (P < 0.05). CONCLUSIONS: Senescent MPCs are likely to contribute to the development of muscle wasting during CKD by producing inflammatory cytokines. Limiting senescence with senolytics ameliorated muscle wasting and improved muscle strength in vivo and restored cultured MPC functions. These results suggest potential new therapeutic targets to improve muscle health and function in CKD.

Dynamic cerebral autoregulation is intact in chronic kidney disease.

Chronic Kidney Disease (CKD) patients experience an elevated risk for cerebrovascular disease. One factor that may contribute to this heightened risk is an impairment in dynamic cerebral autoregulation, the mechanism by which cerebral vessels modulate cerebral blood flow during fluctuations in arterial pressure. We hypothesized that dynamic cerebral autoregulation would be impaired in CKD. To test this hypothesis, we compared dynamic cerebral autoregulation between CKD patients stages III-IV and matched controls (CON) without CKD. Fifteen patients with CKD and 20 CON participants performed 2, 5-minute bouts of repeated sit-to-stand maneuvers at 0.05 Hz and 0.10 Hz while mean arterial pressure (MAP, via finger photoplethysmography) and middle cerebral artery blood velocity (MCAv, via transcranial Doppler ultrasound) were measured continuously. Cerebral autoregulation was characterized by performing a transfer function analysis (TFA) on the MAP-MCAv relationship to derive coherence, phase, gain, and normalized gain (nGain). We observed no group differences in any of the TFA metrics during the repeated sit-to-stand maneuvers. During the 0.05 Hz maneuver, Coherence: CKD = 0.83 ± 0.13, CON = 0.85 ± 0.12, Phase (radians): CKD = 1.39 ± 0.41, CON = 1.25 ± 0.30, Gain (cm/s/mmHg): CKD = 0.69 ± 0.20, CON = 0.71 ± 0.22, nGain (%/mmHg): CKD = 1.26 ± 0.35, CON = 1.20 ± 0.28, p ≥ 0.24. During the 0.10 Hz maneuver (N = 6 CKD and N = 12 CON), Coherence: CKD = 0.61 ± 0.10, CON = 0.67 ± 0.11, Phase (radians): CKD = 1.43 ± 0.26, CON = 1.30 ± 0.23, Gain (cm/s/mmHg): CKD = 0.75 ± 0.15, CON = 0.84 ± 0.26, nGain (%/mmHg): CKD = 1.50 ± 0.28, CON = 1.29 ± 0.24, p ≥ 0.12. Contrary to our hypothesis, dynamic cerebral autoregulation remains intact in CKD stages III-IV. These findings suggest that other mechanisms likely contribute to the increased cerebrovascular disease burden experienced by this population. Future work should determine if other cerebrovascular regulatory mechanisms are impaired and related to cerebrovascular disease risk in CKD.

Aerobic exercise training improves endothelial function and attenuates blood pressure reactivity during maximal exercise in chronic kidney disease.

Patients with chronic kidney disease (CKD) have exaggerated increases in blood pressure during exercise that are associated with endothelial dysfunction. We hypothesized that aerobic exercise training would improve endothelial function and attenuate blood pressure reactivity during exercise in CKD. Sedentary individuals with CKD stages III-IV underwent 12 wk of aerobic cycling exercise (n = 26) or nonaerobic exercise (n = 22, control). Both interventions were performed 3 days/wk and matched for duration. Endothelial function was measured via peripheral arterial tonometry and quantified as reactive hyperemia index (RHI). Peak oxygen uptake (V̇o2peak) was assessed via maximal treadmill exercise testing with concomitant blood pressure monitoring. All measurements were performed at baseline and after the 12-wk intervention. A linear mixed model was used to compare the rate of increase in blood pressure during the test. RHI improved with exercise (Pre = 1.78 ± 0.10 vs. Post = 2.01 ± 0.13, P = 0.03) with no change following stretching (Pre = 1.73 ± 0.08 vs. Post = 1.67 ± 0.10, P = 0.69). Peak systolic blood pressure during the maximal treadmill exercise test was lower after exercise training (Pre = 186 ± 5 mmHg, Post = 174 ± 4 mmHg, P = 0.003) with no change after stretching (Pre = 190 ± 6 mmHg, Post = 190 ± 4 mmHg, P = 0.12). The rate of increase in systolic blood pressure during the V̇o2peak test tended to decrease after training for both groups (-2 mmHg/stage) with no differences between groups (P = 0.97). There was no change in V̇o2peak after either intervention. In conclusion, aerobic exercise training improves endothelial function and attenuates peak blood pressure reactivity during exercise in CKD.NEW & NOTEWORTHY Patients with chronic kidney disease (CKD) exhibit increased blood pressure reactivity during exercise that is associated with endothelial dysfunction. Twelve weeks of structured, aerobic, exercise training improves endothelial function and attenuates peak blood pressure responses during exercise in CKD stages III-IV.

Renin-Angiotensin System Blockade Is Associated with Exercise Capacity, Sympathetic Activity, and Endothelial Function in Patients with Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) patients have exercise intolerance and exaggerated blood pressure reactivity during exercise that are mediated by sympathetic nervous system (SNS) overactivation and decreased nitric oxide (NO) bioavailability. The activation of the renin-angiotensin system (RAS) increases SNS activation and reduces NO synthesis, and prior studies suggest that RAS blockade attenuates declines in physical function. We hypothesized that RAS inhibitor (RASi) use is associated with higher exercise capacity mediated by decreased SNS activity and increased NO-dependent endothelial function in CKD. METHOD: In 35 CKD patients (57 ± 7 years) and 20 controls (CONs) (53 ± 8 years), we measured exercise capacity (peak oxygen consumption [VO2peak]), muscle sympathetic nervous activity (MSNA), and flow-mediated dilation (FMD) for NO-dependent endothelial function. RESULTS: CKD patients treated with RASi (CKD + RASi, n = 25) had greater VO2peak than CKD patients not treated with RASi (CKD no RASi, n = 10), but lower VO2peak than CONs (23.3 ± 5.8 vs. 16.4 ± 2.9, p = 0.007; vs. 30.0 ± 7.7, p = 0.016 mL/min/kg, respectively). CKD + RASi had lower resting MSNA and greater FMD than CKD no RASi. Compared to CONs, CKD + RASi had similar MSNA but lower FMD. VO2peak was positively associated with FMD (r = 0.417, p = 0.038) and was predicted by the combination of FMD and RASi status (r2 = 0.344, p = 0.01) and MSNA and RASi status (r2 = 0.575, p = 0.040) in CKD patients. CONCLUSION: In summary, CKD patients with RASi have higher exercise capacity than those not on RASi. Higher exercise capacity in the RASi-treated group was associated with lower resting SNS activity and higher NO-dependent vascular endothelial function.

Transcutaneous Cervical Vagal Nerve Stimulation in Patients with Posttraumatic Stress Disorder (PTSD): A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 Response to Stress.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a highly disabling condition associated with alterations in multiple neurobiological systems, including increases in inflammatory and sympathetic function, responsible for maintenance of symptoms. Treatment options including medications and psychotherapies have limitations. We previously showed that transcutaneous Vagus Nerve Stimulation (tcVNS) blocks inflammatory (interleukin (IL)-6) responses to stress in PTSD. The purpose of this study was to assess the effects of tcVNS on PTSD symptoms and inflammatory responses to stress. METHODS: Twenty patients with PTSD were randomized to double blind active tcVNS (N=9) or sham (N=11) stimulation in conjunction with exposure to personalized traumatic scripts immediately followed by active or sham tcVNS and measurement of IL-6 and other biomarkers of inflammation. Patients then self administered active or sham tcVNS twice daily for three months. PTSD symptoms were measured with the PTSD Checklist (PCL) and the Clinician Administered PTSD Scale (CAPS), clinical improvement with the Clinical Global Index (CGI) and anxiety with the Hamilton Anxiety Scale (Ham-A) at baseline and one-month intervals followed by a repeat of measurement of biomarkers with traumatic scripts. After three months patients self treated with twice daily open label active tcVNS for another three months followed by assessment with the CGI. RESULTS: Traumatic scripts increased IL-6 in PTSD patients, an effect that was blocked by tcVNS (p<.05). Active tcVNS treatment for three months resulted in a 31% greater reduction in PTSD symptoms compared to sham treatment as measured by the PCL (p=0.013) as well as hyperarousal symptoms and somatic anxiety measured with the Ham-A p<0.05). IL-6 increased from baseline in sham but not tcVNS. Open label tcVNS resulted in improvements measured with the CGI compared to the sham treatment period p<0.05). CONCLUSIONS: These preliminary results suggest that tcVNS reduces inflammatory responses to stress, which may in part underlie beneficial effects on PTSD symptoms.

Augmented exercise pressor response during maximal treadmill exercise is not related to systemic inflammation in stroke survivors.

BACKGROUND: Stroke survivors have exercise intolerance that contributes to reduced quality of life and survival. While exaggerated blood pressure responses during exercise have been documented in other chronic diseases, whether stroke patients have abnormal hemodynamic responses during aerobic exercise remains unexplored. OBJECTIVES: This cross-sectional study aimed to examine whether stroke survivors have exaggerated increases in blood pressure during maximal treadmill exercise and whether these responses may be related to systemic inflammation. METHODS: Forty-six participants (25 stroke survivors, STROKE, and 21 controls, CON) performed a maximal treadmill exercise test via the modified Naughton protocol while blood pressure was measured manually during each treadmill stage. A linear mixed model was used to compare the slope of rise in heart rate and blood pressure within and between groups. Spearmans rho analysis was performed to explore the relationship between these responses and circulating concentrations of inflammatory biomarkers. RESULTS: The STROKE group exhibited a lower VO2peak (16.4 ± 0.8 vs. 30.0 ± 1.8 ml/kg/min, P < .001) and a greater rate of increase in systolic blood pressure compared to CON (17.4 ± 1.5 vs. 9.9 ± 1.4 mmHg/stage, P < .001). We observed no relationship; however, between inflammatory biomarkers and the exaggerated hemodynamic responses in the STROKE group. CONCLUSION: In conclusion, stroke survivors exhibit greater increases in systolic blood pressure during maximal treadmill exercise compared to controls. These responses do not appear to be related to systemic inflammation. Future work should seek to delineate the mechanisms responsible for exaggerated blood pressure responses during exercise in stroke.

α-Adrenergic receptor blockade attenuates pressor response during mental stress in young black adults.

Black individuals exhibit increased blood pressure (BP) responses to sympathetic stimulation that are associated with an increased risk of hypertension (HTN). We tested the hypothesis that α1 -adrenergic blockade inhibits the increased BP response during and after 45-min stress in young normotensive Black adults, which may be mediated, in part, by dampened vasoconstriction and decreased renal sodium retention. Utilizing a double-masked randomized, crossover study design, 51 normotensive Black adults (31 ± 8 yr) were treated with either a placebo or 1 mg/day of prazosin for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before (Rest), during (Stress) and after (Recovery) 45 min of mental stress induced via a competitive video game task. During the Stress period, diastolic BP and total peripheral resistance (TPR) were significantly lower with prazosin compared to placebo (p < .05 for both). Similarly, we observed lower systolic BP, diastolic BP, and TPR during the Recovery period with prazosin versus placebo (p < .05 for both). There was no effect of prazosin on stress-associated UNaV. The change in systolic BP from Rest to Recovery was positively associated with the change in TPR with both treatments (p < .05 for both). In summary, prazosin treatment dampened BP reactivity to 45-min mental stress and lowered post-stress BP over the recovery period, which was linked to reduce TPR in young normotensive Black adults. These results suggest that α1 -adrenergic receptor activity may contribute to BP responses and delayed BP recovery to prolonged mental stress through increased vasoconstriction in Black adults.

Interventions and Manipulations of Interoception.

Interoceptive pathways may be manipulated at various levels to develop interventions to improve symptoms in a range of disorders. Primarily through the lens of the respiratory system, we outline various pathways that can be manipulated at neural, behavioral, and psychological levels to change the representation of and attention to interoceptive signals, which can alter interconnected physiological systems and improve functioning and adaptive behavior. Interventions can alter interoception via neuromodulation of the vagus nerve, slow breathing to change respiratory rate and depth, or awareness processes such as mindfulness-based interventions. Aspects of this framework may be applied to other physiological systems and future research may integrate interventions across multiple levels of manipulation or bodily systems.

Nocturnal blood pressure is associated with sympathetic nerve activity in patients with chronic kidney disease.

Elevated nocturnal blood pressure (BP) and nocturnal non-dipping are frequently observed in patients with chronic kidney disease (CKD) and are stronger predictors of cardiovascular complications and CKD progression than standard office BP. The sympathetic nervous system (SNS) is thought to modulate diurnal hemodynamic changes and the vascular endothelium plays a fundamental role in BP regulation. We hypothesized that SNS overactivity and endothelial dysfunction in CKD are linked to elevated nocturnal BP and non-dipping. In 32 CKD patients with hypertension (56 ± 7 years), office BP, 24-hr ambulatory BP, muscle sympathetic nerve activity (MSNA) and endothelial function via flow-mediated dilation (FMD) were measured. Participants were subsequently divided into dippers (nighttime average BP > 10% lower than the daytime average BP, n = 8) and non-dippers (n = 24). Non-dippers had higher nighttime BP (p < .05), but not office and daytime BP, compared to dippers. MSNA burst incidence (81 ± 13 versus 67 ± 13 bursts/100 HR, p = .019) was higher and brachial artery FMD (1.7 ± 1.5 versus 4.7 ± 1.9%, p < .001) was lower in non-dippers compared to dippers. MSNA and FMD each predicted nighttime systolic (ß = 0.48,-0.46, p = .02, 0.07, respectively) and diastolic BP (ß = 0.38,-0.47, p = .04, 0.03, respectively) in multivariate-adjusted analyses. Our novel findings demonstrate that unfavorable nocturnal BP profiles are associated with elevated SNS activity and endothelial dysfunction in CKD. Specifically, CKD patients with higher nighttime BP and the non-dipping pattern have higher MSNA and lower FMD. These support our hypothesis that SNS overactivation and endothelial dysfunction are linked to the dysregulation of nighttime BP as well as the magnitude of BP lowering at nighttime in CKD.

Sex differences in post-traumatic stress disorder risk: autonomic control and inflammation.

AIM: Over 7 million U.S. adults and about 20% of the military population have post-traumatic stress disorder (PTSD), a debilitating condition that is independently linked to a significantly greater risk of developing cardiovascular disease (CVD). Women have twice the probability of developing PTSD after experiencing a traumatic event compared to men. Existing literatures have reported higher inflammation and autonomic dysfunction including impaired baroreflex sensitivity, increased sympathetic reactivity and decreased parasympathetic activity in PTSD. However, most of these findings stem from studies conducted predominantly in males. METHODS: We attempt in this narrative review to summarize the mixed literature available on sex differences in autonomic dysfunction and inflammation in PTSD, at rest and in response to stress in PTSD. RESULTS: This review reveals that there is a paucity of research exploring autonomic function in females with PTSD. Recent studies have included female participants without probing for sex differences. A small number of studies have been conducted exclusively in women. Available data suggest that sympathetic nervous system output tends to be heightened, while parasympathetic activity and arterial baroreflex sensitivity appear more blunted in females with PTSD. Although few studies have investigated sex differences in inflammation in PTSD, data within females suggest chronic increases in inflammation with PTSD. This autonomic dysregulation and inflammation have also been described in males with PTSD. CONCLUSION: In sum, given the inherent biological differences in CVD clinical presentation and characteristics between men and women, human and animal studies aiming at elucidating sex differences in the pathophysiology of PTSD are needed.