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.

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.

Vascular α1-adrenergic sensitivity is enhanced in chronic kidney disease.

Chronic kidney disease (CKD) is often complicated by difficult-to-control hypertension, in part due to chronic overactivation of the sympathetic nervous system (SNS). CKD patients also exhibit a greater increase in arterial blood pressure for a given increase in sympathetic nerve activation, suggesting an augmented vasoconstrictive response to SNS activation (i.e., neurovascular transduction). One potential mechanism of increased sympathetic neurovascular transduction is heightened sensitivity of the vascular α1-adrenergic receptors (α1ARs), the major effectors of vasoconstriction in response to norepinephrine release at the sympathetic nerve terminals. Therefore, we hypothesized that patients with CKD have increased vascular α1AR sensitivity. We studied 32 patients with CKD stages III and IV (age 59.9 ± 1.3 yr) and 19 age-matched controls (CON, age 63.2 ± 1.6 yr). Using a linear variable differential transformer (LVDT), we measured change in venoconstriction in response to exponentially increasing doses of the selective α1AR agonist phenylephrine (PE) administered sequentially into a dorsal hand vein. Individual semilogarithmic PE dose-response curves were constructed for each participant to determine the PE dose at which 50% of maximum venoconstriction occurred (ED50), reflecting α1AR sensitivity. In support of our hypothesis, CKD patients had a lower PE ED50 than CON (CKD = 2.23 ± 0.11 vs. CON = 2.63 ± 0.20, P = 0.023), demonstrating increased vascular α1AR sensitivity. Additionally, CKD patients had a greater venoconstrictive capacity to PE than CON (P = 0.015). Augmented α1AR sensitivity may contribute mechanistically to enhanced neurovascular transduction in CKD and may explain, in part, the greater blood pressure reactivity exhibited in these patients.

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.

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.

Altered Autonomic Reactivity During Lower Body Negative Pressure in End-Stage Renal Disease.

BACKGROUND: End stage renal disease (ESRD) is characterized by autonomic dysfunction. During orthostatic stress, sympathetic (SNS) activity increases and parasympathetic (PNS) activity decreases to maintain arterial blood pressure (BP). We hypothesized that ESRD patients have impaired ability to adjust cardiac SNS and PNS activity during orthostasis, which could contribute to increased blood pressure variability, orthostatic intolerance and falls. METHODS: We measured beat-to-beat BP and Electrocardiography at baseline and during increasing lower body negative pressure (LBNP) in 20 ESRD patients and 18 matched controls (CON). Heart rate variability was quantified as total power (TP) and standard deviation of the N-N interval, reflecting both SNS and PNS; high frequency (HF), root mean square of successive differences of neighboring N-N intervals (RMSSD), and percent of consecutive N-N intervals differing >50 milliseconds (pNN50), reflecting cardiac PNS activity; and low frequency (LF) and LF/HF, reflecting sympoathovagal balance. BP variability was quantified as the standard deviation in systolic (SDSAP) and diastolic (SDDAP) BP. RESULTS: Baseline HF, RMSSD, and pNN50 were significantly lower in ESRD (P < 0.05). While CON had a significant decrease in HF (P = 0.015), RMSSD (P = 0.003), and pNN50 (P = 0.005) during LBNP, there was no change in heart rate variability in ESRD. There was no significant difference in BP response, but ESRD had a significantly blunted heart rate response during graded LBNP compared to controls (P < 0.001). There was no significant difference in SDSAP or SDDAP during LBNP between groups (P > 0.05). CONCLUSIONS: These data suggest that ESRD patients have impaired autonomic adjustments to orthostatic stress.

Augmented Cardiopulmonary Baroreflex Sensitivity in Intradialytic Hypertension.

INTRODUCTION: End-stage renal disease (ESRD) patients with a paradoxical increase in blood pressure (BP) during hemodialysis (HD), termed intradialytic hypertension (ID-HTN), are at significantly increased risk for mortality and adverse cardiovascular events. ID-HTN affects up to 15% of all HD patients, and the pathophysiologic mechanisms remain unknown. We hypothesized that ESRD patients prone to ID-HTN have heightened volume-sensitive cardiopulmonary baroreflex sensitivity (BRS) that leads to exaggerated increases in sympathetic nervous system (SNS) activation during HD. METHODS: We studied ESRD patients on maintenance HD with ID-HTN (n = 10) and without ID-HTN (controls, n = 12) on an interdialytic day, 24 to 30 hours after their last HD session. We measured continuous muscle sympathetic nerve activity (MSNA), beat-to-beat arterial BP, and electrocardiography (ECG) at baseline, and during graded lower body negative pressure (LBNP). Low-dose LBNP isolates cardiopulmonary BRS, whereas higher doses allow assessment of physiologic responses to orthostatic stress. RESULTS: The ID-HTN patients had significantly higher pre- and post-HD BP, and greater interdialytic fluid weight gain compared to controls. There was a significantly greater increase in MSNA burst incidence (P = 0.044) during graded LBNP in the ID-HTN group, suggesting heightened cardiopulmonary BRS. The ID-HTN group also had a trend toward increased diastolic BP response during LBNP, and had significantly greater increases in BP during the cold pressor test. CONCLUSION: Patients with ID-HTN have augmented cardiopulmonary BRS that may contribute to increased SNS activation and BP response during HD.