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.

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.

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.

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.

Functional sympatholysis is impaired in end-stage renal disease.

Patients with end-stage renal disease (ESRD) have decreased exercise capacity and exercise intolerance that contribute to cardiovascular risk. One potential mechanism underlying exercise intolerance in ESRD is impaired ability to oppose sympathetically mediated vasoconstriction within exercising skeletal muscle (i.e., functional sympatholysis, FS). We hypothesized that ESRD patients have impaired FS compared with healthy (CON) and hypertensive (HTN) controls and that impaired FS is related to circulating levels of the uremic toxin asymmetric dimethyl arginine (ADMA), an endogenous nitric oxide synthase inhibitor. Near-infrared spectroscopy-derived oxygen tissue saturation index (TSI) of the forearm muscle was measured continuously in 33 participants (9 CON, 14 HTN, 10 ESRD) at rest and during low-dose (-20 mmHg) lower body negative pressure (LBNP), moderate rhythmic handgrip exercise, and LBNP with concomitant handgrip exercise (LBNP+handgrip). Resting muscle TSI was lower in ESRD than in CON and HTN groups (CON = 67.8 ± 1.9%, HTN = 67.2 ± 1.1%, ESRD = 62.7 ± 1.5%, P = 0.03). Whereas CON and HTN groups had an attenuation in sympathetically mediated reduction in TSI during LBNP + handgrip compared with LBNP alone (P ≤ 0.05), this response was not present in ESRD (P = 0.71), suggesting impaired FS. There was no difference in plasma [ADMA] between groups (CON = 0.47 ± 0.05 µmol/l, HTN = 0.42 ± 0.06 µmol/l, ESRD = 0.63 ± 0.14 µmol/l, P = 0.106) and no correlation between plasma [ADMA] and resting muscle TSI (P = 0.84) or FS (P = 0.75). Collectively, these findings suggest that ESRD patients have lower muscle perfusion at rest and impaired FS but that these derangements are not related to circulating [ADMA].

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.

Metabolic acidosis augments exercise pressor responses in chronic kidney disease.

Chronic kidney disease (CKD) patients experience augmented blood pressure (BP) reactivity during exercise that is associated with an increased risk of cardiovascular mortality. Exaggerated exercise pressor responses in CKD are in part mediated by augmented sympathetic nerve activation due to heightened muscle mechanoreflex. One mechanism that may lead to sensitization of the muscle mechanoreflex in CKD is metabolic acidosis. We hypothesized that CKD patients with low serum [bicarbonate] would exhibit exaggerated increases in arterial BP, greater reductions in muscle interstitial pH, and fatigue earlier during exercise compared with CKD patients with normal serum bicarbonate concentration ([bicarbonate]). Eighteen CKD participants with normal serum [bicarbonate] (≥24 mmol/l, normal-bicarb) and 9 CKD participants with mild metabolic acidosis ([bicarbonate] range 20-22 mmol/l, low-bicarb) performed rhythmic handgrip (RHG) exercise to volitional fatigue at 40% of maximal voluntary contraction. BP, heart rate, and muscle interstitial pH using near infrared spectroscopy were measured continuously. While mean arterial pressure (MAP) increased with exercise in both groups (P ≤ 0.002), CKD with low-bicarb had an exaggerated MAP response compared with CKD with normal-bicarb (+5.9 ± 1.3 mmHg/30 s vs. +2.6 ± 0.5 mmHg/30 s, P = 0.01). The low-bicarb group reached exhaustion earlier than the normal-bicarb group (179 ± 21 vs. 279 ± 19 s, P = 0.003). There were no differences in the change in muscle interstitial pH during exercise between groups (P = 0.31). CKD patients with metabolic acidosis have augmented exercise-induced increases in BP and poorer exercise tolerance. There was no difference in change in muscle interstitial pH between groups, however, suggesting that augmented exercise BP responses in metabolic acidosis are not due to impaired muscle-buffering capacity.

Acute effects of device-guided slow breathing on sympathetic nerve activity and baroreflex sensitivity in posttraumatic stress disorder.

Patients with posttraumatic stress disorder (PTSD) have elevated sympathetic nervous system reactivity and impaired sympathetic and cardiovagal baroreflex sensitivity (BRS). Device-guided slow breathing (DGB) has been shown to lower blood pressure (BP) and sympathetic activity in other patient populations. We hypothesized that DGB acutely lowers BP, heart rate (HR), and improves BRS in PTSD. In 23 prehypertensive veterans with PTSD, we measured continuous BP, ECG, and muscle sympathetic nerve activity (MSNA) at rest and during 15 min of DGB at 5 breaths/min ( n = 13) or identical sham device breathing at normal rates of 14 breaths/min (sham; n = 10). Sympathetic and cardiovagal BRS was quantified using pharmacological manipulation of BP via the modified Oxford technique at baseline and during the last 5 min of DGB or sham. There was a significant reduction in systolic BP (by -9 ± 2 mmHg, P < 0.001), diastolic BP (by -3 ± 1 mmHg, P = 0.019), mean arterial pressure (by -4 ± 1 mmHg, P = 0.002), and MSNA burst frequency (by -7.8 ± 2.1 bursts/min, P = 0.004) with DGB but no significant change in HR ( P > 0.05). Within the sham group, there was no significant change in diastolic BP, mean arterial pressure, HR, or MSNA burst frequency, but there was a small but significant decrease in systolic BP ( P = 0.034) and MSNA burst incidence ( P = 0.033). Sympathetic BRS increased significantly in the DGB group (-1.08 ± 0.25 to -2.29 ± 0.24 bursts·100 heart beats-1·mmHg-1, P = 0.014) but decreased in the sham group (-1.58 ± 0.34 to -0.82 ± 0.28 bursts·100 heart beats-1·mmHg-1, P = 0.025) (time × device, P = 0.001). There was no significant difference in the change in cardiovagal BRS between the groups (time × device, P = 0.496). DGB acutely lowers BP and MSNA and improves sympathetic but not cardiovagal BRS in prehypertensive veterans with PTSD. NEW & NOTEWORTHY Posttraumatic stress disorder is characterized by augmented sympathetic reactivity, impaired baroreflex sensitivity, and an increased risk for developing hypertension and cardiovascular disease. This is the first study to examine the potential beneficial effects of device-guided slow breathing on hemodynamics, sympathetic activity, and arterial baroreflex sensitivity in prehypertensive veterans with posttraumatic stress disorder.

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.

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.

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.

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.

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.

Sympathoexcitation and impaired arterial baroreflex sensitivity are linked to vascular inflammation in individuals with elevated resting blood pressure.

Elevated Resting Blood Pressure (ERBP) in the prehypertensive range is associated with increased risk of hypertension and cardiovascular disease, the mechanisms of which remain unclear. Prior studies have suggested that ERBP may be associated with overactivation and dysregulation of the sympathetic nervous system (SNS). We hypothesized that compared to normotensives (≤120/80 mmHg), ERBP (120/80-139/89 mmHg) has higher SNS activity, impaired arterial baroreflex sensitivity (BRS), and increased vascular inflammation. Twenty-nine participants were studied: 16 otherwise healthy individuals with ERBP (blood pressure (BP) 130 ± 2/85 ± 2 mmHg) and 13 matched normotensive controls (mean BP 114 ± 2/73 ± 2 mmHg). We measured muscle sympathetic nerve activity (MSNA), beat-to-beat BP, and continuous electrocardiogram at rest and during arterial BRS testing via the modified Oxford technique. Blood was analyzed for the following biomarkers of vascular inflammation: lipoprotein-associated phospholipase A2 (Lp-PLA2), E-selectin, and intercellular adhesion molecule 1 (ICAM-1). Resting MSNA burst frequency (22 ± 2 vs. 16 ± 2 bursts/min, P = 0.036) and burst incidence (36 ± 3 vs. 25 ± 3 bursts/100 heart beats, P = 0.025) were higher in ERBP compared to controls. Cardiovagal BRS was blunted in ERBP compared to controls (13 ± 2 vs. 20 ± 3 msec/mmHg, P = 0.032), while there was no difference in sympathetic BRS between groups. Lp-PLA2 (169 ± 8 vs. 142 ± 9 nmol/min/mL, P = 0.020) and E-selectin (6.89 ± 0.6 vs. 4.45 ± 0.51 ng/mL, P = 0.004) were higher in ERBP versus controls. E-selectin (r = 0.501, P = 0.011) and ICAM-1 (r = 0.481, P = 0.015) were positively correlated with MSNA, while E-selectin was negatively correlated with cardiovagal BRS (r = -0.427, P = 0.030). These findings demonstrate that individuals with ERBP have SNS overactivity and impaired arterial BRS that are linked to biomarkers of vascular inflammation.

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.