Citations

Background: Hypertensive patients have blunted arterial baroreflex sensitivity (BRS). In these patients, BRS is positively related to heart rate variability and inversely related to blood pressure (BP) variability. We hypothesized that this relationship would also be evident in healthy normotensives, and that individuals with higher BRS would have lower ambulatory 24‐hour BP. Methods: 24‐hour ambulatory BP and heart rate was recorded using Spacelabs recorders in 53 healthy, normotensive, non‐obese individuals (32 women, 21 men). Furthermore, BRS (baroreflex control of RR‐interval) was assessed with the modified Oxford technique (sequential bolus administration of sodium nitroprusside and phenylephrine). Results: BRS as well as heart rate and BP variabilities varied greatly among participants. Whereas no relation was observed between BRS and 24‐hour heart rate and BP variabilities, BRS was positively correlated to daytime heart rate variability (R=0.324, p=0.018) and inversely to 24‐hour average mean arterial pressure (R=0.400, p=0.003). Conclusion: In normotensive individuals, higher BRS is related to higher heart rate variability during daytime. Furthermore, BRS was inversely related to 24‐hour mean arterial pressure, consistent with the idea that the baroreflex may have more long‐term influences than previously thought. Supported by NIH grants K23 RR17520, HL 46493, DFG grant He 4605/1‐1.

Head up tilt (HUT) is a meaningful diagnostic tool for baroreflex dysfunction or autonomic failure. We sought to determine if baroreflex sensitivity (BRS), the rise in plasma catecholamines, or 24‐hr ambulatory HR variability (HRV) would correlate with HR and BP during HUT. We performed 60° HUT for 5 min followed by 2 modified Oxford trials in 46 young healthy males and females. Blood pressure (brachial artery) and HR (ECG) were recorded, while arterial epinephrine (Epi) and norepinephrine (NE) were assayed during the final 30 s of HUT. HUT increased HR (mean ± SD: 63 ± 9 to 79 ± 12), MAP (89 ± 7 to 93 ± 8), Epi (28 ± 13 to 61 ± 45), and NE (111 ± 57 to 242 ± 85) (p< 0.05 for all). Individuals with a high 24‐hr HRV had a greater increase in HR during HUT (r= 0.41, P<0.05). Interestingly, a negative correlation was observed between BRS and the NE response to HUT (r= −0.36, p<0.05), such that individuals with low NE response to tilt also had a high BRS. The Epi response was not correlated with any of the measures. These findings suggest that subjects with high vagal activity (high BRS) require a lower sympathetic response (NE) to maintain BP during orthostatic stress. Supported by: K23 RR17520, HL 46493, K12 RR023263 ‐03

Abstract Pain and physical activity are tightly intertwined. Although their relationship has been explored in chronic pain conditions, we know little about the pattern of recovery in activity and its short- and long-term relationship with pain after surgery. We recruited 103 women undergoing elective cesarean delivery and acquired daily pain assessments and hourly steps in 98 of them for 2 months after surgery. Compliance was good, with 78% of subjects missing less than 7 days of activity. Study personnel required daily checking for compliance and 20 minutes per subject per week in study. Activity increased over the first 2 postoperative months in a log(time) manner. The slope of each modeled individual curve for activity was inversely correlated (r = −0.54; P < 0.0001) with worst daily pain. After removing these 2-month trends, pain and activity within an individual day were negatively associated with each point increase in pain being inversely associated with −119 steps (95% confidence interval [CI] = −214 to −25; P = 0.013). A patient's previous experience of pain was not associated with current activity as well as current activity was not associated with future pain scores. These data, although limited by the study of a single operation in a unique social circumstance with low risk of chronic postsurgical pain, demonstrate feasibility of measuring hourly activity for 2 months after surgery. Recovery from pain and inactivity are tightly correlated, and the negative relationship between within-day pain and activity without interday carryover relationships is in stark contrast to findings in chronic pain conditions.

Abstract We know very little about the change in pain in the first 2 months after surgery. To address this gap, we studied 530 women scheduled for elective cesarean delivery who completed daily pain diaries for 2 months after surgery through text messaging. Over 82% of subjects missed fewer than 10 diary entries and were included in the analysis. Completers were more likely to be Caucasian, nonsmokers, and with fewer previous pregnancies than noncompleters. Daily worst pain intensity ratings for the previous 24 hours were fit to a log(time) function and allowed to change to a different function up to 3 times according to a Bayesian criterion. All women had at least one change point, occurring 22 ± 9 days postoperatively, and 81% of women had only one change, most commonly to a linear function at 0 pain. Approximately 9% of women were predicted to have pain 2 months after surgery, similar to previous observations. Cluster analysis revealed 6 trajectories of recovery from pain. Predictors of cluster membership included severity of acute pain, perceived stress, surgical factors, and smoking status. These data demonstrate feasibility but considerable challenges to this approach to data acquisition. The form of the initial process of recovery from pain is common to all women, with divergence of patterns at 2 to 4 weeks after cesarean delivery. The change-point model accurately predicts recovery from pain; its parameters can be used to assess predictors of speed of recovery; and it may be useful for future observational, forecasting, and interventional trials.

In human skin, the vasodilator response to local heating includes a sensory nerve-dependent peak followed by a nadir and then a slower, nitric oxide-mediated, endothelium-dependent vasodilation. To investigate whether chronic sympathectomy diminishes this endothelium-dependent vasodilation, we studied individuals who had previously undergone surgical T2 sympathectomy ( n = 9) and a group of healthy controls ( n = 8). We assessed the cutaneous vascular response (laser-Doppler) to 30 min of local warming to 42.5°C on the ventral forearm (no sympathetic innervation) and the lower legs (sympathetic nerves intact). Lower body negative pressure (LBNP) was measured to confirm sympathetic denervation. During local warming in sympathectomized individuals, vascular conductance reached an initial peak at both sites [achieving 1.73 ± 0.22 laser-Doppler units (LDU)/mmHg in the forearm and 1.92 ± 0.21 LDU/mmHg in the leg]. It then decreased to a nadir in the innervated leg [to 1.77 ± 0.23 LDU/mmHg ( P < 0.05)] but not in the sympathectomized arm (1.69 ± 0.21 LDU/mmHg; P > 0.10). The maximal vasodilation seen during the slower phase was not different between limbs or between groups. Furthermore, LBNP caused a 44% reduction in forearm vascular conductance (FVC) in control subjects, but FVC did not decrease significantly in sympathectomized individuals, confirming sympathetic denervation. These data indicate that endothelial function in human skin is largely preserved after sympathectomy. The altered pattern of the response suggests that the nitric oxide-dependent portion may be accelerated in sympathectomized limbs.

To determine whether endothelial function is altered by chronic surgical sympathectomy, we infused ACh, isoproterenol, nitroprusside (NTP), and the nitric oxide synthase inhibitor N G-mono-methyl-l-arginine (l-NMMA) into the brachial arteries of nine patients 5–64 mo after thoracic sympathectomy for hyperhidrosis. Age- and gender-matched controls were also studied. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Lower body negative pressure was used to assess reflex vasoconstrictor responses. Tyramine, which acts locally and causes norepinephrine release from sympathetic nerves, was also administered via the brachial artery. FBF at rest was 2.5 ± 0.4 ml · dl−1 · min−1 in the patients and 2.5 ± 0.3 ml · dl−1 · min−1 in the controls ( P = 0.95). The normal vasoconstrictor responses to lower body negative pressure were abolished in the patients. By contrast, tyramine produced dose-dependent vasoconstriction in the patients that was identical to that of controls. The dose-response curves to ACh were similar in patients and controls, with maximum values of 19.3 ± 4.4 vs. 25.5 ± 2.8 ml · dl−1 · min−1, respectively. l-NMMA reduced baseline FBF similarly and reduced the maximal FBF response to ACh in both groups (patients 8.9 ± 3.5 vs. controls 9.7 ± 2.5 ml · dl−1 · min−1). The vasodilation to isoproterenol was similar and blunted to the same extent in both groups by l-NMMA. The responses to NTP in patients and controls were similar and not affected byl-NMMA. We conclude that, in humans, chronic surgical sympathectomy does not cause major disruptions in vascular function in the forearm. The normal vasoconstrictor responses to tyramine indicate that there were viable sympathetic nerves in the forearm that were not engaged by LBNP.

Key pointsCommon single nucleotide polymorphisms in the beta‐2 adrenoceptor (ADRB2) gene influence cardiovascular function, but they exist in combinations (haplotypes), so it is crucial to characterize the haplotypes to improve the functional predictive power of ADRB2 gene variation.Dietary sodium affects ADRB2 function.In a large randomized cross‐over phenotyping trial that administered low, normal and high dietary sodium, we determined the interactions between ADRB2 haplotype, receptor density on lymphocytes, cardiovascular haemodynamics during stress manoeuvres, forearm blood flow vasodilator responsiveness and dietary sodium.Healthy young adults were recruited based on the homozygous haplotypes of the ADRB2 gene: Arg16+Gln27, the rare Gly16+Gln27 and Gly16+Glu27.Independent of dietary sodium, the Gly16+Glu27 haplotype had the greatest ADRB2 density and Arg16+Gln27 had the least, suggesting that ADRB2 haplotype influences ADRB2 protein expression, yet the haemodynamic consequences appear modest in healthy humans, necessitating larger trials that explore variation in multiple candidate genes.AbstractDietary sodium affects function of the beta‐2 adrenoceptor (ADRB2). We tested the hypothesis that haplotype variation in the ADRB2 gene would influence the cardiovascular and regional vasodilator responses to sympathoexcitatory manoeuvres following low, normal and high sodium diets, and ADRB2‐mediated forearm vasodilation in the high sodium condition. Seventy‐one healthy young adults were grouped by double homozygous haplotypes: Arg16+Gln27 (n = 31), the rare Gly16+Gln27 (n = 10) and Gly16+Glu27 (n = 30). Using a randomized cross‐over design, subjects were studied following 5 days of controlled low, normal and high sodium with 1 month or longer between diets (and low hormone phase of the menstrual cycle). All three visits utilized ECG and finger plethysmography for haemodynamic measures, and the high sodium visit included a brachial arterial catheter for forearm vasodilator responses to isoprenaline with plethysmography. Lymphocytes were sampled forex vivoanalysis of ADRB2 density and binding conformation. We found a main effect of haplotype on ADRB2 density (P = 0.03) with the Gly16+Glu27 haplotype having the greatest density (low, normal, high sodium: 12.9 ± 0.9, 13.5 ± 0.9 and 13.6 ± 0.8 fmol mg−1protein, respectively) and Arg16+Gln27 having the least (9.3 ± 0.6, 10.1 ± 0.5 and 10.3 ± 0.6 fmol mg−1protein, respectively), but there were no sodium or haplotype effects on receptor binding conformation. In the mental stress trial, there was a main effect of haplotype on cardiac output (P = 0.04), as Arg16+Gln27 had the lowest responses. Handgrip and forearm vasodilation yielded no haplotype differences, and no correlations were present for ADRB2 density and haemodynamics. Our findings support cell‐based evidence that ADRB2 haplotype influences ADRB2 protein expression independent of dietary sodium, yet the haemodynamic consequences appear modest in healthy humans.

Abstract Background: Occupational stress in resident physicians has profound implications for wellness, professionalism, and patient care. This observational pilot trial measured psychological and physiological stress biomarkers before, during, and after the start of anesthesia residency. Methods: Eighteen physician interns scheduled to begin anesthesia residency were recruited for evaluation at three time points: baseline (collected remotely before residency in June 2013); first-month visit 1 (July); and follow-up visit 2 (residency months 3 to 5, September–November). Validated scales were used to measure stress, anxiety, resilience, and wellness at all three time points. During visits 1 and 2, the authors measured resting heart-rate variability, responses to laboratory mental stress (hemodynamic, catecholamine, cortisol, and interleukin-6), and chronic stress indices (C-reactive protein, 24-h ambulatory heart rate and blood pressure, 24-h urinary cortisol and catecholamines, overnight heart-rate variability). Results: Thirteen interns agreed to participate (72% enrollment). There were seven men and six women, aged 27 to 33 yr. The mean ± SD of all study variables are reported. Conclusion: The novelty of this report is the prospective design in a defined cohort of residents newly exposed to the similar occupational stress of the operating environment. Because of the paucity of literature specific to the measures and stress conditions in this investigation, no data were available to generate a priori definition of primary outcomes and a data analytic plan. These findings will allow power analysis for future design of trials examining occupational stress and stress-reducing interventions. Given the importance of physician burnout in our country, the impact of chronic stress on resident wellness requires further study.