Nicholson, Wayne T.

In young women, tonic autonomic nervous system activity contributes less to resting blood pressure than that in men. It is unknown whether the autonomic support of blood pressure increases in postmenopausal women, therefore we examined the effect of autonomic blockade on blood pressure and how this relates to baseline muscle sympathetic nerve activity (MSNA) in women. Five young (23±4 yr) and 6 older (57±3 yr) women were examined before and during autonomic blockade using trimethaphan camsylate (TM). MSNA burst frequency and burst incidence were higher in older women (24±2 vs. 14±3 bursts/min; 41±3 vs. 23±5 bursts/100hb, respectively; p<0.05). Older women had a greater drop in mean arterial pressure (MAP; −25±2 vs. −8±3 mmHg; p<0.01) and total peripheral resistance (−0.7±0.1 vs. −0.2±0.1 AU; p<0.01) during autonomic blockade. MSNA bursts were abolished by TM within minutes. Baseline burst frequency and burst incidence were associated with the decrease in MAP during autonomic blockade (r=−0.64, r=−0.63; respectively; p<0.05). In conclusion, autonomic blockade reduces MAP to a greater extent in older women, and this decrease in blood pressure is associated with resting levels of MSNA. Our results suggest that autonomic support of blood pressure is greater in older women compared to young women. Elevated sympathetic nerve activity may explain the increased incidence of hypertension after menopause.

Dietary sodium loading decreases β‐adrenergic receptor mediated vasodilation in hypertensive men, and paradoxically increases this dilation in normotensive men; no information exists in women. The purpose of this investigation was to test the hypothesis that dietary sodium loading and restriction influences β‐receptor mediated vasodilation in a sex‐dependent manner. Healthy normotensive subjects consumed a high (400 mmol/day, n=36, mean age±SEM 23±1 yr, 23 women) or low (10 mmol/day, n=30, 30±1 yr, 14 women) sodium diet for 5 days prior to study. Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of isoproterenol (ISO: 1, 3, 6, 12 ng/100 ml tissue/min) were measured before and after endothelial NO synthase inhibition with N G ‐monomethyl‐L‐arginine (L‐NMMA). Consistent with prior reports, the FBF response to ISO was greater in men on high sodium compared to men on low sodium (p=0.03, ISO‐by‐sodium interaction). The highest response to ISO was 16.6±1.7 and 11.0±1.1 ml/100 ml tissue/min (high vs. low, p=0.01). After LNMMA the men's response to ISO did not differ based on sodium. In contrast, in women dietary sodium did not affect the response to ISO before or after LNMMA. We conclude that dietary sodium alters β‐adrenergic receptor mediated vasodilation in men, which appears to be dependent on NO. This is the first study to suggest that these mechanisms of vasodilation are resistant to dietary sodium in women. Support: HL‐089331, CTSA RR‐024150

Cerebral vasodilator responses to hypercapnia decrease with aging, and recent data suggests sex differences in cerebrovascular regulation exist. Yet, it is unknown how sex and age interact in response to the stress of cyclooxygenase inhibition. We examined cerebral vasodilator responses to hypercapnia in 7 young men (YM), 8 young women (YW), 7 older men (OM), and 6 older women (OW) before (CON) and during cyclooxygenase (COX) inhibition via indomethacin (INDO). There was no age by sex interaction in middle cerebral artery velocity responses to hypercapnia (MCAv Slope). However, when accounting for mean arterial pressure during hypercapnia, there was an age by sex interaction in cerebrovascular conductance index (CVCi Slope). YM demonstrated higher CVCi Slope (1.27 ± 0.21 AU) compared with YW (0.65 ± 0.10 AU) and older adults (0.58 ± 0.10 AU in OM; 0.66 ± 0.06 AU in OW; p<0.05 for all). There was no difference in CVCi Slope between YW and OW, indicating that the age‐associated reduction in CVCi Slope only pertains to men. During INDO, there was an age by sex interaction for the ΔCVCi Slope (from CON to INDO) with YM having a greater slope compared with both YW (0.72 ± 0.15 vs. 0.27 ± 0.13 AU; p<0.01) and OM (0.26 ± 0.18 AU; p<0.01). Taken together, our results suggest that sex differences exist in the cerebrovascular response to hypercapnia with and without COX inhibition and that the effect of age is different in women compared to men.

β 2 ‐adrenergic receptor (ADRB2) gene polymorphisms influence vasodilation, but studies investigating regional or systemic responses conflict, possibly due to counter‐regulatory baroreflex action during systemic β 2 ‐agonist infusion. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (TERB) during baroreflex inhibition. 40 healthy young adults were recruited according to the double homozygous haplotypes: Arg16+Gln27 (n=13), Gly16+Gln27 (n=6), and Gly16+Glu27 (n=21). Arterial pressure was measured by brachial arterial catheter, cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3–7 mg/min), phenylephrine was titrated to restore blood pressure to baseline. TERB was infused i.v. at 33 and 67 ng/kg/min for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR ( P = 0.06). For SNP position 16, the highest dose of TERB produced lower SVR in Gly16 vs Arg16 ( P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs Arg16 ( P = 0.05). During baroreflex inhibition, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16+Glu27 homozygotes, with greater influence from Gly16. Supported from NIH and DFG.

AbstractIn the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID‐19), including among patients with innate or acquired immunosuppression. However, the association between COVID‐19‐associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched‐control registry study of 143 COVID‐19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID‐19 patients with immunosuppression. We review clinical features and treatment protocols of COVID‐19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID‐19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune‐deficient and immune‐suppressed patients with COVID‐19 warrants further investigation.

Background: Pharmacogenomic (PGx) testing has the potential to provide information on specific drug-metabolizing enzymes that may lead to an absence, reduction, or increase in medication effect in patients. There is a paucity of prospective studies examining PGx testing in the intensive care unit (ICU) setting. Research Aims: To (1) obtain a PGx panel in a sample of cardiovascular (CV) surgical patients with a planned ICU stay and identify phenotypes, and (2) identify PGx variants that may inform treatment regimens and may warrant prescribing adjustments. Design and Methods: Descriptive, single cohort cross-sectional design. Adult (≥18 years) CV patients with an anticipated postoperative ICU stay were enrolled from a large Midwestern tertiary academic medical center. Eligible patients provided informed consent at the time of their CV clinic appointment; PGx testing was then ordered. Pharmacogenomic testing consisted of the Focused Pharmacogenomics panel which included 10 genes and 55 medications. Results: Of the 272 patients screened, 100 (68% male) patients completed PGx testing (mean age 66.2 ± 9.6 years, mean Acute Physiology, Age and Chronic Health Evaluation III score 76.1 ± standard deviation). Pharmacogenomic results were available in the medical record within a median of 52.4 hours (interquartile range: 33.4-80.3). Pharmacogenomic testing results identified 5 CYP2C19 poor metabolizers, 26 CYP2C19 rapid metabolizers, 5 CYP2C19 ultrarapid metabolizers, 6 CYP2D6 poor metabolizers, 5 CYP2D6 poor to intermediate metabolizers, and 2 CYP2D6 rapid metabolizers identified. Overall, 98% of patients had actionable or potentially actionable PGx results, including 82% for warfarin, 65% for propafenone, 65% for tramadol, 46% for oxycodone, 45% for metoprolol, 33% for clopidogrel, 32% for proton pump inhibitors, 25% for statins, and 12% for haloperidol. Conclusions: A significant portion of patients had identified genetic variants that may warrant changes in medication management during and after CV-ICU stay. It remains to be seen if PGx testing leads to improvements in ICU patient outcomes.

Aging increases autonomic support of blood pressure; however, the impact of aerobic fitness on autonomic support of blood pressure has not been addressed in women. As such, we hypothesized that aerobic fitness would be related to the change in blood pressure during ganglionic blockade such that women with greater aerobic fitness would have a blunted fall in blood pressure during ganglionic blockade due to increased vagal tone. Thirteen young premenopausal and 13 older postmenopausal women completed a screening visit where aerobic fitness (maximal oxygen consumption, VO 2max ) was measured. On a separate study day, participants were instrumented for assessment of muscle sympathetic nerve activity, heart rate (electrocardiography), and beat by beat blood pressure (arterial catheter and pressure transducer) and underwent pharmacological blockade of the autonomic ganglia using trimethaphan camyslate. Heart rate, blood pressure, and muscle sympathetic nerve activity were analyzed before and during ganglionic blockade. In young women, there was a significant relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =0.761, P =0.003). In older women, there was no relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =−0.106, P =0.73). Measures of heart rate variability were related to fitness in young women, but not older women (root mean square of successive differences between normal heartbeats, r =0.713, P =0.006 versus r =−0.172, P =0.575). Our data suggest that in young women, autonomic support of blood pressure is attenuated in those that are highly fit; however, this relationship is not significant in older women.

New Findings What is the central question of this study? What is the role of β2‐adrenergic receptor (β2AR) vasodilatation in older postmenopausal women as compared to premenopausal women and the role of nitric oxide (NO) in β2AR‐mediated vasodilatation in both groups of women? What is the main finding and its importance? β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women. Additionally, NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women. Abstractβ2‐Adrenergic receptor (β2AR)‐mediated vasodilatation, which is partially dependent on nitric oxide (NO) formation, is blunted in men at risk for developing hypertension. However, the role of β2AR vasodilatation in hypertension pathophysiology in ageing postmenopausal women is unclear. Therefore, the goals of this study were to determine if forearm vasodilatation to the selective β2AR agonist terbutaline is blunted in older postmenopausal women (59 ± 4 years) compared to young premenopausal women (27 ± 3 years) and to assess NO contribution to β2AR‐mediated vasodilatation in both groups of women. Forearm blood flow (FBF) and forearm vascular conductance (FVC) were measured using venous occlusion plethysmography at baseline and during intra‐arterial infusions of terbutaline at 0.1–2.0 µg (100 ml tissue)−1 min−1 with and without the NO synthase inhibitor l‐NG‐monomethylarginine (l‐NMMA). Mean arterial pressure was significantly greater in postmenopausal women than in young women at baseline (P = 0.01). Baseline FBF and FVC did not differ between young and postmenopausal women (P > 0.05) and rose significantly within each group during terbutaline infusion (P < 0.05). There were significant group × dose interactions for FBF (P = 0.01) and FVC (P = 0.001), indicating vasodilator responses were lower in postmenopausal women. In young women, FVC response to the highest dose of terbutaline tended to be lower with l‐NMMA co‐infusion vs. without l‐NMMA (P = 0.05). There were no significant decreases in FBF or FVC responses to terbutaline in postmenopausal women with l‐NMMA co‐infusion (P > 0.05 for all). These data suggest that β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women, and that NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women.