Curry, Timothy B.

Pulse wave velocity (PWV) and sympathetic nerve activity increase with age. However, it is unknown if the age‐related increase in sympathetic activity influences PWV. We determined the effect of autonomic blockade on peripheral and central arterial stiffness in young (23 ± 4 yr) and older, postmenopausal (57 ± 3 yr) women before and during administration of trimethaphan camsylate. Arterial tonometry was used to measure carotid‐radial (peripheral) and carotid‐femoral (central) PWV. The groups did not differ in height, weight, BMI, or mean arterial pressure (MAP). At baseline, peripheral PWV did not differ between the groups. However, central PWV was significantly greater in older women compared with young women (8.2 vs. 6.1 m/s, respectively; p<0.05). Trimethaphan infusion caused a substantial drop in MAP; therefore, we corrected PWV for the change in MAP. Peripheral PWV was greater in older women compared with young women (0.12 vs. 0.08 m/s·mmHg −1 ; p<0.05). In addition, central PWV remained higher in older women during trimethaphan infusion (0.11 vs. 0.08 m/s·mmHg −1 in young; p<0.05). In conclusion, central PWV was greater in older women before and during autonomic blockade, whereas peripheral PWV was only higher in the older women after autonomic blockade. This suggests that peripheral PWV is influenced by sympathetic activity to a greater extent in young vs. older women. Funded by NIH

Acute ß‐adrenergic blockade (BB) increases aortic wave reflection in young women, however, it is unknown if this effect extends to post‐menopausal women. Thus, we examined systemic BB on aortic wave reflection in 14 post‐menopausal women (58 ± 2 yr). Non‐invasive aortic pressure waveforms were synthesized from high‐fidelity radial pressure waveforms obtained from applanation tonometry before and during systemic BB (0.25mg/kg bolus, with 0.004 mg/kg/min continuous infusion of propranolol). Aortic blood pressure, augmentation index (AIx), AIx adjusted for heart rate (AIx@75), aortic augmented pressure (AP), and wasted left ventricular energy (Ew) were calculated from the aortic pressure waveform. Heart rate (60 ± 2 vs. 51 ± 2 bpm) and mean arterial pressure (95 ± 3 vs. 91 ± 3 mmHg) were reduced with BB (P < 0.05 for both). AIx increased during BB (32 ± 2 vs. 35 ± 2%, P < 0.01), however, AIx@75 was unchanged (25 ± 2 vs. 24 ± 2%, ns). Additionally, AP (20 ± 2 vs. 20 ± 2 mmHg, ns) and Ew (4313 ± 538 vs. 4277 ± 537 dyne*cm2/sec, ns) remained unchanged during BB. When compared to our previously published study in young women, indices of aortic wave reflection were significantly less affected in post‐menopausal women in response to acute systemic BB. Taken together, our data suggest that the negative effects (i.e. increased aortic wave reflection) of non‐selective BB are less pronounced in post‐menopausal women.

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.

Cardio‐vagal tone (CVT) and heart rate variability (HRV) are reduced during hypoglycemia. Carotid body (CB) peripheral chemoreceptors are multi‐modal; therefore we hypothesized a correlation between CB activity and CVT during hypoglycemia. Seven healthy adults (4M/3F) underwent two 180 min hyperinsulemic (2mU/kg FFM/min), hypoglycemic (3.33 mmol/L) clamps one week apart, randomized to normoxia (arterial P O2 (P a O 2 ) 111 ± 6.3 mmHg) or hyperoxia (P a O 2 345 ± 80.6 mmHg) to desensitize the CB. CVT was assessed via the high frequency (HF) component of HRV from 5 min periods of 5‐lead ECG recording under baseline (euglycemia) and hypoglycemia. HF values decreased significantly from baseline during hypoglycemia, however this reduction was attenuated under hyperoxia (Normoxia (N): −69% vs. Hyperoxia (H): −41%, p=0.04). Heart rate increased significantly during hypoglycemia (N: 59.7 bpm ± 2.4 vs. 71.9 ± 4.0; H: 60.6 bpm ± 1.9 vs. 68.5 ± 3, p<0.001), however, this increase was not different between normoxia and hyperoxia, despite differences in CVT and HRV. These data indicate that the CB chemoreceptors may be partially responsible for the reduction in CVT associated with hypoglycemia, and they provide evidence for a role of the CB chemoreceptors in parasympathetic tone to the heart. Future studies are required to determine whether inhibition of the CB may serve to improve CVT function during hypoglycemia. T32 DK07352, F32 DK84624‐01 A1, CTSA 1 UL 1 RR024150 , R01DK 29953

Aortic wave reflection increases with age, and is influenced by numerous factors, including sympathetic nerve activity. The purpose of this study was to examine the effect of autonomic blockade using trimethaphan camsylate on indices of aortic wave reflection in young (23±4 yr) and older postmenopausal (57±3 yr) women and determine if aging alters these interactions. Arterial tonometry was used to non‐invasively measure arterial waveforms from the radial artery before and during trimethaphan infusion. Aortic augmentation index (AI x ), augmented pressure, and left ventricular wasted energy (E w ) were higher in older women compared to young women at baseline (p<0.05). Mean arterial pressure was similar between young (93±5 mmHg) and older women (91±2 mmHg) at baseline. AI x (Δ −12±5%), augmented pressure (Δ −11±4 mmHg), and E w (Δ −2364±1020 dyne·cm 2 ·sec) decreased after autonomic blockade in older women (p<0.05 for all). In addition, the age‐related differences in AI x and aortic wave reflection persisted during autonomic blockade (p<0.05). In conclusion, autonomic blockade reduces augmentation index and aortic wave reflection in older women. Our results suggest that sympathetic activity contributes to the higher aortic wave reflection observed in older women.

We tested the hypothesis that hemodynamic responses would be similar during lower body negative pressure (LBNP) and hemorrhage (HEM). We measured central venous pressure (CVP), mean arterial pressure (MAP), and heart rate (HR) in 6 men during LBNP and HEM. The LBNP protocol consisted of 5‐minute stages at 0, ‐15, ‐30, and ‐45 mmHg of pressure. After a 45 minute break, the HEM protocol began and included 5 minutes at baseline and following three stages of 333 mL of HEM (1 L total). HR during LBNP increased from baseline to ‐45 mmHg (61 ± 3 vs. 86 ± 10 bpm, P < 0.01) while HR was unchanged after 1 L HEM (59 ± 4 vs. 66 ± 5 bpm, P = 0.07). HR was higher during LBNP at ‐30 mmHg vs. HEM at 667 mL (71 ± 7 vs. 63 ± 4 bpm, P = 0.03) and at the final stage (P < 0.01). From baseline, MAP tended to be reduced to a similar degree during ‐45 mmHg LBNP (90.9 ± 3.0 vs. 82.2 ± 4.0 mmHg) and 1 L HEM (89.5 ± 2.1 vs. 80.8 ± 4.0 mmHg) (P = 0.06). From baseline, CVP declined similarly during −45 mmHg LBNP (7.9 ± 1.1 vs. 0.1 ± 1.2 mmHg, P < 0.01) vs. 1 L HEM (5.8 ± 1.1 vs. 1.1 ± 1.4 mmHg, P < 0.01). Using the amalgamated r 2 across each level of LBNP and HEM, HR ( r 2 = 0.98, P < 0.01) and CVP were significantly correlated ( r 2 = 0.98, P < 0.01), but MAP was not ( r 2 = 0.53, P = 0.27). Although LBNP models the changes in MAP and CVP observed in HEM, differences in the HR response to LBNP and HEM require further exploration. Funding: US Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11–1‐0823.

Resting energy expenditure (REE) equations multiplied by a predetermined physical activity factor (PAF) are commonly used to determine energy requirements However, estimated vs. actual REE and PAF among post‐gastric‐bypass surgery (GBS), obese (Ob) and lean (L) adults have not been compared. We hypothesized that GBS, Ob and L adults will have: 1) actual REE lower than estimated and 2) actual PAF lower than estimated. A group of 13 GB, 15 Ob and 11 L adults completed REE measurements by indirect calorimetry following standard clinical procedures. The Harris‐Benedict equation (HB) and pre‐determined PAF were used to estimate energy requirements. Physical activity energy expenditure (PAEE) was determined with accelerometry and PAF with the equation: (Actual REE + accelerometry PAEE)/Actual REE. Two‐way ANOVAs were used to detect differences by group and method, and agreement between methods using Bland & Altman plots. Group differences in actual REE (1631±174, 1830±290, 1441±151 kcal/day, respectively; P<0.01) and HB REE (1600±131, 1970±274, 1542±225 kcal/day, respectively, P<0.01) were observed, with no differences by method. Actual PAEE (269±70, 365±98, 228±112 kcal/day, respectively, P=0.002) yielded PAF ranging from 1.1 to 1.3, while HB PAF ranged from 1.2 to 1.7; causing higher predicted vs. actual energy requirement in all groups. While HB REE appeared adequate, predetermined PAF are not recommended.

The thermic effect of food (TEF) is partially mediated by β‐adrenergic receptors (βAR) and is an important component of daily energy expenditure. Greater sympathetic activity has been associated with decreased BAR responsiveness. We hypothesized that muscle sympathetic nerve activity (MSNA) would be inversely correlated with the βAR component of TEF (TEF β ). We measured MSNA (microneurography) and energy expenditure (EE) (indirect calorimetry) before and for 5 h after a mixed meal (40% daily EE). Measurements were made during systemic βAR blockade with propranolol (BB) and saline (NS) infusion on separate days in 10 healthy subjects (2 female, age 28±2 y, BMI 24.4±0.6 kg/m 2 ). Resting MSNA was 39±3 bursts/100 heartbeats (hb). Within 1 h after the meal, MSNA significantly increased during both NS (12±3 bursts/100 hb) and BB (18±4) but was not significantly different between the two days, (P=0.375). The maximum increase in REE after the meal was 269±29 (NS) and 198±22 (BB) kcal/24 h (P<0.05). TEF β (TEF β = AUC TEF NS – AUC TEF BB ) was 48±20% of total TEF. TEF β was positively correlated with resting MSNA (R 2 =0.70, P<0.05). Contrary to our hypothesis, we found that greater levels of MSNA were associated with greater TEF β . These results indicated that resting MSNA may be an important contributor to daily energy expenditure. Studies are needed to determine if greater MSNA is associated with a resistance to weight gain. The project described was supported by the Mayo Foundation for Medical Education and Research and NIH Grant Numbers K23 DK82424, P30 DK50456, and UL1 RR024150.

Elevated central hemodynamics and arterial stiffness are associated with increased peripheral resistance and higher sympathetic nervous system activity. Additionally, consumption of a meal is known to be sympathoexcitatory. However, the acute effects of a meal on aortic wave reflection and stiffness are unknown. Therefore, we tested the hypothesis that aortic wave reflection and stiffness would increase following a meal. We examined these effects using high‐fidelity radial arterial pressure waveforms and carotid‐femoral pulse wave velocity (PWV), measured non‐invasively via applanation tonometry, before and 60 and 180 min after ingestion of a liquid mixed meal (Ensure, 40% of daily energy expenditure) in 15 healthy adults (25 ± 2 y; 8M/7F). Both peripheral and central pressures were reduced 180 min from baseline. Yet contrary to our hypothesis, augmentation index (15 ± 4 vs. 2 ± 3 vs. 8 ± 3%), augmentation index normalized for heart rate (9 ± 4 vs. −2 ± 3 vs. 3 ± 3%), augmented pressure (6 ± 2 vs. 1 ± 1 vs. 3 ± 1 mmHg) as well as carotid‐femoral PWV (7.3 ± 0.2 vs. 6.7 ± 0.2 vs. 6.7 ± 0.1 m/s) were substantially reduced at 60 and 180 min following the meal (P < 0.05 for all). Taken together, our results suggest that a liquid mixed meal acutely decreases central hemodynamics and arterial stiffness in healthy adults. NIH K23 DK82424 (TC) P30 DK50456 (MNOC) UL1 RR024150 (MCCTSA) HL105467 (DPC)

Vascular function in older women versus young women may differ based on the β‐adrenergic receptor‐mediated contribution to basal vascular tone. Thus, we tested the hypothesis that forearm blood flow (FBF) responses to the β‐receptor agonist isoproterenol (ISO) are blunted in older, postmenopausal women compared to young, premenopausal women. We used venous occlusion plethysmography to measure FBF in young (26 ± 3 yr; n = 13) and older (61 ± 6 yr; n = 12) women. FBF and mean arterial pressure (MAP) were measured at baseline and during ISO infusion at 1.0, 3.0, 6.0, and 12.0 ng/100 ml tissue/min. The two groups did not differ in body mass index or MAP. Baseline FBF (3.7 ± 1.7 vs. 2.9 ± 1.3 ml/100 ml/min, respectively) and forearm vascular conductance (FVC) (0.04 ± 0.02 vs. 0.03 ± 0.01 AU, respectively) were similar between young and older women. FBF and FVC remained similar between the groups for all ISO doses, including the 12.0 ng/100 ml tissue/min dose of ISO, for which the greatest difference between the groups would be expected; FBF was 10.7 ± 2.3 vs. 9.4 ± 2.1 ml/100 ml/min (young vs. older, respectively) and FVC was 0.11 ± 0.02 vs. 0.10 ± 0.02 AU (young vs. older, respectively). In conclusion, β‐adrenergic receptor‐mediated forearm responses to stimulation are similar between young and older women, suggesting that β‐adrenergic receptor response and contribution to vascular tone are preserved with aging in women. Funded by NIH