Curry, Timothy B.

Purpose Obese adults exhibit increased levels of inflammation which may negatively affect blood pressure regulation. Based on existing literature, we hypothesized: 1) baroreflex sensitivity would be lower in obese adults when compared to lean adults and 2) acute ibuprofen (IBU, a cyclooxygenase inhibitor and nonsteroidal anti‐inflammatory agent) administration would increase baroreflex sensitivity in obese adults, with no effect in lean adults. Methods Seven lean (4M, 3F; 25±2 yrs; 23±1 kg/m 2 ) and six obese (5M, 1F; 30±3 yrs; 36±1 kg/m 2 ) adults completed two visits randomized to control (CON) or IBU (800 mg oral). On each visit, blood pressure (intra‐arterial catheter), heart rate (electrocardiogram), and muscle sympathetic nerve activity (MSNA, microneurography) were measured continuously and venous blood was sampled for measures of systemic inflammation [C‐Reactive protein (CRP) and Interleukin‐6 (IL‐6)]. Sympathetic and cardiac baroreflex sensitivity were assessed using the modified Oxford technique, which consisted of a 5‐min resting period, followed by a 100 μg intravenous bolus of sodium nitroprusside. One minute later, subjects were administered a 150 μg intravenous bolus of phenylephrine HCl and data were collected for an additional 2‐min. Results CRP and IL‐6 were higher in obese adults when compared to lean adults, and tended to decrease with IBU (IL‐6: p<0.05; CRP: p=0.14). Cardiac baroreflex sensitivity was lower in obese adults (14±2 vs 24±2 ms/mmHg, p=0.02), whereas sympathetic baroreflex sensitivity was higher in obese adults (−3.6±0.5 vs −2.1±0.5 bursts/100 beats/mmHg, p=0.03) when compared to lean. There was no effect of IBU on cardiac or sympathetic baroreflex sensitivity in either group (p‐value range 0.20 – 0.71). Conclusion In our present group of relatively healthy individuals with obesity, we observed lower cardiovagal baroreflex sensitivity but higher sympathetic baroreflex sensitivity in the obese group compared to lean controls. We found no effect of an acute dose of 800 mg ibuprofen on cardiac or sympathetic baroreflex sensitivity, suggesting that chronic effects of obesity‐related inflammation on baroreflex sensitivity may not be reversed by a single acute pharmacological anti‐inflammatory intervention. Support or Funding Information NIH HL083947 (NC, MJJ), DK082424 (TBC), AG038067 (JNB), and UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). AHA 0750036Z (NC) from the American Heart Association.

Adenosine triphosphate (ATP) is postulated to be a major exercise related vasodilating metabolite. In humans, ATP infusion mimics exercise hyperemia. However, it remains unknown whether ATP can evoke the prolonged vasodilation seen during exercise. Therefore we tested two hypotheses during a three‐hour intra‐arterial infusion of a high dose of ATP (20 μgrams ·100 mL forearm vol −1 ·min −1 ): (1) skeletal muscle blood flow would wane over time (tachyphalaxis); (2) exercise hyperemic responses during ATP administration would be blunted compared to baseline. Nine healthy young participants (25 ± 1 years) performed seven rhythmic handgrip exercise bouts (20% of maximum), two during saline (control) and five during 180 minutes of continuous ATP infusion. Forearm vascular conductance (FVC; ml min −1 (100 mmHg) −1 ) and percent (%) change from control were calculated. Five minutes of ATP infusion resulted in a 710% increase in FVC (4.8±0.3 vs 35.0±1.9 ml min −1 *100 mmHg −1 , P<0.05). FVC did not wane over time with values of 35.0±1.9 and 36±2.6 ml min −1 (100 mmHg) −1 (P>0.05) seen prior to the exercise bouts at 5 vs 150 minutes respectively. With superimposed exercise FVC increased from 35.0±1.9 to 49.6±2.2 ml min −1 *100 mmHg −1 at five minutes and 36.0±2.6 to 54.5±1.1 at 150 min (P<0.05). Our findings demonstrate (1) ATP vasodilation is sustained over time without tachyphalaxis; (2) vasodilator responses to exercise during high dose ATP infusion remain intact. This latter finding questions the extent to which ATP is obligatory for exercise hyperemia. Support or Funding Information This research was supported by National Institutes of Health Research Grants HL‐119337 and by CTSA UL1 TR000135. The Caywood Professorship via the Mayo Foundation also supported this research.

Background The baroreflex maintains blood pressure homeostasis by modulating sympathetic activity in response to changes in arterial pressure. Baroreflex sensitivity (BRS) is blunted by activation of either the chemo‐or cardiopulmonary reflex; however, little is known about the interaction of these two reflexes on BRS. We hypothesized that activation of the chemoreflex during stimulation of the cardiopulmonary reflex would attenuate the reduction in BRS. Methods 10 healthy male volunteers (35±3 years, BMI: 25±1 kg/m 2 ) underwent lower body negative pressure (LBNP) at −15mmHg for 5 minutes to stimulate the cardiopulmonary reflex, with chemoreflex activation (hypoxia; arterial oxygen saturation: 85±1%) and without (normoxia; arterial oxygen saturation: 98±0%). Heart rate (HR; ECG), blood pressure (BP; brachial arterial catheter), oxygen saturation (finger pulse oximeter), and ventilation (expired gases) were recorded continuously. BRS was calculated by arterial pressure waveform analysis (spectrum; WinCPRS) during baseline (BL) and LBNP. Results Baseline HR was higher during hypoxia than normoxia (62±2 vs 77±3 bpm, p<0.001) while baseline systolic BP (SBP) was not statistically differentiated between conditions (151±3 vs 149±5 mmHg, normoxia vs hypoxia, p=0.669). During normoxic LBNP, HR increased (62±2 vs 66±3 bpm, p=0.001) and SBP was unchanged (151±3 vs 151±4 mmHg, BL vs LBNP, p=0.464). During hypoxic LBNP, HR remained unchanged (77±3 vs 76±4 bpm, BL vs LBNP, p=0.693) and SBP tended to decrease (149±5 vs 139±6, BL vs LBNP, p=0.067). Baseline BRS was lower during hypoxia than normoxia (15±2 vs 9±1 ms/mmHg, p=0.012). LBNP caused a similar % reduction in BRS during normoxia and hypoxia (−14±9% vs −10±7%, p=0.772). Conclusions Contrary to our hypothesis, chemoreflex activation during LBNP does not attenuate the reduction in BRS. This suggests that the cardiopulmonary reflex and the chemoreflex blunt BRS through independent mechanisms. Support or Funding Information Funding: W81XWH‐13‐2‐0038

High doses of adenosine (ADO) infused over a prolonged period (3 hours) produces marked vasodilation. However, this vasodilation wanes over time in an isolated canine skeletal muscle preparation. To our knowledge the waning of vasodilation with high doses of ADO has not been shown in humans. In addition, ADO plays a controversial role in exercise hyperemia. Therefore, our primary hypothesis was that in humans during a continuous three‐hour intra‐arterial infusion of a high dose of ADO (23 μgrams ·100 mL forearm vol −1 ·min −1 ) skeletal muscle blood flow would wane over time. Our secondary hypothesis was exercise hyperemic responses during ADO administration would be similar compared to control. Nine healthy young participants (29 ± 2 years) performed rhythmic handgrip (HG) exercise bouts (20% of maximum) during saline and 180 minutes of continuous ADO infusion. Forearm vascular conductance (FVC; ml min −1 (100 mmHg) −1 ) was calculated from measured forearm blood flow and mean blood pressure. FVC during minute 5 versus minute 175 during ADO infusion were 24.22 ± 3.2 versus 23.24 ± 1.95 ml min −1 (100 mmHg) −1 respectively (p>0.05). FVC during exercise increased significantly from baseline (4.78 ± 0.63 to 31.13 ± 4.17 ml min −1 *100 mmHg −1 ) during saline infusion and from (24.22 ± 3.23 to 56.33 ± 4.82 ml min −1 *100 mmHg −1 ) at five minutes and 21.99 ± 1.25 to 59.16 ± 5.21 seen at 150 minutes during ADO infusion. There was no significant difference in the delta FVC (exercise FVC – baseline FVC) between saline exercise bout versus ADO exercise bout (26.34 ± 3.75 versus 32.11 ± 5.55 ml min −1 *100 mmHg −1 ). Our findings show that contrary to the animal model, ADO vasodilatation does not wane in humans. Also, the vasodilator responses to exercise are similar during saline and prolonged ADO infusion compared to control condition. These findings suggest a minimal role of ADO in exercise hyperemia. Support or Funding Information Supported by National Institutes of Health Research Grants HL‐119337 (to M.J. Joyner and F.A. Dinenno) and by CTSA UL1 TR000135. The Caywood Professorship (M.J. Joyner) via the Mayo Foundation also supported this research.

Exercise‐induced rapid onset vasodilation produces a temporary rise in skeletal muscle blood flow in humans. The underlying mechanisms for this rapid hyperemia and regulation of muscle blood flow with single contraction are still not well understood. We tested the hypothesis that during a prolonged high dose intrarterial infusion of adenosine triphosphate (ATP; 20 μgrams ·100 mL forearm vol −1 ·min −1 ), the rapid onset vasodilatory response post‐single exercise contraction would be reduced compared to that of adenosine (ADO; 23 μgrams ·100 mL forearm vol −1 ·min −1 ). 14 healthy young participants (30 ± 1 years) performed a forearm single contraction exercise (20% of maximum) at minute 75 of either ATP (N=8) or ADO (N=6) continuous infusion. Artery diameter and blood velocity were measured using Doppler ultrasound. Forearm vascular conductance (FVC; ml·min −1 ·100 mmHg −1 ), time to peak, and area under curve were calculated. The mean resting FVC was higher during ATP (307.15 ± 50.56) and ADO (353.23 ± 43.98) infusion compared to saline infusion (45.17 ± 5.61 and 47.14 ± 5.57) (p<0.05). Compared to ADO, ATP infusion had a lower delta FVC from post‐ to pre‐contraction (174.06 ± 30.75 vs. 276.53 ± 24.90, p<0.05). Area under the curve and time of peak FVC did not significantly differ between drugs. These results suggest a prolonged ATP infusion may have blunted the rapid vasodilatory response more‐so than ADO. Thus, our findings indicate that ATP may be necessary but not obligatory in the rapid onset vasodilation response post‐single muscle contraction in humans. Support or Funding Information Supported by National Institutes of Health Research Grants HL‐119337 (to M.J. Joyner and F.A. Dinenno) and by CTSA UL1 TR000135. The Caywood Professorship (M.J. Joyner) via the Mayo Foundation also supported this research.

Background Patients with sleep apnea experience repeated, intermittent hypoxic exposures during sleep and are at increased risk of developing hypertension. The mechanisms that contribute to high blood pressure in these patients are not completely understood. In this context, we sought to examine the effect of intermittent hypoxic exposures on baroreflex sensitivity and blood pressure. We hypothesized 3‐hours of intermittent hypoxia would result in a decrease in baroreflex sensitivity in healthy adults. We further hypothesized any decrease baroreflex sensitivity would be related to an increase in blood pressure following intermittent hypoxia. Methods Six (5M/1F) young healthy, non‐obese, subjects without sleep apnea completed 3‐hours of intermittent hypoxia. Intermittent hypoxia consisted of 25‐second exposures to hypoxic gas (0.05 F i O 2 ) separated by 2 minutes of room air breathing, resulting in 25‐hypoxic events per hour in which oxygen saturation (S p O 2 ) was significantly reduced (Normoxia: 97%, Hypoxia: 89%, p<0.01). Beat‐to‐beat heart rate (electrocardiogram) and blood pressure (finger photoplethysmography) were measured continuously. Spontaneous cardiac baroreflex sensitivity was determined using the sequence method (WinCPRS) and data are reported from 10‐minutes of quiet, normoxic rest before and after the intermittent hypoxia protocol. Results We observed a significant reduction in spontaneous cardiac baroreflex sensitivity to falling pressures (“down‐down”) following intermittent hypoxia (Control=22±2, IH=15±2 ms/mmHg; p=0.02). No change in baroreflex sensitivity to rising pressures (“up‐up”) was observed (Control=25±2, IH=20±6 ms/mmHg; p=0.41). A relationship between baroreflex sensitivity and mean arterial blood pressure was observed, such that a reduction in baroreflex sensitivity tended to be related to an increase in blood pressure (“down‐down”: R=−0.45, p=0.14; “up‐up”: R=−0.54, p=0.07). Conclusions Intermittent hypoxia results in a decrease in baroreflex sensitivity, which is related to an increase in blood pressure. These data may have important implications for mechanisms contributing to the risk of hypertension in individuals with sleep apnea. Support or Funding Information DK90541 (MJJ), HL120570 (JKL)

Background Individuals with sleep apnea experience repeated intermittent hypoxic exposures during sleep. Previous work in sleep apnea showed patients have an increased heart rate (HR), corrected QT interval (QTc), QTc dispersion and P‐wave maximum duration and dispersion (max‐min P‐wave duration). Such changes have been linked to increased risk of cardiovascular disease and sudden cardiac death. Unfortunately, the mechanisms contributing to these changes are not completely understood. Given that individuals with sleep apnea experience repeated intermittent hypoxic exposures during sleep, we tested the hypothesis that exposure to intermittent hypoxia (IH) in young healthy adults would result in similar ECG changes to those seen in patients with sleep apnea. Methods To test this hypothesis, we completed ECG analysis of 7 healthy humans (6M/1F, Age=29±5 years, BMI=24±4kg/m 2 ) without sleep apnea before and after 3‐hours of exposure to IH. Subjects were exposed to hypoxic gas (0.05 FiO2) for 25‐seconds separated by 2‐minutes of room air breathing. This resulted in 25 hypoxic events per hour in which oxygen saturation was significantly reduced (Normoxia: 97%, Hypoxia: 89%, p<0.01). ECG analysis was completed in Lab Chart 7 software and consisted of measurement of intervals (RR, PR, QT), durations (P, QRS), and amplitudes (P, Q, R, S, T) during 10 minutes of normoxic quiet rest before and after IH exposure. QTc was calculated using Bazett's formula (QT duration/√HR). Dispersion of QTc and P waves were calculated as max duration ‐min duration. Results HR was significantly increased following IH (60±8 vs. 66±8 beats/min, baseline vs. post‐IH, respectively, p<0.05). There was no significant change in P‐wave maximum duration or dispersion following IH. QT interval was significantly decreased and QTc was significantly increased following IH (QT interval: 377±13 vs. 368±8ms, QTc: 377±22 vs 384±22ms, baseline vs. post‐IH, p<0.05 for both). QTc dispersion was not significantly different from baseline following IH. Conclusions We found that 3 hours of experimentally‐induced IH in young healthy individuals resulted in increased HR, decreased QT interval, and increased QTc. These data suggest that IH exposure experienced by patients with sleep apnea may contribute to ECG changes commonly observed in this population and subsequent increases in cardiovascular morbidity and mortality. Support or Funding Information Funding : DK90541 (MJJ), HL120570 (JKL)

Background We have previously shown that the carotid body chemoreceptors play an important role in glucoregulation. When the carotid bodies are experimentally desensitized in humans, counterregulatory responses to hypoglycemia are attenuated. Whether carotid body activation conversely increases circulating glucose levels was previously unexamined. We hypothesize plasma glucose levels would be increased in young healthy adults after carotid body activation via acute intermittent hypoxia. Methods Seven (6M/1F, 21–34 years) healthy, non‐obese, non‐diabetic, subjects without sleep apnea completed 2 visits randomized to 3‐hours of intermittent hypoxia or continuous normoxia. Oxygen saturation and ventilation (turbine ventilation flow transducer) were measured continuously. Plasma glucose levels and carotid body chemosensitivity (hypoxic ventilatory response, HVR) were measured before and after the 3‐hour protocol. Intermittent hypoxia consisted of 25‐s exposures to hypoxic gas (0.05 FiO 2 ) separated by 2‐min of room air breathing, resulting in 25‐events per hour in which oxygen saturation was significantly reduced (Normoxia: 97%, Hypoxia: 89%, p<0.01). Results No changes in plasma glucose (93 vs 93 mg/dL, p=0.92) or HVR (−0.35 vs. −0.39 L/min/%SpO 2, p=0.56) were observed after 3‐hours of continuous normoxia. In contrast, circulating glucose levels and chemosensitivity increased after intermittent hypoxia when compared to baseline (92 vs 97 mg/dL, p<0.01) and (−0.39 vs −0.60 L/min/%SpO 2 , p=0.04), respectively. Additionally, the rise in glucose was significantly correlated with the rise in carotid body chemosensitivity (R=0.38, p=0.05). Conclusion Circulating glucose levels increased after 3‐hours of intermittent hypoxia. The significant relationship between HVR and circulating glucose suggests that the carotid bodies may play a role in altered glucose handling. These findings may have important implications for the high prevalence of diabetes in patients with sleep apnea. Support or Funding Information DK90541, HL120570

The current study demonstrates that respiratory modulation of sympathetic nerve activity (SNA) is reduced in healthy postmenopausal (PMF) versus premenopausal females (YF). Furthermore, respiratory sympathetic modulation was negatively related to resting blood pressure in postmenopausal females, such that blood pressure was greater in individual with less modulation. Reduced respiratory sympathetic modulation may have implications for the autonomic control of blood pressure in aging postmenopausal females, by contributing to age-related sympathetic activation and reducing acute, respiratory-linked blood pressure variation.

Abstract Two inherited autosomal dominant cancer predisposition conditions - BRCA related hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) - are termed Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a positive impact on public health. Selection of individuals for genetic testing for these conditions is based on personal and family history. The goal of this study was to evaluate whether screening in a tertiary medical center using exome sequencing could efficiently identify carriers of HBOC and LS and to determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines. Participants from three geographically diverse Mayo Clinic practices in the USA (Rochester MN, Phoenix AZ, Jacksonville FL) consented to clinical “Exome+” sequencing (Helix, San Mateo, CA; Mayo GeneGuide, Rochester, MN) in the TAPESTRY study (NCT05212428), which links sequencing data with electronic health records and the return of CDCT1 genetic findings. For this study we focused on two inherited cancer predisposition conditions: BRCA-related HBOC (BRCA1 and BRCA2) and LS (MLH1, MSH2, MSH6, PMS2 and EPCAM). Detailed chart review to collect demographic information, personal and family history, and assessment of clinical practice guidelines for genetic evaluation (National Cancer Control Network 2021). To date, 44,306 patients have enrolled and sequenced in TAPESTRY. Annotation and interpretation of all variants in 7 genes for HBOC and LS resulted in identification of 550 carriers (prevalence 1.24%) which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2 and 0.2% EPCAM). Demographics of the cohort included: 62.7% female, mean age 55.2 years, non-white race 9.6% and 3.8% Hispanic/Latino ethnicity. A personal history of cancer was present in 46.4% of test positive patients, including 22.5% of HBOC patients with breast or ovarian cancer and 20.9% of LS patients with colorectal or uterine cancer. More than half of the patients (52.1%) were newly diagnosed with HBOC and LS based on the results of this study. Overall, 39.2% of HBOC/LS carriers identified through Exome+ sequencing did not satisfy NCCN criteria for genetic evaluation, this was higher for LS (56.2%) compared to HBOC (32%). Amongst those newly diagnosed with HBOC/LS (n=286), NCCN criteria were not satisfied in 60% of cases (78% for LS and 51% for HBOC). Of the pathogenic germline variant carriers who met NCCN guidelines for testing, 34.2% were not aware of their diagnosis prior to participation in this study. Our results emphasize the need for wide genomic screening for CDCT1 cancer predisposition syndromes. Such screening could identify at-risk carriers of HBOC and LS, who would not otherwise be identified through clinical practice guidelines. Citation Format: Emily Gay, Niloy Jewel Samadder, Michelle L. Bublitz, Melanie M. Peterson, Tammy A. Wilson, Lorelei A. Bandel, Sebastian M. Armasu, Robert A. Vierkant, Matthew J. Ferber, Eric W. Klee, Nicholas B. Larson, Teresa M. Kruisselbrink, Timothy B. Curry, Jan B. Egan, Jennifer L. Kemppainen, Jessa S. Bidwell, Jennifer L. Anderson, Tammy M. McAllister, T'Nita S. Walker, Katie L. Kunze, Vanda Lindpere, Michael A. Golafshar, Margaret Klint, Richard J. Presutti, William V. Bobo, Aleksander Sekulic, Jolene M. Summer Bolster, Cheryl L. Willman, Konstantinos N. Lazaridis. Genetic screening in a tertiary medical center identifies carriers of cancer predisposition diseases that would be missed by clinical guidelines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5768.