Citations

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome or sudden cardiac death due to a separation of arterial wall layers. The majority of patients with SCAD are females (>80%) with few to no traditional cardiovascular risk factors. Though the physiological mechanisms that predispose to SCAD are unknown, common triggers for SCAD events include sympathoexcitatory stimuli, such as mental and emotional stress. Additionally, studies report high prevalence of depression and anxiety among patients with SCAD. Our study aimed to investigate cardiovascular responses to mental stress in patients with SCAD. We hypothesized that patients with SCAD would have exaggerated cardiovascular responses to mental stress compared to healthy controls. Methods: Four female patients with SCAD were age-, and BMI-matched with 4 healthy females. Participants underwent 2 minutes of baseline quiet rest, a 5-minute Stroop Color Word Test to induce mental stress, followed by 2 minutes of recovery. Continuous beat-to-beat blood pressure (BP, finger photoplethysmography) and heart rate (HR, 3-lead ECG) were recorded. Venous occlusion plethysmography was used to measure forearm blood flow (FBF). Forearm vascular conductance (FVC) was calculated as FBF/mean BP×100. Data are presented as change from baseline (Δmean±SD). Group data were compared using independent samples t-tests. Results: Resting hemodynamic parameters (Systolic [SBP], Diastolic [DBP], and Mean BP [MBP], Pulse pressure [PP], and HR) and FVC were similar between groups. Patients with SCAD had greater increases in DBP (Δ12±5 vs. Δ1±5 mmHg, p=0.02) and PP (Δ5±3 vs. Δ-7±8 mmHg, p=0.04) during the last minute of mental stress test compared to controls. Although, there were no differences in the changes of SBP (Δ17±7 vs. Δ-1±13 mmHg, p=0.05), MBP (Δ13±6 vs. Δ3±8 mmHg, p=0.08), HR (Δ8±0 vs. Δ10±2 bpm, p=0.12), or FVC (Δ1.5±1.2 vs. Δ1.8±1.3 ml/min/100 mmHg, p=0.80) between groups. During the last minute of recovery, there were no differences in hemodynamic parameters (SBP: Δ6±9 vs. Δ-4±10 mmHg, p=0.23; DBP: Δ2±7 vs. Δ-3±2 mmHg, p=0.22; MBP: Δ3±7 vs. Δ-3±5 mmHg, p=0.22; PP: Δ4±5 vs. Δ-1±8 mmHg, p= 0.35; HR: Δ-1±3 vs. Δ0±3 bpm, p=0.64), or FVC (Δ1.3±1.7 vs. Δ0.5±0.3 ml/min/100 mmHg, p= 0.35) between groups. Conclusion: These preliminary data suggest that patients with SCAD have greater increases in DBP and PP in response to mental stress compared to healthy controls. These exaggerated pressor responses might have implications for the pathophysiology of SCAD. NIH K23 HL155506, T32 DK07352, K01 HL148144, UL1 TR0022377, and AHA 898649. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome via the sudden separation between the coronary arterial wall layers and/or hematoma. The SCAD patient population is >80% female who typically have few or no traditional cardiovascular disease risk factors (e.g., obesity, hypertension). Risk of a recurrent SCAD is reported as high as 19% at 3 years after an initial SCAD. Mechanisms underlying SCAD (re)occurrence are unknown. Common triggers for SCAD include sympathoexcitatory stimuli, including heavy exercise and intense Valsalva-like activities. This study tested the hypothesis that SCAD patients exhibit greater neurocardiovascular responses (e.g., blood pressure, heart rate, muscle sympathetic nerve activity) to isometric handgrip and post-exercise ischemia compared to healthy females. Methods: Eight females with a history of SCAD (age: 56±6 yrs, BMI: 28±4 kg/m2) and 6 age- and BMI-matched healthy female controls (CON, age: 55±8 yrs, BMI: 26±5 kg/m2) participated. Continuous blood pressure (finger photoplethysmography) and heart rate (3-lead ECG) were measured during rest (1 minute), isometric handgrip at 30% maximal voluntary contraction (2 minutes), and post-exercise ischemia at 220 mmHg (2 minutes) to isolate the skeletal muscle metaboreflex. Muscle sympathetic nerve activity (MSNA, peroneal microneurography) was measured in a subset of participants (5 SCAD/4 CON). Data are presented as an absolute change from rest (mean±SD). Two-way independent t-tests were used for statistical analyses. Results: Resting mean blood pressure (SCAD: 96±8 vs CON: 91±9 mmHg, p=0.354), heart rate (SCAD: 56±11 vs CON: 59±10 bpm, p=0.666), and MSNA (SCAD: 50±19 vs CON: 43±32 bursts/100 heartbeats, p=0.697) were not different between groups. Relative to healthy controls, SCAD patients elicited greater increases in mean blood pressure during isometric handgrip (SCAD: Δ9±3 vs CON: Δ4±4 mmHg, p=0.034) and post-exercise ischemia (SCAD: Δ7±4 vs CON: Δ3±3 mmHg, p=0.046). There were no group differences regarding heart rate responses during isometric handgrip (SCAD: Δ3±4 vs CON: Δ4±4 bpm, p=0.359) and post-exercise ischemia (SCAD: Δ3±4 vs CON: Δ2±3 bpm, p=0.861). Responses in MSNA during isometric handgrip (SCAD: Δ12±8 vs CON: Δ9±8 bursts/100 heartbeats, p=0.536) and post-exercise ischemia (SCAD: Δ11±2 vs CON: Δ13±10 bursts/100 heartbeats, p=0.713) also were not different between groups. Conclusion: These preliminary data suggest that compared to healthy females, female patients who experienced a SCAD exhibit greater pressor, but not chronotropic or sympathetic, responses to isometric handgrip and post-exercise ischemia. Exaggerated pressor responses to these perturbations may be a potential risk factor for SCAD (re)occurrence. NIH K23 HL155506, NIH T32 DK07352, NIH K01 HL148144, NIH UL1 TR0022377, and AHA 898649. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Females who experience menopausal hot flashes ([MHF]; episodes of sudden warmth and sweating) have greater risk of developing hypertension than females without MHF. MHF symptom severity and frequency are positively associated with hypertension. Considering that augmented arterial stiffness contributes to hypertension, this work aimed to investigate the relations between MHF severity and frequency with arterial stiffness. We hypothesized that females with moderate to severe MHF symptoms would exhibit greater arterial stiffness compared to females without MHF symptoms. Further, we hypothesized that there would be a positive relation between MHF frequency and arterial stiffness. Methods: Twenty-five females (51±5 [SD] years) with no history of hypertension or cardiovascular disease participated. The Menopausal Rating Scale was used to categorize participants by symptom severity (None MHF: n=7, Mild MHF: n=9, Moderate/Severe MHF: n=9). Participants self-reported MHF frequency over three consecutive days in real time using a hot flash diary (4±5 MHF/day, Range: 0-16). After 15 minutes of supine rest, brachial cuff blood pressures (sphygmomanometer) and heart rate (electrocardiogram) were recorded. Arterial stiffness was measured as pulse wave velocity ([PWV]; SphygmoCor®). PWV was measured using a carotid tonometer simultaneously with a leg cuff to capture blood pressure waveforms at the carotid and femoral sites. Aortic systolic pressure, aortic diastolic pressure, and augmentation index (AIx) were measured via pulse wave analysis ([PWA]; SphygmoCor®) using a brachial cuff. Data were analyzed using one-way analysis of variance (ANOVA) and Spearman Rho (ρ). Results: Age, body mass index, resting mean blood pressure, and resting heart rate were not different among MHF severity groups (P>0.05 for all). PWV was not different among severity groups (None: 6.2±0.67 vs. Mild: 6.4±1.0 vs. Moderate/Severe: 6.6±1.0 cm/s, P=0.72). MHF frequency did not correlate with PWV (P=0.42). Aortic systolic pressure (None: 110±6 vs. Mild: 114±5 vs. Moderate/Severe: 112±11 mmHg, P=0.66), aortic diastolic pressure (None: 76±9 vs. Mild: 77±6 vs. Moderate/Severe: 76±10 mmHg, P=0.93), and AIx (None: 31.9±9.0 vs. Mild: 38.7±11.1 vs. Moderate/Severe: 30.4±7.4 %, P=0.16) were not different among severity groups. MHF frequency did not correlate with metrics of PWA (Systolic: P=0.61; Diastolic: P=0.89, AIx: P=0.42). Conclusion: Arterial stiffness and metrics of PWA were not different among females with varying MHF symptom severity. MHF frequency was also not correlated with aortic stiffness and metrics of PWA. Other mechanisms of vascular function (e.g., autonomic function, vasodilation, and/or vasoconstriction) should be investigated to determine potential contributors of hypertension risk in females with MHF. AHA 898649, NIH T32 DK07352, K01 HL148144, NCATS UL1 TR002377. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Objectives: Upregulation of endothelin-1 (ET-1) and its receptors have been linked to increases in hypoxic sensitivity of the carotid chemoreceptors and the development of hypertension. As such, chemoreflex sensitization has been shown in pre-clinical models to be attenuated by ET-1 receptor blockade. Herein, we sought to assess a role for ET-1 in the maintenance of resting blood pressure (BP) in healthy young men and determine whether chemoreflex control of BP could be altered by ET-1 blockade. We hypothesized endothelin receptor antagonism with oral bosentan would lower resting BP in healthy young men as well as the acute BP response to hypoxia. Methods: Twenty-four healthy young men (31±5 yrs, 26±3 kg/m2) completed two study visits (control, bosentan) separated by a minimum of 1 week. The nonspecific endothelin receptor antagonist bosentan (62.5 mg) was taken by mouth twice daily for 3 days prior to the second study visit. On each visit, beat-by-beat BP was assessed under 3 inspiratory air conditions: 1) steady-state normoxia (FiO2 0.21), 2) chemoreflex excitation produced by acute, graded hypoxia (FiO2 0.05 – 0.21), 3) chemoreflex inhibition elicited by transient hyperoxia (FiO2 1.00). Results: Oral bosentan treatment resulted in an increase in plasma ET-1 (0.9±0.9 to 1.3±0.6 pg/mL, p=0.004), supporting receptor blockade. Resting diastolic and mean BP were reduced following 3 days of bosentan treatment compared to control (diastolic: 73±5 to 69±7 mmHg, p=0.007; mean: 93±7 to 88±7 mmHg, p=0.005) with no change in systolic BP (p=0.507). Notably, the BP response to both acute hypoxia (-0.48±0.38 to -0.25±0.31 mmHg/%, p=0.004) and hyperoxia (main effect of bosentan, p=0.025) were attenuated following bosentan. Conclusions: Acute oral bosentan treatment resulted in a reduction in resting BP in healthy young men. The effect of endothelin receptor inhibition with bosentan further attenuated the rise in BP during chemoreflex excitation via acute, graded hypoxia as well as the fall in BP during chemoreflex inhibition (transient hyperoxia). Together these data support a role for ET-1 in control of resting BP in healthy young men, possibly through a chemoreceptor-mediated mechanism. NIH HL130339 (JL), Mayo Clinic Center for Biomedical Discovery (JL, SB). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardiogenic pulmonary edema is a life-threatening complication in patients with heart failure (HF) resulting from increased alveolar Cl- secretion and inhibition of alveolar epithelial Na+ channels (ENaC). Not all HF patients develop pulmonary edema, despite similar clinical characteristics, suggesting a genetic component to edema formation in response to cardiac failure. The ENaC are crucial for alveolar fluid clearance, with the alpha subunit demonstrating particular importance. We have previously found that genetic variation of the alpha subunit (SCNN1A) of ENaC, an alanine (A) to threonine (T) substitution, influences ion regulation during exercise and in response to albuterol. In the present study, we sought to determine the influence of the threonine variant (T663; AT/TT group) on lung fluid regulation in response to normobaric hypoxia, an environmental condition known to increase pulmonary capillary hydrostatic stress in healthy humans. Lung ion and fluid changes were assessed using exhaled Na+ (ENa+) and the lung diffusing capacity for carbon monoxide and nitric oxide (DLCO and DLNO, respectively) to determine alveolar-capillary membrane conductance (DM). 19 healthy subjects (n=8 vs. 11, %female=50 vs. 62%, age=27±1 vs. 28±2yrs., ht=171±3 vs. 173±2cm, wt=69±6 vs.72±3kg , BMI=23±1 vs.24±1kg/m2 , for AA and AT/TT, respectively) completed two overnight visits in a hypoxic tent simulating just over 5,400m. The visits were randomized to inhaled placebo (P) or inhaled amiloride (Aml, 1.5mg in 5ml normal saline, used to inhibit ENaC activity) with ENa+, DLCO, and DM assessed at baseline and following 12 hours of hypoxic exposure. There was an effect of genotype on the ENa+ response to hypoxia with placebo that was abolished with amiloride, but no effect of genotype on the diffusing capacity of the lung (Table). These results suggest that genetic variation of SCNN1A may influence ion regulation in the lung under conditions of elevated hydrostatic stress.

Hypoxia exacerbates fatigue via central mechanisms after ischemic single-leg exercise. The greater fatigue observed during ischemic dynamic fatiguing exercise with hypoxia inspirate did not differ between the sexes. Hypoxia-induced central limitations are present in acute ischemic exercise and do not appear different in males and females.

Background The risk of hypertension increases as women reach menopause. Our group has recently reported that autonomic support of blood pressure (BP) is increased in post‐menopausal women. Given regular exercise is known to decrease the risk of developing hypertension, we investigated the role of aerobic fitness on autonomic support of BP in women. We hypothesized that trained premenopausal, but not postmenopausal, women would have less autonomic support of BP than age‐matched untrained women. Methods Twelve healthy, young premenopausal (27±1yrs) and 10 older postmenopausal (56±1yrs) women completed VO 2max tests on cycle ergometers. The participants were then stratified by fitness level based on VO 2max percentiles from the American College of Sports Medicine's Guidelines (≤50 th percentile = untrained; >50 th percentile = trained; premenopausal: 7 untrained, 5 trained; postmenopausal: 5 untrained, 5 trained). On a separate day muscle sympathetic nerve activity (MSNA, microneurography, peroneal nerve), heart rate (electrocardiography), and blood pressure (brachial arterial catheter) were recorded before and during ganglionic blockade using trimethaphan camsylate (dose:1.5–7mg/min). Stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were calculated from the blood pressure waveform (WinCPRS). Results Muscle sympathetic nerve activity was higher in trained young women than in untrained young women (burst incidence: 35±11 vs. 12±2 bursts/100 heart beats, p=0.03). Young trained women had a smaller reduction in mean arterial pressure (MAP) with trimethaphan than young untrained women (ΔMAP:−5±3 vs. −15±4mmHg, p=0.01), despite a larger reduction in total peripheral resistance (ΔTPR: −6±1 vs. −2±1mmHg*min/L, p=0.02). The trained young women were able to maintain their MAP due to a greater increase in cardiac output (ΔCO: 1.4±0.4 vs. −0.3±0.3L/min, p= 0.01). In older postmenopausal women, MSNA and the fall in BP, CO, and TPR with trimethaphan were not different between trained and untrained individuals (p= 0.81, 0.16, 0.52 and 0.09, respectively). Conclusion Baseline MSNA was higher in trained premenopausal women when compared to untrained premenopausal women; however, aerobic fitness did not influence baseline MSNA in postmenopausal women. In young trained women, the fall in MAP following ganglionic blockade was only one‐third of the response seen in young untrained women. Baseline MSNA and the change in MAP, CO, and TPR with ganglionic blockade were not different between trained and untrained postmenopausal women. These data suggest aerobic fitness reduces autonomic support of blood pressure in young trained women, but not in trained postmenopausal women. Support or Funding Information Support: HL83947 (MJJ); HL131151 (SEB), DK 7352‐37 (SEB), HL118154 (JNB)

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)