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Background Endothelial dysfunction and increased arterial stiffness are both associated with increased risk of cardiovascular events and mortality . Vascular aging has been characterized by deteriorating endothelial function accompanied by increasing vascular stiffness that occurs with increasing chronological age, with the onset of these changes varying by sex. Deteriorating large artery vascular function has been reported across the menopause transition in women, but it is unclear if this relationship extends to the cutaneous microvasculature, which may have critical implications for both thermal regulation and general cardiovascular health. Purpose & Hypothesis The primary purpose of this study was to determine the impact of sex and menopausal stage on cutaneous endothelial dependent (EDD) vasodilation. We hypothesized that cutaneous EDD vasodilation would decrease in women in a graded manner across the transition from pre, to peri, to postmenopause with differences compared to age matched men. Secondly, we hypothesized that there would be no differences in cutaneous EDD vasodilation between natural and surgical (i.e., hysterectomy) menopause. Methods Premenopausal, (n=8, 44±5y), perimenopausal (n=6, 51±2y), and postmenopausal women (n=9, 60±7y) as well as men age matched to the postmenopausal group (n=6, 59±7y) volunteered for this study. Cutaneous EDD vasodilation was measured by local iontophoresis of Acetylcholine (Ach) administration into the forearm vasculature. Red blood cell flux was determined by laser Doppler flowmetry at baseline and after 200µL of Ach. CVC was calculated as the quotient of red blood cell flux and mean arterial pressure and expressed as the percentage increased from baseline (CVC%). Differences were determined using a 1‐way ANOVA. Data are presented as mean ± standard error. Results Forearm microvascular CVC% was significantly different among groups (P=0.01) after Ach administration. Post hoc analyses revealed an attenuated CVC% response in postmenopausal women (691±150%; P=0.02) and men (733±127%; P=0.05) compared to premenopausal women (1398±247%). There were no differences detected between peri‐ and premenopausal women (1290±140% vs. 1398±247%; P=0.95). Further, we performed a subanalysis in our postmenopausal group which included surgical (n=3) and natural (n=8) postmenopausal women. No differences were present between surgical and natural postmenopausal women (P=0.87), while both the surgical (646±163%; P=0.08) and natural (713±221%; P=0.05) postmenopausal women appeared to have decreased CVC responses compared to premenopausal women (1398±247%). Conclusions Our findings indicate that cutaneous EDD vasodilation decreases from pre‐ to postmenopause in healthy women. Our data suggests that decreases in microvascular function agrees with reported decrements in large vessel vascular function associated with the menopause transition.

Introduction: Patients undergoing cardiac rehabilitation (CR) exhibit various degrees of illness severity and high prevalence of chronic conditions (CC). Cardiorespiratory fitness (CRF) is a key predictor of outcomes in patients with cardiovascular disease. Participation in CR is associated with increased CRF, reduced future cardiovascular events, and mortality. Peak oxygen uptake (VO 2 ) is the gold-standard method to evaluate CRF; however, the burden of multimorbidity and its impact on CRF improvement has not been extensively studied. Methods: We included 618 patients who were ≥ 18 years old and underwent cardiopulmonary exercise testing prior to and after CR at Mayo Clinic. Using the Rochester Epidemiology Project records- linkage system, we assessed the prevalence of 18 CC defined by the US Department of Health and Human Services. To evaluate changes in peak VO 2 in patients with multimorbidity (categorized as ≥6 CC), we created logistic regression models adjusting for age, sex, and baseline peak VO 2 . Results: Mean age was 61.5 ± 11.0 years and 75.5% were male. Most patients (81.2%) attended ≥18 CR sessions. Half (50.4%) of patients had at least 6 CC (median 6; range 0-13). Overall, peak VO 2 at baseline was 20.7 ± 6.3 mL/kg per min and the percent change in peak VO 2 following CR was 11.4% ± 21.6%, Figure 1A . Multimorbidity was associated with lower improvement in peak VO 2 following CR compared to patients with <6 CC (7.5% vs 11.4%, p=0.0001). Furthermore, across categories of CRF improvement (i.e., 1%, 5%, and 10% percent change in peak VO 2 ) lower multimorbidity was associated with a 1.5-2-fold increase in CRF when compared to those with higher multimorbidity (≥6 CC), Figure 1B . Conclusions: Patients entering CR have a high multimorbidity burden. Our results suggest that multimorbidity in CR patients attenuates improvement in peak VO 2 . Individualized interventions should focus on managing and reducing multimorbidity to minimize the negative impact on CRF improvement.

Introduction: High intensity interval training (HIIT) during early outpatient cardiac rehabilitation (CR) improves peak oxygen uptake (VO 2 ) and reduces mortality in patients with cardiovascular disease. In a CR setting, prescribing interval intensity using rating of perceived exertion (RPE) is more feasible than using percent of VO 2peak . Additionally, prescribing HIIT with RPE may allow for progressive changes in the VO 2 response throughout a single HIIT session. However, the acute cardiopulmonary responses during individual intervals of HIIT prescribed via RPE in CR are unknown. Hypothesis: We hypothesized that VO 2peak would increase and time-to-peak (TTP) would shorten across high-intensity intervals during a single HITT session prescribed with RPE. Methods: Patients with CAD (N=14; 2 women; 56±9 yrs; 30.46±4.7 kg/m 2 ) referred to CR after an acute coronary event completed a minimum of 25 supervised HIIT sessions during which VO 2 was measured continuously. Each HIIT session included 5 or more (6±1 sessions) 1-minute high intensity intervals (target RPE: 15-17) separated by a 3 to 5-minute low intensity interval (target RPE: <12). The first and last HIIT sessions were used for analysis. VO 2peak was defined as the highest 3-breath averaged VO 2 during or up to 1 minute following each high intensity interval. Results: RPE was 15±2 and 11±2 during the high and low intensity intervals, respectively. Compared to the first HIIT session, VO 2peak was greater during the high intensity intervals of the last HIIT session (25.4±1.5 vs. 21.8±1.1 mL/kg/min; p=0.04). During the first and last HIIT sessions, VO 2peak increased across high intensity intervals (p<0.001). Although TTP was not significantly reduced across intervals during the first HIIT session (p=0.14), TTP was reduced across intervals during the last HIIT session (first interval: 67±19 vs. last interval: 58±9 s; p<0.01). Conclusions: Prescribing HIIT with RPE resulted in increased VO 2peak across high intensity intervals within single HIIT sessions and shortened TTP during high intensity intervals across CR. These findings provide evidence for a priming effect on VO 2peak during HIIT which may contribute to greater cardiopulmonary adaptations in CAD patients.

Introduction: Cardiac rehabilitation (CR) is associated with improvements in exercise capacity (peak oxygen uptake (VO 2 peak)); however, 23% of CR patients do not improve VO 2 peak following CR. CR adherence (i.e. number of CR sessions attended) has been proposed to play an important role in VO 2 peak improvement following CR, but has not been investigated. Identifying clinical predictors of VO 2 peak improvement are critical as the degree of VO 2 peak improvement is associated with improved long-term outcomes in these patients. Purpose: To determine if clinical characteristics and number of CR sessions attended were predictive of patients who exhibited improvement in VO 2 peak following CR. Methods: Using the Rochester Epidemiology Project records-linkage system, we identified all consecutive patients >18 years old from Olmsted County, Minnesota who underwent cardiopulmonary exercise testing prior to and following CR from 1999 to 2017. Regression models were created to assess clinical predictors of VO 2 peak improvement (>0% baseline) following CR. Results: The analysis included 804 patients (75% men) with a mean age of 60.7±12.4 years. Of the 804 patients, 609 (76%) patients exhibited VO 2 peak improvement following CR. Significant univariate predictors of VO 2 peak improvement included younger age (OR: 0.99, 95% CI: 0.97-1.00), lower pre-CR VO 2 peak (OR: 0.97, 95% CI: 0.94-0.99), history of peripheral artery disease (OR: 0.48, 95% CI: 0.32-0.73), and smoking (OR: 0.63, 95% CI: 0.45-0.90). Significant independent predictors of VO 2 peak improvement from a multivariate analysis included younger age (OR: 0.98, 95% CI: 0.96-1.00), number of CR sessions (OR: 1.02, 95% CI: 1.01-1.03), lower pre-CR VO 2 peak (OR: 0.94, 95% CI: 0.91-0.96), history of peripheral artery disease (OR: 0.42, 95% CI: 0.27-0.66), and smoking (OR: 0.56, 95% CI: 0.39-0.82). Conclusions: These findings demonstrate the importance of CR adherence and individual clinical characteristics in influencing VO 2 peak improvement following CR in patients with CVD. These findings may influence the clinical practice by providing specific clinical characteristics to account for when personalizing the CR treatment plan to maximize positive outcomes.

Introduction: Peripheral factors contribute to exercise limitations in heart failure (HF) with preserved ejection fraction (HFpEF) and may be related to excess regional adiposity. Slowed oxygen uptake (VO 2 ) kinetics are common in HF with reduced ejection fraction (HFrEF) and reflect peripheral O 2 transport impairments and abnormal muscle metabolic control. Differences in VO 2 kinetics between HFpEF and HFrEF may reveal phenotype-specific impairments in peripheral O 2 transport but remain unknown. Hypothesis: We hypothesized that VO 2 kinetics are slower in HFpEF (compared to HFrEF) and associated with greater leg adiposity. Methods: Patients with HFpEF (n=12; 3 women; 66±6 yrs; 29±3 kg/m 2 ; ejection fraction: 59±5%), HFrEF (n=12; 3 women; 62±9 yrs; 28±4 kg/m 2 ; ejection fraction: 37±8%), and controls (n=12; 3 women; 65±5 yrs; 28±3 kg/m 2 ) cycled at 20 W for 5 minutes prior to a maximal exercise test to determine VO 2peak . Age, sex, and BMI were matched by design and were not different among groups (p>0.05). A monoexponential function with a time delay was used to describe the VO 2 transition from rest to 20 W and calculate the O 2 deficit. Leg fat mass was measured via dual energy X-ray absorptiometry. Results: VO 2peak was lower in HFpEF (18.6±6.2 mL/kg/min) and HFrEF (19.0±3.7 mL/kg/min) compared to controls (26.0±3.1; both p<0.05). Amplitude (HFpEF: 507±97 mL/min; HFrEF: 443±91 mL/min; controls: 477±117 mL/min) and time delay (HFpEF: 16±9 s; HFrEF: 11±7 s; controls: 11±6 s) were not different among groups (p>0.05). The time constant was slower in HFrEF compared to controls (45±9 s vs. 32±6 s; p=0.03) and further slowed in HFpEF (66±18 s; p<0.001). The O 2 deficit was significantly greater in HFpEF (895±201 mL) and HFrEF (649±131 mL) compared to controls (590±125 mL; both p<0.05). There were no differences in percent leg fat mass among groups (HFpEF: 33±8%; HFrEF: 31±6%; controls: 34±9%) and no associations were detected between percent leg fat mass and any VO 2 parameters (all p>0.05). Conclusions: Patients with HFpEF exhibited slower VO 2 kinetics compared to HFrEF with no association to leg adiposity. These data suggest differences in peripheral O 2 transport and intramuscular metabolic control abnormalities between HF phenotypes.

Introduction: Heart failure patients with preserved ejection fraction (HFpEF) may exhibit inspiratory muscle dysfunction potentially contributing to exercise intolerance. Activation of neural afferents in response to inspiratory muscle contraction (metaboreflex) elicits increases in mean arterial pressure (MAP) and leg vascular resistance (LVR) through enhanced sympathetic outflow leading to decreases in leg blood flow (LBF) in healthy humans. It is unknown if HFpEF patients exhibit exaggerated cardiovascular responses to inspiratory muscle metaboreflex activation. Hypothesis: We hypothesize that patients with HFpEF will exhibit a greater increase in MAP and LVR with a decrease in LBF during inspiratory muscle metaboreflex activation than controls. Methods: HFpEF patients (n=15, 10M/5W, 69±10 yrs; 33±4 kg/m2) and controls (n=14; 10M/4W; 70±8 yrs; 28±4 kg/m2) performed inspiratory resistive breathing tasks (IRBT) at 2% and 60% of their maximal inspiratory pressure. During the IRBTs, the breathing frequency was 20 breaths/min with a 50% duty cycle. At rest and during the IRBTs, MAP was measured by photoplethysmography, venous norepinephrine was measured, LBF was measured by near-infrared spectroscopy and indocyanine green dye injections, and LVR was calculated. Results: During the 2% IRBT, there were no differences between groups in the changes from rest in MAP (HFpEF: 2±4 vs. CTL: 3±4 mmHg) or LBF (HFpEF: 1±14 vs. CTL: 1±12%) (both, p>0.05). During the 60% IRBT, venous norepinephrine increased from rest in HFpEF and controls (p<0.05), while no differences existed between groups (p>0.05). During the 60% IRBT, HFpEF patients, compared to controls, exhibited a greater increase from rest in MAP (HFpEF: 16±7 vs. CTL: 10±6 mmHg) and LVR (HFpEF: 76±45 vs. CTL: 32±19%) coupled with a greater decrease in LBF (HFpEF: -32±14 vs. CTL: -17±9%) (all, p<0.05). Conclusions: These data indicate that patients with HFpEF exhibit exaggerated cardiovascular responses with inspiratory muscle metaboreflex activation compared to healthy individuals. These findings have important implications for the integrative physiology of exercise in HFpEF patients.

Patients with HFrEF exhibit severe exercise intolerance. One of the primary peripheral mechanisms contributing to exercise intolerance in patients with HFrEF is locomotor muscle group III/IV afferent feedback. However, it is unknown whether these afferents impact the central and peripheral responses during submaximal cycling exercise. Herein, we demonstrate that inhibition of locomotor muscle group III/IV afferent feedback elicited increases in stroke volume during submaximal exercise in HFrEF, but not in healthy controls.

Cardiovascular disease is a leading cause of morbidity and mortality in males and females in the United States and globally. Cardiac rehabilitation (CR) is recommended by the American Heart Association/American College of Cardiology for secondary prevention for patients with cardiovascular disease. CR participation is associated with improved cardiovascular disease risk factor management, quality of life, and exercise capacity as well as reductions in hospital admissions and mortality. Despite these advantageous clinical outcomes, significant sex disparities exist in outpatient phase II CR programming. This article reviews sex differences that are present in the spectrum of care provided by outpatient phase II CR programming (ie, from referral to clinical management). We first review CR participation by detailing the sex disparities in the rates of CR referral, enrollment, and completion. In doing so, we discuss patient, health care provider, and social/environmental level barriers to CR participation with a particular emphasis on those barriers that majorly impact females. We also evaluate sex differences in the core components incorporated into CR programming (eg, patient assessment, exercise training, hypertension management). Next, we review strategies to mitigate these sex differences in CR participation with a focus on automatic CR referral, female-only CR programming, and hybrid CR. Finally, we outline knowledge gaps and areas of future research to minimize and prevent sex differences in CR programming.

Locomotor and respiratory muscle feedback via group III/IV afferents influences the blood pressure response during exercise. Specifically, stimulation of the inspiratory and locomotor muscle afferents (via inspiratory loading (IL) and subsystolic circulatory occlusion (CUFF), respectively) increases the blood pressure response during exercise with combined IL and CUFF (IL+CUFF) further augmenting the blood pressure response. Sex differences in blood pressure have been observed in both IL and CUFF when investigated individually, while the influence of sex hormones is unclear. It is unknown if sex and menstrual cycle phase influences the blood pressure response to IL+CUFF during exercise. Purpose To determine if sex and menstrual cycle phase influence the blood pressure response during IL+CUFF in men and premenopausal women. We hypothesized that women will exhibit attenuated increases in blood pressure compared to age‐matched men during IL, CUFF, and IL+CUFF, while no differences would be present across the menstrual cycle. Methods To date, 13 adults (7M/6W; M: 28±6 vs. W: 29±4 yrs, p=0.30; M: 27±5 vs. W: 25±2 kg/m 2 , p=0.85) have participated in this study. Participants performed four 10 min exercise bouts at 40% of their peak oxygen uptake. The participants performed spontaneously breathing (SB) during the first 5 minutes and voluntary hyperventilation (i.e. breathing frequency of 40 breaths/min with 50% duty cycle) during the last 5 minutes. During this last 5 min, IL (30% maximal inspiratory pressure), CUFF (80 mmHg), IL + CUFF, or no intervention (CTL) occurred in a randomized order. Women completed the study protocol twice, once during midluteal (ML) phase and once during early follicular (EF) phase. Blood pressure was measured using manual sphygmomanometry. Changes in systolic blood pressure (ΔSBP), diastolic blood pressure (ΔDBP), and mean arterial pressure (ΔMAP) were determined by subtracting values obtained during IL, CUFF, IL+CUFF, or CTL from SB. Results There were no significant differences in ΔMAP across groups during CTL (M: 5±5; ML 2±2; EF: 2±2 mmHg, all p>0.24), IL (M: 11±4; ML 10±2; EF 12±5 mmHg, all p>0.60), CUFF (M: 19±6; ML 16±4; EF 20±2 mmHg, all p>0.20), or IL + CUFF (M: 24±5; ML 23±6; EF 23±3 mmHg, all p>0.82). There were no significant differences in ΔSBP across groups during CTL (M: 5±4; ML 5±4; EF: 8±13 mmHg, all p>0.49), IL (M: 17±6; ML 17±5; EF 19±8 mmHg, all p>0.63), CUFF (M: 24±12; ML 23±7; EF 28±5 mmHg, all p>0.31), or IL + CUFF (M: 34±8; ML 33±11; EF 33±8 mmHg, all p>0.94). There were no significant differences in ΔDBP across group during CTL (M: 5±8; ML 0±1; EF: −1±4 mmHg, all p>0.05), IL (M: 8±3; ML 7±2; EF 9±4 mmHg, all p>0.71), CUFF (M: 16±4; ML 13±4; EF 16±2 mmHg, all p>0.20), or IL + CUFF (M: 19±6; ML 18±6; EF 18±3 mmHg, all p>0.75). Conclusion With this limited sample size, our data suggest that neither sex nor menstrual cycle phase influences the blood pressure response with IL, CUFF or IL+CUFF. Support or Funding Information NIH HL126638 AHA 18POST3990251 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Introduction Peripheral nervous system feedback arising from mechanically and metabolically sensitive afferents (Group III/IV, respectively) are central components of the exercise pressor reflex. Experimentally, locomotor venous distention can be simulated via subsytolic regional circulatory occlusion (SubRCO) thereby augmenting the exercise pressor reflex. Furthermore, high pedal frequency increases type II muscle fiber recruitment during exercise likely increasing non‐oxidative metabolism. To date, studies investigating the influence of aging on the exercise pressor reflex have presented conflicting data with most utilizing small muscle mass exercise (e.g. handgrip). Therefore, the purpose of this study was to determine the influence of SubRCO, pedal frequency, and the combination thereof on blood pressure (BP) during exercise in older and younger adults. We hypothesized that during exercise 1) independent of pedal frequencies and age, SubRCO will augment BP and 2) older adults will have greater increases in BP at high pedal frequencies with and without SubRCO compared younger adults. Methods 10 younger (22±2 yrs; 4M/6W; 24±4 kg/m 2 ) and 10 older (63±10yrs; 4M/6W; 24±4 kg/m 2 ) adults participated in two study visits each consisting of two cycling exercise sessions at 20 W, with bilateral upper thigh pressure cuffs. Participants engaged in 3 minutes of exercise at 35 (LOW) or 100 (HIGH) rpm with 5 additional minutes of exercise at that rpm with no cuffing (CTL) or SubRCO in randomized order. Systolic and diastolic blood pressure (SBP and DBP, respectively) were measured via manual sphygmomanometry. Mean arterial pressure (MAP) was calculated as (SBP‐DBP)/3+DBP and the changes in MAP from rest are reported. Results During LOW, SubRCO resulted in greater MAP than CTL in younger (CTL: 4±7; SubRCO: 13±7 mmHg) and older adults (CTL: 4±6; SubRCO: 13±4 mmHg) (both p<0.01). During HIGH, SubRCO resulted in greater MAP than CTL in younger (CTL: 7±4; SubRCO: 20±6 mmHg) and older adults (CTL: 20±9; SubRCO: 31±8 mmHg) (both p<0.01). Younger and older adults had greater increases in MAP during HIGH CTL and SubRCO compared to LOW CTL and SubRCO, respectively (all, p<0.01). Within LOW, there were no differences between younger and older adults during CTL or SubRCO (all, p>0.05). Within HIGH, older adults had greater increases in MAP than younger adults during CTL and SubRCO (both p<0.01). Conclusion These data support the hypothesis that older compared to younger adults have a greater BP response at higher pedal frequencies during exercise. Our results suggest that aging contributes to a greater exercise pressor response to exercise, possibly due to greater feedback from group III/IV afferents. Support or Funding Information NIH HL126638AHA 18POST3990251 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .