Olson, Thomas P.

Introduction The exercise pressor reflex contributes to cardiovascular regulation during exercise. The primary components of the exercise pressor reflex response are the mechanically and metabolically sensitive skeletal muscle afferents (group III and IV, respectively). Experimentally, subsystolic regional circulatory occlusion (SubRCO) leads to venous distention, stimulating primarily group III afferents, thereby augmenting the exercise pressor reflex. Previous studies have reported sex differences in the metaboreflex induced exercise pressor reflex induced cardiovascular responses. Specifically, pre‐menopausal women, compared to age‐matched men, were found to have attenuated cardiovascular responses with mechanoreflex stimulation. However, it is unclear if sex differences are also present in the cardiovascular responses during exercise with locomotor limb venous distention. Therefore, the purpose of this study was to determine the influence of SubRCO during submaximal exercise in men and women. We hypothesized that women will have attenuated increases in mean arterial pressure (MAP) and systemic vascular resistance (SVR) than men during exercise with SubRCO. Methods Twelve men and thirteen women completed two study visits (Age: M: 30±6vs. W: 27±8yrs, p>0.05; BMI: M: 25.4±3.6 vs. W: 22±3 kg/m 2 , p<0.05). The first visit consisted of a peak exercise ergometry test. The second visit consisted of constant‐load cycle ergometry at 30% peak workload with different SubRCO pressures via bilateral upper thigh pressure cuffs. The cuffs remained uninflated (0 mmHg) (CTL) during the first three min of exercise, then were intermittently inflated to 20, 40, 60, 80, or 100 mmHg for two minutes (randomized order). Each inflation period was followed by a 2minute deflation period where the participant continued to exercise. Cardiacoutput (Q) and MAP were measured via continuous hemodynamic photoplethysmography and systemic vascular resistance (SVR) was calculated. Data were reported as delta changes from CTL. Results Compared to 0 mmHg, MAP increased with SubRCO inflation pressures of 60, 80, and 100mmHg in men and women during submaximal exercise (all, p<0.05); however, no differences were present between groups (60 mmHg: M: 6.2±4.2 vs. W: 8.0±5.2; 80mmHg: M: 11.6±5.5 vs. W: 15.1±4.8; 100 mmHg: M: 18.2±6.6 vs. W: 20.5±7.2 mmHg(all, p>0.05)). Similarly, SVR increased with cuff inflation pressures of60, 80, and 100 mmHg compared to 0 mmHg in men and women (p<0.05), while no differences existed between groups (60 mmHg: M: 0.3±0.4 vs W: 0.4±0.5;80 mmHg: M: 0.9±0.5 vs W: 1.1± 0.9; 100 mmHg M: 1.3±0.8vs W: 1.5±0.8mmHg/L/min (all, p>0.05)). In contrast, Q did not change with cuff inflation pressures of 20, 40, 60, 80, or100 mmHg compared to 0 mmHg in men or women during submaximal exercise(p>0.05). Conclusion In contrast to our hypothesis, the MAP and SVR responses were not different between men and women with SubRCO during submaximal exercise. Our findings suggest that sex differences are not present in the cardiovascular response to low‐intensity constant‐load exercise with stimulation of the exercise pressor reflex via lower limb venous distention.

Introduction It is well established that the exercise pressor reflex contributes to cardiovascular control (e.g. mean arterial pressure (MAP)) during exercise. One arm of the exercise pressor reflex includes the metabolically sensitive group IV afferents (i.e. metaboreflex). The metaboreflex‐induced cardiovascular responses to exercise are incompletely understood, especially in women across the aging spectrum. For example, post‐menopausal women have greater increases in MAP and systemic vascular resistance (SVR) during locomotor muscle exercise compared to pre‐menopausal women. However, it is unclear if an exaggerated metaboreflex arising from the locomotor muscles is contributing to these cardiovascular adjustments with exercise in post‐menopausal women. We hypothesized that 1) post‐menopausal women will have an augmented MAP response with isolated metaboreflex activation compared to pre‐menopausal women and 2) the exaggerated increase in MAP in the post‐menopausal women will be primarily due to greater increases in SVR. Methods Pre‐ (n= 10, 25±3yrs, 24±3 kg/m 2 ) and post‐menopausal women (n=12, 58±4yrs, 24±3 kg/m 2 ) performed 2 sessions of cycling exercise at 20 W for 5 min with bilateral upper thigh pressure tourniquets inflated to 90 mmHg. At end exercise, the recovery was randomized to post‐exercise circulatory occlusion (PECO) to isolate the metaboreflex (via bilateral upper thigh pressure tourniquets rapidly inflated to suprasystolic pressure for 2 min) or normal recovery (NR) without intervention. Systolic and diastolic blood pressure were measured via manual sphygmomanometry and MAP was calculated. Cardiac output was measured via open circuit acetylene wash‐in and systemic vascular resistance (SVR) was calculated. Data is reported as the absolute change from rest to recovery. Results MAP was elevated during PECO compared to NR in both groups (p<0.05), while MAP during PECO was greater in post‐ compared to pre‐menopausal women (20±9 vs. 13±5 mmHg, respectively) (p<0.05). Similarly, SVR was elevated during PECO compared to NR in both groups (p<0.05), while SVR was greater during PECO in post‐ compared to pre‐menopausal women (5±3 vs. 3±1 mmHg/L/min, respectively) (p<0.05). In contrast, cardiac output was not different between NR and PECO in either pre‐ (NR: 0.3±1 vs. PECO: −0.2±1 L/min) and post‐menopausal (NR: −0.1±1 vs. PECO: −0.7±0.9 L/min) (all, p>0.05). Conclusion These data demonstrate that isolated metaboreflex stimulation following whole‐body exercise results in exaggerated increases in MAP and SVR in post‐ compared to pre‐menopausal women. These data suggest that exercise pressor reflex‐mediated control of MAP during exercise is accentuated in post‐menopausal women with menopause status.

Objective Cardiovascular adjustments to exercise, including increases in blood pressure (MAP) and heart rate, occur in response to several neural mechanisms. Specifically, stimulation of respiratory (via inspiratory loading (IL)) and locomotor muscle (via subsystolic cuff inflation (CUFF)) neurologic feedback via group III/IV afferents augments the MAP response during exercise. Further, we have recently shown that simultaneous stimulation of the respiratory and locomotor muscle afferents during exercise potentiates the MAP increase compared to when these reflexes are stimulated individually. To date, interventional strategies to attenuate the augmented MAP during IL+CUFF have not been investigated. Previous studies have shown that inspiratory muscle training (IMT) attenuates the IL‐induced increase in MAP at rest in healthy adults. We hypothesized that 8 weeks of IMT will attenuate the IL+CUFF‐induced increase in MAP during exercise in healthy adults. Methods Twenty adults were recruited and randomized to the IMT (n=10) or sham group (n=10). Participants performed 8 weeks of IMT twice a day, 7 days a week at 50% (IMT) or 10% (sham) maximum inspiratory pressure (MIP). On separate visits, participants performed an incremental cycling test to volitional fatigue and a 10 min cycling exercise bout at 40% maximal oxygen uptake Pre‐ and Post‐IMT. The exercise bout consisted of 5 min of spontaneous breathing followed by 5 min of voluntary hyperventilation (i.e. breathing frequency of 40 breaths per min) with IL (30% MIP) and bilateral locomotor subsystolic cuff inflation (80 mmHg). Systolic and diastolic blood pressure (SBP and DBP, respectively) were measured using manual sphygmomanometry and MAP was calculated. SBP and MAP were reported as the change from rest. Dyspnea was measured via Borg scale (1–10). Results After 8 weeks, MIP increased in the IMT (Pre: 99±26 vs. Post: 127±26 cmH 2 O, p<0.05), but not the sham group (Pre: 126±29 vs. Post: 129±28 cmH 2 O, p>0.05). Pre‐IMT, the increase in MAP with IL+CUFF was not different between groups (IMT: 28±6 vs. sham: 31±7 mmHg) (p>0.05). Post‐IMT, the increase in MAP with IL+CUFF was attenuated in IMT, but not sham (IMT: 23±7 vs. sham: 32±5 mmHg) (p<0.05). Pre‐IMT, the increase in SBP with IL+CUFF was not different between groups (IMT: 49±12 vs. sham: 53±16 mmHg) (p>0.05). Post‐IMT, the increase in SBP with IL+CUFF was attenuated in IMT, but not sham (IMT: 42±12 vs. sham: 57±14 mmHg) (both, p<0.05). The increase in DBP with IL+CUFF was not different between groups Pre or Post‐IMT (both, p>0.05). Lastly, dyspnea was not different Pre‐IMT between groups (IMT: 4±3 vs. sham: 4±2 Borg (1–10)) (p>0.05), but was lower in the IMT, but not sham Post‐IMT (IMT: 2±2 vs. sham: 4±1 Borg (1–10)) (p<0.05). Conclusions These data demonstrate that IMT attenuates the MAP response when the respiratory and locomotor afferents are stimulated simultaneously. These findings have important clinical implications for populations that exhibit exaggerated respiratory and locomotor muscle reflexes during exercise. Support or Funding Information This work was supported by the National Institutes of Health [HL126638 to TPO] and American Heart Association [18POST3990251 to JRS].

Reflexes arising from the respiratory and locomotor muscles influence cardiovascular regulation during exercise. However, it is unclear how the respiratory and locomotor muscle reflexes interact when simultaneously stimulated. Herein, we demonstrate that stimulation of the respiratory and locomotor muscle reflexes yielded additive cardiovascular responses during submaximal exercise.

New Findings What is the central question of this study? How do locomotor muscle metabo‐ and mechanoreceptor expression compare in heart failure patients and controls? Do relationships exist between the protein expression and cardiopulmonary responses during exercise with locomotor muscle neural afferent feedback inhibition? What is the main finding and its importance? Heart failure patients exhibited greater protein expression of transient receptor potential vanilloid type 1 and cyclooxygenase‐2 than controls. These findings are important as they identify receptors that may underlie the augmented locomotor muscle neural afferent feedback in heart failure. AbstractHeart failure patients with reduced ejection fraction (HFrEF) exhibit abnormal locomotor group III/IV afferent feedback during exercise; however, the underlying mechanisms are unclear. Therefore, the purpose of this study was to determine (1) metabo‐ and mechanoreceptor expression in HFrEF and controls and (2) relationships between receptor expression and changes in cardiopulmonary responses with afferent inhibition. Ten controls and six HFrEF performed 5 min of cycling exercise at 65% peak workload with lumbar intrathecal fentanyl (FENT) or placebo (PLA). Arterial blood pressure and catecholamines were measured via radial artery catheter. A vastus lateralis muscle biopsy was performed to quantify cyclooxygenase‐2 (COX‐2), purinergic 2X3 (P2X3), transient receptor potential vanilloid type 1 (TRPV1), acid‐sensing ion channel 3 (ASIC3), Piezo 1 and Piezo 2 protein expression. TRPV1 and COX‐2 protein expression was greater in HFrEF than controls (both P < 0.04), while P2X3, ASIC3, and Piezo 1 and 2 were not different between groups (all P > 0.16). In all participants, COX‐2 protein expression was related to the percentage change in ventilation (r = −0.66) and mean arterial pressure (MAP) (r = −0.82) (both P < 0.01) with FENT (relative to PLA) during exercise. In controls, TRPV1 protein expression was related to the percentage change in systolic blood pressure (r = −0.77, P = 0.02) and MAP (r = −0.72, P = 0.03) with FENT (relative to PLA) during exercise. TRPV1 and COX‐2 protein levels are elevated in HFrEF compared to controls. These findings suggest that the elevated TRPV1 and COX‐2 expression may contribute to the exaggerated locomotor muscle afferent feedback during cycling exercise in HFrEF.

Aims Patients with hypertrophic obstructive cardiomyopathy (HOCM) have impaired exercise capacity. The gold standard therapy for patients with HOCM is septal myectomy surgery; however, changes in maximum oxygen uptake (VO2peak) following myectomy are variable, with VO2peak decreasing in some patients. Therefore, we evaluated changes in VO2peak following surgical myectomy to determine clinical predictors of those exhibiting decreased VO2peak post-myectomy. Methods HOCM patients ( N = 295) who performed symptom limited cardiopulmonary exercise testing prior to and following surgical myectomy were included for analysis. The VO2peak non-responder group ( n = 128) was defined as <0% change in VO2peak from pre- to post-myectomy. Step-wise regression models using demographics, clinical, and physiologic characteristics were created to determine predictors of hypertrophic cardiomyopathy patients in the VO2peak non-responder group. Results Independent predictors of the VO2peak non-responder group included higher pre-myectomy VO2peak (% predicted), older age, women, history of dyslipidemia, lack of cardiac rehabilitation enrollment, and lower body mass index (all p < 0.03). Forty-three (14.6%) patients reached the primary end-point of all-cause mortality during a median follow up of 11.25 years (interquartile range 6.94 to 16.40). After adjustment for age, sex, beta-blocker use, coronary artery disease history, and body mass index, the VO2peak non-responder group had greater risk of death compared with the VO2peak responder group (adjusted hazard ratio: 1.77, 95% confidence interval: 1.06–3.34, p = 0.01). Conclusion This large hypertrophic cardiomyopathy cohort demonstrated that demographic (i.e. female sex), lack of cardiac rehabilitation enrollment, and cardiovascular risk factors (i.e. history of dyslipidemia) are predictive of those patients that did not exhibit increases in VO2peak following septal myectomy surgery.

Body mass index (BMI) does not differentiate fat and lean mass or the distribution of adipose tissue. The purpose of this study was to examine the prevalence of metabolic syndrome (MetS) among patients entering outpatient cardiac rehabilitation (CR) across fat mass index (FMI) categories compared with BMI. This retrospective cross-sectional study evaluated dual-energy x-ray absorptiometry in 483 CR patients from 1 January 2014, through 31 December 2017. Clinical data were extracted from the electronic health record. Patients were grouped by FMI and BMI categories. Mean (SD) age of patients was 64.3 (14) years. The normal FMI category had 15 patients; excess fat, 74; and obese, 384. In contrast, 93, 174, and 216 were in the normal, overweight, and obese BMI categories, respectively. Prevalence of MetS was 0 (0%) in normal, 5 (1%) in excess fat, and 167 (54%) in obese FMI, with 97% in the obese category. MetS prevalence was 4 patients (0.8%) in normal, 39 (8%) in overweight, and 129 (27%) in obese BMI categories, with 75% of MetS in the obese category. FMI more accurately classified CR patients with metabolically abnormal fat (p < 0.001). FMI is a more sensitive index than BMI for metabolically abnormal fat of outpatient CR patients.

Following implantation of continuous-flow left ventricular assist devices, mechanical off-loading results in improved resting hemodynamics; however, peak exercise capacity generally does not increase substantially. This study evaluated patients supported by continuous-flow left ventricular assist devices who were invasively monitored during exercise to define parameters that underpin exercise capacity and outcomes. A review of all patients supported by continuous-flow left ventricular assist devices who underwent supine bicycle ergometry exercise testing with measurement of pulmonary gas exchange during right heart catheterization for evaluation of dyspnea at one institution between 2007 and 2018 was performed (n = 22). The primary outcome of this investigation was death or heart failure hospitalization. Although resting filling pressures were relatively preserved, resting cardiac index (Fick) was low (2.1 ± 0.5 mL/kg/min). An impaired cardiac output reserve was present in 75% of patients. On univariate modeling, patients with supine exercise–induced hypoxemia (O 2 saturation <90%) experienced significantly diminished hospitalization-free survival (unadjusted hazard ratio = 11.0, confidence interval = 2.4–57.2, p = 0.003), which persisted despite adjustment for right heart catheterization peak VO 2 and peak cardiac output (adjusted hazard ratio = 25, confidence interval = 3.6–322, p = 0.001). Our findings suggest that supine exercise testing provides additional prognostic utility in the continuous-flow left ventricular assist device population.

Abstract Aims Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. Methods and results Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P &lt; 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P &lt; 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P &lt; 0.0001) and inversely correlated with PA compliance (r = −0.52 and −0.43, both P &lt; 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s′ and e′ tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e′, r = −0.59 and −0.67, both P &lt; 0.001), reduced cardiac output responses to exercise (r = −0.59 and −0.61, both P &lt; 0.0001), and more severely impaired peak VO2 (r = −0.60 and −0.67, both P &lt; 0.0001). Conclusion Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. Clinical trial registration NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search