Smith, Joshua R.

Abstract Over 50 years ago, John Wahren and Lennart Jorfeldt published a manuscript in Clinical Science where they detailed a series of studies of leg blood flow during exercise. They used a novel approach to indicator dye dilution: continuous arterial infusions of dye using venous samples. This technique allowed them to describe for the first time the fundamental relationships between large muscle group exercise, muscle blood flow, and pulmonary and muscle oxygen uptake. They also defined mechanical efficiency, a key measurement of muscle function. This paper formed the basis for research into muscle blood flow and exercise in health and disease and continued to be cited by modern research. In this commentary, we describe the innovations they made, the key observations that came out of their results, and the importance of this manuscript to current research.

Respiratory muscle dysfunction is thought to contribute to exercise intolerance in heart failure with preserved ejection fraction (HFpEF); however, the underlying mechanisms are unknown. In the present study, patients with HFpEF had greater increases in leg muscle vascular resistance index and greater decreases in leg muscle blood flow index compared with controls during inspiratory resistive breathing (to activate the metaboreflex). Furthermore, respiratory muscle blood flow index responses normalized to pressure generation during inspiratory resistive breathing were exaggerated in HFpEF compared with controls.

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: 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: 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 .