Keller‐Ross, Manda L.

Heart rate variability (HRV) is a widely utilized approach for investigating cardiovascular health and human performance. Methodological approaches, analyses, and interpretations of HRV can vary extensively, and scientific debates on HRV reliability and utility remain. These debates have been amplified in recent years by the rapid growth and ubiquity of wearable devices, and their incorporation into scientific research studies. The present guidelines paper takes an evidence-based approach to propose more consistent and rigorous measurement and interpretation of HRV within human cardiovascular research and application. First, HRV has some utility as a cardiovascular risk stratification tool, but is not appropriate to employ as a specific marker of cardiac sympathetic outflow or sympathovagal balance. While time-domain and spectral analysis can more accurately reflect respiratory modulation of cardiac vagal (parasympathetic) activity, caution is necessary to avoid overinterpretation, particularly with respect to the concept of “vagal tone”. Numerous experimental, demographic, and environmental factors influence HRV assessment, interpretation, and reliability. Specifically, it is critical to account for non-modifiable (age, sex, race/ethnicity, etc.) and modifiable (i.e., exercise, physical fitness, etc.) factors within participant samples. Furthermore, technical approaches such as the HRV input signal (e.g., electrocardiography vs. photoplethysmography), length of recording, location of recordings (i.e., laboratory vs. field), respiratory rate and depth, and analytical approaches (i.e., time vs. frequency domain) can all impact rigor, reliability, and study interpretations. Finally, with respect to the rapid advancements of HRV assessment using wearable technology, investigators should interpret and contextualize findings within the limitations outlined in this guideline review.

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.

Abstract This case study investigated the impact of SCS on alterations in blood pressure during constant-load exercise in a female patient with heart failure. Three different SCS frequencies [No SCS (~0 Hz), Low SCS (~100 Hz), and High SCS (~1000 Hz)] with and without ischaemic stimulation of the legs (cuffs) were randomly applied during constant-load exercise. To determine cardiovascular and ventilatory responses to exercise following SCS frequencies, BP, heart rate (HR), and respiratory gas exchange were measured. This experiment was duplicated in visit 1 and visit 2 with a random application of SCS frequency order and the data were averaged. There were no significant differences among three frequencies with no leg ischaemia. However, High SCS demonstrated lower BP, HR, and respiratory gas exchange relative to No SCS and Low SCS. SCS may be effective in improving cardiovascular and ventilatory responses in HF and high-frequency stimulation provides more clinical benefit; however, further studies are needed.

Background Neurophysiological coupling between ventilation and locomotor muscle group III/IV muscle afferent fibers during exercise is an important relationship that favorably influences ventilation in young healthy adults. In contrast, we have shown that group III/IV locomotor muscle afferents provoke aberrant ventilation in aging heart failure patients, which is suggested to be a primary effect of heart failure. However, there remains a limited understanding of the effect of aging in the absence of cardiovascular disease on the group III/IV muscle afferent pathway. Subsystolic circulatory occlusion to elicit venous distension has been suggested to stimulate locomotor muscle afferent neurologic feedback. The purpose of this study was to compare ventilatory responses in young vs aging healthy adults during submaximal constant‐load exercise with intermittent bilateral subsystolic occlusion of locomotor muscles. Methods Healthy adults completed 2 visits (10 young [YNG] vs 9 OLD; age 22±1 vs 66±3 yrs, BSA 1.8±0.1 vs 1.9±0.1 m 2 ; % predicted peak VO 2 99±7 vs 115±7 %; peak workload 188±16 vs 144±9 W, respectively; age and workload P <0.05). Visit 1: peak exercise ergometry test. Visit 2: constant‐load cycle ergometry at 30% peak workload (YNG=56±5 vs OLD=43±3 W, P <0.05) with the first 3 min without cuffing (0 mm Hg) and intermittent subsystolic bilateral thigh cuff inflations to 20, 40, 60, 80, or 100 mm Hg for 2 min (randomized), with 2 min deflation between occlusions thereafter. Minute ventilation (V E ), respiratory rate (RR), tidal volume (V T ), oxygen uptake (VO 2 ) indexed to weight, carbon dioxide output (VCO 2 ), respiratory exchange ratio (RER), V E /VCO 2 , and end tidal partial pressure CO 2 (P ET CO 2 ) were measured continuously via breath by breath system. Results At rest, V E , RR, V T , or RER did not differ in YNG vs OLD ( P >0.05); whereas VO 2 (6.3±0.3 vs 3.9±0.2 mL/kg/min) and VCO 2 (0.3±0.0 vs 0.2± 0.0 L/min) were higher in YNG vs OLD (respectively, P <0.05). During all exercise occlusions, V E was higher in YNG vs OLD, with the largest difference at 100 mm Hg (36.7±1.7 vs 30.2±1.6 L/min, respectively, P <0.05). However, the % change from rest to 0 mm Hg or each cuff occlusion resulted in no differences in YNG vs OLD for V E ( P >0.05). In contrast, in YNG vs OLD, the largest % change from 0 mm Hg to the cuff occlusion resulting in between group differences included V E (3.3±3.0 vs 17.3±3.6 at 80 mm Hg, P <0.05), VCO 2 (2.3±2.3 vs 20.8±3.4 at 100 mm Hg, P <0.05) and V E /VCO 2 (7.0±2.6 vs 0.5±1.8 at 100 mm Hg, P <0.05). In addition, there was a trend for significant differences between YNG and OLD for V T (−1.2±4.4 vs 5.9±4.1 % at 80 mm Hg, P =0.15), VO 2 (−2.1±1.5 vs 3.3±1.8 %, at 100 mm Hg, P =0.09) and P ET CO 2 (−6.4±1.9 vs −2.3±1.4 % at 100 mm Hg, P =0.11). Conclusions These data suggest that aging is associated with altered ventilatory responses to venous occlusion of locomotor muscles during constant load submaximal exercise. These changes may be a result of an increased contribution of locomotor muscle afferents on ventilatory control with aging. Support or Funding Information none

Activation of group III/IV skeletal muscle afferents (ergoreflex) and hypoxia (chemoreflex) are two potent stimuli of the sympathetic nervous system during exercise. Venous distention by graded sub‐systolic occlusion contributes to the ergoreflex during exercise. Although the ergoreflex causes greater increases in blood pressure (BP) compared with the chemoreflex, the interaction of the ergoreflex and hypoxia during lower extremity dynamic exercise is unknown. Objective To determine the effect of hypoxia and graded cuff occlusion on hemodynamic responses during low‐intensity cycling exercise. Methods 19 healthy adults (9 men, 25±5 yr) completed two sessions. Session 1 included a maximal cycle ergometry exercise test. Session 2 included two randomized bouts (hypoxia: 12.5% FiO 2 and normoxia: 21% FiO 2 ) of constant‐load cycling at 30% peak workload for 3 min (control, CTL) followed by randomized inflation of bilateral thigh pressure tourniquets to 20, 40, 60, 80, 100 mmHg for 2 min with 2 min of deflation between occlusions. The bouts were separated by 30 minutes of rest. Blood pressure, heart rate and cardiac output (CO) were measured continuously. Results During hypoxia, the average SPO 2 was 80%. Venous occlusion and hypoxia had differential effects on mean arterial pressure (MAP, occlusion × hypoxia, p=0.02). Significant increases of MAP from CTL occurred at 60 (Δ9 ± 6mmHg), 80 (Δ15 ± 8mmHg), and 100mmHg (Δ17 ± 9mmHg) under normoxia (p<0.05). MAP only increased at 100mmHg (Δ14 ± 9mmHg) under hypoxia (p<0.05). Under hypoxia, MAP was much greater at CTL and 20mmHg as compared to normoxia (p<0.05). SBP exhibited responses similar to MAP under hypoxia (100mmHg increase, p<0.001, occlusion × hypoxia interaction, p=0.02). CO was greater with venous occlusion as mediated by increases in HR (p<0.001). In addition, CO increased under hypoxia (p=0.007) but had no interaction with venous occlusion. Conclusion During low pressure venous occlusion, hypoxia had a greater effect on BP, but as pressure increased (60–100mmHg), there were no significant differences in BP between normoxia and hypoxia. Therefore, sympathetically mediated increases of BP during exercise attributed to hypoxia may negate any responses mediated by the ergoreflex when elicited by venous occlusion at low pressures.

Introduction Healthy aging in adults is associated with attenuated cardiac output (Q) for a given exercise workload compared to younger healthy adults. This is important because skeletal muscle perfusion pressure during exercise is dependent on coordinated adjustments between cardiac and vascular hemodynamics. Cardiac power (CP) quantifies the flow and peripheral pressure generating capacity of the heart, and may be the strongest measure of cardiac function during exercise. Group III/IV muscle afferents are suggested to favorably influence Q and arterial pressure during exercise in young healthy adults. However, the influence of group III/IV afferents on cardiac hemodynamic and arterial pressure coupling during exercise remains unclear across the aging spectrum. Venous distension via subsystolic circulatory occlusion of locomotor muscles is suggested to increase group III/IV afferent outflow. The aim of this study was to assess the influence of subsystolic circulatory occlusion of locomotor muscles on CP in young vs aging healthy adults. Methods Healthy adults completed 2 visits (10 young [YNG] vs 9 OLD; age 22±1 vs 66±3 yrs, BSA 1.8±0.1 vs 1.9±0.1 m 2 ; % predicted peak VO 2 99±7 vs 115±7 %; peak workload 188±16 vs 144±9 W, respectively; age and workload P <0.05). Visit 1: peak exercise test. Visit 2: constant load cycle ergometry at 30% peak workload (YNG=56±5 vs OLD=43±3 W, P <0.05) with the first 3 min without cuffing (0 mm Hg), but thereafter included intermittent subsystolic bilateral thigh cuff inflations to 20, 40, 60, 80, or 100 mm Hg for 2 min (randomized), with 2 min deflation between inflations. Non‐invasive Q and mean arterial (MAP) pressure were measured using continuous hemodynamic photoplethysmography. We calculated CP=Q*MAP. Q and CP were indexed to BSA. Results At rest, MAP did not differ in YNG vs OLD, but Q and CP were higher in YNG vs OLD (P<0.05), which persisted throughout each exercise cuff occlusion. In YNG, the greatest increase in CP from 0 mm Hg occurred at 100 mm Hg (754±48 vs 899±48 L/min/m 2 · mm Hg, P <0.05) due to increased MAP (19±4%, P <0.05) but not Q (1±2%, P >0.05). In OLD, Q, MAP, and CP did not differ between 0 mm Hg and any occlusion ( P >0.05). The % increase in Q from rest to 0, 20, 60, 80, and 100 mm Hg was higher in YNG vs OLD ( P <0.05). The % increase in MAP from rest to any occlusion did not differ in YNG vs OLD ( P >0.05). The % increase in CP from rest to occlusions of 60 (130±9 vs 98±11%), 80 (142±9 vs 108±20%), and 100 (158±11 vs 114±14%) were higher in YNG vs OLD (all P <0.05). Within YNG, the % increase in CP from rest to 100 mm Hg was higher than the % increase from rest to 0, 20, 40, or 60 mm Hg ( P <0.05), driven by increased MAP ( P <0.05). Within OLD, these differences for % increase in CP did not occur despite MAP that was similar to YNG ( P >0.05). Conclusions These data suggest that CP is attenuated in OLD vs YNG healthy adults during subsystolic circulatory occlusion of locomotor muscles during submaximal constant load exercise. The reduced CP generation in older adults is related to a blunted increase in Q mediated by attenuated influence of group III/IV muscle afferents on cardiac function during exercise.

Heightened anxiety is associated with an increased risk for cardiovascular diseases such as coronary heart disease and hypertension. While hyperactivity of the sympathetic nervous system has been suggested to mediate this relationship, direct measures of muscle sympathetic nerve activity (MSNA) in people with elevated anxiety have indicated little, if any, alterations in baseline sympathetic function. However, studies examining anxiety and MSNA have been limited by small sample sizes and lack of detail on anxiety severity, limiting the ability to investigate subtle interactions. The present study assessed associations between trait anxiety, mean arterial pressure (MAP), and MSNA using a large, representative sample of healthy young men and women, with an exploratory assessment of sex-specific interactions. We hypothesized that heightened trait anxiety would be associated with elevated resting MAP and MSNA. Trait anxiety was assessed using the Spielberger Trait Anxiety Inventory (STAI) in 97 healthy adults (52 male, 45 female; 25±1 years; 26±1 kg/m2). In each participant, the average of three seated brachial blood pressures was recorded and used in subsequent analysis. All participants underwent an autonomic function test that simultaneously assessed heart rate (HR), beat-to-beat blood pressure, MSNA burst frequency (BF) and incidence (BI) during 5-10 minutes of supine rest. MSNA recordings were captured in 91 participants. Multiple regression was used to test the relationship between STAI, MAP, MSNA, and HR while accounting for age and sex. Sex-specific interactions were explored with correlations controlling for age. The regression model significantly predicted MAP (R2=.196, P<0.001), BF (R2=.136, P=0.005), and BI (R2=.150, P=0.003), but not HR (R2=.055, P=0.155). STAI scores were independently associated with MAP (β=.207, P=0.029), BF (β=.245, P=0.016), and BI (β=.224, P=0.027). In males, STAI was correlated with MAP (R=.277, P=0.049), BF (R=.363, P=0.009), and BI (R=.346, P=0.013), but not HR (R=.140, P=0.326). In contrast, STAI was not associated with MAP (R=.174, P=0.260), BF (R=.094, P=0.574), BI (R=.069, P=0.681), or HR (R=.226, P=0.141) in females. In a large sample of healthy adults, our results highlight the relationship between the severity of trait anxiety, resting blood pressure, and sympathetic outflow, with a more pronounced relationship in males. Support: NIH (AA-024892, 1R15HL140596-01, AG064038-01A1, U54GM115371; P20GM103474, 2TL1 TR002318). This is the full abstract presented at the American Physiology Summit 2023 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.

Anxiety is associated with development of cardiovascular disease. Although the sympathetic nervous system is a likely mediator of this relationship, populations with chronic anxiety have shown little, if any, alteration in resting levels of directly recorded muscle sympathetic nerve activity (MSNA). The present study is the first to reveal an independent relationship between trait anxiety, resting blood pressure, and MSNA in a large cohort of healthy males and females devoid of cardiometabolic comorbidities.

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.

BACKGROUND Increased activation of Group III/IV skeletal muscle afferents is suggested to play a role in exercise intolerance in heart failure (HF). PURPOSE The purpose of this study was to examine if skeletal muscle afferent feedback inhibition improves exercise tolerance in HF. METHODS 8 HF patients [59±8 yr, mean±SD] participated in two randomized incremental recumbent cycling exercise sessions to peak capacity (peak oxygen consumption, VO 2 ). Session 1: The synthetic opioid fentanyl (50 mcg), known to block afferent feedback, was injected intrathecally (INJ) in the lumbar spine (L3‐L4 intervertebral space) prior to exercise. Session 2: Participants were prepared similarly with a sham injection (placebo, PLA). Gas exchange, dyspnea and RPE were measured. RESULTS HF patients exercised for a longer duration (Δ3±3 min, p=0.02) and reached a higher power output (PLA:109±30 vs. INJ:128±34 W, p=0.02) with locomotor afferent inhibition. Additionally, peak VO 2 was non‐significantly greater (PLA:18.7±3.3 vs. INJ:21.8±4.4 ml/kg/min, p=0.10). With INJ workload matched to peak PLA workload, RPE was reduced (PLA:18±2 vs. INJ:15±2, respectively, p=0.005) and dyspnea was lower (PLA:7.5±2 vs. INJ:4.2±1, p=0.003) with no difference in VO 2 (p>0.05). CONCLUSION Inhibition of group III/IV locomotor muscle afferent feedback contributes to improved exercise tolerance and exertional symptoms in HF patients.