Inorganic Nitrite to Amplify the Benefits and Tolerability of Exercise Training in Heart Failure With Preserved Ejection Fraction: The INABLE-Training Trial.

OBJECTIVE: To determine whether nitrite can enhance exercise training (ET) effects in heart failure with preserved ejection fraction (HFpEF). METHODS: In this multicenter, double-blind, placebo-controlled, randomized trial conducted at 1 urban and 9 rural outreach centers between November 22, 2016, and December 9, 2021, patients with HFpEF underwent ET along with inorganic nitrite 40 mg or placebo 3 times daily. The primary end point was peak oxygen consumption (VO2). Secondary end points included Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS, range 0 to 100; higher scores reflect better health status), 6-minute walk distance, and actigraphy. RESULTS: Of 92 patients randomized, 73 completed the trial because of protocol modifications necessitated by loss of drug availability. Most patients were older than 65 years (80%), were obese (75%), and lived in rural settings (63%). At baseline, median peak VO2 (14.1 mL·kg-1·min-1) and KCCQ-OSS (63.7) were severely reduced. Exercise training improved peak VO2 (+0.8 mL·kg-1·min-1; 95% CI, 0.3 to 1.2; P<.001) and KCCQ-OSS (+5.5; 95% CI, 2.5 to 8.6; P<.001). Nitrite was well tolerated, but treatment with nitrite did not affect the change in peak VO2 with ET (nitrite effect, -0.13; 95% CI, -1.03 to 0.76; P=.77) or KCCQ-OSS (-1.2; 95% CI, -7.2 to 4.9; P=.71). This pattern was consistent across other secondary outcomes. CONCLUSION: For patients with HFpEF, ET administered for 12 weeks in a predominantly rural setting improved exercise capacity and health status, but compared with placebo, treatment with inorganic nitrite did not enhance the benefit from ET. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02713126.

Cardiorespiratory fitness and morbidity and mortality in patients with non-small cell lung cancer: a prospective study with propensity score weighting.

INTRODUCTION: This study aimed to investigate the association between cardiorespiratory fitness (CRF) and perioperative morbidity and long-term mortality in operable patients with early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This prospective study included consecutive patients with early-stage NSCLC who underwent presurgical cardiopulmonary exercise testing between November 2014 and December 2019 (registration number: ChiCTR2100048120). Logistic and Cox proportional hazards regression were applied to evaluate the correlation between CRF and perioperative complications and long-term mortality, respectively. Propensity score overlap weighting was used to adjust for the covariates. We performed sensitivity analyses to determine the stability of our results. RESULTS: A total of 895 patients were followed for a median of 40 months [interquartile range 25]. The median age of the patients was 59 years [range 26-83], and 62.5% were male. During the study period, 156 perioperative complications and 146 deaths were observed. Low CRF was associated with a higher risk of death (62.9 versus 33.6 per 1000 person-years; weighted incidence rate difference, 29.34 [95% CI, 0.32 to 58.36] per 1000 person-years) and perioperative morbidity (241.6 versus 141.9 per 1000 surgeries; weighted incidence rate difference, 99.72 [95% CI, 34.75 to 164.70] per 1000 surgeries). A CRF of ≤ 20 ml/kg/min was significantly associated with a high risk of long-term mortality (weighted hazard ratio, 1.98 [95% CI, 1.31 to 2.98], p < 0.001) and perioperative morbidity (weighted odds ratio, 1.93 [1.28 to 2.90], p = 0.002) compared to higher CRF. CONCLUSION: The study found that low CRF is significantly associated with increased perioperative morbidity and long-term mortality in operable patients with early-stage NSCLC.

Low cardiorespiratory fitness is significantly associated with increased perioperative morbidity and long-term mortality in operable patients with early-stage non-small cell lung cancer.Future research is recommended to investigate the potential prognostic role of integrating cardiorespiratory fitness into the currently used prognosis algorithm for patients with non-small cell lung cancer.

Prognostic role of minute ventilation/carbon dioxide production slope for perioperative morbidity and long-term survival in resectable patients with nonsmall-cell lung cancer: a prospective study using propensity score overlap weighting.

BACKGROUND: The role of minute ventilation/carbon dioxide production ( / CO 2 ) slope, a ventilation efficiency marker, in predicting short-term and long-term health outcomes for patients with nonsmall-cell lung cancer (NSCLC) undergoing lung resection has not been well investigated. MATERIAL AND METHODS: This prospective cohort study consecutively enrolled NSCLC patients who underwent a presurgical cardiopulmonary exercise test from November 2014 to December 2019. The association of / CO 2 slope with relapse-free survival (RFS), overall survival (OS), and perioperative mortality was evaluated using the Cox proportional hazards and logistic models. Covariates were adjusted using propensity score overlap weighting. The optimal cut-off point of the E/ CO 2 slope was estimated using the receiver operating characteristics curve. Internal validation was completed through bootstrap resampling. RESULTS: A cohort of 895 patients [median age (interquartile range), 59 (13) years; 62.5% male] was followed for a median of 40 (range, 1-85) months. Throughout the study, there were 247 relapses or deaths and 156 perioperative complications. The incidence rates per 1000 person-years for relapses or deaths were 108.8 and 79.6 among patients with high and low E/ CO 2 slopes, respectively [weighted incidence rate difference per 1000 person-years, 29.21 (95% CI, 7.30-51.12)]. A E/ CO 2 slope of greater than or equal to 31 was associated with shorter RFS [hazard ratio for relapse or death, 1.38 (95% CI, 1.02-1.88), P =0.04] and poorer OS [hazard ratio for death, 1.69 (1.15-2.48), P =0.02] compared to a lower / CO 2 slope. A high E/ CO 2 slope increased the risk of perioperative morbidity compared with a low E/ CO 2 slope [odds ratio, 2.32 (1.54-3.49), P <0.001]. CONCLUSIONS: In patients with operable NSCLC, a high E/ CO 2 slope was significantly associated with elevated risks of poorer RFS, OS, and perioperative morbidity.

Rate-Adaptive Atrial Pacing for Heart Failure With Preserved Ejection Fraction: The RAPID-HF Randomized Clinical Trial.

Importance: Reduced heart rate during exercise is common and associated with impaired aerobic capacity in heart failure with preserved ejection fraction (HFpEF), but it remains unknown if restoring exertional heart rate through atrial pacing would be beneficial. Objective: To determine if implanting and programming a pacemaker for rate-adaptive atrial pacing would improve exercise performance in patients with HFpEF and chronotropic incompetence. Design, Setting, and Participants: Single-center, double-blind, randomized, crossover trial testing the effects of rate-adaptive atrial pacing in patients with symptomatic HFpEF and chronotropic incompetence at a tertiary referral center (Mayo Clinic) in Rochester, Minnesota. Patients were recruited between 2014 and 2022 with 16-week follow-up (last date of follow-up, May 9, 2022). Cardiac output during exercise was measured by the acetylene rebreathe technique. Interventions: A total of 32 patients were recruited; of these, 29 underwent pacemaker implantation and were randomized to atrial rate responsive pacing or no pacing first for 4 weeks, followed by a 4-week washout period and then crossover for an additional 4 weeks. Main Outcomes and Measures: The primary end point was oxygen consumption (V̇o2) at anaerobic threshold (V̇o2,AT); secondary end points were peak V̇o2, ventilatory efficiency (V̇e/V̇co2 slope), patient-reported health status by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Results: Of the 29 patients randomized, the mean age was 66 years (SD, 9.7) and 13 (45%) were women. In the absence of pacing, peak V̇o2 and V̇o2 at anaerobic threshold (V̇o2,AT) were both correlated with peak exercise heart rate (r = 0.46-0.51, P < .02 for both). Pacing increased heart rate during low-level and peak exercise (16/min [95% CI, 10 to 23], P < .001; 14/min [95% CI, 7 to 21], P < .001), but there was no significant change in V̇o2,AT (pacing off, 10.4 [SD, 2.9] mL/kg/min; pacing on, 10.7 [SD, 2.6] mL/kg/min; absolute difference, 0.3 [95% CI, -0.5 to 1.0] mL/kg/min; P = .46), peak V̇o2, minute ventilation (V̇e)/carbon dioxide production (V̇co2) slope, KCCQ-OSS, or NT-proBNP level. Despite the increase in heart rate, atrial pacing had no significant effect on cardiac output with exercise, owing to a decrease in stroke volume (-24 mL [95% CI, -43 to -5 mL]; P = .02). Adverse events judged to be related to the pacemaker device were observed in 6 of 29 participants (21%). Conclusions and Relevance: In patients with HFpEF and chronotropic incompetence, implantation of a pacemaker to enhance exercise heart rate did not result in an improvement in exercise capacity and was associated with increased adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT02145351.

A New Era in Cardiac Rehabilitation Delivery: Research Gaps, Questions, Strategies, and Priorities.

Cardiac rehabilitation (CR) is a guideline-recommended, multidisciplinary program of exercise training, risk factor management, and psychosocial counseling for people with cardiovascular disease (CVD) that is beneficial but underused and with substantial disparities in referral, access, and participation. The emergence of new virtual and remote delivery models has the potential to improve access to and participation in CR and ultimately improve outcomes for people with CVD. Although data suggest that new delivery models for CR have safety and efficacy similar to traditional in-person CR, questions remain regarding which participants are most likely to benefit from these models, how and where such programs should be delivered, and their effect on outcomes in diverse populations. In this review, we describe important gaps in evidence, identify relevant research questions, and propose strategies for addressing them. We highlight 4 research priorities: (1) including diverse populations in all CR research; (2) leveraging implementation methodologies to enhance equitable delivery of CR; (3) clarifying which populations are most likely to benefit from virtual and remote CR; and (4) comparing traditional in-person CR with virtual and remote CR in diverse populations using multicenter studies of important clinical, psychosocial, and cost-effectiveness outcomes that are relevant to patients, caregivers, providers, health systems, and payors. By framing these important questions, we hope to advance toward a goal of delivering high-quality CR to as many people as possible to improve outcomes in those with CVD.

Higher Work of Breathing During Exercise in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: It is unknown if pulmonary alterations in heart failure with preserved ejection fraction (HFpEF) impact respiratory mechanics during exercise. RESEARCH QUESTION: Are the operating lung volumes, work of breathing (Wb), and power of breathing (Pb) abnormal in patients with HFpEF during exercise? STUDY DESIGN AND METHODS: Patients with HFpEF (n = 8; median age, 71 years [interquartile range (IQR), 66-80 years]) and control participants (n = 9; median age, 68 years [IQR, 64-74 years]) performed incremental cycling to volitional exhaustion. Esophageal pressure, end-expiratory lung volume (EELV), inspiratory lung volume (EILV), and ventilatory variables were compared at similar absolute (30 and 50 L/min) and relative (45% of peak, 70% of peak, and 100% of peak) minute ventilation (V.E) during exercise. RESULTS: During exercise, EELVs were not different between patients with HFpEF and control participants (P > .13 for all). EILVs were lower in patients with HFpEF than control participants at 45% and 70% V.E peak (P < .03 for all). Dynamic lung compliance was lower in patients with HFpEF than control participants at 30 L/min, 50 L/min, 45% V.E peak, and 100% V.E peak (P < .04 for all). Compared with control participants, patients with HFpEF showed higher total Wb and Pb at 30 L/min (Wb: median, 1.08 J/L [IQR, 0.93-1.82 J/L] vs 0.52 J/L [IQR, 0.43-0.71 J/L]; Pb: median, 36 J/min [IQR, 30-59 J/min] vs 17 J/min [IQR, 11-23 J/min] and 50 L/min; Wb: median, 1.40 J/L [IQR, 1.27-1.68 J/L] vs 0.90 J/L [IQR, 0.74-1.05 J/L]; Pb: median, 73 J/min [IQR, 60-83 J/min] vs 45 J/min [IQR, 33-63 J/min]; P < .01 for all). At 30 and 50 L/min, inspiratory and expiratory resistive Wb and Pb were higher in patients with HFpEF than control participants (P < .04 for all). Total Wb was higher for patients with HFpEF than control participants at 45% of V.E peak (P = .02). Total Pb was higher for control participants than patients with HFpEF at 100% V.E peak because of higher inspiratory resistive Pb (P < .04 for both). INTERPRETATION: These data demonstrate the HFpEF syndrome is associated with pulmonary alterations eliciting a greater Pb during exercise resulting from greater inspiratory and expiratory resistive Pb.

Quantifying muscle blood flow: a transformative breakthrough in the science of human exercise physiology.

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.

Inspiratory and leg muscle blood flows during inspiratory muscle metaboreflex activation in heart failure with preserved ejection fraction.

The purpose of this study was to determine the cardiovascular consequences elicited by activation of the inspiratory muscle metaboreflex in patients with heart failure with preserved ejection fraction (HFpEF) and controls. Patients with HFpEF (n = 15; 69 ± 10 yr; 33 ± 4 kg/m2) and controls (n = 14; 70 ± 8 yr; 28 ± 4 kg/m2) performed an inspiratory loading trial at 60% maximal inspiratory pressure (PIMAX) until task failure. Mean arterial pressure (MAP) was measured continuously. Near-infrared spectroscopy and bolus injections of indocyanine green dye were used to determine the percent change in blood flow index (%ΔBFI) from baseline to the final minute of inspiratory loading in the vastus lateralis and sternocleidomastoid muscles. Vascular resistance index (VRI) was calculated. Time to task failure was shorter in HFpEF than in controls (339 ± 197 s vs. 626 ± 403 s; P = 0.02). Compared with controls, patients with HFpEF had a greater increase from baseline in MAP (16 ± 7 vs. 10 ± 6 mmHg) and vastus lateralis VRI (76 ± 45 vs. 32 ± 19%) as well as a greater decrease in vastus lateralis %ΔBFI (-32 ± 14 vs. -17 ± 9%) (all, P < 0.05). Sternocleidomastoid %ΔBFI normalized to absolute inspiratory pressure was higher in HFpEF compared with controls (8.0 ± 5.0 vs. 4.0 ± 1.9% per cmH2O·s; P = 0.03). These data indicate that patients with HFpEF exhibit exaggerated cardiovascular responses with inspiratory muscle metaboreflex activation compared with controls.NEW & NOTEWORTHY 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.

Predictors of Changes in Peak Oxygen Uptake After Outpatient Cardiac Rehabilitation: Importance of Cardiac Rehabilitation Attendance.

Objective: To determine whether the number of cardiac rehabilitation (CR) sessions attended and selected clinical characteristics were predictive of patients who exhibited improvement in peak oxygen uptake (VO2peak) after CR. Patients and Methods: Using the Rochester Epidemiology Project records-linkage system, we identified all consecutive patients aged 18 years or older from Olmsted County, Minnesota, who underwent cardiopulmonary exercise testing before and after CR from 1999 to 2017. Regression models were created to assess the clinical predictors of VO2peak improvement (>0% baseline) after CR. Results: The analysis included 671 patients, of which 524 (78%) patients exhibited VO2peak improvement after CR. The significant univariate predictors of VO2peak improvement included younger age (odds ratio [OR], 0.98; 95% CI, 0.96-0.99), lower pre-CR VO2peak (OR, 0.96; 95% CI, 0.94-0.99), and no history of peripheral artery disease (OR, 0.50; 95% CI, 0.31-0.81) (all, P<.005). The significant independent predictors of VO2peak improvement from the multivariable analysis included the number of CR sessions (OR, 1.04; 95% CI, 1.02-1.05), younger age (OR, 0.96; 95% CI, 0.94-0.98), lower pre-CR VO2peak (OR, 0.92; 95% CI, 0.89-0.95), and no history of peripheral artery disease (OR, 0.47; 95% CI, 0.28-0.78) (all, P<.005). Conclusion: These findings highlight the importance of patient participation in CR sessions and individual clinical characteristics in influencing VO2peak improvement after CR in patients with cardiovascular disease.

Novel Virtual World-Based Cardiac Rehabilitation Program to Broaden Access to Underserved Populations: A Patient Perspective.

This report describes Destination Rehab, a novel virtual world-based cardiac rehabilitation program, which aims to increase cardiac rehabilitation access to underserved populations. We highlight the experience of a cardiac patient whose successful participation in the program allowed her to overcome significant psychosocial and access barriers to cardiac rehabilitation.

Cardiopulmonary exercise test in patients with obstructive hypertrophic cardiomyopathy.

OBJECTIVE: The study objective was to analyze performance on cardiopulmonary exercise testing and its prognostic value in patients with obstructive hypertrophic cardiomyopathy undergoing septal myectomy. METHODS: We reviewed patients with obstructive hypertrophic cardiomyopathy who had cardiopulmonary exercise testing before septal myectomy from 2005 to 2016. Causes of functional impairment and their impact on survival were analyzed. RESULTS: A total of 752 patients had cardiopulmonary exercise testing at a median of 16 days (interquartile range, 2-56) before myectomy. The median exercise time was 6.6 (5.3-8.0) minutes. Functional aerobic capacity was 64% (53%-75%) of predicted, and metabolic equivalent of task was 5.2 (4.1-6.4). The peak oxygen consumption was 18.0 (14.2-21.9) mL/kg/min, which was 60% (49%-72%) of the predicted value. The primary causes for low peak oxygen consumption were impaired cardiac output (73.7%), limited heart rate reserve (52.0%), and obesity (48.2%). Resting outflow tract gradient correlated poorly to peak oxygen consumption, but the use of beta-blockers was associated with reduced peak oxygen consumption. During a median (interquartile range) of 9.0 (6.8-11.7) years of follow-up, the estimated 5- and 10-year survivals were 97% and 91%, respectively. Greater adjusted peak oxygen consumption (hazard ratio, 0.98; P = .011) and abnormal pulse oxygen increase (hazard ratio, 0.44; P = .003) were independently associated with better long-term survival after myectomy. CONCLUSIONS: Among patients with hypertrophic cardiomyopathy undergoing septal myectomy, functional capacity is severely impaired despite receiving optimal medical treatment. We identified risk factors of reduced long-term survival from preoperative cardiopulmonary exercise testing that may aid risk stratification in patients undergoing septal myectomy.

Identification of Patients with Preclinical Heart Failure with preserved Ejection Fraction Using the H2FPEF Score.

Heart failure with preserved ejection fraction (HFpEF) is a common disorder with few effective treatments. There is currently no evidence-based method to identify preclinical HFpEF. The H2FPEF score is a validated instrument to identify patients with overt HFpEF. Here we show the H2FPEF score can identify individuals with preclinical HFpEF. Among individuals where heart failure was excluded (n=160), increasing H2FPEF score was shown to be associated with greater left atrial dilation, left ventricular hypertrophy, and more severe diastolic dysfunction. Patients with increasing H2FPEF score displayed higher pulmonary artery pressures, higher left heart filling pressures, lower cardiac index, and more severely impaired aerobic capacity during exercise. In summary, we show that among adults without heart failure, higher H2FPEF score is associated with subclinical abnormalities that resemble those observed in HFpEF. These findings broaden the external validity of the H2FPEF score and suggest that this instrument may help identify patients positioned to benefit from preventive interventions.

Age-Related Differences for Cardiorespiratory Fitness Improvement in Patients Undergoing Cardiac Rehabilitation.

Objective: We investigated age-related differences for peak oxygen uptake (peak VO2) improvement with exercise training during cardiac rehabilitation (CR). Patients and Methods: This was a retrospective cohort study of the Mayo Clinic Rochester CR program including adult patients who attended CR (≥1 session) for any eligible indication between 1999 and 2017 and who had a cardiopulmonary exercise test pre and post CR with VO2 data (peak respiratory exchange ratio ≥1.0). Younger (20-49 yrs), midlife (50-64 yrs), and older adults (≥65 yrs) were compared using ANOVA for delta and percent change in peak VO2; and percentage of peak VO2 responders (>0% change). Results: 708 patients (age: 60.8 ± 12.1 years; 24% female) met inclusion criteria. Delta and percent change in peak VO2 was lower for older adults (1.6 ± 3.2 mL.kg.min-1; 12 ± 27%) compared with younger (3.7 ± 4.0 mL.kg.min-1, p < 0.001; 23 ± 28%, p = 0.002) and midlife adults (2.8 ± 3.8 mL.kg.min-1, p < 0.001; 17 ± 28%, p = 0.04). For midlife, delta change, but not percent change in peak VO2 was significantly lower (p = 0.02) compared with younger. Percentage of responders was only different between older and younger (72 vs. 86%; p = 0.008). Sensitivity analyses in non-surgical patients showed similar differences for delta change, and differences in percent change remained significant between older and younger adults (10 ± 20% vs. 16 ± 18%; p = 0.04). Conclusions: In CR patients, older adults had lower improvement in cardiorespiratory fitness than younger and midlife adults. While excluding surgical patients reduced age-related differences, older adults still had lower cardiorespiratory fitness improvement during CR. These findings may have implications for individualizing CR programming in aging populations to reduce future cardiovascular risk.

Sex Differences in Cardiac Rehabilitation Outcomes.

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.

Influence of locomotor muscle group III/IV afferents on cardiovascular and ventilatory responses in human heart failure during submaximal exercise.

The purpose of this study is to determine the influence of locomotor muscle group III/IV afferent inhibition on central and peripheral hemodynamics at multiple levels of submaximal cycling exercise in patients with heart failure with reduced ejection fraction (HFrEF). Eleven patients with HFrEF and nine healthy matched controls were recruited. The participants performed a multiple stage [i.e., 30 W, 50%peak workload (WL), and a workload eliciting a respiratory exchange ratio (RER) of ∼1.0] exercise test with lumbar intrathecal fentanyl (FENT) or placebo (PLA). Cardiac output ([Formula: see text]tot) was measured via open-circuit acetylene wash-in technique and stroke volume was calculated. Leg blood flow ([Formula: see text]l) was measured via constant infusion thermodilution and leg vascular conductance (LVC) was calculated. Radial artery and femoral venous blood gases were measured. For HFrEF, stroke volume was higher at the 30 W (FENT: 110 ± 21 vs. PLA: 100 ± 18 mL), 50%peak WL (FENT: 113 ± 22 vs. PLA: 103 ± 23 mL), and RER = 1.0 (FENT: 119 ± 28 vs. PLA: 110 ± 26 mL) stages, whereas heart rate and systemic vascular resistance were lower with fentanyl than with placebo (all, P < 0.05). [Formula: see text]tot in HFrEF and [Formula: see text]tot, stroke volume, and heart rate in controls were not different between fentanyl and placebo (all, P > 0.19). During submaximal exercise, controls and patients with HFrEF exhibited increased leg vascular conductance (LVC) with fentanyl compared with placebo (all, P < 0.04), whereas no differences were present in [Formula: see text]l or O2 delivery with fentanyl (all, P > 0.20). Taken together, these findings provide support for locomotor muscle group III/IV afferents playing a role in integrative control mechanisms during submaximal cycling exercise in patients with HFrEF and older controls.NEW & NOTEWORTHY 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.