Exercise Intolerance In Patients Research Articles

The Role of Cardiopulmonary Exercise Testing in Assessment of Patients with Interstitial Lung Disease

Abstract Background Cardiopulmonary exercise testing (CPET) is considered as the gold standard for evaluating the causes of exercise intolerance in patients with pulmonary and cardiac disease, and is based on the principle that system failure typically occurs while the system (e.g muscle-energetic, cardiovascular or pulmonary) is under stress. Objective To evaluate the role of cardiopulmonary exercise test in assessment of patients with interstitial lung disease. Patients and Methods This is observational study included 30 consecutive examined with the diagnosis of ILDs in Kobry El Kopa military hospital. The study was carried out over the period from February 2016 to August 2019. All patients with dyspnea to be investigated and ILDs diagnosed and assessed in rehabilitation department who undergo cardio pulmonary exercise test. Results Reduction on the compliance of the lung and/ or chest wall cause change in lung volumes and tachypnea during exercise. Also agreed with harris EzeAo Who showed that alterations on breathing pattern such as lower Vt, increased respiratory effort, rapid shallow breathing were reported in individual with interstitial lung diseases. Conclusion The pathophysiology of ILD has a negative impact on the ventilatory, cardiovascular, and skeletal muscle responses to exercise, thereby leading to exertional dyspnea and reduced exercise capacity. CPET is an excellent tool for assessing the severity of exertional dyspnea and mechanisms of exercise limitation in patients with various forms of cardiorespiratory disease; however, its application in ILD has remained limited. A growing body of evidence supports the use of CPET in patients with ILD. CPET is currently used to assess functional capacity, to inform exercise prescription, and to evaluate the effects of various interventions. Recent findings highlight that, in addition to its current uses, CPET-derived measures may help improve the management of patients with ILD. Despite these recent advances, additional research is required in order to confirm the utility of CPET in this population.

#1767 Effect of heart failure and atrial fibrillation on cardiorespiratory fitness in hemodialysis patients

Abstract Background and Aims Heart failure (HF) and atrial fibrillation (AF) are highly prevalent in hemodialysis. They are well-known significant modifiers of the disease associations with cardiovascular outcomes, but there is a lack of evidence regarding the effects of HF and AF on cardiorespiratory fitness. This study is the first to examine the possible association of the presence of HF and AF with exercise intolerance in patients undergoing hemodialysis. Method This analysis included 40 sex- and age-matched participants [10 hemodialysis patients with HF or AF, 10 hemodialysis patients without HF or AF, 10 patients with HF or AF without chronic kidney disease (CKD) and 10 healthy controls) that underwent CPET and spirometry examinations. Results VO2peak (ml/min/kg) showed a graded increase between hemodialysis patients with HF or AF, hemodialysis patients without HF or AF, non-CKD patients with HF or AF and controls (13.17 ± 2.45 vs 15.26 ± 3.29 vs 19.64 ± 5.84 vs 25.11 ± 6.94 ml/min/kg, p < 0.001); VO2peak (ml/min) followed the same pattern (1172 ± 197 vs 1269 ± 314 vs 1817 ± 583 vs 1952 ± 592 ml/min respectively, p = 0.001). VO2peak (%predicted), VO2AT (ml/kg/min), VO2AT (ml/min) and maximal work load significantly differ between the study groups, with a tendency for higher values from hemodialysis patients to non-CKD patients with HF or AF and to healthy controls. FEV1 and FVC levels were similar between the study groups. In the whole population, VO2peak (ml/kg/min) showed a positive correlation with hemoglobin (r = 0.663, p < 0.001) and negative correlations with high-sensitivity cardiac troponin I (r = −0.493, p = 0.001) and BNP (r = −0.479, p = 0.002). Conclusion Hemodialysis patients have low exercise tolerance, and the presence of HF or AF is associated with further decreased values of VO2peak, the most important determinant of cardiorespiratory fitness.

Identification of three mechanistic pathways for iron-deficient heart failure.

Current understanding of iron-deficient heart failure is based on blood tests that are thought to reflect systemic iron stores, but the available evidence suggests greater complexity. The entry and egress of circulating iron is controlled by erythroblasts, which (in severe iron deficiency) will sacrifice erythropoiesis to supply iron to other organs, e.g. the heart. Marked hypoferraemia (typically with anaemia) can drive the depletion of cardiomyocyte iron, impairing contractile performance and explaining why a transferrin saturation < ≈15%-16% predicts the ability of intravenous iron to reduce the risk of major heart failure events in long-term trials (Type 1 iron-deficient heart failure). However, heart failure may be accompanied by intracellular iron depletion within skeletal muscle and cardiomyocytes, which is disproportionate to the findings of systemic iron biomarkers. Inflammation- and deconditioning-mediated skeletal muscle dysfunction-a primary cause of dyspnoea and exercise intolerance in patients with heart failure-is accompanied by intracellular skeletal myocyte iron depletion, which can be exacerbated by even mild hypoferraemia, explaining why symptoms and functional capacity improve following intravenous iron, regardless of baseline haemoglobin or changes in haemoglobin (Type 2 iron-deficient heart failure). Additionally, patients with advanced heart failure show myocardial iron depletion due to both diminished entry into and enhanced egress of iron from the myocardium; the changes in iron proteins in the cardiomyocytes of these patients are opposite to those expected from systemic iron deficiency. Nevertheless, iron supplementation can prevent ventricular remodelling and cardiomyopathy produced by experimental injury in the absence of systemic iron deficiency (Type 3 iron-deficient heart failure). These observations, taken collectively, support the possibility of three different mechanistic pathways for the development of iron-deficient heart failure: one that is driven through systemic iron depletion and impaired erythropoiesis and two that are characterized by disproportionate depletion of intracellular iron in skeletal and cardiac muscle. These mechanisms are not mutually exclusive, and all pathways may be operative at the same time or may occur sequentially in the same patients.

Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition

Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration. To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC. In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited. After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise. The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC. Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: -6.8 mL/kg/min; 95% CI, -10.7 to -2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: -37 Nm; 95% CI, -67 to -7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, -26.5 minutes/d; 95% CI, -42.0 to -11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing. In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC. ClinicalTrials.gov Identifier: NCT05445830.

Unraveling the Mechanisms Behind Exercise Intolerance and Recovery in Long COVID

BackgroundPatients suffering from long COVID may exhibit autonomic dysregulation. However, the association between autonomic dysregulation and exercise intolerance and the impact of therapeutic interventions on its modulation remains unclear. This study investigated the relationship between heart rate recovery at the first minute (HRR1), a proxy for autonomic imbalance, and exercise intolerance in patients with long COVID. Additionally, the study aimed to assess the effects of a 12-week home-based inspiratory muscle training program on autonomic modulation in this patient population. MethodsThis study is a post hoc subanalysis of a randomized trial in which 26 patients with long COVID were randomly assigned to receive either a 12-week inspiratory muscle training program or usual care alone (NCT05279430). The data were analyzed using Pearson's correlation and linear mixed regression analysis. ResultsThe mean age was 50.4 ± 12.2 years, and 11 (42.3%) were women. Baseline HRR1 was significantly correlated with maximal functional capacity (peakVO2) (r = 0.402, P = .041). Patients with lower baseline HRR1 (≤22 bpm) exhibited higher resting heart rates and lower peakVO2. Inspiratory muscle training led to a more substantial increase in peakVO2 in patients with lower HRR1 at baseline (P = .019). Additionally, a significant improvement in HRR1 was observed in the IMT group compared to the usual care group after 12-week (Δ +9.39, 95% CI = 2.4-16.4, P = .010). ConclusionLower baseline HRR1 is associated with exercise intolerance in long COVID patients and may serve as a valuable criterion for identifying individuals likely to benefit more from a home-based inspiratory muscle training program.

Abstract 13795: Reduced Fetuin-A Levels Are Associated With Exercise Intolerance in Patients With Heart Failure and Predict the Risk of Adverse Outcomes

Background: Impaired exercise tolerance is a feature of heart failure (HF) and predicts adverse outcomes in patients with HF. Hepatokines are proteins synthesized and secreted by the liver, which regulate systemic metabolisms of peripheral tissues. However, the clinical impact of hepatokines on exercise capacity has not been well understood. Aims: Our objective was to investigate the relevance of a hepatokine, Fetuin-A, in relation to exercise capacity in HF. Methods and Results: We conducted a prospective study involving 120 consecutive hospitalized patients (mean 57.3 years old, 75.0% male) with HF who underwent cardiopulmonary exercise testing. The serum concentration of Fetuin-A was measured by an enzyme-linked immunosorbent assay. Patients with impaired exercise tolerance (peak oxygen uptake (VO 2 ) &lt; 14.0 mL/kg/m) exhibited lower Fetuin-A levels than those without ( Figure A ). Correlation analysis revealed that Fetuin-A was positively correlated with peak VO 2 and negatively correlated with minute ventilation to carbon dioxide production ratio and its slope. We then followed up patients and found 12 composites of cardiac events that included 5 cardiac death and 7 worsening HF. Based on classification and regression tree to determine the cut-off of Fetuin-A, Kaplan-Meier analysis revealed that patients with lower Fetuin-A levels (&lt; 22.2 ng/mL) and impaired exercise tolerance had the highest risk of cardiac events ( Figure B ). In a multivariable Cox proportional hazard model, the presence of both lower Fetuin-A and exercise intolerance was independently associated with an increased risk of cardiac events (hazard ratio, 18.8; P = 0.009). Conclusions: Reduced Fetuin-A levels were associated with exercise intolerance in patients with HF, and those with decreased levels of both Fetuin-A and peak VO 2 were at the highest risk of adverse outcomes.

Consequences of group III/IV afferent feedback and respiratory muscle work on exercise tolerance in heart failure with reduced ejection fraction.

Exercise intolerance and exertional dyspnoea are the cardinal symptoms of heart failure with reduced ejection fraction (HFrEF). In HFrEF, abnormal autonomic and cardiopulmonary responses arising from locomotor muscle group III/IV afferent feedback is one of the primary mechanisms contributing to exercise intolerance. HFrEF patients also have pulmonary system and respiratory muscle abnormalities that impair exercise tolerance. Thus, the primary impetus for this review was to describe the mechanistic consequences of locomotor muscle group III/IV afferent feedback and respiratory muscle work in HFrEF. To address this, we first discuss the abnormal autonomic and cardiopulmonary responses mediated by locomotor muscle afferent feedback in HFrEF. Next, we outline how respiratory muscle work impairs exercise tolerance in HFrEF through its effects on locomotor muscle O2 delivery. We then discuss the direct and indirect evidence supporting an interaction between locomotor muscle group III/IV afferent feedback and respiratory muscle work during exercise in HFrEF. Last, we outline future research directions related to locomotor and respiratory muscle abnormalities to progress the field forward in understanding the pathophysiology of exercise intolerance in HFrEF. NEW FINDINGS: What is the topic of this review? This review is focused on understanding the role that locomotor muscle group III/IV afferent feedback and respiratory muscle work play in the pathophysiology of exercise intolerance in patients with heart failure. What advances does it highlight? This review proposes that the concomitant effects of locomotor muscle afferent feedback and respiratory muscle work worsen exercise tolerance and exacerbate exertional dyspnoea in patients with heart failure.

A Review Article on Exercise Intolerance in Long COVID: Unmasking the Causes and Optimizing Treatment Strategies.

There is a growing body of research on SARS-CoV-2 (PASC), previously known as the post-COVID syndrome, a chronic condition characterized by symptoms that persist after SARS-CoV-2 infection. Among these symptoms, feelings of physical exhaustion and prolonged fatigue are particularly prevalent and can significantly impact patients' quality of life. These symptoms are associated with reduced overall physical capacity, decreased daily physical activity, malaise after intense training, and intolerance to physical activity (IFA). IFA, described as a reduced ability to perform physical activities typical for the patient's age, can often lead to a sedentary lifestyle. Prolonged physical inactivity can cause deterioration in the overall physical condition and disrupt mitochondrial function, triggering a vicious cycle of gradual symptom worsening. The underlying causes of PASC remain unclear; however, several biochemical mechanisms have been discussed to explain the body's energy depletion, and a multidisciplinary approach that combines physical and cognitive rehabilitation and lifestyle interventions such as exercise and diet modifications has been suggested to improve the overall health and well-being of PASC patients. This critical review aims to review the existing research on the possible causes and links among chronic fatigue, reduced physical activity, and exercise intolerance in patients with PASC. Further research into the underlying causes and treatment of PASC and the importance of developing individualized treatment is needed to address each patient's unique health requirements.

Neural control of the circulation during exercise in heart failure with reduced and preserved ejection fraction.

Patients with heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) exhibit severe exercise intolerance that may be due, in part, to inappropriate cardiovascular and hemodynamic adjustments to exercise. Several neural mechanisms and locally released vasoactive substances work in concert through complex interactions to ensure proper adjustments to meet the metabolic demands of the contracting skeletal muscle. Specifically, accumulating evidence suggests that disease-related alterations in neural mechanisms (e.g., central command, exercise pressor reflex, arterial baroreflex, and cardiopulmonary baroreflex) contribute to heightened sympathetic activation and impaired ability to attenuate sympathetic vasoconstrictor responsiveness that may contribute to reduced skeletal muscle blood flow and severe exercise intolerance in patients with HFrEF. In contrast, little is known regarding these important aspects of physiology in patients with HFpEF, though emerging data reveal heightened sympathetic activation and attenuated skeletal muscle blood flow during exercise in this patient population that may be attributable to dysregulated neural control of the circulation. The overall goal of this review is to provide a brief overview of the current understanding of disease-related alterations in the integrative neural cardiovascular responses to exercise in both HFrEF and HFpEF phenotypes, with a focus on sympathetic nervous system regulation during exercise.

Structural and functional impairments of skeletal muscle in patients with postacute sequelae of SARS-CoV-2 infection.

Following acute coronavirus disease 2019 (COVID-19), a substantial proportion of patients showed symptoms and sequelae for several months, namely the postacute sequelae of COVID-19 (PASC) syndrome. Major phenomena are exercise intolerance, muscle weakness, and fatigue. We aimed to investigate the physiopathology of exercise intolerance in patients with PASC syndrome by structural and functional analyses of skeletal muscle. At least 3 mo after infection, nonhospitalized patients with PASC (n = 11, age: 54 ± 11 yr; PASC) and patients without long-term symptoms (n = 12, age: 49 ± 9 yr; CTRL) visited the laboratory on four nonconsecutive days. Spirometry, lung diffusion capacity, and quality of life were assessed at rest. A cardiopulmonary incremental exercise test was performed. Oxygen consumption (V̇o2) kinetics were determined by moderate-intensity exercises. Muscle oxidative capacity (k) was assessed by near-infrared spectroscopy. Histochemical analysis, O2 flux (JO2) by high-resolution respirometry, and quantification of key molecular markers of mitochondrial biogenesis and dynamics were performed in vastus lateralis biopsies. Pulmonary and cardiac functions were within normal range in all patients. V̇o2peak was lower in PASC than CTRL (24.7 ± 5.0 vs. 32.9 ± 7.4 mL·min-1·kg-1, respectively, P < 0.05). V̇o2 kinetics was slower in PASC than CTRL (41 ± 12 vs. 30 ± 9 s-1, P < 0.05). k was lower in PASC than CTRL (1.54 ± 0.49 vs. 2.07 ± 0.51 min-1, P < 0.05). Citrate synthase, peroxisome proliferator-activated receptor-γ coactivator (PGC)1α, and JO2 for mitochondrial complex II were significantly lower in PASC vs. CTRL (all P values <0.05). In our cohort of patients with PASC, we showed limited exercise tolerance mainly due to "peripheral" determinants. Substantial reductions were observed for biomarkers of mitochondrial function, content, and biogenesis. PASC syndrome, therefore, appears to negatively impact skeletal muscle function, although the disease is a heterogeneous condition.NEW & NOTEWORTHY Several months after mild acute SARS-CoV-2 infection, a substantial proportion of patients present persisting, and often debilitating, symptoms and sequelae. These patients show reduced quality of life due to exercise intolerance, muscle weakness, and fatigue. The present study supports the hypothesis that "peripheral" impairments at skeletal muscle level, namely, reduced mitochondrial function and markers of mitochondrial biogenesis, are major determinants of exercise intolerance and fatigue, "central" phenomena at respiratory, and cardiac level being less relevant.

Post-exercise left atrial conduit strain predicted hemodynamic change in heart failure with preserved ejection fraction.

Left ventricle function directly impacts left atrial (LA) conduit function, and LA conduit strain is associated with exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Pulmonary capillary wedge pressure (PCWP) before and during exercise is the current gold standard for diagnosing HFpEF. Post-exercise ΔPCWP can lead to worse long-term outcomes. This study examined the correlation between LA strain and post-exercise ΔPCWP in patients with HFpEF. We enrolled 100 subjects, including 74 with HFpEF and 26 with non-cardiac dyspnea, from November 2017 to December 2020. Subjects underwent echocardiography, invasive cardiac catheterization, and expired gas analysis at rest and during exercise. Arterial blood pressure, right atrial pressure, pulmonary artery pressure, and PCWP were recorded during cardiac catheterization. Cardiac output, stroke volume, pulmonary vascular resistance, pulmonary artery compliance, systemic vascular resistance, and LV stroke work were calculated using standard formulas. Exercise LA conduit strain significantly correlated with both post-exercise ΔPCWP (r = - 0.707, p < 0.001) and exercise PCWP (r = - 0.659; p < 0.001). Exercise LA conduit strain differentiated patients who did and did not meet the 2016 European Society of Cardiology HFpEF criteria with an area under the curve of 0.69 (95% confidence interval, 0.548-0.831) using a cutoff value of 14.25, with a sensitivity of 0.64 and a specificity of 0.68. Exercise LA conduit strain significantly correlates with post-exercise ΔPCWP and has a comparable power to identify patients with HFpEF. Additional studies are warranted to confirm the ability of LA conduit strain to predict long-term outcomes among patients with HFpEF. Exercise left atrial conduit strain was highly associated with the difference of post-exercise pulmonary capillary wedge pressure and may indicate increased mortality risk in patients with heart failure with preserved ejection fraction, and also has comparable diagnostic ability. • Left atrial conduit strain is associated with exercise intolerance in patients with heart failure with preserved ejection fraction. • Left atrial conduit strain during exercise can identify patients with heart failure with preserved ejection fraction. • Exercise left atrial conduit strain significantly correlates with the difference of pulmonary capillary wedge pressure during and before exercise which might predict the long-term outcomes of heart failure with preserved ejection fraction patients.

Systemic Determinants of Exercise Intolerance in Patients With Fibrotic Interstitial Lung Disease and Severely Impaired DLCO.

The precise mechanisms driving poor exercise tolerance in patients with fibrotic interstitial lung diseases (fibrotic ILDs) showing a severe impairment in single-breath lung diffusing capacity for carbon monoxide (DLCO < 40% predicted) are not fully understood. Rather than only reflecting impaired O2 transfer, a severely impaired DLCO may signal deranged integrative physiologic adjustments to exercise that jointly increase the burden of exertional symptoms in fibrotic ILD. Sixty-seven subjects (46 with idiopathic pulmonary fibrosis, 24 showing DLCO < 40%) and 22 controls underwent pulmonary function tests and an incremental cardiopulmonary exercise test with serial measurements of operating lung volumes and 0-10 Borg dyspnea and leg discomfort scores. Subjects from the DLCO < 40% group showed lower spirometric values, more severe restriction, and lower alveolar volume and transfer coefficient compared to controls and participants with less impaired DLCO (P < .05). Peak work rate was ∼45% (vs controls) and ∼20% (vs DLCO > 40%) lower in the former group, being associated with lower (and flatter) O2 pulse, an earlier lactate (anaerobic) threshold, heightened submaximal ventilation, and lower SpO2 . Moreover, critically high inspiratory constrains were reached at lower exercise intensities in the DLCO < 40% group (P < .05). In association with the greatest leg discomfort scores, they reported the highest dyspnea scores at a given work rate. Between-group differences lessened or disappeared when dyspnea intensity was related to indexes of increased demand-capacity imbalance, that is, decreasing submaximal, dynamic ventilatory reserve, and inspiratory reserve volume/total lung capacity (P > .05). A severely reduced DLCO in fibrotic ILD signals multiple interconnected derangements (cardiovascular impairment, an early shift to anaerobic metabolism, excess ventilation, inspiratory constraints, and hypoxemia) that ultimately lead to limiting respiratory (dyspnea) and peripheral (leg discomfort) symptoms. DLCO < 40%, therefore, might help in clinical decision-making to indicate the patient with fibrotic ILD who might derive particular benefit from pharmacologic and non-pharmacologic interventions aimed at lessening these systemic abnormalities.

Mechanisms and Severity of Exercise Intolerance Following COVID-19 and Similar Viral Infections: A Comparative Review.

Approximately 19% of the population is suffering from "Long COVID", also known as post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), which often results in exercise intolerance. As COVID infections continue to be common, studying the long-term consequences of coronavirus disease (COVID) on physical function has become increasingly important. This narrative review will aim to summarize the current literature surrounding exercise intolerance following COVID infection in terms of mechanism, current management approaches, and comparison with similar conditionsand will aim to define limitations in the current literature. Multiple organ systems have been implicated in the onset of long-lasting exercise intolerance post-COVID, including cardiac impairment, endothelial dysfunction, decreased VO2 max and oxygen extraction, deconditioning due to bed rest, and fatigue. Treatment modalities for severe COVID have also been shown to cause myopathy and/or worsen deconditioning. Besides COVID-specific pathophysiology, general febrile illness as commonly experienced during infection will cause hypermetabolic muscle catabolism, impaired cooling, and dehydration, which acutely cause exercise intolerance. The mechanisms of exercise intolerance seen with PASC also appear similar to post-infectious fatigue syndrome and infectious mononucleosis. However, the severity and duration of the exercise intolerance seen with PASC is greater than that of any of the isolated mechanisms described above and thus is likely a combination of the proposed mechanisms. Physicians should consider post-infectious fatigue syndrome (PIFS), especially if fatigue persists after six months following COVID recovery. It is important for physicians, patients, and social systems to anticipate exercise intolerance lasting for weeks to months in patients with long COVID. These findings underscore the importance of long-term management of patients with COVID and the need for ongoing research to identify effective treatments for exercise intolerance in this population. By recognizing and addressing exercise intolerance in patients with long COVID, clinicians can provide proper supportive interventions, such as exercise programs, physical therapy, and mental health counseling, to improve patient outcomes.

Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction

The pathophysiology of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains incompletely understood. Multiple lines of evidence suggest that abnormal skeletal muscle metabolism is a key contributor, but the mechanisms underlying metabolic dysfunction remain unresolved. To evaluate the associations of skeletal muscle mitochondrial function using respirometric analysis of biopsied muscle fiber bundles from patients with HFpEF with exercise performance. In this cross-sectional study, muscle fiber bundles prepared from fresh vastus lateralis biopsies were analyzed by high-resolution respirometry to provide detailed analyses of mitochondrial oxidative phosphorylation, including maximal capacity and the individual contributions of complex I-linked and complex II-linked respiration. These bioenergetic data were compared between patients with stable chronic HFpEF older than 60 years and age-matched healthy control (HC) participants and analyzed for intergroup differences and associations with exercise performance. All participants were treated at a university referral center, were clinically stable, and were not undergoing regular exercise or diet programs. Data were collected from March 2016 to December 2017, and data were analyzed from November 2020 to May 2021. Skeletal muscle mitochondrial function, including maximal capacity and respiration linked to complex I and complex II. Exercise performance was assessed by peak exercise oxygen consumption, 6-minute walk distance, and the Short Physical Performance Battery. Of 72 included patients, 50 (69%) were women, and the mean (SD) age was 69.6 (6.1) years. Skeletal muscle mitochondrial function measures were all markedly lower in skeletal muscle fibers obtained from patients with HFpEF compared with HCs, even when adjusting for age, sex, and body mass index. Maximal capacity was strongly and significantly correlated with peak exercise oxygen consumption (R = 0.69; P < .001), 6-minute walk distance (R = 0.70; P < .001), and Short Physical Performance Battery score (R = 0.46; P < .001). In this study, patients with HFpEF had marked abnormalities in skeletal muscle mitochondrial function. Severely reduced maximal capacity and complex I-linked and complex II-linked respiration were associated with exercise intolerance and represent promising therapeutic targets.

Diagnostic Accuracy of Global Longitudinal Strain for Detecting Exercise Intolerance in Patients with Ischemic Heart Disease.

Global longitudinal strain (GLS) is a sensitive and reproducible predictive factor in patients with ischemic heart disease (IHD), although its correlation with exercise tolerance is unknown. We aimed to identify the correlation between global longitudinal strain (GLS) and cardiopulmonary exercise testing (CPX) parameters and assess the prognostic implications and accuracy of GLS in predicting exercise intolerance in populations with ischemic heart disease (IHD) using CPET criteria. Prospectively, 108 patients with IHD underwent CPX and 2D speckle-tracking echocardiography. Correlation between GLS and multiple CPX variables was assessed using Spearman's correlation analysis and univariate regression analysis. A receiver operating characteristic (ROC) curve analysis was performed on GLS to detect exercise intolerance. GLS was correlated with peak oxygen uptake (peak VO2; r = -0.438, p = 0.000), %PPeak VO2 (-0.369, p = 0.000), peak metabolic equivalents (METs@peak; r = -0.438, p &lt; 0.01), and the minute ventilation-carbon dioxide production (VE/VCO2) slope (r = 0.257, p &lt; 0.01). Weak-to-moderate correlations were also identified for the respiratory exchange rate at the anaerobic threshold (RER@AT), end-tidal carbon dioxide at the anaerobic threshold (PETCO2@AT), oxygen consumption at the anaerobic threshold (VO2@AT), carbon dioxide production at the anaerobic threshold (VCO2@AT), and metabolic equivalents at the anaerobic threshold (METs@AT; p &lt; 0.01). On multivariate analysis, the results showed that age, the BMI, and GLS are independent predictors for reduced exercise capacity in patients with IHD (p &lt; 0.01). The area under the ROC curve value of GLS for identifying patients with a peak VO2 of &lt;14 mL/kg/min was 0.73 (p = 0.000). As a sensitive echocardiographic assessment of patients with ischemic heart disease, global longitudinal strain is an independent predictor of reduced exercise capacity and has a sensitivity of 74.2% and a specificity of 66.7% to detect exercise intolerance.

Impact of small-airway disease on exercise intolerance and long-term outcomes in patients with heart failure and reduced or preserved ejection fraction

Abstract Introduction Exercise intolerance in patients with heart failure (HF) is a strong indicator of a poor prognosis. As the respiratory impairment in HF patients, the small airway is reportedly more susceptible than central airways, which results in increased airway resistance and may cause poor outcomes. However, the impact of small-airway disease (SAD) on exercise intolerance and prognosis in patients with HF is still unclear. Purpose We investigated the associations between SAD and exercise intolerance in patients with HF, and the clinical significance of SAD for long-term clinical events with a reduced or preserved ejection fraction. Methods We reviewed 1015 patients with HF (mean age, 66.9±14.6 years; male, 64.5%) admitted for medical treatment. Patients with a prior history of chronic respiratory disease or an obstructive lung pattern – defined as the forced expiratory volume (%) in 1 s relative to &amp;lt;70% forced vital capacity using spirometry – were excluded. Characteristics including HF aetiology, comorbidities conditions, medications, blood parameters, and echocardiographic variables were obtained from clinical records. All patients underwent spirometry at hospital discharge, and SAD was defined as the maximum mid-expiratory flow (%) relative to a &amp;lt;60% predicted value. At hospital discharge, we measured 6-min walk distance (6MWD), and &amp;lt;300 m was considered as exercise intolerance. The primary endpoint was a composite clinical event of all-cause death and/or unplanned readmission for HF. Multivariate logistic regression analysis was used to assess the association between SAD and exercise intolerance. The multivariate Cox proportional hazard model was used to clarify whether SAD was an independent predictor for the incidence of clinical events. We also performed subgroup analyses in each multivariate analysis based on a left ventricular ejection fraction (LVEF) of 40%. Result SAD was observed in 479 (47.2%) patients. LVEF subgroups included 458 (45.1%) and 518 (51.0%) patients with LVEF &amp;lt;40% and ≥40%, respectively. After adjusting for clinical characteristics, SAD was independently associated with 6MWD &amp;lt;300 m (Figure 1). Moreover, this association was consistently observed in the LVEF &amp;lt;40% and ≥40% (Figure 1). During the median follow-up period of 1.5 years, all-cause death/readmission occurred in 431 patients (42.5%), and the incidence rate was 17.5/100 person-years. In the multivariate Cox proportional hazard model, SAD was independently associated with lower event-free survival rates in all patients and the LVEF &amp;lt;40% subgroup, but not LVEF ≥40% subgroup (Figure 2A, B, and C, respectively). Conclusion This study is the first to reveal that SAD is associated with exercise intolerance in patients with HF regardless of LVEF. Moreover, SAD may have a predictive significance for long-term outcomes in patients with HF and subgroups with reduced, but not preserved ejection fraction. Funding Acknowledgement Type of funding sources: None.

Heart Failure with Preserved Ejection Fraction: Pathogenesis, Diagnosis, Exercise, and Medical Therapies.

Heart failure with preserved ejection fraction (HFpEF) accounts for more than one-half of total heart failure cases, with a high prevalence and poor prognosis, especially in older and female patients. Patients with HFpEF are characterized by hypertension, left ventricular hypertrophy, and diastolic dysfunction, and the main symptoms are dyspnea and exercise intolerance. HFpEF is currently poorly studied, and pharmacological treatment for HFpEF is still underexplored. Accumulating clinical trials have shown that exercise could exert benefits on diastolic dysfunction and quality of life in patients with HFpEF. However, there is a high limitation for applying exercise therapy due to exercise intolerance in patients with HFpEF. Key effectors of exercise-protection could be novel therapeutic targets for developing drugs to prevent and treat HFpEF. In this review article, we provide an overview of the pathogenic factors, diagnostic methods, research animal models, the mechanisms of exercise-mediated cardiac protection, and current treatments for HFpEF.

Reflex Sympathetic Vasoconstriction And Functional Sympatholysis In Patients With Heart Failure With Preserved Ejection Fraction.

INTRODUCTION: Vascular impairments resulting in blood flow limitations to exercising muscle likely contribute to marked exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Blood flow to exercising muscle is modulated by the interaction of sympathetic nervous system (SNS)-mediated vasoconstriction and factors related to muscle contraction that counteract this vasoconstriction, so-called “functional sympatholysis”. While there is emerging evidence for SNS overactivity during exercise in patients with HFpEF, functional sympatholysis has not been assessed in this patient group. PURPOSE: To determine the effect of SNS-mediated vasoconstriction on exercising muscle blood flow and the efficacy of functional sympatholysis in HFpEF vs. age-matched control (CON) subjects. METHODS: 4 CON (2 male, 70 ± 2 yrs) and 5 Class II/III patients with HFpEF (2 male, 70 ± 4 yrs) participated in this study. Forearm blood flow (FBF, ultrasound Doppler), mean arterial blood pressure (MAP, Finometer), and forearm vascular conductance (FVC) were evaluated at rest and during rhythmic handgrip exercise (30% maximum voluntary contraction, 3-min bout, 1 Hz) before and after SNS activation evoked by lower body negative pressure (LBNP -20 mmHg). Hemodynamic changes (%Δ) in response to LBNP at rest and during exercise were compared between groups, and the magnitude of functional sympatholysis was calculated as the difference between LBNP-induced %Δ FVC from rest to exercise. RESULTS: At rest, %Δ FBF in response to LBNP was similar between CON vs. HFpEF (-24 ± 4% vs. 17 ± 5%), while %Δ FVC was significantly greater in CON vs. HFpEF (-23 ± 4% vs. -10 ± 3%, P < 0.05). During exercise, LBNP reduced FBF (-1 ± 2% vs. -6 ± 3%) and FVC (-1 ± 3% vs. -6 ± 3%) to a similar degree between groups. However, the magnitude of sympatholysis was significantly greater in CON vs. HFpEF (-23 ± 4% vs. -3 ± 4%, P < 0.05). LBNP-induced changes in MAP were not different between CON vs. HFpEF at rest (-1 ± 2% vs. -3 ± 1%) or during exercise (0 ± 2% vs. 1 ± 2%). CONCLUSION: These data suggest impaired functional sympatholysis in HFpEF, indicating that SNS-mediated vasoconstriction may contribute to blood flow limitations underpinning exercise intolerance in HFpEF

Locomotor Muscle Afferent Inhibition Augments Activation Of Locomotor Muscles In Heart Failure Patients During Exercise

Exercise intolerance is a hallmark feature of heart failure with reduced ejection fraction (HFrEF). Locomotor muscle afferent feedback contributes to exercise intolerance in patients with HFrEF. Locomotor muscle afferent inhibition via intrathecal fentanyl, compared to the sham condition (SHAM), results in increased peak workload, cardiac output, and leg oxygen delivery during maximal exercise. To date, the impact of locomotor muscle afferent feedback inhibition on locomotor muscle activation responses during exercise in patients with HFrEF have not been investigated. PURPOSE: To determine the effect of intrathecal fentanyl on vastus lateralis (VL) muscle activation during incremental exercise in patients with HFrEF. METHODS: Patients with HFrEF (n = 7, EF: 35 ± 13%, age: 60 ± 9 yrs, BMI 28.7 ± 5.5 kg/m2) performed an incremental cycle test to task failure with lumbar intrathecal fentanyl (FENT) or SHAM (in randomized order). Electromyography (EMG) of the VL was measured and the root-mean square (RMS) of 10 contractions were averaged at 30 W, 50 W, 70 W, and peak workload. Changes in RMS were normalized as a percent of the SHAM response (unloaded = 0%; peak workload = 100%). RESULTS: Peak workload was significantly greater with FENT compared to SHAM (129 ± 30 vs. 114 ± 31 W, p = 0.04). VL RMS was not different at 30 W between FENT and SHAM (FENT: 44 ± 22 vs. SHAM: 17 ± 33%, p = 0.06). However, VL RMS was greater with FENT compared to SHAM at 50 W (FENT: 82 ± 61 vs. SHAM: 31 ± 24%), 70 W (FENT: 96 ± 56 vs. SHAM: 45 ± 29%), and peak workload (FENT: 167 ± 55 vs. SHAM: 92 ± 10%) (all, p < 0.04). There was no significant relationship between the change in peak workload and VL RMS with FENT with both normalized as a percent of the SHAM response (p = 0.09). CONCLUSION: These data suggest that locomotor muscle afferent feedback may contribute to exercise intolerance via inhibition of locomotor muscle activation during exercise in patients with HFrEF.

Inhibition of peripheral chemoreceptors improves ventilatory efficiency during exercise in heart failure with preserved ejection fraction − a role of tonic activity and acute reflex response

Peripheral chemoreceptors (PChRs) play a significant role in maintaining adequate oxygenation in the bloodstream. PChRs functionality comprises two components: tonic activity (PChT) which regulates ventilation during normoxia and acute reflex response (peripheral chemosensitivity, PChS), which increases ventilation following a specific stimulus. There is a clear link between augmented PChS and exercise intolerance in patients with heart failure with reduced ejection fraction. It has been also shown that inhibition of PChRs leads to the improvement in exercise capacity. However, it has not been established yet: 1) whether similar mechanisms take part in heart failure with preserved ejection fraction (HFpEF) and 2) which component of PChRs functionality (PChT vs. PChS) is responsible for the benefit seen after the acute experimental blockade. To answer those questions we enrolled 12 stable patients with HFpEF. All participants underwent an assessment of PChT (attenuation of minute ventilation in response to low-dose dopamine infusion), PChS (enhancement of minute ventilation in response to hypoxia) and a symptom-limited cardiopulmonary exercise test on cycle ergometer. All tests were placebo-controlled, double-blinded and performed in a randomized order. Under resting conditions and at normoxia dopamine attenuated minute ventilation and systemic vascular resistance (p = 0.03 for both). These changes were not seen with placebo. Dopamine also decreased ventilatory and mean arterial pressure responses to hypoxia (p < 0.05 for both). Inhibition of PChRs led to a decrease in V˙E/V˙CO2 comparing to placebo (36 ± 3.6 vs. 34.3 ± 3.7, p = 0.04), with no effect on peak oxygen consumption. We found a significant relationship between PChT and the relative decrement of V˙E/V˙CO2 on dopamine comparing to placebo (R = 0.76, p = 0.005). There was a trend for correlation between PChS (on placebo) and V˙E/V˙CO2 during placebo infusion (R = 0.56, p = 0.059), but the relative improvement in V˙E/V˙CO2 was not related to the change in PChS (dopamine vs. placebo). We did not find a significant relationship between PChT and PChS. In conclusion, inhibition of PChRs in HFpEF population improves ventilatory efficiency during exercise. Increased PChS is associated with worse (higher) V˙E/V˙CO2, whereas PChT predicts an improvement in V˙E/V˙CO2 after PChRs inhibition. This results may be meaningful for patient selection in further clinical trials involving PChRs modulation.