Role of Exercise in Pulmonary Hypertension: Evidence from Bench to Bedside.

Background: Pulmonary hypertension (PH) is a debilitating condition characterized by elevated pulmonary arterial pressure and progressive vascular remodelling, leading to exercise intolerance. The progression of PAH is regulated at a cellular and molecular level which influences various physiological processes. Exercise plays an important role in improving function in PH. Although the signalling pathways that regulate cardio-protection through exercise have not been fully understood, the positive impact of exercise on the various physiological systems is well established. Summary: Exercise has emerged as a potential adjunctive therapy for PH, with growing evidence supporting its beneficial effects on various aspects of the disease pathophysiology. This review highlights the contributions of cellular and molecular pathways and physiological processes to exercise intolerance. Preclinical studies have provided insight into the mechanisms underlying exercise-induced improvements in PH which are modulated through improvements in endothelial function, inflammation, oxidative stress, and mitochondrial function. Along with preclinical studies, various clinical studies have demonstrated that exercise training can lead to significant improvements in exercise capacity, haemodynamics, quality of life, and functional status. Moreover, exercise interventions have been shown to improve skeletal muscle function and enhance pulmonary vascular remodelling, contributing to overall disease management. Further research efforts aimed at better understanding the role of exercise in PH pathophysiology, and refining exercise interventions are warranted to realize its full potential in the management of this complex disease. Key Messages: Despite the promising benefits of exercise in PH, several challenges remain, including the optimal intensity, duration, and type of exercise training, as well as patient selection criteria and long-term adherence. Additionally, the mechanisms underlying the observed improvements require further elucidation to optimize exercise protocols and personalize treatment strategies. Nonetheless, exercise represents a promising therapeutic approach that can complement existing pharmacological therapies and improve outcomes in PH patients.

Functional-Molecular Mechanisms of Sympathetic-Parasympathetic Dysfunction in PVC-Induced Cardiomyopathy Revealed by Dual Stressor PVC-Exercise Challenge.

BACKGROUND: The significance of autonomic dysfunction in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown. OBJECTIVE: Utilizing a novel "dual stressor" provocative challenge combining exercise with premature ventricular contraction (PVCs), the authors characterized the functional and molecular mechanisms of cardiac autonomic (cardiac autonomic nervous system) remodeling in a PVC-CM animal model. METHODS: In 15 canines (8 experimental, 7 sham), we implanted pacemakers and neurotelemetry devices and subjected animals to 12 weeks of bigeminal PVCs to induce PVC-CM. Sympathetic nerve activity (SNA), vagal nerve activity (VNA), and heart rate were continuously recorded before, during, and after treadmill exercise challenge with and without PVCs, at baseline and after development of PVC-CM. Western blot and enzyme-linked immunosorbent assay were used to evaluate molecular markers of neural remodeling. RESULTS: Exercise triggered an increase in both SNA and VNA followed by late VNA withdrawal. With PVCs, the degree of exercise-induced SNA augmentation was magnified, whereas late VNA withdrawal became blunted. After PVC-CM development, SNA was increased at rest but failed to adequately augment during exercise, especially with PVCs, coupled with impaired VNA and heart rate recovery after exercise. In the remodeled cardiac autonomic nervous system, there was widespread sympathetic hyperinnervation and elevated transcardiac norepinephrine levels but unchanged parasympathetic innervation, indicating sympathetic overload. However, cardiac nerve growth factor was paradoxically downregulated, suggesting an antineurotrophic counteradaptive response to PVC-triggered sympathetic overload. CONCLUSIONS: Sympathetic overload, sympathetic dysfunction, and parasympathetic dysfunction in PVC-CM are unmasked by combined exercise and PVC challenge. Reduced cardiac neurotrophic factor might underlie the mechanisms of this dysfunction. Neuromodulation therapies to restore autonomic function could constitute a novel therapeutic approach for PVC-CM.

Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3's expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.

Cardiopulmonary determinants of reduced exercise tolerance in Fabry disease.

Fabry disease (FD), also known as Anderson-Fabry disease, is a hereditary disorder of glycosphingolipid metabolism, caused by a deficiency of the lysosomal alpha-galactosidase A enzyme. This causes a progressive accumulation of glycosphingolipids in tissues and organs which represents the main pathogenetic mechanism of FD. The disease is progressive and multisystemic and is characterized by early symptoms and late complications (renal, cardiac and neurological dysfunction). Fatigue and exercise intolerance are early common symptoms in FD patients but the specific causes are still to be defined. In this narrative review, we deal with the contribution of cardiac and pulmonary dysfunctions in determining fatigue and exercise intolerance in FD patients.

Exercise MR of Skeletal Muscles, the Heart, and the Brain.

Magnetic resonance (MR) imaging (MRI) is routinely used to evaluate organ morphology and pathology in the human body at rest or in combination with pharmacological stress as an exercise surrogate. With MR during actual physical exercise, we can assess functional characteristics of tissues and organs under real-life stress conditions. This is particularly relevant in patients with limited exercise capacity or exercise intolerance, and where complaints typically present only during physical activity, such as in neuromuscular disorders, inherited metabolic diseases, and heart failure. This review describes practical and physiological aspects of exercise MR of skeletal muscles, the heart, and the brain. The acute effects of physical exercise on these organs are addressed in the light of various dynamic quantitative MR readouts, including phosphorus-31 MR spectroscopy (31P-MRS) of tissue energy metabolism, phase-contrast MRI of blood flow and muscle contraction, real-time cine MRI of cardiac performance, and arterial spin labeling MRI of muscle and brain perfusion. Exercise MR will help advancing our understanding of underlying mechanisms that contribute to exercise intolerance, which often proceed structural and anatomical changes in disease. Its potential to detect disease-driven alterations in organ function, perfusion, and metabolism under physiological stress renders exercise MR stress testing a powerful noninvasive imaging modality to aid in disease diagnosis and risk stratification. Although not yet integrated in most clinical workflows, and while some applications still require thorough validation, exercise MR has established itself as a comprehensive and versatile modality for characterizing physiology in health and disease in a noninvasive and quantitative way. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 1.

The cardiovascular changes underlying a low cardiac output with exercise in patients with type 2 diabetes mellitus.

The significant morbidity and premature mortality of type 2 diabetes mellitus (T2DM) is largely associated with its cardiovascular consequences. Focus has long been on the arterial atheromatosis of DM giving rise to early stroke and myocardial infarctions, whereas less attention has been given to its non-ischemic cardiovascular consequences. Irrespective of ischemic changes, T2DM is associated with heart failure (HF) most commonly with preserved ejection fraction (HFpEF). Largely due to increasing population ages, hypertension, obesity and T2DM, HFpEF is becoming the most prevalent form of heart failure. Unfortunately, randomized controlled trials of HFpEF have largely been futile, and it now seems logical to address the important different phenotypes of HFpEF to understand their underlying pathophysiology. In the early phases, HFpEF is associated with a significantly impaired ability to increase cardiac output with exercise. The lowered cardiac output with exercise results from both cardiac and peripheral causes. T2DM is associated with left ventricular (LV) diastolic dysfunction based on LV hypertrophy with myocardial disperse fibrosis and significantly impaired ability for myocardial blood flow increments with exercise. T2DM is also associated with impaired ability for skeletal muscle vasodilation during exercise, and as is the case in the myocardium, such changes may be related to vascular rarefaction. The present review discusses the underlying phenotypical changes of the heart and peripheral vascular system and their importance for an adequate increase in cardiac output. Since many of the described cardiovascular changes with T2DM must be considered difficult to change if fully developed, it is suggested that patients with T2DM are early evaluated with respect to their cardiovascular compromise.

An autosomal recessive variant in PYGM causes myophosphorylase deficiency in Red Angus composite cattle.

BACKGROUND: Between 2020 and 2022, eight calves in a Nebraska herd (composite Simmental, Red Angus, Gelbvieh) displayed exercise intolerance during forced activity. In some cases, the calves collapsed and did not recover. Available sire pedigrees contained a paternal ancestor within 2-4 generations in all affected calves. Pedigrees of the calves' dams were unavailable, however, the cows were ranch-raised and retained from prior breeding seasons, where bulls used for breeding occasionally had a common ancestor. Therefore, it was hypothesized that a de novo autosomal recessive variant was causative of exercise intolerance in these calves. RESULTS: A genome-wide association analysis utilizing SNP data from 6 affected calves and 715 herd mates, followed by whole-genome sequencing of 2 affected calves led to the identification of a variant in the gene PYGM (BTA29:g.42989581G > A). The variant, confirmed to be present in the skeletal muscle transcriptome, was predicted to produce a premature stop codon (p.Arg650*). The protein product of PYGM, myophosphorylase, breaks down glycogen in skeletal muscle. Glycogen concentrations were fluorometrically assayed as glucose residues demonstrating significantly elevated glycogen concentrations in affected calves compared to cattle carrying the variant and to wild-type controls. The absence of the PYGM protein product in skeletal muscle was confirmed by immunohistochemistry and label-free quantitative proteomics analysis; muscle degeneration was confirmed in biopsy and necropsy samples. Elevated skeletal muscle glycogen persisted after harvest, resulting in a high pH and dark-cutting beef, which is negatively perceived by consumers and results in an economic loss to the industry. Carriers of the variant did not exhibit differences in meat quality or any measures of animal well-being. CONCLUSIONS: Myophosphorylase deficiency poses welfare concerns for affected animals and negatively impacts the final product. The association of the recessive genotype with dark-cutting beef further demonstrates the importance of genetics to not only animal health but to the quality of their product. Although cattle heterozygous for the variant may not immediately affect the beef industry, identifying carriers will enable selection and breeding strategies to prevent the production of affected calves.

Exercise limitation in hypertrophic cardiomyopathy: combined stress echocardiography and cardiopulmonary exercise test.

AIMS: The study aims to investigate exercise-limiting factors in hypertrophic cardiomyopathy (HCM) using combined stress echocardiography and cardiopulmonary exercise test. METHODS AND RESULTS: A symptom-limited ramp bicycle exercise test was performed in the semi-supine position on a tilting dedicated ergometer. Echocardiographic images were obtained concurrently with gas exchange measurements along predefined stages of exercise. Oxygen extraction was calculated using the Fick equation at each activity level. Thirty-six HCM patients (mean age 67 ± 6 years, 72% men, 18 obstructive HCM) were compared with age and sex-matched 29 controls. At rest, compared with controls, E/E' ratio (6.26 ± 2.3 vs. 14 ± 2.5, P < 0.001) and systolic pulmonary artery pressures (SPAP) (22.6 ± 3.4 vs. 34 ± 6.2 mmHg, P = 0.023) were increased. Along with the stages of exercise (unloaded; anaerobic threshold; peak), diastolic function worsened (E/e' 8.9 ± 2.6 vs. 13.8 ± 3.6 P = 0.011; 9.4 ± 2.3 vs. 18.6 ± 3.3 P = 0.001; 8.7 ± 1.9 vs. 21.5 ± 4, P < 0.001), SPAP increased (23 ± 2.7 vs. 33 ± 4.4, P = 0.013; 26 ± 3.2 vs. 40 ± 2.9, P < 0.001; 26 ± 3.5 vs. 45 ± 7 mmHg, P < 0.001), and oxygen consumption (6.6 ± 1.7 vs. 6.8 ± 1.6, P = 0.86; 18.1 ± 2.2 vs. 14.6 ± 1.5, P = 0.008; 20.3 ± 3 vs. 15.1 ± 2.1 mL/kg/min, P = 0.01) was reduced. Oxygen pulse was blunted (6.3 ± 1.8 vs. 6.2 ± 1.9, P = 0.79; 10 ± 2.1 vs. 8.8 ± 1.6, P = 0.063; 12.2 ± 2 vs. 8.2 ± 2.3 mL/beat, P = 0.002) due to an insufficient increase in both stroke volume (92.3 ± 17 vs. 77.3 ± 14.5 P = 0.021; 101 ± 19.1 vs. 87.3 ± 15.7 P = 0.06; 96.5 ± 12.2 vs. 83.6 ± 16.1 mL, P = 0.034) and oxygen extraction (0.07 ± 0.03 vs. 0.07 ± 0.02, P = 0.47; 0.13 ± 0.02 vs. 0.10 ± 0.03, P = 0.013; 0.13 ± 0.03 vs. 0.11 ± 0.03, P = 0.03). Diastolic dysfunction, elevated SPAP, and the presence of atrial fibrillation were associated with reduced exercise capacity. CONCLUSIONS: Both central and peripheral cardiovascular limitations are involved in exercise intolerance in HCM. Diastolic dysfunction seems to be the main driver for this limitation.

Cardiovascular Imaging-Derived Skeletal Muscle Mass Correlates With Fitness and Survival in Patients With Univentricular Circulation.

Aims This study aims to retrospectively quantify skeletal muscle mass from cardiovascular imaging studies in total cavopulmonary connection (TCPC) patients and to correlate calculated muscle mass with clinical outcomes. Materials and methods Ninety-one TCPC patients at a mean age of 24.0 ±5.5 years (37 women; 40.7%) who underwent chest computed tomography (CT) or cardiac magnetic resonance imaging (MRI) as part of their follow-up were identified in a single-center database. The cross-sectional skeletal muscle index (SMI) at the Th4 and Th12 levels was calculated from CT images, and the dorsal skeletal muscle area (SMA) at the Th12 level was measured from an MRI. Results Calculated SMI at Th12 level was 38.0 (34.5; 42.0) cm2.m-2 or 89.6 (81.9; 101.6) % of predicted values. The median follow-up from CT was 5.9 (3.1; 8.5) years, and the composite endpoint (death N=5, heart transplant N=6) was reached in a total of 11 (26.8%) patients. Patients with SMI (Th12) less than 90% of predicted values had a hazard ratio of 5.8 (95% CI: 1.2; 28.3) (p=0.03) for endpoint achievement. In the MRI group, dorsal SMA at the Th12 level was 27.6 ±5.1 cm2 in men and 20.0 ±5.8 cm2 in women. Correlations were found between SMA/kg and peak oxygen uptake (VO2 peak) (r=0.48, p=0.0005) and fat-free mass (r=0.63, p<0.0001), respectively. Conclusions A low SMI at the Th12 level was associated with a higher risk of death or cardiac transplantation. Evaluation of skeletal muscle mass using cardiovascular imaging methods allows rapid identification of individuals at risk of sarcopenia.

Association between dietary phosphate intake and skeletal muscle energetics in adults without cardiovascular disease.

Highly bioavailable inorganic phosphate (Pi) is present in large quantities in the typical Western diet and represents a large fraction of total phosphate intake. Dietary Pi excess induces exercise intolerance and skeletal muscle mitochondrial dysfunction in normal mice. However, the relevance of this to humans remains unknown. The study was conducted on 13 individuals without a history of cardiopulmonary disease (46% female, 15% Black participants) enrolled in the pilot-phase of the Dallas Heart and Mind Study. Total dietary phosphate was estimated from 24-h dietary recall (ASA24). Muscle ATP synthesis was measured at rest, and phosphocreatinine (PCr) dynamics was measured during plantar flexion exercise using 7-T 31P magnetic resonance (MR) spectroscopy in the calf muscle. Correlation was assessed between dietary phosphate intake normalized to total caloric intake, resting ATP synthesis, and PCr depletion during exercise. Higher dietary phosphate intake was associated with lower resting ATP synthesis (r = -0.62, P = 0.03), and with higher levels of PCr depletion during plantar flexion exercise relative to the resting period (r = -0.72; P = 0.004). These associations remain significant after adjustment for age and estimated glomerular filtration rate (both P < 0.05). High dietary phosphate intake was also associated with lower serum Klotho levels, and Klotho levels are in turn associated with PCr depletion and higher ADP accumulation post exercise. Our study suggests that higher dietary phosphate is associated with reduced skeletal muscle mitochondrial function at rest and exercise in humans providing new insight into potential mechanisms linking the Western diet to impaired energy metabolism.NEW & NOTEWORTHY This is the first translational research study directly demonstrating the adverse effects of dietary phosphate on muscle energy metabolism in humans. Importantly, our data show that dietary phosphate is associated with impaired muscle ATP synthesis at rest and during exercise, independent of age and renal function. This is a new biologic paradigm with significant clinical dietary implications.

Impairment of the adrenergic reserve associated with exercise intolerance in a murine model of heart failure with preserved ejection fraction.

AIM: Exercise intolerance is the central symptom in patients with heart failure with preserved ejection fraction. In the present study, we investigated the adrenergic reserve both in vivo and in cardiomyocytes of a murine cardiometabolic HFpEF model. METHODS: 12-week-old male C57BL/6J mice were fed regular chow (control) or a high-fat diet and L-NAME (HFpEF) for 15 weeks. At 27 weeks, we performed (stress) echocardiography and exercise testing and measured the adrenergic reserve and its modulation by nitric oxide and reactive oxygen species in left ventricular cardiomyocytes. RESULTS: HFpEF mice (preserved left ventricular ejection fraction, increased E/e', pulmonary congestion [wet lung weight/TL]) exhibited reduced exercise capacity and a reduction of stroke volume and cardiac output with adrenergic stress. In ventricular cardiomyocytes isolated from HFpEF mice, sarcomere shortening had a higher amplitude and faster relaxation compared to control animals. Increased shortening was caused by a shift of myofilament calcium sensitivity. With addition of isoproterenol, there were no differences in sarcomere function between HFpEF and control mice. This resulted in a reduced inotropic and lusitropic reserve in HFpEF cardiomyocytes. Preincubation with inhibitors of nitric oxide synthases or glutathione partially restored the adrenergic reserve in cardiomyocytes in HFpEF. CONCLUSION: In this murine HFpEF model, the cardiac output reserve on adrenergic stimulation is impaired. In ventricular cardiomyocytes, we found a congruent loss of the adrenergic inotropic and lusitropic reserve. This was caused by increased contractility and faster relaxation at rest, partially mediated by nitro-oxidative signaling.

Low-intensity rehabilitation in persistent post COVID-19 dyspnoea: the value of Spa health resort as appropriate setting.

Background: Post COVID-19 syndrome is a frequent disabling outcome, leading to a delay in social reintegration and return to working life. Study design: This was a prospective observational cohort study. The main objective was to explore the effectiveness of a Spa rehabilitation treatment on the improvement of post COVID-19 dyspnoea and fatigue, also analyzing the relationship between such symptoms. Additionally, it was assessed if different clinical characteristics could predispose patients in experiencing post COVID-19 symptoms or could influence the effectiveness of a Spa intervention. Methods: From July to November 2021, 187 post COVID-19 patients were enrolled in the study. All the patients complained persi-sting dyspnoea, whose impact on daily activities was assessed using the modified Medical Research Council dyspnoea scale. 144 patients (77.0%) reported also fatigue. The Spa treatment was started at least 3 months after COVID-19 acute phase. At the end of the treatment, patients were asked to rate the improvement in the dyspnoea and fatigue sensation. 118 patients also underwent the modified Borg Dyspnoea Scale for severity estimation of Exertion Dyspnoea and the Barthel index for severity estimation of Physical Limitation. Results: 165 out of 187 patients (88.2%) reported an improvement in dyspnoea, while 116 out 144 patients (80.6%) reported an improvement in both dyspnoea and fatigue. On a total of 118 subjects, a clinically significant improvement in the modified Borg Dyspnoea Scale (i.e. Delta Borg equal or more than -2.0 points) was reached by the 50.8% of patients, while a clinically significant improvement in the Barthel index (i.e. Delta Barthel equal or more than +10.0 points) was reached by the 51.7% of them. The 31.4% of patients reached a minimal clinically important improvement in both the modified Borg Dyspnoea Scale and the Barthel index. No risk factors were associated to a clinically impacting dyspnoea at entry, while a BMI>30 Kg/m2 was the main risk factor for chronic fatigue. Presence of respiratory comorbidities, obesity and severe acute COVID-19 (phenotype 4) configured risk factors for the lack of improvement of dyspnoea after the treatment, while no risk factors were associated to a lack of improvement for fatigue. Older age, obesity and comorbidities seemed to make more difficult to reach a clinically meaningful improvement in the modified Borg Dyspnoea Scale and the Barthel index after treatment. Female gender may imply more physical limitation at entry, while male patients seem to show less improvement in the Barthel index after treatment. Conclusions: Dyspnoea and fatigue were confirmed to be important post COVID-19 symptoms even in younger subjects of wor-king age and subjects with absent or modest pulmonary alterations at distance from acute COVID-19. A Spa health resort seems to be an effective "low-intensity" setting for a rehabilitation program of such patients. There is a strong relationship in terms of improvement between dyspnoea and fatigue, even if risk factors for their occurrence appear to be different. The improvement in exertion dyspnoea and physical limitation seemed to be less mutually related, probably due to a greater complexity in the asses-sment questionnaires. Some risk factors may predict a lack of improvement in symptoms after treatment.

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Evolving from the Post COVID-19 Syndrome.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID-19 Syndrome (PCS). A fraction of the PCS patients develop the full clinical picture of ME/CFS. New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and the expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure. Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing the constriction of resistance vessels and of precapillary sphincters, which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis, which is already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion. The detrimental coincidence of microcirculatory and precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in predisposed patients because the interaction causes a particular kind of perfusion disturbance-capillary ischemia/reperfusion-which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter, in turn, worsens the vascular situation through the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.

Mechanisms underlying exercise intolerance in long COVID: An accumulation of multisystem dysfunction.

The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS-CoV-2 virus ("long COVID") is not fully understood. Cases were recruited from a long COVID clinic (N = 32; 44 ± 12 years; 10 (31%) men), and age-/sex-matched healthy controls (HC) (N = 19; 40 ± 13 years; 6 (32%) men) from University College London staff and students. We assessed exercise performance, lung and cardiac function, vascular health, skeletal muscle oxidative capacity, and autonomic nervous system (ANS) function. Key outcome measures for each physiological system were compared between groups using potential outcome means (95% confidence intervals) adjusted for potential confounders. Long COVID participant outcomes were compared to normative values. When compared to HC, cases exhibited reduced oxygen uptake efficiency slope (1847 (1679, 2016) vs. 2176 (1978, 2373) mL/min, p = 0.002) and anaerobic threshold (13.2 (12.2, 14.3) vs. 15.6 (14.4, 17.2) mL/kg/min, p < 0.001), and lower oxidative capacity, measured using near infrared spectroscopy (τ: 38.7 (31.9, 45.6) vs. 24.6 (19.1, 30.1) s, p = 0.001). In cases, ANS measures fell below normal limits in 39%. Long COVID is associated with reduced measures of exercise performance and skeletal muscle oxidative capacity in the absence of evidence of microvascular dysfunction, suggesting mitochondrial pathology. There was evidence of attendant ANS dysregulation in a significant proportion. These multisystem factors might contribute to impaired exercise tolerance in long COVID sufferers.

Fatigue as hallmark of Fabry disease: role of bioenergetic alterations.

Fabry disease (FD) is a lysosomal storage disorder due to the impaired activity of the α-galactosidase A (GLA) enzyme which induces Gb3 deposition and multiorgan dysfunction. Exercise intolerance and fatigue are frequent and early findings in FD patients, representing a self-standing clinical phenotype with a significant impact on the patient's quality of life. Several determinants can trigger fatigability in Fabry patients, including psychological factors, cardiopulmonary dysfunctions, and primary alterations of skeletal muscle. The "metabolic hypothesis" to explain skeletal muscle symptoms and fatigability in Fabry patients is growing acknowledged. In this report, we will focus on the primary alterations of the motor system emphasizing the role of skeletal muscle metabolic disarrangement in determining the altered exercise tolerance in Fabry patients. We will discuss the most recent findings about the metabolic profile associated with Fabry disease offering new insights for diagnosis, management, and therapy.

Phenotyping cardiopulmonary exercise testing measures in heart failure with reduced ejection fraction: A comparison between Italy and Brazil.

BACKGROUND: While patients with heart failure (HF) with reduced left ventricular ejection fraction (HFrEF) constitutes a global health crisis the incidence, prevalence and prognosis of the disease may differ depending on the continent and country. OBJECTIVE: To profile, analyze and compare cardiopulmonary exercise testing (CPET) data of patients with HFrEF between Italian and Brazilian cohorts. METHODS: In this observational study, a total of 630 patients with clinical and functional diagnosis of HFrEF (315 patients from Brazil and 315 patients from Italy) performed CPET. RESULTS: Although Brazilian patients were slightly younger (Brazil 60±10 vs Italy 64±11 p<0.001) with a better peak oxygen consumption (V̇O2), circulatory power and left ventricular ejection fraction (LVEF) (p<0.01), ventilatory inefficiency and oscillation ventilation was higher when compared to the Italian cohort. When stratifying patients with LVEF≤30 % and age≥60 years, Brazilian patients presented worse ventilatory efficiency, and lower peak V̇O2 compared to the Italian cohort. CONCLUSION: Patients with HFrEF from Brazil exhibited higher ventilatory inefficiency and a greater prevalence of oscillatory ventilation during CPET compared to patients with the same diagnosis from Italy.

Impact of body position on hemodynamic measurements during exercise: A tale of two bikes.

The addition of exercise testing during right heart catheterization (RHC) is often required to accurately diagnose causes of exercise intolerance like early pulmonary vascular disease, occult left heart disease, and preload insufficiency. We tested the influence of body position (supine vs. seated) on hemodynamic classification both at rest and during exercise. We enrolled patients with exercise intolerance due to dyspnea who were referred for exercise RHC at the Cleveland Clinic. Patients were randomized (1:1) to exercise in seated or supine position to a goal of 60 W followed by maximal exercise in the alternate position. We analyzed 17 patients aged 60.3 ± 10.9 years, including 13 females. At rest in the sitting position, patients had significantly lower right atrial pressure (RAP), mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure (PAWP) and cardiac index (CI). In every stage of exercise (20, 40, and 60 W), the RAP, mPAP, and PAWP were lower in the sitting position. Exercise in the sitting position allowed the identification of preload insufficiency in nine patients. Exercise in either position increased the identification of postcapillary pulmonary hypertension (PH). Body position significantly influences hemodynamics at rest and with exercise; however, mPAP/CO and PAWP/CO were not positionally affected. Hemodynamic measurements in the seated position allowed the detection of preload insufficiency, a condition that was predominantly identified as no PH during supine exercise.

Exercise Intolerance After Mild Traumatic Brain Injury Occurs in All Subtypes in the Adult Population.

Thematically grouped symptom clusters are present during the acute timeline of post-mild traumatic brain injuries (mTBI), representing clinical profiles called subtypes. Exercise intolerance has not been evaluated within the subtype classifications and, because guidelines support early submaximal aerobic exercise, further knowledge is required in regard to the exercise capabilities among the concussion subtypes. This cross-sectional study (n = 78) aimed to characterize the presence of exercise intolerance within the clinical subtypes and to explore performance on the Buffalo Concussion Treadmill Test (BCTT) in the adult subacute (2-12 weeks post-injury) mTBI population. All participants were evaluated using the BCTT to determine exercise tolerance. We first used the Neurobehavioral Symptom Inventory (NSI) questionnaire to assign each participant a primary subtype(s). To further explore all five subtypes (headache, cognitive, vestibular, ocular motor, and mood), participants were assessed using a multitude of thematically grouped assessments including self-reported questionnaires, clinical tests of vestibular and ocular motor function, balance function, and computerized cognitive testing. Thirty-seven (47%) subjects were exercise tolerant and 41 (53%) were exercise intolerant. There was no difference in the distribution of primary subtypes between the exercise tolerant and exercise intolerant groups. In addition, no significant differences were found between the exercise tolerant and exercise intolerant groups on other thematically grouped subtype assessments. The exercise intolerant group had a significantly higher resting heart rate (HR), lower percentage of age-predicted maximum HR achieved, lower Borg Rate of Perceived Exertion (RPE), and could walk on the treadmill for less time (lower duration) compared with the exercise tolerant group. The current findings suggest that exercise intolerance is common and pervasive across all five mTBI subtypes. A comprehensive mTBI assessment should include evaluation for exercise intolerance regardless of the primary clustering of symptoms and across patient populations. Therefore, early referral to physical therapists, athletic trainers, or medical clinics that can perform the BCTT may be helpful to initiate appropriate exercise prescriptions for patients with mTBI.