Systemic exertion intolerance

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease (ME/CFS/SEID) is a condition diagnosed primarily based on clinical symptoms, including prolonged fatigue and post-exertional malaise; however, there is no specific test for the disease. Additionally, diagnosis can be challenging since healthcare professionals may lack sufficient knowledge about the disease. Prior studies have shown that patients with ME/CFS/SEID have low serum acylcarnitine levels, which may serve as a surrogate test for patients suspected of having this disease...

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Many cardiovascular diseases originate from growth retardation, inflammation, and malnutrition during early postnatal development. The nature of this phenomenon is not completely understood. Here we aimed to verify the hypothesis that systemic inflammation triggered by neonatal lactose intolerance (NLI) may exert long-term pathologic effects on cardiac developmental programs and cardiomyocyte transcriptome regulation. Using the rat model of NLI triggered by lactase overloading with lactose and the methods of cytophotometry, image analysis, and mRNA-seq, we evaluated cardiomyocyte ploidy, signs of DNA damage, and NLI-associated long-term transcriptomic changes of genes and gene modules that differed qualitatively (i...

Cardiopulmonary exercise testing (CPET) is the clinical standard for children with congenital heart disease (CHD), heart failure (HF) being assessed for transplantation candidacy, and subjects with unexplained dyspnea on exertion. Heart, lung, skeletal muscle, peripheral vasculature, and cellular metabolism impairment frequently lead to circulatory, ventilatory, and gas exchange abnormalities during exercise. An integrated analysis of the multi-system response to exercise can be beneficial for differential diagnosis of exercise intolerance...

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2 ) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2 peak-mild) and severely reduced (EO2 peak-severe) EO2 groups according to the median peak EO2 value...

TOPIC IMPORTANCE: Postacute sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from COVID-19. Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood. REVIEW FINDINGS: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC...

The hormone leptin is known to robustly suppress food intake by acting upon the leptin receptor (LepR) signaling system residing within the agouti-related protein (AgRP) neurons of the hypothalamus. However, clinical studies indicate that leptin is undesirable as a therapeutic regiment for obesity, which is at least partly attributed to the poorly understood complex secondary structure and key signaling mechanism of the leptin-responsive neural circuit. Here, we show that the LepR-expressing portal neurons send GABAergic projections to a cohort of α3-GABAA receptor expressing neurons within the dorsomedial hypothalamic nucleus (DMH) for the control of leptin-mediated obesity phenotype...

BACKGROUND: Mast cell activation syndrome (MCAS) is a clinically heterogeneous disease with allergy-like symptoms and abdominal complaints. Its etiology is only partially understood and it is often overlooked. AIMS: The aim of this study was to identify subgroups of MCAS patients to facilitate diagnosis and allow a personalized therapy. METHODS: Based on data from 250 MCAS patients, hierarchical and two-step cluster analyses as well as association analyses were performed...

Introduction: Exercise intolerance is a common clinical manifestation in patients with sickle cell disease (SCD), though the mechanisms are incompletely understood. Methods: Here we leverage a murine mouse model of sickle cell disease, the Berkeley mouse, to characterize response to exercise via determination of critical speed (CS), a functional measurement of mouse running speed upon exerting to exhaustion. Results: Upon observing a wide distribution in critical speed phenotypes, we systematically determined metabolic aberrations in plasma and organs-including heart, kidney, liver, lung, and spleen-from mice ranked based on critical speed performances (top vs...

Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure; its prevalence is increasing, and outcomes are worsening. Affected patients often experience severe exertional dyspnea and debilitating fatigue, as well as poor quality of life, frequent hospitalizations, and a high mortality rate. Until recently, most pharmacological intervention trials for HFpEF yielded neutral primary outcomes. In contrast, trials of exercise-based interventions have consistently demonstrated large, significant, clinically meaningful improvements in symptoms, objectively determined exercise capacity, and usually quality of life...

The normal function of skeletal muscle and adipose tissue ensures whole-body glucose homeostasis. Ca2+ release channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) plays a vital role in regulating diet-induced obesity and disorders, but its functions in peripheral tissue regulating glucose homeostasis remain unexplored. In this study, mice with Ip3r1 specific knockout in skeletal muscle or adipocytes were used for investigating the mediatory role of IP3R1 on whole-body glucose homeostasis under normal or high-fat diet...

BACKGROUND: Exogenous glucocorticoids (CGs) possess relevant therapeutic effects but exert diabetogenic actions when in excess. Thus, ligands with potential therapeutic applications and fewer adverse effects are needed. To this, we analyzed whether mometasone furoate (MF), a CG expected to cause fewer side effects, given through systemic routes, could maintain the anti-inflammatory actions without relevant repercussions on metabolism. METHODS: The anti-inflammatory effect of MF was evaluated with both peritonitis and colitis models in rodents...

Myalgic encephalitis/chronic fatigue syndrome, an intractable disease characterized by profound fatigue, sleep disturbance, cognitive impairment, and orthostatic intolerance, among other features, often occurs after infectious episodes. Patients experience various types of chronic pain; however, post-exertional malaise is the most significant feature, which requires pacing. In this article, I summarize the current diagnostic and therapeutic approaches and describe recent biological research in this domain.

Heart failure with preserved ejection fraction (HFpEF) is a multifactorial clinical syndrome involving a rather complex pathophysiologic substrate and quite a challenging diagnosis. Exercise intolerance is a major feature of HFpEF, and in many cases, diagnosis is suspected in subjects presenting with exertional dyspnea. Cardiopulmonary exercise testing (CPET) is a noninvasive, dynamic technique that provides an integrative evaluation of cardiovascular, pulmonary, hematopoietic, neuropsychological, and metabolic functions during maximal or submaximal exercise...

AIMS: No studies have comprehensively compared the efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors, renin-angiotensin system (RAS) inhibitors, and angiotensin receptor neprilysin (ARN) inhibitors based on different type of heart failure, including heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The aim of this network meta-analysis was to evaluate the relative efficacy of SGLT2 inhibitor (SGLT2i), RAS inhibitor (RASi) and ARN inhibitor (ARNI) in different types of heart failure...

Exposure to extreme environmental heat or cold during military activities can impose severe thermal strain, leading to impairments in task performance and increasing the risk of exertional heat (including heat stroke) and cold injuries that can be life-threatening. Substantial individual variability in physiological tolerance to thermal stress necessitates an individualized approach to mitigate the deleterious effects of thermal stress, such as physiological monitoring of individual thermal strain. During heat exposure, measurements of deep-body (Tc ) and skin temperatures and heart rate can provide some indication of thermal strain...

BACKGROUND: Exercise intolerance is a defining characteristic of heart failure with preserved ejection fraction (HFpEF). A marked rise in pulmonary capillary wedge pressure (PCWP) during exertion is pathognomonic for HFpEF and is thought to be a key cause of exercise intolerance. If true, acutely lowering PCWP should improve exercise capacity. To test this hypothesis, we evaluated peak exercise capacity with and without nitroglycerin to acutely lower PCWP during exercise in patients with HFpEF...

BACKGROUND: Patients with post-acute sequelae of COVID-19 (PASC) often experience the addition of new symptoms after recovery from COVID-19 illness. These may include orthostatic intolerance and autonomic dysfunction, and postural orthostatic tachycardia syndrome has been described to occur in a proportion of patients with PASC. CASE SUMMARY: In this report, we present a 32-year-old pregnant woman (G3P2) who experiences severe orthostatic symptoms as part of her PASC syndrome, which is decoupled from normal physiologic changes of pregnancy...

A 59-year-old woman sought treatment for 5 weeks of progressive exercise intolerance. At the time of presentation, dyspnea limited her ability to speak in complete sentences. She also reported new orthopnea. Her respiratory symptoms improved with rest and while standing. She endorsed associated intermittent low-grade fevers, cough productive of scant clear sputum, lower extremity swelling, bloating, weight loss, and reduced appetite. She had undergone two recent admissions with similar symptoms to other hospitals, during which she was treated empirically for community-acquired pneumonia and discharged after workups for infectious disease were unrevealing...

Exercise intolerance remains a major unmet medical need in patients with heart failure (HF). Skeletal myopathy is currently considered as the major limiting factor for exercise capacity in HF patients. On the other hand, emerging evidence suggest that physical exercise can decrease morbidity and mortality in HF patients. Therefore, mechanistic insights into skeletal myopathy may uncover critical aspects for therapeutic interventions to improve exercise performance in HF. Emerging data reviewed in this article suggest that the assessment of circulating myokines (molecules synthesized and secreted by skeletal muscle in response to contraction that display autocrine, paracrine and endocrine actions) may provide new insights into the pathophysiology, phenotyping and prognostic stratification of HF-related skeletal myopathy...