Advances in Mass Spectrometry-Based Blood Metabolomics Profiling for Non-Cancer Diseases: A Comprehensive Review.

Blood metabolomics profiling using mass spectrometry has emerged as a powerful approach for investigating non-cancer diseases and understanding their underlying metabolic alterations. Blood, as a readily accessible physiological fluid, contains a diverse repertoire of metabolites derived from various physiological systems. Mass spectrometry offers a universal and precise analytical platform for the comprehensive analysis of blood metabolites, encompassing proteins, lipids, peptides, glycans, and immunoglobulins. In this comprehensive review, we present an overview of the research landscape in mass spectrometry-based blood metabolomics profiling. While the field of metabolomics research is primarily focused on cancer, this review specifically highlights studies related to non-cancer diseases, aiming to bring attention to valuable research that often remains overshadowed. Employing natural language processing methods, we processed 507 articles to provide insights into the application of metabolomic studies for specific diseases and physiological systems. The review encompasses a wide range of non-cancer diseases, with emphasis on cardiovascular disease, reproductive disease, diabetes, inflammation, and immunodeficiency states. By analyzing blood samples, researchers gain valuable insights into the metabolic perturbations associated with these diseases, potentially leading to the identification of novel biomarkers and the development of personalized therapeutic approaches. Furthermore, we provide a comprehensive overview of various mass spectrometry approaches utilized in blood metabolomics research, including GC-MS, LC-MS, and others discussing their advantages and limitations. To enhance the scope, we propose including recent review articles supporting the applicability of GC×GC-MS for metabolomics-based studies. This addition will contribute to a more exhaustive understanding of the available analytical techniques. The Integration of mass spectrometry-based blood profiling into clinical practice holds promise for improving disease diagnosis, treatment monitoring, and patient outcomes. By unraveling the complex metabolic alterations associated with non-cancer diseases, researchers and healthcare professionals can pave the way for precision medicine and personalized therapeutic interventions. Continuous advancements in mass spectrometry technology and data analysis methods will further enhance the potential of blood metabolomics profiling in non-cancer diseases, facilitating its translation from the laboratory to routine clinical application.

High temperature and hyperkalemia cause exit block of action potentials at the atrioventricular junction of rainbow trout (Oncorhynchus mykiss) heart.

At critically high temperatures, atrioventricular (AV) block causes ventricular bradycardia and collapse of cardiac output in fish. Here, the possible role of the AV canal in high temperature-induced heart failure was examined. To this end, optical mapping was used to measure action potential (AP) conduction in isolated AV junction preparations of the rainbow trout (Oncorhynchus mykiss) heart during acute warming/cooling in the presence of 4 or 8 mM external K+ concentration. The preparation included the AV canal and some atrial and ventricular tissue at its edges, and it was paced either from atrial or ventricular side at a frequency of 0.67 Hz (40 beats min-1) to trigger forward (anterograde) and backward (retrograde) conduction, respectively. The propagation of AP was fast in atrial and ventricular tissues, but much slower in the AV canal, causing an AV delay. Acute warming from 15 °C to 27 °C or cooling from 15 °C to 5 °C did not impair AP conduction in the AV canal, as both anterograde and retrograde excitations propagated regularly through the AV canal. In contrast, anterograde conduction through the AV canal did not trigger ventricular excitation at the boundary zone between the AV canal and the ventricle when extracellular K+ concentration was raised from 4 mM to 8 mM at 27 °C. Also, the retrograde conduction was blocked at the border between the AV canal and the atrium in high K+ at 27 °C. These findings suggest that the AV canal is resistant against high temperatures (and high K+), but the ventricular muscle cannot be excited by APs coming from the AV canal when temperature and external K+ concentration are simultaneously elevated. Therefore, bradycardia at high temperatures in fish may occur due to inability of AP of the AV canal to trigger ventricular AP at the junctional zone between the AV canal and the proximal part of the ventricle.

Parameter variations in personalized electrophysiological models of human heart ventricles.

The objectives of this study were to evaluate the accuracy of personalized numerical simulations of the electrical activity in human ventricles by comparing simulated electrocardiograms (ECGs) with real patients' ECGs and analyzing the sensitivity of the model output to variations in the model parameters. We used standard 12-lead ECGs and up to 224 unipolar body-surface ECGs to record three patients with cardiac resynchronization therapy devices and three patients with focal ventricular tachycardia. Patient-tailored geometrical models of the ventricles, atria, large vessels, liver, and spine were created using computed tomography data. Ten cases of focal ventricular activation were simulated using the bidomain model and the TNNP 2006 cellular model. The population-based values of electrical conductivities and other model parameters were used for accuracy analysis, and their variations were used for sensitivity analysis. The mean correlation coefficient between the simulated and real ECGs varied significantly (from r = 0.29 to r = 0.86) among the simulated cases. A strong mean correlation (r > 0.7) was found in eight of the ten model cases. The accuracy of the ECG simulation varied widely in the same patient depending on the localization of the excitation origin. The sensitivity analysis revealed that variations in the anisotropy ratio, blood conductivity, and cellular apicobasal heterogeneity had the strongest influence on transmembrane potential, while variation in lung conductivity had the greatest influence on body-surface ECGs. Futhermore, the anisotropy ratio predominantly affected the latest activation time and repolarization time dispersion, while the cellular apicobasal heterogeneity mainly affected the dispersion of action potential duration, and variation in lung conductivity mainly led to changes in the amplitudes of ECGs and cardiac electrograms. We also found that the effects of certain parameter variations had specific regional patterns on the cardiac and body surfaces. These observations are useful for further developing personalized cardiac models.

The susceptibility of the rat pulmonary and caval vein myocardium to the catecholamine-induced ectopy changes oppositely in postnatal development.

KEY POINTS: The developmental changes of the caval (SVC) and pulmonary vein (PV) myocardium electrophysiology are traced throughout postnatal ontogenesis. The myocardium in SVC as well as in PV demonstrate age-dependent differences in the ability to maintain resting membrane potential, to manifest automaticity in a form of ectopic action potentials in basal condition and in responses to the adrenergic stimulation. Electrophysiological characteristics of two distinct types of thoracic vein myocardium change in an opposite manner during early postnatal ontogenesis with increased proarrhythmicity of pulmonary and decreased automaticity in caval veins. Predisposition of PV cardiac tissue to proarrhythmycity develops during ontogenesis in time correlation with the establishment of sympathetic innervation of the tissue. The electrophysiological properties of caval vein cardiac tissue shift from a pacemaker-like phenotype to atrial phenotype in accompaniment with sympathetic nerve growth and adrenergic receptor expression changes. ABSTRACT: The thoracic vein myocardium is considered as a main source for atrial fibrillation initiation due to its high susceptibility to ectopic activity. The mechanism by which and when pulmonary (PV) and superior vena cava (SVC) became proarrhythmic during postnatal ontogenesis is still unknown. In this study, we traced postnatal changes of electrophysiology in a correlation with the sympathetic innervation and adrenergic receptor distribution to reveal developmental differences in proarrhythmicity occurrence in PV and SVC myocardium. A standard microelectrode technique was used to assess the changes in ability to maintain resting membrane potential (RMP), generate spontaneous action potentials (SAP) and adrenergically induced ectopy in multicellular SVC and PV preparations of rats of different postnatal ages. Immunofluorescence imaging was used to trace postnatal changes in sympathetic innervation, ß1- and α1A-adrenergic receptor (AR) distribution. We revealed that the ability to generate SAP and susceptibility to adrenergic stimulation changes during postnatal ontogenesis in an opposite manner in PV and SVC myocardium. While SAP occurrence decreases with age in SVC myocardium, it significantly increases in PV cardiac tissue. PV myocardium starts to demonstrate RMP instability and proarrhythmic activity from the 14th day of postnatal life which correlates with the appearance of the sympathetic innervation of the thoracic veins. In addition, postnatal attenuation of SVC myocardium automaticity occurs concomitantly with sympathetic innervation establishment and increase in ß1-ARs, but not α1A-AR levels. Our results support the contention that SVC and PV myocardium electrophysiology change during postnatal development, resulting in higher PV proarrhythmicity in adults.