Changes In Contractility Research Articles

Mechanisms of atrial-fibrillation-induced ventricular dysfunction and recovery in the human left ventricular myocardium

Abstract Background Atrial fibrillation (AF) frequently occurs alongside heart failure (HF). Clinical studies indicate improved left ventricular (LV) function following rhythm restoration but the underlying myocardial processes remain unclear. Purpose This study investigated effects of AF and its termination on human LV myocardium as well as potential molecular mechanisms involved in the AF-induced LV dysfunction. Methods Human LV tissue slices obtained from HF patients were long-term cultivated in-vitro. AF was simulated by tachy-arrhythmic culture pacing at 100 bpm with 30% irregularity for 7 days and contractile LV function was compared to slices undergoing sinus rhythm (SR)-simulation (60 bpm/0%). After 7 days, rhythm restoration was simulated by switching to SR-simulation. To elucidate cellular mechanisms involved in AF-induced LV dysfunction, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) were subjected to AF-simulation and examined via epifluorescence microscopy (FURA-2) and confocal microscopy (Fluo-4). Additionally, to investigate the impact of reactive oxygen species (ROS) on cardiomyocytes, iPSC-CM were subjected to treatment with the ROS-scavenger N-acetylcysteine (NAC). Results AF-simulation caused a progressive decline in systolic force of human LV myocardium (n=14 slices) with significantly reduced twitch amplitudes compared to SR-simulation (n=11). Within just 5 days of AF-termination, a significant recovery in LV function was observed, indicated by improved systolic contraction amplitudes. IPSC-CM measurements revealed a significant reduction in systolic Ca2+-transient amplitudes as well as an increased diastolic Ca2+ leak after AF-simulation (n=41) compared to SR-simulation (n=44). However, 5 days after SR-restoration, iPSC-CM exhibited no significant differences anymore, indicating a fast recovery of systolic Ca2+-cycling. We further investigated the impact of ROS on LV function and could show that Ca2+-transient amplitude was preserved after AF-simulation in iPSC-CM when treated with NAC (n=35), suggesting an interplay of ROS with the Ca2+-homeostasis of cardiomyocytes. Conclusions This study demonstrates that AF impairs LV function in human HF myocardium. However, the involved changes in contractility and cardiomyocyte Ca2+ handling are reversible upon AF termination leading to improved LV function already within few days after AF cessation. Moreover, we provided an indication for an interplay of ROS with the Ca2+ homeostasis, endorsing an AF-induced LV-dysfunction, which merits further investigation.

Effect of fatigue on intermuscular EMG-EMG coupling during bench press exercise at 60% 1RM workload in males.

To explore the neuromuscular control mechanism and quantifying the fatigue response during bench press exercise is important references to prescribe an appropriate exercise program. However, current literature struggles to provide a concrete conclusion on the changes of intermuscular EMG-EMG coupling between synergistic and antagonist muscles during the exercise. Thus, the current study was designed to reveal fatigue-related changes of intermuscular EMG-EMG coupling during bench press exercise. Thirty-one healthy male participants performed a bench press exercise on the Smith machine at 60% One Repetition Maximum (1RM) workload to exhaustion, while surface electromyographic signals (sEMG) were collected from triceps brachii (TB), biceps brachii (BB), anterior deltoid (AD), posterior deltoid (PD), and pectoralis major (PM). Surface EMG signals were divided into the first half and second half of the bench press exercise. Phase synchronization index (PSI) was calculated between sEMG of synergistic muscle pairs AD-TB, AD-PM and antagonist muscle pairs BB-TB, AD-PD. EMG power of TB, AD, PD, PM muscles in alpha (8-12 Hz) frequency band and EMG power of each muscle in beta (15-35 Hz), and gamma (35-60 Hz) frequency bands were all increased during the second half of contraction compared with the first half of contraction. PSI of gamma frequency band was significantly decreased in BB-TB muscle pair while EMG-EMG coupling of AD-TB in gamma frequency band was significantly increased during the second half of contraction compared to the first half of contraction. The results indicated a decrease of interconnection between synchronized cortical neurons and the motoneuron pool of BB and TB, and an increase of interconnection between AD-TB muscles during fatiguing bench press exercise at 60% 1RM workload. The changes of intermuscular coupling may be related to the supraspinal modulations to compensate for the decrease of muscle force as well as a result of unbalanced changes of agonist and antagonist muscle contractility.

37 - The change of detrusor contractility at 5 years after transurethral resection of the prostate: a single center prospective observational study

37 - The change of detrusor contractility at 5 years after transurethral resection of the prostate: a single center prospective observational study

Association of the echocardiographic parameters with the physical dimension of quality of life

Heart failure (HF) is determined by pathophysiologic changes in the left ventricle (LV) that occur before the onset of clinical symptoms; these changes can lead to mitral insufficiency that will maintain and favor ventricular dysfunction. An associated change in contractility occurs which will maintain the vicious circle. 252 patients with HF were included in this cross-sectional analysis. Patients were divided into two groups, Group I-S/V (n = 55) and Group II-CT (n = 197) to comparatively assess cardi-ac parameters according to the administered therapy and to determine their correlation with quality of life domains. 2D measurements were performed to determine ultrasound parameters. The WHOQOL-BREF questionnaire was used to assess the quality of life. When analyzing the mean values of the determined echocardiographic parame-ters, significant differences in LV ejection fraction (LVEF) (p < 0.03) Results: Analysing the mean values of the echocardiographic parameters determined, significant differences in LV ejection fraction (LV ejection fraction (LVEF) (p < 0.001) and right ventricular diameter (p = 0.030) were found between the two study groups. The incidence of aortic regurgitation and tricuspid regurgitation was higher in the I-S/V group (40% vs. 25%, p = 0.001, respec-tively 47% vs. 35%, p = 0.03). Mitral regurgitation was present in relatively similar per-centages. Testing the association of echocardiographic parameters with quality of life do-mains showed a significant association of LVEF with physical health and relationship with the environment (p = 0.002, r = 0.143, respectively p = 0.041, r = 0.129). Physical dimension and relationship with the environment are more affected in pa-tients with low LVEF. Routine echocardiographic evaluation is essential in the global as-sessment of the HF patient and may suggest a low quality of life with impaired physical dimension.

Airborne polystyrene nanoplastics exposure leads to heart failure via ECM-receptor interaction and PI3K/AKT/BCL-2 pathways

Environmental contamination has been recognized as a significant threat to human well-being, and recent findings of microplastic presence in human cardiac tissues have raised concerns. However, research on the effects of airborne nanoplastics (NPs) on cardiac physiology remains limited. We utilized a comprehensive body exposure apparatus to simulate the impact of airborne polystyrene NPs pollution, focusing on understanding how airborne NPs affect cardiac morphology and function. Following two weeks of NPs exposure, mice exhibited a 23.89 ± 8.30 % reduction in heart mass, a 20.05 ± 2.97 % decrease in heart rate as detected, and a myocardial electrical conduction block. Echocardiography showed significant changes in cardiac contractility, with increases in cardiac ejection fraction and stroke volume of 13.00 ± 3.00 % and 43.00 ± 17.00 %, respectively. In addition, histologic assessments revealed signs of ventricular hypertrophy, ventricular myocardial hypertrophy, and myocardial necrotic fibrosis. Of particular interest, our mechanistic investigations highlighted the harmful effects of NPs on cardiac structure and function, mediated through extracellular matrix (ECM) receptor interactions and the PI3K/AKT/BCL-2 signaling pathway. The insights gained provide a foundation for understanding the risks posed by airborne NPs to human cardiac health, emphasizing the need for increased vigilance and implementation of mitigation strategies in environmental management.

Dedifferentiation- and aging-induced loss of mechanical contractility and polarity in vascular smooth muscle cells: Heterogeneous changes in macroscopic and microscopic behavior of cells in serial passage culture

Dedifferentiation and aging of vascular smooth muscle cells (VSMCs) are associated with serious vascular diseases, such as arteriosclerosis and aneurysm. However, how cell dedifferentiation and aging affect cellular mechanical behaviors at the single-cell and intracellular structure levels remains unclear. An in-depth understanding of these interactions is extremely important for understanding the mechanism underlying VSMC mechanical integrity and homeostatic regulation of vascular walls. Herein, we systematically investigated changes in VSMC morphology, structure, contractility, and motility during dedifferentiation and aging induced by serial passage culture using traction force microscopy with elastic micropillar substrates, laser nanodissection of cytoskeletons, confocal fluorescence microscopy, and atomic force microscopy. We found that VSMC dedifferentiation started in the middle stage of serial passage culture, accompanied by a transient cell spreading in the cell width and decrease in contractile protein expression. Dedifferentiated VSMCs showed a significant decrease in the contraction and stiffness of individual actin stress fibers; however, their overall cell traction forces were maintained. Simultaneously, a significant increase in cell motility and the number of actin fibers was observed in dedifferentiated VSMCs, which may be associated with the enhancement of cell migration and disruption of cell/tissue integrity during the early stage of vascular diseases. As cell senescence progressed in the later stage of serial passage culture, VSMCs displayed reduced cell spreading and migration with decrease in the overall cell traction forces and drastic reduction in mechanical polarity of cell structures and forces. These results suggested that cell senescence causes loss of mechanical contractility and polarity in VSMCs, which may be an important factor in vascular disease progression. The experimental systems established in this study can be powerful tools for understanding the mechanisms underlying cellular dedifferentiation and aging from a biomechanical perspective.

Real-Time Wireless Sensing of Cardiomyocyte Contractility by Integrating Magnetic Microbeam and Oriented Nanofibers.

In vitro cardiomyocyte mechano-sensing platform is crucial for evaluating the mechanical performance of cardiac tissues and will be an indispensable tool for application in drug discovery and disease mechanism study. Magnetic sensing offers significant advantages in real-time, in situ wireless monitoring and resistance to ion interference. However, due to the mismatch between the stiffness of traditional rigid magnetic material and myocardial tissue, sensitivity is insufficient and it is difficult to achieve cell structure induction and three-dimensional cultivation. Herein, a magnetic sensing platform that integrates a neodymium-iron-boron/polydimethylsiloxane (NdFeB/PDMS) flexible microbeam with suspended and ordered polycaprolactone (PCL) nanofiber membranes was developed, providing a three-dimensional anisotropic culture environment for cardiomyocyte growth and simultaneously realizing in situ wireless contractility monitoring. The as-prepared sensor presented an ultrahigh sensitivity of 442.2 μV/μm and a deflection resolution of 2 μm. By continuously monitoring the cardiomyocyte growth status and drug stimulation feedback, we verified the capability of the platform to capture dynamic changes in cardiomyocyte contractility. This platform provides a perspective tool for evaluating cardiomyocyte maturity and drug performance.

Abstract Mo117: Investigation of Mechanisms to Modulate Contractility in 13-Lined Ground Squirrels

Introduction: During hibernation, 13-lined ground squirrels cycle between torpor and intermittent bouts of arousal (IBA). Bouts of IBA last 12-48 hours, during which heart rates rise from 2-4 bpm in torpor to 300 bpm during IBA before returning to torpor. Thus, rates of contractility and relaxation and their mechanisms must rapidly change. Phosphorylation of cardiac troponin I (cTnI) at serine 23/24 (pSer23/24) has been shown to decrease calcium sensitivity and increase the rate of myocardial relaxation, enabling faster heart rates. Heat shock protein 27 (HSP27) has been shown to protect contractility by stabilizing troponin. Hypothesis: We hypothesized that cTnI Ser23/24 phosphorylation would be higher in summer and IBA and that HSP27 would be found in higher quantities during torpor and IBA. Methods and Results: Left ventricular tissue (summer, n=8; torpor, n=8; IBA, n=8) was solubilized, separated by SDS-PAGE, and blotted with antibodies for quantification. The pSer23/24 to total troponin ratios were higher in summer compared to torpor (1.22±0.75 vs 0.32±0.19, p=0.003) and IBA (0.57±0.19, p=0.03), but not different between IBA and torpor. No significant season-dependence was observed for the serine 43 cTnI phosphorylation to total troponin ratio (torpor 1.45±0.69, summer 1.05±0.34, IBA 1.15±0.84). No significant season-dependence was observed in HSP27 (normalized to GAPDH) (summer 0.09±0.02, IBA 0.14±0.10, torpor 0.16±0.08). Nor was there a significant season-dependence observed in HSP90 (normalized to GAPDH) (summer 1.57±0.66, IBA 1.13±0.19, torpor 1.22±0.21). Conclusions: None of these mechanisms fully explain the rapid change in contractility observed during the hibernating periods of 13-lined ground squirrels. Other post-translational modifications of troponin or modifiers of HSP activity may modify the reported results. Such regulation may identify new treatments for humans where rapid changes in heart rate or contractility occur.

Load Dependency of Ventricular Pump Function: Impact on the Non-Invasive Evaluation of the Severity and the Prognostic Relevance of Myocardial Dysfunction.

Ventricular pump function, which is determined by myocyte contractility, preload and afterload, and, additionally, also significantly influenced by heart rhythm, synchrony of intraventricular contraction and ventricular interdependence, explains the difficulties in establishing the contribution of myocardial contractile dysfunction to the development and progression of heart failure. Estimating myocardial contractility is one of the most difficult challenges because the most commonly used clinical measurements of cardiac performance cannot differentiate contractility changes from alterations in ventricular loading conditions. Under both physiological and pathological conditions, there is also a permanent complex interaction between myocardial contractility, ventricular anatomy and hemodynamic loading conditions. All this explains why no single parameter can alone reveal the real picture of ventricular dysfunction. Over time there has been increasing recognition that a load-independent contractility parameter cannot truly exist, because loading itself changes the myofilament force-generating capacity. Because the use of a single parameter is inadequate, it is necessary to perform multiparametric evaluations and also apply integrative approaches using parameter combinations which include details about ventricular loading conditions. This is particularly important for evaluating the highly afterload-sensitive right ventricular function. In this regard, the existence of certain reluctance particularly to the implementation of non-invasively obtainable parameter combinations in the routine clinical praxis should be reconsidered in the future. Among the non-invasive approaches used to evaluate ventricular function in connection with its current loading conditions, assessment of the relationship between ventricular contraction (e.g., myocardial displacement or deformation) and pressure overload, or the relationship between ejection volume (or ejection velocity) and pressure overload, as well as the relationship between ventricular dilation and pressure overload, were found useful for therapeutic decision-making. In the future, it will be unavoidable to take the load dependency of ventricular function much more into consideration. A solid basis for achieving this goal will be obtainable by intensifying the clinical research necessary to provide more evidence for the practical importance of this largely unsolved problem.

Mechanisms of a novel regulatory light chain-dependent cardiac myosin inhibitor.

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart characterized by thickening of the left ventricle (LV), hypercontractility, and impaired relaxation. HCM is caused primarily by heritable mutations in sarcomeric proteins, such as β myosin heavy chain. Until recently, medications in clinical use for HCM did not directly target the underlying contractile changes in the sarcomere. Here, we investigate a novel small molecule, RLC-1, identified in a bovine cardiac myofibril high-throughput screen. RLC-1 is highly dependent on the presence of a regulatory light chain to bind to cardiac myosin and modulate its ATPase activity. In demembranated rat LV trabeculae, RLC-1 decreased maximal Ca2+-activated force and Ca2+ sensitivity of force, while it increased the submaximal rate constant for tension redevelopment. In myofibrils isolated from rat LV, both maximal and submaximal Ca2+-activated force are reduced by nearly 50%. Additionally, the fast and slow phases of relaxation were approximately twice as fast as DMSO controls, and the duration of the slow phase was shorter. Structurally, x-ray diffraction studies showed that RLC-1 moved myosin heads away from the thick filament backbone and decreased the order of myosin heads, which is different from other myosin inhibitors. In intact trabeculae and isolated cardiomyocytes, RLC-1 treatment resulted in decreased peak twitch magnitude and faster activation and relaxation kinetics. In conclusion, RLC-1 accelerated kinetics and decreased force production in the demembranated tissue, intact tissue, and intact whole cells, resulting in a smaller cardiac twitch, which could improve the underlying contractile changes associated with HCM.

FORENSIC-MEDICAL FEATURES OF THE HEART IN CASES OF ACUTE CORONARY INSUFFICIENCY WITH SUDDEN CARDIAC DEATH

The article provides an assessment of changes in the endocardium of the atria and ventricles of the heart in cases of sudden cardiac death due to acute coronary insufficiency. In cases of sudden death due to acute coronary insufficiency, distinct focal pathological changes were observed in the connective tissue of the endocardium of the left atrium and ventricle, manifested by loss of fibrillar structures and fragmentation of its non-cellular elements. This corresponded to local contractile changes in the cardiomyocytes, localised in the subendocardial space of the affected parts of the heart, leading to local fragmentation and an increase in the thickness of the endocardial folds. In addition, the loss of their characteristic waviness and the acquisition of linearity were observed. These changes are considered to be manifestations of morpho-functional disorders of the endocardium of the specified heart segments. The aim of the study was to determine the characteristics of endocardial changes in the atria and ventricles in cases of sudden death due to acute ischaemic heart disease. Materials and Methods. The study material included 12 hearts from young and middle-aged individuals without cardiovascular disease (control group) and 12 hearts from working-age individuals who died suddenly of acute ischaemic heart disease. Conclusions: At the time of death from acute ischaemic heart disease, there were pronounced focal pathological changes in cellular and non-cellular components in the connective tissue of the endocardium of the left atrium and ventricle. These changes caused focal contractile changes in cardiomyocytes localised in the subendocardial layer of the myocardium of the left ventricle. The identified changes in the subendocardial layer of the myocardium caused focal thickening, fragmentation, and increased thickness of the endocardial folds, their undulation, which can be considered as manifestations of morpho-functional disorders of the endocardium.

Detection of contractility changes in the heart from arterial blood pressure data using symmetric Projection Attractor Reconstruction

The potential for unintended drug induced changes in cardiac contractility is a major concern in medicines development. Whilst direct left ventricular pressure (LVP) measurement is the gold standard for measuring cardiac contractility in vivo, it is resource intensive and poses a welfare burden on research animals. In contrast, arterial blood pressure (BP) measurement has fewer challenges. Symmetric Projection Attractor Reconstruction (SPAR) is a signal processing technique which transforms physiological time-series signals into a corresponding visual image (‘attractor’), amplifying morphology changes within physiological waveforms. It was hypothesized that SPAR analysis of BP signals would provide a surrogate measure of cardiac contractility by specifically amplifying the maximum slope of the systolic upstroke. BP (abdominal aorta) signals obtained from beagle dogs, treated with positive and negative inotropes, were retrospectively analysed to identify signal features that correlated with the maximum upslope of the LVP signal from simultaneously acquired LVP recordings. SPAR transformation of BP signals quantified drug induced changes in the maximum slope of the systolic upstroke. We identified key SPAR metrics that provided >0.8 correlation with the LVP maximum upslope, outperforming the BP systolic upstroke alone. This was observed for all 4 different drugs, doses and time points evaluated across studies. Thus, we conclude that the SPAR measures derived from the BP signal could be used as a first pass in vivo screen to flag any risk of drug induced changes in cardiac contractility during the conduct of non-clinical medicines development, potentially reducing or replacing the need to perform direct left ventricular measurements.

Aging aggravates aortic aneurysm and dissection via miR-1204-MYLK signaling axis in mice

The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates β-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-β signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.

Functional consequences of changes in the distribution of Ca2+ extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte

The sarcolemmal Ca2+ efflux pathways, Na+-Ca2+-exchanger (NCX) and Ca2+-ATPase (PMCA), play a crucial role in the regulation of intracellular Ca2+ load and Ca2+ transient in cardiomyocytes. The distribution of these pathways between the t-tubular and surface membrane of ventricular cardiomyocytes varies between species and is not clear in human. Moreover, several studies suggest that this distribution changes during the development and heart diseases. However, the consequences of NCX and PMCA redistribution in human ventricular cardiomyocytes have not yet been elucidated. In this study, we aimed to address this point by using a mathematical model of the human ventricular myocyte incorporating t-tubules, dyadic spaces, and subsarcolemmal spaces. Effects of various combinations of t-tubular fractions of NCX and PMCA were explored, using values between 0.2 and 1 as reported in animal experiments under normal and pathological conditions. Small variations in the action potential duration (≤ 2%), but significant changes in the peak value of cytosolic Ca2+ transient (up to 17%) were observed at stimulation frequencies corresponding to the human heart rate at rest and during activity. The analysis of model results revealed that the changes in Ca2+ transient induced by redistribution of NCX and PMCA were mainly caused by alterations in Ca2+ concentrations in the subsarcolemmal spaces and cytosol during the diastolic phase of the stimulation cycle. The results suggest that redistribution of both transporters between the t-tubular and surface membranes contributes to changes in contractility in human ventricular cardiomyocytes during their development and heart disease and may promote arrhythmogenesis.

Bias-Free Cardiac Monitoring Capsule.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Patients often fail to recognize the early signs of CVDs, which display irregularities in cardiac contractility and may ultimately lead to heart failure. Therefore, continuously monitoring the abnormal changes in cardiac contractility may represent a novel approach to long-term CVD surveillance. Here, a zero-power consumption and implantable bias-free cardiac monitoring capsule (BCMC) is introduced based on the triboelectric effect for cardiac contractility monitoring in situ. The output performance of BCMC is improved over 10 times with nanoparticle self-adsorption method. This device can be implanted into the right ventricle of swine using catheter intervention to detect the change of cardiac contractility and the corresponding CVDs. The physiological signals can be wirelessly transmitted to a mobile terminal for analysis through the acquisition and transmission module. This work contributes to a new option for precise monitoring and early diagnosis of CVDs.

Contractility assessment using aligned human iPSC-derived cardiomyocytes

IntroductionCardiac safety assessment, such as lethal arrhythmias and contractility dysfunction, is critical during drug development. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been shown to be useful in predicting drug-induced proarrhythmic risk through international validation studies. Although cardiac contractility is another key function, fit-for-purpose hiPSC-CMs in evaluating drug-induced contractile dysfunction remain poorly understood. In this study, we investigated whether alignment of hiPSC-CMs on nanopatterned culture plates can assess drug-induced contractile changes more efficiently than non-aligned monolayer culture. MethodsAligned hiPSC-CMs were obtained by culturing on 96-well culture plates with a ridge-groove-ridge nanopattern on the bottom surface, while non-aligned hiPSC-CMs were cultured on regular 96-well plates. Next-generation sequencing and qPCR experiments were performed for gene expression analysis. Contractility of the hiPSC-CMs was assessed using an imaging-based motion analysis system. ResultsWhen cultured on nanopatterned plates, hiPSC-CMs exhibited an aligned morphology and enhanced expression of genes encoding proteins that regulate contractility, including myosin heavy chain, calcium channel, and ryanodine receptor. Compared to cultures on regular plates, the aligned hiPSC-CMs also showed both enhanced contraction and relaxation velocity. In addition, the aligned hiPSC-CMs showed a more physiological response to positive and negative inotropic agents, such as isoproterenol and verapamil. DiscussionTaken together, the aligned hiPSC-CMs exhibited enhanced structural and functional properties, leading to an improved capacity for contractility assessment compared to the non-aligned cells. These findings suggest that the aligned hiPSC-CMs can be used to evaluate drug-induced cardiac contractile changes.

Pharyngeal adaptation to bolus properties in patients with Parkinson’s disease

PurposeDysphagia is common in people with Parkinson’s disease (PD). Yet, literature describing swallow function in PD using high-resolution manometry is limited. This study explored swallowing pressure metrics for varied bolus conditions in people with PD.MethodA solid-state unidirectional catheter was used to acquire manometric data for triplicate swallows (5 ml, 10 ml, 20 ml; IDDSI 0, 2 & 4). Penetration-aspiration severity was rated during videofluoroscopy. Patient-reported measures included PDQ-8: Parkinson’s Disease Questionnaire-8 and EAT-10: Eating Assessment Tool-10. Quantitative manometric swallow analysis was completed through Swallow Gateway™. Metrics were compared to published normative values and generalized linear model tests explored modulatory effects.Results21 participants (76% male; mean age 69.6 years, SD 7.1) with mild-moderate severity PD were studied. Two patients (9%) aspirated for single bolus thin liquid and paste trials and 15 patients (73%) scored > 3 EAT-10. Standardized PDQ-8 scores correlated with EAT-10 (p < 0.05). Abnormality in UES relaxation and distension was demonstrated by high UES integrated relaxation pressure and low UES maximum admittance (UES MaxAdm) values across varied bolus conditions. Participants demonstrated abnormally elevated pharyngeal contractility and increased post-swallow upper-esophageal sphincter (UES) contractility for thinner liquid trials. Alterations in volume and viscosity had significant effects on the bolus timing metric—distention to contraction latency. UES peak pressure measures were altered in relation to bolus viscosity.ConclusionThis study identifies early pharyngoesophageal contractile changes in relation to bolus volume and viscosity in PD patients, associated with subtle deterioration of self-reported swallow scores. Manometric evaluation may offer insight into PD-related swallowing changes and help optimize diagnostics and treatment planning

Role of STIM1 in stretch-induced signaling in human airway smooth muscle.

Alteration in the normal mechanical forces of breathing can contribute to changes in contractility and remodeling characteristic of airway diseases, but the mechanisms that mediate these effects in airway cells are still under investigation. Airway smooth muscle (ASM) cells contribute to both contractility and extracellular matrix (ECM) remodeling. In this study, we explored ASM mechanisms activated by mechanical stretch, focusing on mechanosensitive piezo channels and the key Ca2+ regulatory protein stromal interaction molecule 1 (STIM1). Expression of Ca2+ regulatory proteins, including STIM1, Orai1, and caveolin-1, mechanosensitive ion channels Piezo-1 and Piezo-2, and NLRP3 inflammasomes were upregulated by 10% static stretch superimposed on 5% cyclic stretch. These effects were blunted by STIM1 siRNA. Histamine-induced [Ca2+]i responses and inflammasome activation were similarly blunted by STIM1 knockdown. These data show that the effects of mechanical stretch in human ASM cells are mediated through STIM1, which activates multiple pathways, including Piezo channels and the inflammasome, leading to potential downstream changes in contractility and ECM remodeling.NEW & NOTEWORTHY Mechanical forces on the airway can contribute to altered contractility and remodeling in airway diseases, but the mechanisms are not clearly understood. Using human airway smooth muscle cells exposed to cyclic forces with static stretch to mimic breathing and static pressure, we found that the effects of stretch are mediated through STIM1, resulting in the activation of multiple pathways, including Piezo channels and the inflammasome, with potential downstream influences on contractility and remodeling.

Identification of Peripheral Fatigue through Exercise-Induced Changes in Muscle Contractility.

The aim of this study was to assess whether tensiomyography is a tool sensitive enough to detect peripheral fatigue. Twenty-six strength-trained men were split into two groups: 1) a fatigued group (FG), who performed a full-squat (SQ) standardized warm-up plus 3 x 8 SQs with 75% 1RM with a 5-min rest interval, and 2) a non-fatigued group (NFG), who only did the SQ standardized warm-up. The countermovement jump (CMJ), maximal isometric force (MIF) in the SQ at 90º knee flexion, and TMG in vastus medialis (VM) and vastus lateralis (VL) muscles were assessed pre- and post-protocols. Data were analyzed through mixed ANOVA, logistic regression analysis, and receiver-operating curves. There were significant group x time interactions (p < 0.01) for CMJ height, MIF, maximal radial displacement (Dm), and radial displacement velocity (Vrd90) since the FG acutely decreased in these variables, while no significant changes were observed for the NFG. The logistic regression showed a significant model for detecting fatigue, whether it used the CMJ or MIF, with only the relative change in VL-Vrd90 as a fatigue predictor. The determination of the area under the curve showed that Dm and Vrd90 had good to excellent discriminative ability. Dm and Vrd90 are sensitive to detect fatigue in VL and VM muscles in resistance training contexts.

The effect of high intensity interval training on muscle contractile function 8 weeks following chemically-induced ovarian failure

The negative effects of ovariectomy on muscle contractile function have been well-characterized, however, the effects of gradual ovarian failure (i.e., perimenopausal transition into late-stage menopause) on muscle function over the lifespan have received less attention. Furthermore, whether exercise training can mitigate changes in muscle contractile function associated with menopause is unclear. The objective of this study, using a chemically-induced ovarian failure mouse model (4-vinylcyclohexene diepoxide; VCD), was to investigate time-course changes in muscle contractility of sedentary controls and the potential of high intensity interval training to mitigate any deleterious effects of ovarian failure. Starting at 11wks old, mice were injected with 160mg/kg/day of VCD for 15 days. Twenty-eight (VCD-trained: n=10, VCD-sedentary: n=10, control: n=8) CD1 female mice were used in this study, with the VCD-trained group beginning training at the onset of ovarian failure for a total of 8 weeks. Contractile properties of the plantar flexors were assessed using an in-vivo set-up 8 weeks following the onset of ovarian failure. As well, a fatigue task (repeated maximal isometric contractions until torque decreased by 60%) was performed. Recovery was measured immediately after, and up to 10min following task termination. Upon completion of mechanical testing, mice were sacrificed and intact muscle fibres were isolated from the flexor digitorum brevis, and myoplasmic free Ca2+ (tetanic [Ca2+]i) concentrations were measured across stimulation frequencies of 10-200 Hz and throughout 50 tetanic contractions (70Hz) to replicate our fatigue task. There was no difference in pre-fatigue values across groups for peak twitch torque, peak 100Hz torque, RTD, 10:100Hz torque, tetanic [Ca2+]i during low (10Hz) and high Hz (100Hz) stimulation, and all were reduced similarly immediately following the fatigue task. Repetitions to task failure was similar across groups and tetanic [Ca2+]i during repetitive contractions (n=50) was reduced similarly across groups. As well, all groups recovered similarly across these measures. Torque and RTD did not recover fully by 10min for either measure, while 10Hz, 100Hz and 10:100Hz tetanic [Ca2+]i was recovered immediately following the fatigue task. Given 10Hz torque was relatively maintained following the fatigue task, and there was a ~40% decline in 100Hz torque, the 10:100Hz ratio increased throughout recovery — this, combined with the [Ca2+] data indicate that calcium sensitivity and release are unlikely contributors to impaired force production following the fatigue task across groups. The present study aimed to assess the impact of training on muscle contractility using a mouse model of gradual ovarian failure. Unlike other models of ovarian failure, there does not seem to be any impairment in muscular performance at the joint level in our VCD-mice, and they responded similarly across groups in response to repetitive fatiguing contractions and exercise training. Supported by NSERC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.