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Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). β-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac β-adrenoceptors (βARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local βAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different βAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by β1AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)-dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca2+) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced β1AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the β1AR-cyclic adenosine monophosphate-protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with β1AR were observed. Stimulating β1AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament β1AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca2+ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.

Skeletal muscle actin (ACTA1) mutations are a prevalent cause of skeletal myopathies consistent with ACTA1's high expression in skeletal muscle. Rare de novo mutations in ACTA1 associated with combined cardiac and skeletal myopathies have been reported, but ACTA1 represents only ~20% of the total actin pool in cardiomyocytes, making its role in cardiomyopathy controversial. Here we demonstrate how a mutation in an actin isoform expressed at low levels in cardiomyocytes can cause cardiomyopathy by focusing on a unique ACTA1 variant, R256H. We previously identified this variant in a family with dilated cardiomyopathy, who had reduced systolic function without clinical skeletal myopathy. Using a battery of multiscale biophysical tools, we show that R256H has potent effects on ACTA1 function at the molecular scale and in human cardiomyocytes. Importantly, we demonstrate that R256H acts in a dominant manner, where the incorporation of small amounts of mutant protein into thin filaments is sufficient to disrupt molecular contractility, and that this effect is dependent on the presence of troponin and tropomyosin. To understand the structural basis of this change in regulation, we resolved a structure of R256H filaments using cryoelectron microscopy, and we see alterations in actin's structure that have the potential to disrupt interactions with tropomyosin. Finally, we show that ACTA1R256H/+ human-induced pluripotent stem cell cardiomyocytes demonstrate reduced contractility and sarcomeric organization. Taken together, we demonstrate that R256H has multiple effects on ACTA1 function that are sufficient to cause reduced contractility and establish a likely causative relationship between ACTA1 R256H and clinical cardiomyopathy. [ABSTRACT FROM AUTHOR]

Introduction: Cells generate mechanical forces mainly through myosin motor activity on the actin cytoskeleton. In C. elegans, actomyosin stress fibers drive contractility of the smooth muscle-like cells of the spermatheca, a distensible, tube-shaped tissue in the hermaphrodite reproductive system and the site of oocyte fertilization. Stretching of the spermathecal cells by oocyte entry triggers activation of the small GTPase Rho. In this study, we asked how forces are distributed in vivo, and explored how spermathecal tissue responds to alterations in myosin activity. Methods: In animals expressing GFP labeled actin or apical membrane complexes, we severed these structures using femtosecond laser ablation and quantified retractions. RNA interference was used to deplete key contractility regulators. Results: We show that the basal actomyosin fibers are under tension in the occupied spermatheca. Reducing actomyosin contractility by depletion of the phospholipase C-e/PLC-1 or non-muscle myosin II/NMY-1, leads to distended spermathecae occupied by one or more embryos, but does not alter tension on the basal actomyosin fibers. However, activating myosin through depletion of the Rho GAP SPV-1 increases tension on the actomyosin fibers, consistent with earlier studies showing Rho drives spermathecal contractility. On the inner surface of the spermathecal tube, tension on the apical junctions is decreased by depletion of PLC-1 and NMY-1. Surprisingly, when basal contractility is increased through SPV-1 depletion, the tension on apical junctions also decreases, with the most significant effect on the junctions aligned in perpendicular to the axis of the spermatheca. Discussion: Our results suggest that much of the tension on the basal actin fibers in the occupied spermatheca is due to the presence of the embryo. Additionally, increased tension on the outer basal surface may compress the apical side, leading to lower tensions apically. The three dimensional shape of the spermatheca plays a role in force distribution and contractility during ovulation. [ABSTRACT FROM AUTHOR]

Background: Following injury, older adults exhibit slow recovery of muscle function. Age-related impairment of sarcolemmal membrane repair may contribute to myocyte death, increasing the need for myogenesis and prolonging recovery. Dietary fish oil (FO) is a common nutritional supplement that may alter plasma membrane composition to enhance the response to membrane injury. Methods: We assessed effects of an 8-week dietary intervention on muscle contractile recovery in aged (22 mo.) rats on control (n = 5) or FO (control + 33 g/kg FO (45% eicosapentaenoic acid; 10% docosahexaenoic acid); n = 5) diets 1-week after contusion injury, as well as adult (8 mo., n = 8) rats on the control diet. Results: Recovery was reduced in aged rats on the control diet vs. adults (63 vs. 80%; p = 0.042), while those on the FO diet recovered similarly to (78%) adults. To directly assess sarcolemma injury, C2C12 cells were cultured in media with and without FO (1, 10, and 100 μg/mL; 24 or 48 h) and injured with an infrared laser in medium containing FM4-64 dye as a marker of sarcolemmal injury. FO reduced the area under the FM4-64 fluorescence-time curve at all concentrations after both 24 and 48 h supplementation. Conclusions: These preliminary data suggest FO might aid recovery of muscle function following injury in older adults by enhancing membrane resealing and repair. [ABSTRACT FROM AUTHOR]

A computational model enables the extraction of two critical myocardial tissue properties: activation time (AT) and contractility (Con) from recorded cardiac strains. However, interference between these parameters reduces the precision and accuracy of the extraction process. This study investigates whether leveraging features in the parameter space can enhance parameter extraction. We utilized a computational model to simulate sarcomere mechanics, creating a parameter space grid of 41 × 41 AT and Con pairs. Each pair generated a simulated strain pattern, and by scanning the grid, we identified cohorts of similar strain patterns for each simulation. These cohorts were represented as binary images—synthetic fingerprints—where the position and shape of each blob indicated extraction uniqueness. We also generated a measurement fingerprint for a strain pattern from a patient with left bundle branch block and compared it to the synthetic fingerprints to calculate a proximity map based on their similarity. This approach allowed us to extract AT and Con using both the measurement fingerprint and the proximity map, corresponding to simple optimization and enhanced parameter extraction methods, respectively. Each synthetic fingerprint consisted of a single connected blob whose size and shape varied characteristically within the parameter space. The AT values extracted from the measurement fingerprint and the proximity map ranged from −59 to 19 ms and from −16 to 14 ms, respectively, while Con values ranged from 48% to 110% and from 85% to 110%, respectively. This study demonstrates that similarity in simulations leads to an asymmetric distribution of parameter values in the parameter space. By using a proximity map, this distortion is considered, significantly improving the accuracy of parameter extraction. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Ryanodine receptor 1 (RYR1)‐related myopathies associated with variants in the RYR1 gene present with a wide range of symptoms and severity. Two of the milder phenotypes associated with dominant pathogenic variants in RYR1 are rhabdomyolysis and myalgia. Only a few studies have investigated the muscle function and structure of individuals with RYR1‐related rhabdomyolysis/myalgia objectively, showing inconsistent results. This study aimed to describe structural changes and contractility of muscles in individuals with RYR1‐related rhabdomyolysis/myalgia. Methods: We investigated 15 individuals with dominant variants in the RYR1‐gene and compared them with 15 age‐, sex‐, and body mass index (BMI)‐matched controls using MRI, stationary isokinetic dynamometry, and comprehensive clinical evaluation. Results: No significant differences were found between individuals with RYR1‐related rhabdomyolysis/myalgia and healthy controls in peak torque, fat fraction, cross‐sectional area, contractile cross‐sectional area, or contractility (p >.05) in muscles of the lower back (MRI data only), thigh, or calf. On clinical examination, three individuals exhibited weakness in hip or back extension on the Medical Research Council (MRC) test and eight had muscle hypertrophy. Individuals with weakness were not hypertrophic. Discussion: Most individuals with RYR1‐related rhabdomyolysis/myalgia have close to normal strength, and normal fat fraction and contractility of muscles, and therefore constitute a mild phenotype of RYR1‐related myopathies. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is a leading cause of morbidity and mortality, and exercise-training (TRN) is known to reduce risk factors and protect the heart from ischemia and reperfusion injury. Though the cardioprotective effects of exercise are well-documented, underlying mechanisms are not well understood. This review highlights recent findings and focuses on cardiac factors with emphasis on K+ channel control of the action potential duration (APD), β-adrenergic and adenosine regulation of cardiomyocyte function, and mitochondrial Ca2+ regulation. TRN-induced prolongation and shortening of the APD at low and high activation rates, respectively, is discussed in the context of a reduced response of the sarcolemma delayed rectifier potassium channel (IK) and increased content and activation of the sarcolemma KATP channel. A proposed mechanism underlying the latter is presented, including the phosphatidylinositol-3kinase/protein kinase B pathway. TRN induced increases in cardiomyocyte contractility and the response to adrenergic agonists are discussed. The TRN-induced protection from reperfusion injury is highlighted by the increased content and activation of the sarcolemma KATP channel and the increased phosphorylated glycogen synthase kinase-3β, which aid in preventing mitochondrial Ca2+ overload and mitochondria-triggered apoptosis. Finally, a brief section is presented on the increased incidences of atrial fibrillation associated with age and in life-long exercisers. [ABSTRACT FROM AUTHOR]

Pregnant individuals with obesity (body mass index, BMI ≥ 30 kg/m2) are more likely to experience prolonged labor and have double the risk of cesarean compared with individuals with normal weight (BMI < 25 kg/m2). The aim of this study was to evaluate whether obesity in pregnancy is associated with reduced spontaneous and oxytocin-stimulated myometrial contractile activity using ex vivo preparations. We also assessed the relationship between maternal BMI and the expression of oxytocin (OXTR) and prostaglandin (FP) receptors in the myometrial tissue. We enrolled 73 individuals with a singleton gestation undergoing scheduled cesarean delivery at term in a prospective cohort study. This included 49 individuals with a pre-pregnancy BMI ≥ 30 kg/m2 and 24 with BMI < 25.0 kg/m2. After delivery, a small strip of myometrium was excised from the upper edge of the hysterotomy. Baseline spontaneous and oxytocin stimulated myometrial contractile activity was measured using ex vivo preparations. Additionally, expression of oxytocin and prostaglandin receptors from myometrial samples were compared using qRT-PCR and western blot techniques. Spontaneous and oxytocin-stimulated contraction frequency, duration, and force were not significantly different in myometrial samples from the obese and normal-weight individuals. Myometrial OXTR gene and protein expression was also similar in the two groups. While FP gene expression was lower in the myometrial samples from the obese group, protein expression did not differ. These data help to address an important knowledge gap related to the biological mechanisms underlying the association between maternal obesity and dysfunctional labor. [ABSTRACT FROM AUTHOR]

Missense mutations in cardiac myosin binding protein C (cMyBP-C) are known to cause hypertrophic cardiomyopathy (HCM). The W792R mutation in the C6 domain of cMyBP-C causes severe, early onset HCM in humans, yet its impact on the function of cMyBP-C and the mechanism through which it causes disease remain unknown. To fully characterize the effect of the W792R mutation on cardiac morphology and function in vivo, we generated a murine knock-in model. We crossed heterozygous W792RWR mice to produce homozygous mutant W792RRR, heterozygous W792RWR , and control W792RWW mice. W792RRR mice present with cardiac hypertrophy, myofibrillar disarray and fibrosis by postnatal day 10 (PND10), and do not survive past PND21. Full-length cMyBP-C is present at similar levels in W792RWW, W792RWR and W792RRR mice and is properly incorporated into the sarcomere. Heterozygous W792RWR mice displayed normal heart morphology and contractility. Permeabilized myocardium from PND10 W792RRR mice showed increased Ca2+ sensitivity, accelerated cross-bridge cycling kinetics, decreased cooperativity in the activation of force, and increased expression of hypertrophy-related genes. In silico modeling suggests that the W792R mutation destabilizes the fold of the C6 domain and increases torsion in the C5-C7 region, possibly impacting regulatory interactions of cMyBP-C with myosin and actin. Based on the data presented here, we propose a model in which mutant W792R cMyBP-C preferentially forms Ca2+ sensitizing interactions with actin, rather than inhibitory interactions with myosin. The W792R-cMyBP-C mouse model provides mechanistic insights into the pathology of this mutation and may provide a mechanism by which other central domain missense mutations in cMyBP-C may alter contractility, leading to HCM. [Display omitted] • Mutations in cardiac myosin binding protein C (cMyBP-C) are a leading cause of hypertrophic cardiomyopathy. • The W792R mutation in the central C6 domain of cMyBP-C leads to severe disease in humans through unknown mechanisms. • Mutant W792R cMyBP-C is stably expressed and is appropriately localized within the sarcomere of W792R knock-in mice. • Homozygous W792R leads to a severe, early onset heart failure phenotype that is not compatible with life. • The W792R mutation is predicted to disrupt the orientation of C6 and its neighboring domains, altering cMyBP-C function. [ABSTRACT FROM AUTHOR]

• Combining information derived from both the amplitude and shape of right ventricular pressure waveform with other data sources provides the basis for a more comprehensive bedside assessment of right ventricular function. Continuous measurement of pressure in the right atrium and pulmonary artery has commonly been used to monitor right ventricular function in critically ill and surgical patients. This approach is largely based upon the assumption that right atrial and pulmonary arterial pressures provide accurate surrogates for diastolic filling and peak right ventricular pressures, respectively. However, due to both technical and physiologic factors, this assumption is not always true. Accordingly, recent studies have begun to emphasize the potential clinical value of also measuring right ventricular pressure at the bedside. This has highlighted both past and emerging research demonstrating the utility of analyzing not only the amplitude of right ventricular pressure but also the shape of the pressure waveform. This brief review summarizes data demonstrating that combining conventional measurements of right ventricular pressure with variables derived from waveform shape allows for more comprehensive and ideally continuous bedside assessment of right ventricular function, particularly when combined with stroke volume measurement or 3D echocardiography, and discusses the potential use of right ventricular pressure analysis in computational models for evaluating cardiac function. [ABSTRACT FROM AUTHOR]

Aims Identifying the imaging method that best predicts all-cause mortality, cardiovascular adverse events, and heart failure risk is crucial for tailoring optimal management. Potential prognostic markers include left ventricular (LV) myocardial mass, ejection fraction, myocardial strain, stroke work, contraction fraction, pressure–strain product, and a new measurement called global longitudinal active strain density (GLASED). This study sought to compare the utility of 23 potential LV prognostic markers of structure and contractile function in a community-based cohort. Methods and results The impact of cardiovascular magnetic resonance image–derived markers extracted by machine learning algorithms was compared with the future risk of adverse events in a group of 44 957 UK Biobank participants. Most markers, including the LV ejection fraction, have limited prognostic value. GLASED was significantly associated with all-cause mortality and major adverse cardiovascular events, with the largest hazard ratio, highest ranking, and differentiated risk in all three tertiles (P ≤ 0.0003). Conclusion GLASED predicted all-cause mortality and major cardiovascular adverse events better than conventional markers of risk and is recommended for assessing patient prognosis. [ABSTRACT FROM AUTHOR]

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Mechano‐electric regulations (MER) play an important role in the maintenance of cardiac performance. Mechano‐calcium and mechano‐electric feedback (MCF and MEF) pathways adjust the cardiomyocyte contractile force according to mechanical perturbations and affects electro‐mechanical coupling. MER integrates all these regulations in one unit resulting in a complex phenomenon. Computational modelling is a useful tool to accelerate the mechanistic understanding of complex experimental phenomena. We have developed a novel model that integrates the MER loop for human atrial cardiomyocytes with proper consideration of feedforward and feedback pathways. The model couples a modified version of the action potential (AP) Koivumäki model with the contraction model by Quarteroni group. The model simulates iso‐sarcometric and isometric twitches and the feedback effects on AP and Ca2+‐handling. The model showed a biphasic response of Ca2+ transient (CaT) peak to increasing pacing rates and highlights the possible mechanisms involved. The model has shown a shift of the threshold for AP and CaT alternans from 4.6 to 4 Hz under post‐operative atrial fibrillation, induced by depressed SERCA activity. The alternans incidence was dependent on a chain of mechanisms including RyRs availability time, MCF coupling, CaMKII phosphorylation, and the stretch levels. As a result, the model predicted a 10% slowdown of conduction velocity for a 20% stretch, suggesting a role of stretch in creation of substrate formation for atrial fibrillation. Overall, we conclude that the developed model provides a physiological CaT followed by a physiological twitch. This model can open pathways for the future studies of human atrial electromechanics. Key points: With the availability of human atrial cellular data, interest in atrial‐specific model integration has been enhanced.We have developed a detailed mathematical model of human atrial cardiomyocytes including the mechano‐electric regulatory loop. The model has gone through calibration and evaluation phases against a wide collection of available human in‐vitro data.The usefulness of the model for analysing clinical problems has been preliminaryly tested by simulating the increased incidence of Ca2+ transient and action potential alternans at high rates in post‐operative atrial fibrillation condition.The model determines the possible role of mechano‐electric feedback in alternans incidence, which can increase vulnerability to atrial arrhythmias by varying stretch levels.We found that our physiologically accurate description of Ca2+ handling can reproduce many experimental phenomena and can help to gain insights into the underlying pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Systemic arterial hypertension is accompanied by autonomic impairments that, if not contained, promotes cardiac functional and morphological damages. Pyridostigmine bromide (PYR) treatment results in positive effects on autonomic control and beneficial cardiac remodeling. These findings were also observed after aerobic physical training (APT). However, little is known about PYR effects on left ventricular contractility, mainly when it is combined with APT. We aimed to investigate the effects of chronic acetylcholinesterase inhibition on cardiac autonomic tone balance, coronary bed reactivity, and left ventricular contractility in spontaneously hypertensive rats (SHR) submitted to APT. Male SHR (18 weeks) were divided into two groups (N = 16): untrained and submitted to APT for 14 weeks (18th to 32nd week). Half of each group was treated with PYR (15 mg/kg/day) for two weeks (31st to 32nd week). The experimental protocol consisted of recording hemodynamic parameters, double autonomic blockade with atropine and propranolol, and assessment of coronary bed reactivity and ventricular contractility in isolated hearts using the Langendorff technique. PYR and APT reduced blood pressure, heart rate, and sympathetic influence on the heart. The Langendorff technique showed that APT increased coronary perfusion pressure and left ventricle contractility in response to coronary flow and β-agonist administration. However, treatment with PYR annulled the effects of APT. In conclusion, although chronic treatment with PYR reduces cardiac sympathetic tonic influence, it does not favor coronary bed reactivity and cardiac contractility gains. PYR treatment in the trained SHR group nullified the coronary vascular reactivity and cardiac contractility gains. [ABSTRACT FROM AUTHOR]

Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the SLC4A4 gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain. No cardiac manifestations have been reported from patients with pRTA, but studies in adult rats with virally induced reduction in cardiac NBCe1-B expression indicate that NBCe1-B loss leads to cardiac hypertrophy and prolonged QT intervals in rodents. NBCe1-null mice die shortly after weaning, so the consequence of congenital, global NBCe1 loss on the heart is unknown. To circumvent this issue, we characterized the cardiac function of NBCe1-B/C-null (KOb/c) mice that survive up to 2 months of age and which, due to the uninterrupted expression of NBCe1-A, do not exhibit the confounding acidemia of the globally null mice. In contrast to the viral knockdown model, cardiac hypertrophy was not present in KOb/c mice as assessed by heart-weight-to-body-weight ratios and cardiomyocyte cross-sectional area. However, echocardiographic analysis revealed reduced left ventricular ejection fraction, and intraventricular pressure–volume measurements demonstrated reduced load-independent contractility. We also observed increased QT length variation in KOb/c mice. Finally, using the calcium indicator Fura-2 AM, we observed a significant reduction in the amplitude of Ca2+ transients in paced KOb/c cardiomyocytes. These data indicate that congenital, global absence of NBCe1-B/C leads to impaired cardiac contractility and increased QT length variation in juvenile mice. It remains to be determined whether the cardiac phenotype in KOb/c mice is influenced by the absence of NBCe1-B/C from neuronal and endocrine tissues. [ABSTRACT FROM AUTHOR]

Abstract Systemic arterial hypertension is accompanied by autonomic impairments that, if not contained, promotes cardiac functional and morphological damages. Pyridostigmine bromide (PYR) treatment results in positive effects on autonomic control and beneficial cardiac remodeling. These findings were also observed after aerobic physical training (APT). However, little is known about PYR effects on left ventricular contractility, mainly when it is combined with APT. We aimed to investigate the effects of chronic acetylcholinesterase inhibition on cardiac autonomic tone balance, coronary bed reactivity, and left ventricular contractility in spontaneously hypertensive rats (SHR) submitted to APT. Male SHR (18 weeks) were divided into two groups (N = 16): untrained and submitted to APT for 14 weeks (18th to 32nd week). Half of each group was treated with PYR (15 mg/kg/day) for two weeks (31st to 32nd week). The experimental protocol consisted of recording hemodynamic parameters, double autonomic blockade with atropine and propranolol, and assessment of coronary bed reactivity and ventricular contractility in isolated hearts using the Langendorff technique. PYR and APT reduced blood pressure, heart rate, and sympathetic influence on the heart. The Langendorff technique showed that APT increased coronary perfusion pressure and left ventricle contractility in response to coronary flow and β-agonist administration. However, treatment with PYR annulled the effects of APT. In conclusion, although chronic treatment with PYR reduces cardiac sympathetic tonic influence, it does not favor coronary bed reactivity and cardiac contractility gains. PYR treatment in the trained SHR group nullified the coronary vascular reactivity and cardiac contractility gains.

Cellular contractility, migration, and extracellular matrix (ECM) mechanics are critical for a wide range of biological processes including embryonic development, wound healing, tissue morphogenesis, and regeneration. Even though the distinct response of cells near the tissue periphery has been previously observed in cell-laden microtissues, including faster kinetics and more prominent cell-ECM interactions, there are currently no models that can fully combine coupled surface and bulk mechanics and kinetics to recapitulate the morphogenic response of these constructs. Mailand et al. (Biophys J 117(5):975–986, 2019) had shown the importance of active elastocapillarity in cell-laden microtissues, but modeling the distinct mechanosensitive migration of cells on the periphery and the interior of highly deforming tissues has not been possible thus far, especially in the presence of active elastocapillary effects. This paper presents a framework for understanding the interplay between cellular contractility, migration, and ECM mechanics in dynamically morphing soft tissues accounting for distinct cellular responses in the bulk and the surface of tissues. The major novelty of this approach is that it enables modeling the distinct migratory and contractile response of cells residing on the tissue surface and the bulk, where concurrently the morphing soft tissues undergo large deformations driven by cell contractility. Additionally, the simulation results capture the changes in shape and cell concentration for wounded and intact microtissues, enabling the interpretation of experimental data. The numerical procedure that accounts for mechanosensitive stress generation, large deformations, diffusive migration in the bulk and a distinct mechanism for diffusive migration on deforming surfaces is inspired from recent work on bulk and surface poroelasticity of hydrogels involving elastocapillary effects, but in this work, a two-field weak form is proposed and is able to alleviate numerical instabilities that were observed in the original method that utilized a three-field mixed finite element formulation. [ABSTRACT FROM AUTHOR]

Abstract Chronic heart failure is one of the most common reasons for hospitalization. Current risk stratification is based on ejection fraction, whereas many arrhythmic events occur in patients with relatively preserved ejection fraction. We aim to investigate the mechanistic link between proarrhythmic abnormalities, reduced contractility and diastolic dysfunction in heart failure, using electromechanical modelling and simulations of human failing cardiomyocytes. We constructed, calibrated and validated populations of human electromechanical models of failing cardiomyocytes, that were able to reproduce the prolonged action potential, reduced contractility and diastolic dysfunction as observed in human data, as well as increased propensity to proarrhythmic incidents such as early afterdepolarization and beat-to-beat alternans. Our simulation data reveal that proarrhythmic incidents tend to occur in failing myocytes with lower diastolic tension, rather than with lower contractility, due to the relative preserved SERCA and sodium calcium exchanger current. These results support the inclusion of end-diastolic volume to be potentially beneficial in the risk stratifications of heart failure patients.

Abstract Background Global longitudinal active strain energy density (GLASED) is an innovative method for assessing myocardial function and quantifies the work performed per unit volume of the left ventricular myocardium. The GLASED, measured using MRI, is the best prognostic marker currently available. This study aimed to evaluate the feasibility of measuring the GLASED using echocardiography and to investigate potential differences in the GLASED among athletes based on age and sex. Methods An echocardiographic study was conducted with male controls, male and female young athletes, and male and female veteran athletes. GLASED was calculated from the myocardial stress and strain. Results The mean age (in years) of the young athletes was 21.6 for males and 21.4 for females, while the mean age of the veteran athletes was 53.5 for males and 54.2 for females. GLASED was found to be highest in young male athletes (2.40 kJ/m3) and lowest in female veterans (1.96 kJ/m3). Veteran males exhibited lower values (1.96 kJ/m3) than young male athletes did (P

This article explores the movement of sarcomeres in the heart muscle and the role of the protein titin in this process. It challenges previous beliefs by showing that sarcomeres do not all move in synchrony during muscle contraction. The asynchrony is influenced by factors such as sarcomere length and calcium levels. The article suggests that this asynchrony may contribute to impaired heart function in conditions like dilated cardiomyopathy. Further research is needed to understand the link between sarcomere movement and heart disease. [Extracted from the article]

Aortic stenosis (AS) and mitral regurgitation (MR) result in different patterns of left ventricular remodeling and hypertrophy. We characterized left ventricular wall stress (LVWS) profiles in pressure and volume-overloaded systems, examined the relationship between baseline LVWS and cardiac remodeling, and assessed the acute effects of valve intervention on LVWS using invasive pressures combined with cardiac magnetic resonance (CMR) imaging measures of left ventricular volumes/mass. A total of 47 patients with severe AS undergoing transcatheter aortic valve replacement (TAVR) and 15 patients with severe MR undergoing MitraClip (MC) underwent a 6-minute walk test (6MWT), transthoracic echocardiogram, and CMR before their procedures. Catheters in the left ventricle were used to record hemodynamic changes before and after valve/clip deployment. This was integrated with CMR data to calculate LVWS before and after intervention. The TAVR group demonstrated significant reductions in systolic LVWS post procedure (median 24.7 Pa [IQR: 14 Pa] pre vs median 17.3 Pa [IQR: 12 Pa] post; P < 0.001). The MC group demonstrated significant reductions in diastolic LVWS (median 6.4 Pa [IQR: 5 Pa] pre vs median 4.3 Pa [IQR: 4.1 Pa] post; P = 0.021) with no significant change in systolic LVWS (30.6 ±1.61 pre vs 33 ±2.47 Pa post; P = 0.16). There was an inverse correlation between baseline systolic LVWS and 6MWT in the TAVR group (r = −0.31; P = 0.04). TAVR results in significant reductions in systolic LVWS acutely. MC results in significant reductions in diastolic LVWS. Higher baseline systolic LVWS in TAVR is associated with shorter 6MWT suggesting that in AS, LVWS may be a useful marker of early decompensation. [ABSTRACT FROM AUTHOR]

Chronic hypoxia plays a central role in diverse pulmonary pathologies, but its effects on longitudinal changes in the biomechanical behavior of proximal pulmonary arteries remain poorly understood. Similarly, effects of normoxic recovery have not been well studied. Here, we report hypoxia-induced changes in composition, vasoactivity, and passive biaxial mechanics in the main branch pulmonary artery of male C57BL/6J mice exposed to 10% FiO2 for 1, 2, or 3 weeks. We observed significant changes in extracellular matrix, and consequently wall mechanics, as early as 1 week of hypoxia. While circumferential stress and stiffness returned toward normal values by 2–3 weeks of hypoxia, area fractions of cytoplasm and thin collagen fibers did not return toward normal until after 1 week of normoxic recovery. By contrast, elastic energy storage and overall distensibility remained reduced after 3 weeks of hypoxia as well as following 1 week of normoxic recovery. While smooth muscle and endothelial cell responses were attenuated under hypoxia, smooth muscle but not endothelial cell responses recovered following 1 week of subsequent normoxia. Collectively, these data suggest that homeostatic processes were unable to preserve or restore overall function, at least over a brief period of normoxic recovery. Longitudinal changes are critical in understanding large pulmonary artery remodeling under hypoxia, and its reversal, and will inform predictive models of vascular adaptation. [ABSTRACT FROM AUTHOR]

Recent reports of myocardial recovery after mechanical unloading with left ventricular assist devices (LVADs) have challenged the prevailing notion that end-stage heart failure (HF) is irreversible. To improve our understanding of this phenomenon, we comprehensively analysed the structural, functional, and energetic changes in failing human cardiomyocytes after LVAD implantation. Based on a prospectively registered protocol (PROSPERO-CRD42022380214), 30 eligible studies were identified from 940 records with a pooled population of 648 patients predominantly with non-ischaemic cardiomyopathy. LVAD led to a substantial regression in myocyte size similar to that of donor hearts (standardised mean difference, −1.29; p<0.001). The meta-regression analysis revealed that HF duration was a significant modifier on the changes in myocyte size. There were some suggestions of fibrosis reversal (−5.17%; p=0.009); however, this was insignificant after sensitivity analysis. Developed force did not improve in cardiac trabeculae (n=5 studies); however, non-physiological isometric contractions were tested. At the myocyte level (n=4 studies), contractile kinetics improved where the time-to-peak force reduced by 41.7%–50.7% and time to 50% relaxation fell by 47.4%–62.1% (p<0.05). Qualitatively, LVAD enhanced substrate utilisation and mitochondrial function (n=6 studies). Most studies were at a high risk of bias. The regression of maladaptive hypertrophy, partial fibrosis reversal, and normalisation in metabolic pathways after LVAD may be a testament to the heart's remarkable plasticity, even in the advanced stages of HF. However, inconsistencies exist in force-generating capabilities. Using more physiological force-length work-loop assays, addressing the high risks of bias and clinical heterogeneity are crucial to better understand the phenomenon of reverse remodelling. [ABSTRACT FROM AUTHOR]

Chronic heart failure is one of the most common reasons for hospitalization. Current risk stratification is based on ejection fraction, whereas many arrhythmic events occur in patients with relatively preserved ejection fraction. We aim to investigate the mechanistic link between proarrhythmic abnormalities, reduced contractility and diastolic dysfunction in heart failure, using electromechanical modelling and simulations of human failing cardiomyocytes. We constructed, calibrated and validated populations of human electromechanical models of failing cardiomyocytes, that were able to reproduce the prolonged action potential, reduced contractility and diastolic dysfunction as observed in human data, as well as increased propensity to proarrhythmic incidents such as early afterdepolarization and beat-to-beat alternans. Our simulation data reveal that proarrhythmic incidents tend to occur in failing myocytes with lower diastolic tension, rather than with lower contractility, due to the relative preserved SERCA and sodium calcium exchanger current. These results support the inclusion of end-diastolic volume to be potentially beneficial in the risk stratifications of heart failure patients. [ABSTRACT FROM AUTHOR]

Background: Global longitudinal active strain energy density (GLASED) is an innovative method for assessing myocardial function and quantifies the work performed per unit volume of the left ventricular myocardium. The GLASED, measured using MRI, is the best prognostic marker currently available. This study aimed to evaluate the feasibility of measuring the GLASED using echocardiography and to investigate potential differences in the GLASED among athletes based on age and sex. Methods: An echocardiographic study was conducted with male controls, male and female young athletes, and male and female veteran athletes. GLASED was calculated from the myocardial stress and strain. Results: The mean age (in years) of the young athletes was 21.6 for males and 21.4 for females, while the mean age of the veteran athletes was 53.5 for males and 54.2 for females. GLASED was found to be highest in young male athletes (2.40 kJ/m3) and lowest in female veterans (1.96 kJ/m3). Veteran males exhibited lower values (1.96 kJ/m3) than young male athletes did (P < 0.001). Young females demonstrated greater GLASED (2.28 kJ/m3) than did veteran females (P < 0.01). However, no significant difference in the GLASED was observed between male and female veterans. Conclusion: Our findings demonstrated the feasibility of measuring GLASED using echocardiography. GLASED values were greater in young male athletes than in female athletes and decreased with age, suggesting possible physiological differences in their myocardium. The sex-related differences observed in GLASED values among young athletes were no longer present in veteran athletes. We postulate that measuring the GLASED may serve as a useful additional screening tool for cardiac diseases in athletes, particularly for those with borderline phenotypes of hypertrophic and dilated cardiomyopathies. [ABSTRACT FROM AUTHOR]

Aim: Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction and development of emphysema. Among the comorbidities associated with COPD, skeletal muscle dysfunction is known to affect exercise capacity and the survival rate of patients. Pulmonary rehabilitation (PR), via exercise training, is essential for COPD patients. However, the response to PR is most often moderate. An animal model that recapitulates critical features of chronic human disease and provides access to muscle function should therefore be useful to improve PR benefits. Methods: We used a rat model of induced emphysema based on pulmonary instillations of elastase (ELA) and lipopolysaccharides (LPS). We assessed the long‐term effects of ELA/LPS and the potential effectiveness of endurance training on the skeletal muscle function. In vivo strength of the animals, and ex vivo contractility, endurance, type 1 fiber proportion, fiber cross‐sectional area, and capillarization of both soleus and extensor digitorum longus (EDL) were assessed. Results: An impaired overall muscle strength with decreased force, reduced capillarization, and atrophy of type 1 fiber of EDL was observed in ELA/LPS rats. Soleus was not affected. Endurance training was able to reduce fatigability, and increase type 1 fiber proportion and capillarization of soleus, and improve force, endurance, and capillarization of EDL in control and ELA/LPS rats. Conclusion: Our rat model of induced emphysema, which shares some features with the phenotype present in patients with COPD, could represent a suitable model to study skeletal muscle dysfunction and the effects of exercise training on muscle function in patients. [ABSTRACT FROM AUTHOR]

Muscle isometric torque fluctuates according to time-of-day with such variation owed to the influence of circadian molecular clock genes. Satellite cells (SCs), the muscle stem cell population, also express molecular clock genes with several contractile-related genes oscillating in a diurnal pattern. Currently, limited evidence exists regarding the relationship between SCs and contractility, although long-term SC ablation alters muscle contractile function. Whether there are acute alterations in contractility following SC ablation and with respect to the time-of-day is unknown. We investigated whether short-term SC ablation affected contractile function at two times of day and whether any such alterations led to different extents of eccentric contraction-induced injury. Using an established mouse model to deplete SCs, we characterized muscle clock gene expression and ex vivo contractility at two times-of-day (morning: 0700 and afternoon: 1500). Morning-SC+ animals demonstrated ∼25%–30% reductions in tetanic/eccentric specific forces and, after eccentric injury, exhibited ∼30% less force-loss and ∼50% less dystrophinnegative fibers versus SC− counterparts; no differences were noted between Afternoon groups (Morning-SC+: −5.63 ± 0.61, Morning-SC−: −7.93 ± 0.61; N/cm2; P < 0.05) (Morning-SC+: 32 ± 2.1, Morning-SC−: 64 ± 10.2; dystrophinnegative fibers; P < 0.05). As Ca++ kinetics underpin force generation, we also evaluated caffeine-induced contracture force as an indirect marker of Ca++ availability and found similar force reductions in Morning-SC+ vs. SC− mice. We conclude that force production is reduced in the presence of SCs in the morning but not in the afternoon, suggesting that SCs may have a time-of-day influence over contractile function. NEW & NOTEWORTHY: Muscle isometric torque fluctuates according to time-of-day with such variation owed to molecular clock regulation. Satellite cells (SCs) have recently demonstrated diurnal characteristics related to muscle physiology. In our work, force production was reduced in the presence versus absence of SCs in the morning but, not in the afternoon. Morning-SC+ animals, producing lower force, sustained lesser degrees of injury versus SC− counterparts. One potential mechanism underpinning lower forces produced appears to be lower calcium availability. [ABSTRACT FROM AUTHOR]

Cell migration through 3D environments is essential to development, disease, and regeneration processes. Conceptual models of migration have been developed primarily on the basis of 2D cell behaviors, but a general understanding of 3D cell migration is still lacking due to the added complexity of the extracellular matrix. Here, using a multiplexed biophysical imaging approach for single-cell analysis of human cell lines, we show how the subprocesses of adhesion, contractility, actin cytoskeletal dynamics, and matrix remodeling integrate to produce heterogeneous migration behaviors. This single-cell analysis identifies three modes of cell speed and persistence coupling, driven by distinct modes of coordination between matrix remodeling and protrusive activity. The framework that emerges establishes a predictive model linking cell trajectories to distinct subprocess coordination states.

9p21.3 locus polymorphisms have the strongest correlation with coronary artery disease, but as a noncoding locus, disease connection is enigmatic. The lncRNA ANRIL found in 9p21.3 may regulate vascular smooth muscle cell (VSMC) phenotype to contribute to disease risk. We observed significant heterogeneity in induced pluripotent stem cell-derived VSMCs from patients homozygous for risk versus isogenic knockout or nonrisk haplotypes. Subpopulations of risk haplotype cells exhibited variable morphology, proliferation, contraction, and adhesion. When sorted by adhesion, risk VSMCs parsed into synthetic and contractile subpopulations, i.e., weakly adherent and strongly adherent, respectively. Of note, >90% of differentially expressed genes coregulated by haplotype and adhesion and were associated with Rho GTPases, i.e., contractility. Weakly adherent subpopulations expressed more short isoforms of ANRIL, and when overexpressed in knockout cells, ANRIL suppressed adhesion, contractility, and αSMA expression. These data suggest that variable lncRNA penetrance may drive mixed functional outcomes that confound pathology.

IntroductionCells generate mechanical forces mainly through myosin motor activity on the actin cytoskeleton. In C. elegans, actomyosin stress fibers drive contractility of the smooth muscle-like cells of the spermatheca, a distensible, tube-shaped tissue in the hermaphrodite reproductive system and the site of oocyte fertilization. Stretching of the spermathecal cells by oocyte entry triggers activation of the small GTPase Rho. In this study, we asked how forces are distributed in vivo, and explored how spermathecal tissue responds to alterations in myosin activity.MethodsIn animals expressing GFP labeled actin or apical membrane complexes, we severed these structures using femtosecond laser ablation and quantified retractions. RNA interference was used to deplete key contractility regulators.ResultsWe show that the basal actomyosin fibers are under tension in the occupied spermatheca. Reducing actomyosin contractility by depletion of the phospholipase C-ε/PLC-1 or non-muscle myosin II/NMY-1, leads to distended spermathecae occupied by one or more embryos, but does not alter tension on the basal actomyosin fibers. However, activating myosin through depletion of the Rho GAP SPV-1 increases tension on the actomyosin fibers, consistent with earlier studies showing Rho drives spermathecal contractility. On the inner surface of the spermathecal tube, tension on the apical junctions is decreased by depletion of PLC-1 and NMY-1. Surprisingly, when basal contractility is increased through SPV-1 depletion, the tension on apical junctions also decreases, with the most significant effect on the junctions aligned in perpendicular to the axis of the spermatheca.DiscussionOur results suggest that much of the tension on the basal actin fibers in the occupied spermatheca is due to the presence of the embryo. Additionally, increased tension on the outer basal surface may compress the apical side, leading to lower tensions apically. The three dimensional shape of the spermatheca plays a role in force distribution and contractility during ovulation.

Proposes To investigate the toxicological mechanism of hexavalent chromium, the effects of hexavalent chromium on the heart, gastrocnemius muscle and action potential of sciatic nerve trunk in bullfrog were studied from the perspective of electrophysiology. Methods The bullfrog hearts were treated with different concentrations of potassium dichromate solution by intraperitoneal injection and isolated heart perfusion, and the effects of hexavalent chromium on heart rate and contractility in vivo and in vitro were determined. The gastrocnemius muscle was wrapped with a gauze soaked in potassium dichromate solution, and the contractility of gastrocnemius muscle was measured. The effect of hexavalent chromium on conduction velocity of sciatic nerve trunk was measured by extracellular electrode guidance. Findings The results show that potassium dichromate has an inhibitory effect on heart rate and contractility, and the mechanism may be related to the inhibition of Ttype and L-type calcium channels activity by hexavalent chromium; However, 1 mg/L chromium increases the heart rate of in vivo frog heart after 15 to 30 min, which may be due to the “hormetic effect”; 0.001 to 10 mg/L hexavalent chromium has a concentration-dependent enhancement effect on gastrocnemius contractility, showing a positive inotropic effect, which may be the result of “hormetic effect”; Hexavalent chromium at 100 mg/L inhibits the gastrocnemius contractility, showing a negative inotropic effect, the mechanism is related to the inhibitory effect of hexavalent chromium on ryanodine receptor (RyR); Hexavalent chromium reduces the conduction velocity of sciatic nerve trunk action potential in a concentration and time-dependent manner, and the mechanism was related to the inactivation of voltage-gated Na+ channels by hexavalent chromium. Conclusions Hexavalent chromium has toxicity on heart, skeletal muscle, and nerve, which could provide some electrophysiological experimental basis for the toxicity study of hexavalent chromium.

Abstract Background Preterm labor is caused by multiple etiologies, including intra-amniotic infection and/or intra-amniotic inflammation, vascular disorders, cervical disease, decidual senescence, and breakdown of maternal–fetal tolerance. Accumulating evidence in vivo and in vitro has shown that an allergic reaction, including anaphylaxis, can induce preterm uterine contractions. This report describes a case of a pregnant woman who developed anaphylaxis and regular uterine contractions after the ingestion of a strawberry-coated biscuit. We also review the mechanism of allergic reaction (hypersensitivity)-induced preterm labor. Case presentation A 31-year-old woman (gravida 1, para 0) at 30+2 weeks of gestation was admitted to the labor and delivery unit with regular uterine contractions and anaphylactic symptoms after she ingested a strawberry-coated biscuit as a snack. The uterine contractions resolved after the treatment of anaphylaxis by administering antihistamines and epinephrine. The patient subsequently delivered at 39+3 weeks of gestation. The amniotic fluid profile showed no infection or inflammation. A postpartum skin-prick test confirmed a positive type 1 hypersensitivity reaction to the strawberry-coated biscuit. Conclusions We report a case of anaphylaxis-induced uterine contractility in which uterine contractions subsided after the treatment of anaphylaxis. The absence of intra-amniotic infection and/or intra-amniotic inflammation and the cause of the anaphylaxis were confirmed. Our findings indicate that maternal allergic reactions may be one of the mechanisms of preterm labor.

Actin is a highly conserved and fundamental protein in eukaryotes and participates in a broad spectrum of cellular functions. Cells maintain a conserved ratio of actin isoforms, with muscle and non‐muscle actins representing the main actin isoforms in muscle and non‐muscle cells, respectively. Actin isoforms have specific and redundant functional roles and display different biochemistries, cellular localization, and interactions with myosins and actin‐binding proteins. Understanding the specific roles of actin isoforms from the structural and functional perspective is crucial for elucidating the intricacies of cytoskeletal dynamics and regulation and their implications in health and disease. Here, we review how the structure contributes to the functional mechanisms of actin isoforms with a special emphasis on the questions of how post‐translational modifications and disease‐linked mutations affect actin isoforms biochemistry, function, and interaction with actin‐binding proteins and myosin motors. [ABSTRACT FROM AUTHOR]

PKD1 (polycystin 1) and PKD2 (polycystin 2) are expressed in a variety of different cell types, including arterial smooth muscle and endothelial cells. PKD1 is a transmembrane domain protein with a large extracellular N‐terminus that is proposed to act as a mechanosensor and receptor. PKD2 is a member of the transient receptor potential (TRP) channel superfamily which is also termed TRPP1. Mutations in the genes which encode PKD1 and PKD2 lead to autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most prevalent monogenic disorders in humans and is associated with extrarenal and vascular complications, including hypertension. Recent studies have uncovered mechanisms of activation and physiological functions of PKD1 and PKD2 in arterial smooth muscle and endothelial cells. It has also been found that PKD function is altered in the vasculature during ADPKD and hypertension. We will summarize this work and discuss future possibilities for this area of research. [ABSTRACT FROM AUTHOR]

Objective Delayed cord clamping (DCC) has been recently adopted in neonatal resuscitation. The immediate cardiac hemodynamic effects related to DCC more than 30 seconds was not studied. We aimed to study the effect of DCC at 120 seconds compared with 30 seconds on multiple hemodynamic variables in full-term infants using an electrical cardiometry (EC) device. Study Design Present study is a randomized clinical trial. The study was conducted with full-term infants who were delivered at the Obstetrics and Gynecology Department in Cairo University Hospital. Sixty-eight full term infants were successfully enrolled in this trial. Cardiac output (CO) and other hemodynamic parameters were evaluated in this study by EC device. Hemoglobin, glucose, and bilirubin concentrations were measured at 24 hours. Newborn infants were assigned randomly into group 1: DCC at 30 seconds, and group 2: DCC at 120 seconds, based on the time of cord clamping. Results Stroke volume (SV) (mL) and CO (L/min) were significantly higher in group 2 compared with group 1 at 5 minutes (6.71 vs. 5.35 and 1.09 vs. 0.75), 10 minutes (6.43 vs. 5.59 and 0.88 vs. 0.77), 15 minutes (6.45 vs. 5.60 and 0.89 vs. 0.76), and 24 hours (6.67 vs. 5.75 and 0.91vs. 0.81), respectively. Index of contractility (ICON; units) was significantly increased in group 2 at 5 minutes compared with group1 (114.2 vs. 83.8). Hematocrit (%) and total bilirubin concentrations (mg/dL) at 24 hours were significantly increased in group 2 compared with group 1 (51.5 vs. 40.5 and 3.8 vs. 2.9, respectively). Conclusion Stroke volume and cardiac output are significantly higher in neonates with DCC at 120 seconds compared with 30 seconds that continues for the first 24 hours. Key Points CO is significantly increased with DCC at 120 seconds. SV is significantly increased with DCC at 120 seconds. Such effects continued during the entire 24 hours of life in full-term infants. [ABSTRACT FROM AUTHOR]

It remains unclear why some patients develop heart failure without evidence of structural damage. One theory relates to impaired myocardial energetics and ventricular-arterial decoupling as the heart works against adverse mechanical load. In this original study, we propose the novel concept of myocardial fatigue to capture this phenomenon and aim to investigate this using human cardiomyocytes subjected to a modern work-loop contractility model that closely mimics in vivo cardiac cycles. This proof-of-concept study (NCT04899635) will use human myocardial tissue samples from patients undergoing cardiac surgery to develop a reproducible protocol to isolate robust calcium-tolerant cardiomyocytes. Thereafter, work-loop contractility experiments will be performed over a range of preload, afterload and cycle frequency as a function of time to elicit any reversible reduction in contractile performance (i.e. fatigue). This will provide novel insight into mechanisms behind heart failure and myocardial recovery and serve as a valuable research platform in translational cardiovascular research. [ABSTRACT FROM AUTHOR]

Background: Preterm labor is caused by multiple etiologies, including intra-amniotic infection and/or intra-amniotic inflammation, vascular disorders, cervical disease, decidual senescence, and breakdown of maternal–fetal tolerance. Accumulating evidence in vivo and in vitro has shown that an allergic reaction, including anaphylaxis, can induce preterm uterine contractions. This report describes a case of a pregnant woman who developed anaphylaxis and regular uterine contractions after the ingestion of a strawberry-coated biscuit. We also review the mechanism of allergic reaction (hypersensitivity)-induced preterm labor. Case presentation A 31-year-old woman (gravida 1, para 0) at 30+2 weeks of gestation was admitted to the labor and delivery unit with regular uterine contractions and anaphylactic symptoms after she ingested a strawberry-coated biscuit as a snack. The uterine contractions resolved after the treatment of anaphylaxis by administering antihistamines and epinephrine. The patient subsequently delivered at 39+3 weeks of gestation. The amniotic fluid profile showed no infection or inflammation. A postpartum skin-prick test confirmed a positive type 1 hypersensitivity reaction to the strawberry-coated biscuit. Conclusions: We report a case of anaphylaxis-induced uterine contractility in which uterine contractions subsided after the treatment of anaphylaxis. The absence of intra-amniotic infection and/or intra-amniotic inflammation and the cause of the anaphylaxis were confirmed. Our findings indicate that maternal allergic reactions may be one of the mechanisms of preterm labor. [ABSTRACT FROM AUTHOR]

Background: Pericytes are multifunctional contractile cells that reside on capillaries. Pericytes are critical regulators of cerebral blood flow and blood–brain barrier function, and pericyte dysfunction may contribute to the pathophysiology of human neurological diseases including Alzheimers disease, multiple sclerosis, and stroke. Induced pluripotent stem cell (iPSC)-derived pericytes (iPericytes) are a promising tool for vascular research. However, it is unclear how iPericytes functionally compare to primary human brain vascular pericytes (HBVPs). Methods: We differentiated iPSCs into iPericytes of either the mesoderm or neural crest lineage using established protocols. We compared iPericyte and HBVP morphologies, quantified gene expression by qPCR and bulk RNA sequencing, and visualised pericyte protein markers by immunocytochemistry. To determine whether the gene expression of neural crest iPericytes, mesoderm iPericytes or HBVPs correlated with their functional characteristics in vitro, we quantified EdU incorporation following exposure to the key pericyte mitogen, platelet derived growth factor (PDGF)-BB and, contraction and relaxation in response to the vasoconstrictor endothelin-1 or vasodilator adenosine, respectively. Results: iPericytes were morphologically similar to HBVPs and expressed canonical pericyte markers. However, iPericytes had 1864 differentially expressed genes compared to HBVPs, while there were 797 genes differentially expressed between neural crest and mesoderm iPericytes. Consistent with the ability of HBVPs to respond to PDGF-BB signalling, PDGF-BB enhanced and a PDGF receptor-beta inhibitor impaired iPericyte proliferation. Administration of endothelin-1 led to iPericyte contraction and adenosine led to iPericyte relaxation, of a magnitude similar to the response evoked in HBVPs. We determined that neural crest iPericytes were less susceptible to PDGFR beta inhibition, but responded most robustly to vasoconstrictive mediators. Conclusions: iPericytes express pericyte-associated genes and proteins and, exhibit an appropriate physiological response upon exposure to a key endogenous mitogen or vasoactive mediators. Therefore, the generation of functional iPericytes would be suitable for use in future investigations exploring pericyte function or dysfunction in neurological diseases. [ABSTRACT FROM AUTHOR]

Background and Aims: Some achalasia patients exhibit esophageal contractile activity on follow‐up after treatment, yet its importance remains unclear. We aimed to identify factors associated with presence of contractility after treatment and to assess its impact on timed barium esophagram (TBE) and clinical outcomes. Methods: Patients with type I or II achalasia on baseline high‐resolution manometry (HRM) who completed HRM, TBE, and functional lumen imaging probe (FLIP) after treatment were retrospectively identified. Contractility was defined on post‐treatment HRM as presence of at least 1 supine swallow with DCI ≥100 mmHg s cm. Key Results: One hundred twenty‐two patients were included (mean age 48 ± 17 years, 50% female). At follow‐up evaluation after treatment (54% peroral endoscopic myotomy, 24% pneumatic dilation, 22% laparoscopic Heller myotomy), 61 (50%) patients had contractility on HRM. Patients with contractility (compared to those without) more frequently had type II achalasia (84% vs 57%, p = 0.001) and a post‐treatment normal EGJ opening classification on FLIP (69% vs 49%; p < 0.001). In the subgroup of patients with post‐treatment integrated relaxation pressure <15 mmHg and normal EGJ opening on FLIP (n = 53), those with contractility had a lower median column height on TBE at 1 min (4 vs 7 cm, p = 0.002) and 5 min (0 vs 5 cm, p = 0.001). In patients with "abnormal" EGJ metrics, patients with contractility showed lower symptom scores (median Eckardt score 2 vs 3, p = 0.03). Conclusions & Inferences: Occurring more frequently in type II achalasia, and if adequate EGJ opening is achieved after treatment, esophageal contractility may contribute to improved esophageal emptying and improved symptoms in non‐spastic achalasia. Preservation of esophageal body muscle could improve outcomes in these patients. [ABSTRACT FROM AUTHOR]

Remimazolam is a newly developed ultra‐short‐acting benzodiazepine that exerts sedative effects. This study aimed to clarify the effects of remimazolam on cardiac contractility. In a randomised‐parallel group trial, haemodynamic parameters were compared between propofol (n = 11) and remimazolam (n = 12) groups during the induction of general anaesthesia in patients undergoing non‐cardiac surgery. In a preclinical study, the direct effects of remimazolam on cardiac contractility were also evaluated using isolated rat hearts. RNA sequence data obtained from rat and human hearts were analysed to assess the expression patterns of the cardiac γ‐aminobutyric acid type A (GABAA) receptor subunits. In a clinical study, the proportional change of the maximum rate of arterial pressure rise was milder during the study period in the remimazolam group (propofol: −52.6 [10.2] (mean [standard deviation])% vs. remimazolam: −39.7% [10.5%], p = 0.007). In a preclinical study, remimazolam did not exert a negative effect on left ventricle developed pressure, whereas propofol did exert a negative effect after bolus administration of a high dose (propofol: −26.9% [3.5%] vs. remimazolam: −1.1 [6.9%], p < 0.001). Analysis of the RNA sequence revealed a lack of γ subunits, which are part of the major benzodiazepine binding site of the GABAA receptor, in rat and human hearts. These results indicate that remimazolam does not have a direct negative effect on cardiac contractility, which might contribute to its milder effect on cardiac contractility during the induction of general anaesthesia. The expression patterns of cardiac GABAA receptor subunits might be associated with the unique pharmacokinetics of benzodiazepines in the heart. [ABSTRACT FROM AUTHOR]

The molecular mechanisms of sarcomere proteins underlie the contractile function of the heart. Although our understanding of the sarcomere has grown tremendously, the focus has been on ventricular sarcomere isoforms due to the critical role of the ventricle in health and disease. However, atrial-specific or -enriched myofilament protein isoforms, as well as isoforms that become expressed in disease, provide insight into ways this complex molecular machine is fine-tuned. Here, we explore how atrialenriched sarcomere protein composition modulates contractile function to fulfill the physiological requirements of atrial function. We review how atrial dysfunction negatively affects the ventricle and the many cardiovascular diseases that have atrial dysfunction as a comorbidity. We also cover the pathophysiology of mutations in atrial-enriched contractile proteins and how they can cause primary atrial myopathies. Finally, we explore what is known about contractile function in various forms of atrial fibrillation. The differences in atrial function in health and disease underscore the importance of better studying atrial contractility, especially as therapeutics currently in development to modulate cardiac contractility may have different effects on atrial sarcomere function. [ABSTRACT FROM AUTHOR]

Abstract Background/objectives Myocardial infarction (MI) frequently leads to cardiac remodeling and failure with impaired life quality, playing an important role in cardiovascular deaths. Although physical exercise is a well-recognized effective non-pharmacological therapy for cardiovascular diseases, the effects of strength training (ST) on the structural and functional aspects of cardiac remodeling need to be further documented. In this study, we aimed to investigate the role of a linear block ST protocol in the rat model of MI. Methods and results After 6 weeks of MI induction or sham surgery, male adult rats performed ST for the following 12 weeks. The ladder-based ST program was organized in three mesocycles of 4 weeks, with one load increment for each block according to the maximal carrying load test. After 12 weeks, the infarcted-trained rats exhibited an increase in performance, associated with reduced cardiac hypertrophy and pulmonary congestion compared with the untrained group. Despite not changing MI size, the ST program partially prevented cardiac dilatation and ventricular dysfunction assessed by echocardiography and hemodynamics, and interstitial fibrosis evaluated by histology. In addition, isolated cardiac muscles from infarcted-trained rats had improved contractility parameters in a steady state, and in response to calcium or stimuli pauses. Conclusions The ST in infarcted rats increased the capacity to carry mass, associated with attenuation of cardiac remodeling and pulmonary congestion with improving cardiac function that could be attributed, at least in part, to the improvement of myocardial contractility.

[Display omitted] [ABSTRACT FROM AUTHOR]

Background/objectives: Myocardial infarction (MI) frequently leads to cardiac remodeling and failure with impaired life quality, playing an important role in cardiovascular deaths. Although physical exercise is a well-recognized effective non-pharmacological therapy for cardiovascular diseases, the effects of strength training (ST) on the structural and functional aspects of cardiac remodeling need to be further documented. In this study, we aimed to investigate the role of a linear block ST protocol in the rat model of MI. Methods and results: After 6 weeks of MI induction or sham surgery, male adult rats performed ST for the following 12 weeks. The ladder-based ST program was organized in three mesocycles of 4 weeks, with one load increment for each block according to the maximal carrying load test. After 12 weeks, the infarcted-trained rats exhibited an increase in performance, associated with reduced cardiac hypertrophy and pulmonary congestion compared with the untrained group. Despite not changing MI size, the ST program partially prevented cardiac dilatation and ventricular dysfunction assessed by echocardiography and hemodynamics, and interstitial fibrosis evaluated by histology. In addition, isolated cardiac muscles from infarcted-trained rats had improved contractility parameters in a steady state, and in response to calcium or stimuli pauses. Conclusions: The ST in infarcted rats increased the capacity to carry mass, associated with attenuation of cardiac remodeling and pulmonary congestion with improving cardiac function that could be attributed, at least in part, to the improvement of myocardial contractility. [ABSTRACT FROM AUTHOR]

Aims Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by an HCM sarcomere mutation. Methods and results Contractility was measured of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harbouring an HCM mutation cultured in 2D and in 3D engineered heart tissue (EHT). Mutations in the gene encoding β-myosin heavy chain (MYH7 -R403Q) or cardiac troponin T (TNNT2 -R92Q) were investigated. In 2D, intracellular [Ca2+], action potential and ion currents were determined. HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM. SGLT2i enhance the relaxation of hiPSC-CMs, to a larger extent in HCM compared to control hiPSC-CMs. Moreover, SGLT2i-effects on relaxation in R403Q EHT increased with culture duration, i.e. hiPSC-CMs maturation. Canagliflozin's effects on relaxation were more pronounced than empagliflozin and dapagliflozin. SGLT2i acutely altered Ca2+ handling in HCM hiPSC-CMs. Analyses of SGLT2i-mediated mechanisms that may underlie enhanced relaxation in mutant hiPSC-CMs excluded SGLT2, Na+/H+ exchanger, peak and late Nav1.5 currents, and L-type Ca2+ current, but indicate an important role for the Na+/Ca2+ exchanger. Indeed, electrophysiological measurements in mutant hiPSC-CM indicate that SGLT2i altered Na+/Ca2+ exchange current. Conclusion SGLT2i (canagliflozin > dapagliflozin > empagliflozin) acutely enhance relaxation in human EHT, especially in HCM and upon prolonged culture. SGLT2i may represent a potential therapy to correct early cardiac dysfunction in HCM. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration involves the breakdown of the discs of the spine due to genetics, aging, or faulty mechanical loading. As part of the progression of the disease, nucleus pulposus cells lose their phenotypic characteristics, inducing inflammation and extracellular matrix (ECM) alterations that result in a loss of disc mechanical homeostasis. Fibronectin is one ECM molecule that has been shown to be upregulated in disc degeneration and plays an important role in the progression of a wide variety of fibrotic diseases. Fragments of fibronectin have also long been associated with both osteoarthritis and disc degeneration. The goal of this work is to test the effects of fibronectin on disc cell phenotype, mechanosensing, and inflammatory signaling. We identify that fibronectin increases the activation of cellular contractility, the mechanosensitive transcription factor Yes‐associated protein, and the inflammatory transcription factor nuclear factor‐κB. This results in decreased production and expression of proteoglycans, which are required to maintain healthy disc function. Thus, fibronectin is a potential regulator of phenotypic changes in disc degeneration, and a potential target for treating disc degeneration at the cellular level. Understanding the role of fibronectin, and its potential as a therapeutic target, could provide new approaches for preventing or reversing disc degeneration. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to evaluate the association between fetal cardiac deformation analysis (CDA) and cardiac function with severe adverse perinatal outcomes in fetuses with isolated left congenital diaphragmatic hernia (CDH). Methods: CDA in each ventricle (contractility, size, and shape), evaluated by speckle tracking and novel FetalHQ software, and markers of cardiac function (E/A ratios, pulmonary and aortic peak systolic velocities, and sigmoid annular valve diameters), were evaluated in fetuses with isolated left CDH. Two evaluations were performed: at referral (CDA and function) and within 3 weeks of delivery (CDA). Severe adverse neonatal outcomes were considered neonatal death (ND) or survival with CDH-associated pulmonary hypertension (CDH-PH). Differences and associations between CDA, cardiac function, and severe adverse outcomes were estimated. Results: Fifty fetuses were included, and seventeen (34%) had severe adverse neonatal outcomes (11 ND and 6 survivors with CDH-PH). At first evaluation, the prevalence of a small left ventricle was 34% (17/50) with a higher prevalence among neonates presenting severe adverse outcomes (58.8 [10/17] vs. 21.2% [7/33]; p = 0.01; OR, 5.03 [1.4–19.1; p = 0.01]) and among those presenting with neonatal mortality (8/11 [72.7] vs. 9/39 [23.0%]; p = 0.03; OR, 8.9 [1.9–40.7; p = 0.005]). No differences in cardiac function or strain were noted between fetuses with or without severe adverse outcomes. Within 3 weeks of delivery, the prevalence of small left ventricle was higher (19/34; 55.8%) with a more globular shape (reduced transverse/longitudinal ratio). A globular right ventricle was significantly associated with ND or survival with CDH-PH (OR, 14.2 [1.5–138.3]; p = 0.02). Conclusion: Fetuses with isolated CDH at risk of perinatal death or survival with CDH-PH had a higher prevalence of a small left ventricle and abnormal shape of the right ventricle. [ABSTRACT FROM AUTHOR]