Synchronous Contraction Research Articles

A Predictive Nomogram for the Occurrence of Gastroesophageal Reflux Disease After Sleeve Gastrectomy: A Study Based on Preoperative HERM.

Gastroesophageal reflux disease (GERD) is a common complication after laparoscopic sleeve gastrectomy (LSG); This study aimed to construct a model that can predict the incidence of GERD after LSG by exploring the correlation between the results of high-resolution esophageal manometry (HREM) and the incidence of GERD after LSG. We collected the clinical data of patients who had undergone HREM before bariatric surgery from September 2013 to September 2019 at the bariatric center of our hospital. The Gerd-Q scores during the postoperative follow-up were collected to determine the incidence of GERD. A logistic regression analysis was performed to explore the correlation of the HREM results and general clinical data with the incidence of GERD after LSG. The percentage of synchronous contractions, lower esophageal sphincter (LES) resting pressure, and history of smoking were correlated with the development of GERD after LSG, with the history of smoking and percentage of synchronous contractions as risk factors and LES resting pressure as a protective factor. The training set showed an area under the ROC curve (AUC) of the nomogram model of 0.847. The validation set showed an AUC of 0.761. The decision and clinical impact curves showed a high clinical value for the prediction model. The HREM results correlated with the development of GERD after LSG, with the percentage of synchronous contractions and LES resting pressure showing predictive value. Combined with the history of smoking, the predictive model showed a high confidence and clinical value.

Successful cardiac resynchronization therapy reduces negative septal work in patient-specific models of dyssynchronous heart failure.

In patients with dyssynchronous heart failure (DHF), cardiac conduction abnormalities cause the regional distribution of myocardial work to be non-homogeneous. Cardiac resynchronization therapy (CRT) using an implantable, programmed biventricular pacemaker/defibrillator, can improve the synchrony of contraction between the right and left ventricles in DHF, resulting in reduced morbidity and mortality and increased quality of life. Since regional work depends on wall stress, which cannot be measured in patients, we used computational methods to investigate regional work distributions and their changes after CRT. We used three-dimensional multi-scale patient-specific computational models parameterized by anatomic, functional, hemodynamic, and electrophysiological measurements in eight patients with heart failure and left bundle branch block (LBBB) who received CRT. To increase clinical translatability, we also explored whether streamlined computational methods provide accurate estimates of regional myocardial work. We found that CRT increased global myocardial work efficiency with significant improvements in non-responders. Reverse ventricular remodeling after CRT was greatest in patients with the highest heterogeneity of regional work at baseline, however the efficacy of CRT was not related to the decrease in overall work heterogeneity or to the reduction in late-activated regions of high myocardial work. Rather, decreases in early-activated regions of myocardium performing negative myocardial work following CRT best explained patient variations in reverse remodeling. These findings were also observed when regional myocardial work was estimated using ventricular pressure as a surrogate for myocardial stress and changes in endocardial surface area as a surrogate for strain. These new findings suggest that CRT promotes reverse ventricular remodeling in human dyssynchronous heart failure by increasing regional myocardial work in early-activated regions of the ventricles, where dyssynchrony is specifically associated with hypoperfusion, late systolic stretch, and altered metabolic activity and that measurement of these changes can be performed using streamlined approaches.

Abstract We042: Gelatin hydrogel elasticity influences TBX18-induced pacemaker cell behavior

Introduction: Extracellular matrix (ECM) stiffness plays a role in determining cell behavior during development and maintenance of organ function. Polystyrene dishes typically show an elastic modulus of 1 gigaPa, which is far from the elastic modulus of 10 to 15 kiloPa for myocardium. Gelatin, a derivative of collagen, is a major structural scaffolding in the myocardium including the sinoatrial node. Hypothesis: We hypothesized that gelatin hydrogel at varying stiffness serves as a platform to modulate the automaticity of cardiac pacemaker cells. Methods: Freshly isolated neonatal rat ventricular myocytes (NRVMs) were cultured as monolayers on regular, plastic cell culture plate or on 3%, 5%, and 10% gelatin hydrogel that represents a stiffness of 1.3 ± 0.3, 6.4 ± 1.5, and 13.6 ± 3.5 kPa, respectively. All cell culture surface was coated with fibronectin. NRVMs were transduced with Adv-TBX18 or Adv-GFP at day 0 (d0). Results: TBX18-NRVMs showed significantly more spontaneous synchronous contractions on the gelatin hydrogel (22 ± 12, 29 ± 1, 33 ± 9 on 3, 5, or 10% gelatin, respectively) than on plastic (10 ± 11) at d4. Control, GFP-NRVMs showed few spontaneous synchronous contractions regardless of the cell culture platform (3 ± 4, 2 ± 3, 0 ± 0 bpm at 3, 5, 10% gelatin, respectively; 3 ± 7 bpm on plastic, n = 5 to 6 wells/group) at d4. TBX18-NRVMs exhibited significantly more spontaneous synchronous Ca 2+ transients/min on 10% gelatin hydrogel (33 ± 2) than on 3% gelatin hydrogel (9 ± 2) or 5% gelatin hydrogel (19 ± 8) (n = 3, p<0.05) at d8. Immunostaining revealed that Hcn4 protein expression in TBX18-NRVMs was higher on 10% gelatin than on plastic at d2. The percentage of vimentin+ nonmyocytes in TBX18-NRVMs was higher on 10% gelatin (39.5 ± 2.2 %) compared to either on 5% (26.6 ± 1.7%) or on 3% gelatin (27.5 ± 4.2) at d6. Conclusions: Our data indicate that spontaneous and synchronized contractions of TBX18-induced pacemaker cells were significantly higher on gelatin hydrogel with myocardium-like stiffness compared to those grown on plastic culture medium. The data suggest that modulating ECM stiffness may impact the automaticity of cardiac pacemaker tissues, and could serve as a platform to study sinus node dysfunction.

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.

Inhibition of autophagy prevents cardiac dysfunction at early stages of cardiomyopathy in Bag3-deficient hearts

The HSP70 co-chaperone BAG3 targets unfolded proteins to degradation via chaperone assisted selective autophagy (CASA), thereby playing pivotal roles in the proteostasis of adult cardiomyocytes (CMs). However, the complex functions of BAG3 for regulating autophagy in cardiac disease are not completely understood. Here, we demonstrate that conditional inactivation of Bag3 in murine CMs leads to age-dependent dysregulation of autophagy, associated with progressive cardiomyopathy. Surprisingly, Bag3-deficient CMs show increased canonical and non-canonical autophagic flux in the juvenile period when first signs of cardiac dysfunction appear, but reduced autophagy during later stages of the disease. Juvenile Bag3-deficient CMs are characterized by decreased levels of soluble proteins involved in synchronous contraction of the heart, including the gap junction protein Connexin 43 (CX43). Reiterative administration of chloroquine (CQ), an inhibitor of canonical and non-canonical autophagy, but not inactivation of Atg5, restores normal concentrations of soluble cardiac proteins in juvenile Bag3-deficient CMs without an increase of detergent-insoluble proteins, leading to complete recovery of early-stage cardiac dysfunction in Bag3-deficient mice. We conclude that loss of Bag3 in CMs leads to age-dependent differences in autophagy and cardiac dysfunction. Increased non-canonical autophagic flux in the juvenile period removes soluble proteins involved in cardiac contraction, leading to early-stage cardiomyopathy, which is prevented by reiterative CQ treatment.

Atrioventricular Interval Modulation (AVIM) therapy for ambulatory systolic blood pressure (aSBP) reduction with a dual chamber pacemaker: comparison of conduction system vs. right ventricular pacing

Abstract Background AVIM is a pacing algorithm incorporated into dual-chamber pacemakers to treat hypertension. AVIM delivers repeating sequences of short and longer atrioventricular delays leading to reduced preload and afterload. The therapy lowers blood pressure while simultaneously modulating the autonomic nervous system. The marked blood pressure reducing capability of AVIM has been already confirmed by a previous randomized clinical trial using conventional right ventricular (RV) pacing. Nevertheless, whether a similar blood pressure reduction could be also achieved by AVIM when conduction system pacing (CSP) is applied instead of RV pacing has not been investigated yet. Considering the facts that CSP using Left Bundle Branch Area Pacing (LBBAP) has been found to elicit more synchronous ventricular contraction and improved hemodynamics compared to RV pacing and AVIM is associated with a signficant burden of ventricular pacing, it is tempting to hypothesize that AVIM with CSP could be particularly beneficial. Purpose To compare the effects of AVIM therapy when delivered via an LBBAP location with the effects when delivered using a traditional RV lead location. Methods This single-center study evaluated subjects indicated for a dual chamber pacemaker who also had uncontrolled hypertension despite a stable dose of ³ 1 antihypertensive drug. Leads were placed in the RV or the LBBAP position. Subjects entered a run-in period of 4 weeks in which baseline office (oSBP)and 24-hour aSBP were measured. Subjects with baseline aSBP >130 mmHg and oSBP>140 mmHg at week 4 were included in the study. AVIM therapy was activated and a 24-hour aSBP was performed immediately after activation. Results Using a dedicated CSP pacemaker lab setup, CSP was performed in 5 patients with the Select Secure electrode (model 3830-69 cm) delivered via a fixed curve sheath (C315HIS). During the run in phase, in 3 out of the 5 CSP-AVIM patients, high blood pressure did not reach the level of inclusion and therefore these patients were not used for further analysis. In the remaining two patients, AVIM was activated. These two patients had a V6 stimulus-peak time of 69 ms and 61 ms, while V1 stimulus peak time was: 121ms and 109ms respectively. The effect of AVIM on 24-hour aSBP in the activated CSP-AVIM patients was compared to the average effect seen in patients from the same center enrolled in the prior randomized study with leads in the RV. Table 1 shows individual aSBP values for the two patient groups. Results suggest that delivery of AVIM therapy through leads in either position generates a significant reduction in blood pressure: -24.1 mmHg vs. -15.4 mmHg when the lead is placed in LBBAP or RV positions respectively. Conclusion These results demonstrate a significant reduction in aSBP in both lead locations. Additional studies evaluating larger sample sizes are required to assess if specific lead positions are preferable.Table 1

Comparison between left bundle branch area pacing and right ventricular pacing: ventricular electromechanical synchrony and risk of atrial high-rate episodes.

The electromechanical dyssynchrony associated with right ventricular pacing (RVP) has been found to have adverse impact on clinical outcomes. Several studies have shown that left bundle branch area pacing (LBBAP) has superior pacing parameters compared with RVP. We aimed to assess the difference in ventricular electromechanical synchrony and investigate the risk of atrial high-rate episodes (AHREs) in patients with LBBAP and RVP. We consecutively identified 40 patients with atrioventricular block and no prior atrial fibrillation. They were divided according to the ventricular pacing sites: the LBBAP group and the RVP group (including the right ventricular apical pacing (RVA) group and the right side ventricular septal pacing (RVS) group). Evaluation of ventricular electromechanical synchrony was implemented using electrocardiogram and two-dimensional speckle tracking echocardiography (2D-STE). AHRE was defined as event with an atrial frequency of ≥176 bpm lasting for ≥6 min recorded by pacemakers during follow-up. The paced QRS duration of the LBBAP group was significantly shorter than that of the other two groups: LBBAP 113.56 ± 9.66 ms vs. RVA 164.73 ± 14.49 ms, p < 0.001; LBBAP 113.56 ± 9.66 ms vs. RVS 148.23 ± 17.3 ms, p < 0.001. The LBBAP group showed shorter maximum difference (TDmax), and standard deviation (SD) of the time to peak systolic strain among the 18 left ventricular segments, and time of septal-to-posterior wall motion delay (SPWMD) compared with the RVA group (TDmax, 87.56 ± 56.01 ms vs. 189.85 ± 91.88 ms, p = 0.001; SD, 25.40 ± 14.61 ms vs. 67.13 ± 27.40 ms, p < 0.001; SPWMD, 28.75 ± 21.89 ms vs. 99.09 ± 46.56 ms, p < 0.001) and the RVS group (TDmax, 87.56 ± 56.01 ms vs. 156.46 ± 55.54 ms, p = 0.003; SD, 25.40 ± 14.61 ms vs. 49.02 ± 17.85 ms, p = 0.001; SPWMD, 28.75 ± 21.89 ms vs. 91.54 ± 26.67 ms, p < 0.001). The interventricular mechanical delay (IVMD) was shorter in the LBBAP group compared with the RVA group (-5.38 ± 9.31 ms vs. 44.82 ± 16.42 ms, p < 0.001) and the RVS group (-5.38 ± 9.31 ms vs. 25.31 ± 21.36 ms, p < 0.001). Comparing the RVA group and the RVS group, the paced QRS duration and IVMD were significantly shorter in the RVS group (QRS duration, 164.73 ± 14.49 ms vs. 148.23 ± 17.3 ms, p = 0.02; IVMD, 44.82 ± 16.42 ms vs. 25.31 ± 21.36 ms, p = 0.022). During follow-up, 2/16 (12.5%) LBBAP patients, 4/11 (36.4%) RVA patients, and 8/13 (61.5%) RVS patients had recorded novel AHREs. LBBAP was proven to be independently associated with decreased risk of AHREs than RVP (log-rank p = 0.043). LBBAP generates narrower paced QRS and better intro-left ventricular and biventricular contraction synchronization compared with traditional RVP. LBBAP was associated with a decreased risk of AHREs compared with RVP.

Semiology and Neurophysiology of Clonic Seizures: A Report of 39 Patients.

Clonic seizures are currently defined as repetitive and rhythmic myoclonic contractions of a specific body part, producing twitching movements at a frequency of 0.2-5 Hz. There are few studies in the literature that have reported a detailed analysis of the semiology, neurophysiology, and lateralizing value of clonic seizures. In this article, we aim to report our findings from a retrospective review of 39 patients. We identified 39 patients (48 seizures) from our center who had been admitted with clonic seizures between 2016 and 2022. We performed a retrospective review of their video-EEG recordings for semiology and ictal EEG findings. Seventeen patients also had simultaneous surface-EMG (sEMG) electrodes placed on affected body parts, which were analyzed as well. The most common initial affected body parts were face, arm, and hand. In most of the cases, seizures propagated from lower face to upper face and distal hand to proximal arm. The most common seizure-onset zone was the perirolandic region, and the most common EEG seizure pattern was paroxysmal rhythmic monomorphic activity. The lateralizing value for EEG seizure onset to contralateral hemisphere in unilateral clonic seizures (n = 39) was 100%. All seizures recorded with sEMG electrodes demonstrated synchronous brief tetanic contractions of agonists and antagonists, alternating with synchronous silent periods. Arrhythmic clonic seizures were associated with periodic epileptiform discharges on the EEG, whereas rhythmic clonic seizures were associated with paroxysmal rhythmic monomorphic activity. Overall, the most common etiology was cerebrovascular injuries, followed by tumors. Clonic seizures are characterized by synchronized brief tetanic contractions of agonist and antagonistic muscles alternating with synchronized silent periods, giving rise to the visible twitching. The most common seizure onset zone is in the perirolandic region, which is consistent with the symptomatogenic zone being in the primary motor area. The lateralizing value of unilateral clonic seizures for seizure onset in the contralateral hemisphere is 100%.

In Vitro Modulation of Spontaneous Activity in Embryonic Cardiomyocytes Cultured on Poly(vinyl alcohol)/Bioglass Type 58S Electrospun Scaffolds.

Because of the physiological and cardiac changes associated with cardiovascular disease, tissue engineering can potentially restore the biological functions of cardiac tissue through the fabrication of scaffolds. In the present study, hybrid nanofiber scaffolds of poly (vinyl alcohol) (PVA) and bioglass type 58S (58SiO2-33CaO-9P2O5, Bg) were fabricated, and their effect on the spontaneous activity of chick embryonic cardiomyocytes in vitro was determined. PVA/Bg nanofibers were produced by electrospinning and stabilized by chemical crosslinking with glutaraldehyde. The electrospun scaffolds were analyzed to determine their chemical structure, morphology, and thermal transitions. The crosslinked scaffolds were more stable to degradation in water. A Bg concentration of 25% in the hybrid scaffolds improved thermal stability and decreased degradation in water after PVA crosslinking. Cardiomyocytes showed increased adhesion and contractility in cells seeded on hybrid scaffolds with higher Bg concentrations. In addition, the effect of Ca2+ ions released from the bioglass on the contraction patterns of cultured cardiomyocytes was investigated. The results suggest that the scaffolds with 25% Bg led to a uniform beating frequency that resulted in synchronous contraction patterns.

A Simple Analysis and Scoring of Zebrafish Larvae Cardiac Performance in Teratogenicity Study using Light Microscopy and ImageJ Software

Background: Zebrafish is one of the suitable model organisms for teratogenicity study. One of the organs assessed during the study is the heart. There has been an established scoring system for the cardiac morphology, but not cardiac performance. Furthermore, the assessment of cardiac function in zebrafish often use expensive instruments and complicated methods. Materials and Methods: Cardiac performance scoring method and system was proposed for zebrafish larvae aged 5 dpf. Observation was done using light microscope and the video of the observation was taken using smartphone or camera. The videos were then converted and rendered to be compatible with the ImageJ program using the measure function and time series analyzer plugin. The assessed parameters were the heart rate and rhythm, strength of heart contraction, and synchronicity between atrium and ventricle. Results: The scoring system was formulated based on the assessments towards healthy control 5 dpf zebrafish larvae and references. The score for cardiac performance ranged from 3 – 6, with score 3 representing arrhythmic, weak, and asynchronous contractions, while score 6 representing rhythmic, strong, and synchronous contraction. The scoring system was also valid to point out the difference in cardiac performance between healthy control zebrafish larvae and larvae that previously exposed to lithium as teratogenic agent (p = 0.000). Conclusions: The scoring methods and system developed in this study allowed for a non – expensive and simple assessment of cardiac performance in zebrafish larvae aged 5 dpf, especially for a teratogenicity study.

Pressure overload is associated with right ventricular dyssynchrony in heart failure with reduced ejection fraction.

The determinants and relevance of right ventricular (RV) mechanical dyssynchrony in heart failure with reduced ejection fraction (HFrEF) are poorly understood. We hypothesized that increased afterload may adversely affect the synchrony of RV contraction. A total of 148 patients with HFrEF and 36 controls underwent echocardiography, right heart catheterization, and gated single-photon emission computed tomography to measure RV chamber volumes and mechanical dyssynchrony (phase standard deviation of systolic displacement timing). Exams were repeated after preload (N=135) and afterload (N=15) modulation. Patients with HFrEF showed higher RV dyssynchrony compared with controls (40.6±17.5° vs. 27.8±9.1°, P<0.001). The magnitude of RV dyssynchrony in HFrEF correlated with larger RV and left ventricular (LV) volumes, lower RV ejection fraction (RVEF) and LV ejection fraction, reduced intrinsic contractility, increased heart rate, higher pulmonary artery (PA) load, and impaired RV-PA coupling (all P≤0.01). Low RVEF was the strongest predictor of RV dyssynchrony. Left bundle branch block (BBB) was associated with greater RV dyssynchrony than right BBB, regardless of QRS duration. RV afterload reduction by sildenafil improved RV dyssynchrony (P=0.004), whereas preload change with passive leg raise had modest effect. Patients in the highest tertiles of RV dyssynchrony had an increased risk of adverse clinical events compared with those in the lower tertile [T2/T3 vs. T1: hazard ratio 1.98 (95% confidence interval 1.20-3.24), P=0.007]. RV dyssynchrony is associated with RV remodelling, dysfunction, adverse haemodynamics, and greater risk for adverse clinical events. RV dyssynchrony is mitigated by acute RV afterload reduction and could be a potential therapeutic target to improve RV performance in HFrEF.

Engineered Heart Tissues for Standard 96-Well Tissue Culture Plates.

Engineered heart tissues (EHTs) have been shown to be a valuable platform for disease investigation and therapeutic testing by increasing human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) maturity and better recreating the native cardiac environment. The protocol detailed in this chapter describes the generation of miniaturized EHTs (mEHTs) incorporating hiPSC-CMs and human stromal cells in a fibrin hydrogel. This platform utilizes an array of silicone posts designed to fit in a standard 96-well tissue culture plate. Stromal cells and hiPSC-CMs are cast in a fibrin matrix suspended between two silicone posts, forming an mEHT that produces synchronous muscle contractions. The platform presented here has the potential to be used for high throughput characterization and screening of disease phenotypes and novel therapeutics through measurements of the myocardial function, including contractile force and calcium handling, and its compatibility withimmunostaining.

Current Role of Conduction System Pacing in Patients Requiring Permanent Pacing.

His bundle pacing (HBP) and left bundle branch pacing (LBBP) are novel methods of pacing directly pacing the cardiac conduction system. HBP while developed more than two decades ago, only recently moved into the clinical mainstream. In contrast to conventional cardiac pacing, conduction system pacing including HBP and LBBP utilizes the native electrical system of the heart to rapidly disseminate the electrical impulse and generate a more synchronous ventricular contraction. Widespread adoption of conduction system pacing has resulted in a wealth of observational data, registries, and some early randomized controlled clinical trials. While much remains to be learned about conduction system pacing and its role in electrophysiology, data available thus far is very promising. In this review of conduction system pacing, the authors review the emergence of conduction system pacing and its contemporary role in patients requiring permanent cardiac pacing.

Efficient generation of a self-organizing neuromuscular junction model from human pluripotent stem cells

The complex neuromuscular network that controls body movements is the target of severe diseases that result in paralysis and death. Here, we report the development of a robust and efficient self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells that can be maintained long-term in simple adherent conditions. The timely application of specific patterning signals instructs the simultaneous development and differentiation of position-specific brachial spinal neurons, skeletal muscles, and terminal Schwann cells. High-content imaging reveals self-organized bundles of aligned muscle fibers surrounded by innervating motor neurons that form functional neuromuscular junctions. Optogenetic activation and pharmacological interventions show that the spinal neurons actively instruct the synchronous skeletal muscle contraction. The generation of a soNMJ model from spinal muscular atrophy patient-specific iPSCs reveals that the number of NMJs and muscle contraction is severely affected, resembling the patient’s pathology. In the future, the soNMJ model could be used for high-throughput studies in disease modeling and drug development. Thus, this model will allow us to address unmet needs in the neuromuscular disease field.

Late Miocene to present synchronous extension and contraction in the eastern Pamir: Insights from inversion of thermochronologic data across the southern Muztaghata dome

Late Cenozoic gneiss domes cover ∼30% of the surface of the Pamir salient in the northwestern end of the India−Asia collision zone. The highest peaks of the Pamir are in the east, where the ∼250-km-long, ∼N−S-trending Kongur Shan extensional system controls the topography. We combined 115 new apatite (U-Th-Sm)/He and zircon (U-Th)/He single-grain dates from 18 samples and previous thermochronologic data with three-dimensional thermokinematic models to constrain the thermo-tectonic history of the southern portion of the Muztaghata dome, one of the largest gneiss domes in the eastern Pamir. The new cooling dates from the western boundary of the southern Muztaghata dome generally increase with distance from the southern Kongur Shan fault and are related to normal faulting along the fault at near-surface levels over the last 6.5 m.y. The new dates across the central−eastern portion of the dome outline the previously recorded U-shaped date pattern at a higher spatial resolution. The modeling indicates that this pattern is most likely the result of uplift and erosion above a flat-ramp-flat thrust fault at depth over the last 7 m.y. Modeling does not resolve how topographic changes may have affected the observed distribution of cooling dates, but it indicates a faster thrust-slip rate associated with an increase in relief and a slower one associated with steady-state topography. Our results suggest that the modern topography along the southern Muztaghata dome, similar to the rest of the eastern Pamir salient, is shaped by normal faulting at shallow depth, but its growth may still be governed by contraction and crustal thickening at depth.

Multi-channel electrohysterography enabled uterine contraction characterization and its effect in delivery assessment

Uterine contractions are routinely monitored by tocodynamometer (TOCO) at late stage of pregnancy to predict the onset of labor. However, TOCO reveals no information on the synchrony and coherence of contractions, which are important contributors to a successful delivery. The electrohysterography (EHG) is a recording of the electrical activities that trigger the local muscles to contract. The spatial–temporal information embedded in multiple channel EHG signals make them ideal for characterizing the synchrony and coherence of uterine contraction. To proceed, contractile time-windows are identified from TOCO signals and are then used to segment out the simultaneously recorded EHG signals of different channels. We construct sample entropy SamEn and Concordance Correlation based feature ψ from these EHG segments to quantify the synchrony and coherence of contraction. To test the effectiveness of the proposed method, 122 EHG recordings in the Icelandic EHG database were divided into two groups according to the time difference between the gestational ages at recording and at delivery (TTD). Both SamEn and ψ show clear difference in the two groups (p<10−5) even when measurements were made 120 h before delivery. Receiver operating characteristic curve analysis of these two features gave AUC values of 0.834 and 0.726 for discriminating imminent labor defined with TTD ≤ 24 h. The SamEn was significantly smaller in women (0.1433) of imminent labor group than in women (0.3774) of the pregnancy group. Using an optimal cutoff value of SamEn to identify imminent labor gives sensitivity, specificity, and accuracy as high as 0.909, 0.712 and 0.743, respectively. These results demonstrate superiority in comparing to the existing SOTA methods. This study is the first research work focusing on characterizing the synchrony property of contractions from the electrohysterography signals. Despite the very limited dataset used in the validation process, the promising results open a new direction to the use of electrohysterography in obstetrics.

An injectable conductive hydrogel with dual responsive release of rosmarinic acid improves cardiac function and promotes repair after myocardial infarction.

Myocardial infarction (MI) causes irreversible damage to the heart muscle, seriously threatening the lives of patients. Injectable hydrogels have attracted extensive attention in the treatment of MI. By promoting the coupling of mechanical and electrical signals between cardiomyocytes, combined with synergistic therapeutic strategies targeting the pathological processes of inflammation, proliferation, and fibrotic remodeling after MI, it is expected to improve the therapeutic effect. In this study, a pH/ROS dual-responsive injectable hydrogel was developed by modifying xanthan gum and gelatin with reversible imine bond and boronic ester bond double crosslinking. By encapsulating polydopamine-rosmarinic acid nanoparticles to achieve on-demand drug release in response to the microenvironment of MI, thereby exerting anti-inflammatory, anti-apoptotic, and anti-fibrosis effects. By adding conductive composites to improve the conductivity and mechanical strength of the hydrogel, restore electrical signal transmission in the infarct area, promote synchronous contraction of cardiomyocytes, avoid induced arrhythmias, and induce angiogenesis. Furthermore, the multifunctional hydrogel promoted the expression of cardiac-specific markers to restore cardiac function after MI. The in vivo and in vitro results demonstrate the effectiveness of this synergistic comprehensive treatment strategy in MI treatment, showing great application potential to promote the repair of infarcted hearts.

Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes

BackgroundPolymorphic ventricular tachycardia (PMVT) is a rare genetic disease associated with structurally normal hearts which in 8% of cases can lead to sudden cardiac death, typically exercise-induced. We previously showed a link between the RyR2-H29D mutation and a clinical phenotype of short-coupled PMVT at rest using patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs). In the present study, we evaluated the effects of clinical and experimental anti-arrhythmic drugs on the intracellular Ca2+ handling, contractile and molecular properties in PMVT hiPSC-CMs in order to model a personalized medicine approach in vitro.MethodsPreviously, a blood sample from a patient carrying the RyR2-H29D mutation was collected and reprogrammed into several clones of RyR2-H29D hiPSCs, and in addition we generated an isogenic control by reverting the RyR2-H29D mutation using CRIPSR/Cas9 technology. Here, we tested 4 drugs with anti-arrhythmic properties: propranolol, verapamil, flecainide, and the Rycal S107. We performed fluorescence confocal microscopy, video-image-based analyses and biochemical analyses to investigate the impact of these drugs on the functional and molecular features of the PMVT RyR2-H29D hiPSC-CMs.ResultsThe voltage-dependent Ca2+ channel inhibitor verapamil did not prevent the aberrant release of sarcoplasmic reticulum (SR) Ca2+ in the RyR2-H29D hiPSC-CMs, whereas it was prevented by S107, flecainide or propranolol. Cardiac tissue comprised of RyR2-H29D hiPSC-CMs exhibited aberrant contractile properties that were largely prevented by S107, flecainide and propranolol. These 3 drugs also recovered synchronous contraction in RyR2-H29D cardiac tissue, while verapamil did not. At the biochemical level, S107 was the only drug able to restore calstabin2 binding to RyR2 as observed in the isogenic control.ConclusionsBy testing 4 drugs on patient-specific PMVT hiPSC-CMs, we concluded that S107 and flecainide are the most potent molecules in terms of preventing the abnormal SR Ca2+ release and contractile properties in RyR2-H29D hiPSC-CMs, whereas the effect of propranolol is partial, and verapamil appears ineffective. In contrast with the 3 other drugs, S107 was able to prevent a major post-translational modification of RyR2-H29D mutant channels, the loss of calstabin2 binding to RyR2. Using patient-specific hiPSC and CRISPR/Cas9 technologies, we showed that S107 is the most efficient in vitro candidate for treating the short-coupled PMVT at rest.

Measuring Cardiac Dyssynchrony with DENSE (Displacement Encoding with Stimulated Echoes)-A Systematic Review.

In this review, we introduce the displacement encoding with stimulated echoes (DENSE) method for measuring myocardial dyssynchrony using cardiovascular magnetic resonance (CMR) imaging. We provide an overview of research findings related to DENSE from the past two decades and discuss other techniques used for dyssynchrony evaluation. Additionally, the review discusses the potential uses of DENSE in clinical practice. A search was conducted to identify relevant articles published from January 2000 through January 2023 using the Scopus, Web of Science, PubMed and Cochrane databases. The following search term was used: (DENSE OR 'displacement encoding with stimulated echoes' OR CURE) AND (dyssynchrony* OR asynchron* OR synchron*) AND (MRI OR 'magnetic resonance' OR CMR). After removing duplicates, researchers screened a total of 174 papers. Papers that were not related to the topic, reviews, general overview articles and case reports were excluded, leaving 35 articles for further analysis. Of these, 14 studies focused on cardiac dyssynchrony estimation with DENSE, while the remaining 21 studies served as background material. The studies used various methods for presenting synchronicity, such as circumferential uniformity ratio estimate (CURE), CURE-singular value decomposition (SVD), radial uniformity ratio estimate (RURE), longitudinal uniformity ratio estimate (LURE), time to onset of shortening (TOS) and dyssynchrony index (DI). Most of the dyssynchrony studies concentrated on human heart failure, but congenital heart diseases and obesity were also evaluated. The researchers found that DENSE demonstrated high reproducibility and was found useful for detecting cardiac resynchronisation therapy (CRT) responders, optimising CRT device settings and assessing right ventricle synchronicity. In addition, studies showed a correlation between cardiac fibrosis and mechanical dyssynchrony in humans, as well as a decrease in the synchrony of contraction in the left ventricle in obese mice. DENSE shows promise as a tool for quantifying myocardial function and dyssynchrony, with advantages over other cardiac dyssynchrony evaluation methods. However, there remain challenges related to DENSE due to the relatively time-consuming imaging and analysis process. Improvements in imaging and analysing technology, as well as possible artificial intelligence solutions, may help overcome these challenges and lead to more widespread clinical use of DENSE.

Additive manufacturing of low-temperature co-fired ceramic substrates and surface conductors based on material jetting

Integrated manufacturing of ceramic substrates and surface conductors using 3D material jetting (MJ) technology is a novel additive manufacturing route for low-temperature co-fired ceramics (LTCC). This study evaluates the rheological and jetting properties of LTCC nanoceramic inks with varying solids contents. Ceramic inks with 35 % solid content were found to be the optimal choice with high particle concentration and Ohnesorge numbers (Oh) below 1. The fabrication process used two piezoelectric printheads to inject nanoceramic ink and nanosilver ink to create a ceramic substrate and a surface interdigital electrode (IDE). The substrate sintering shrinkage was 21.5 % and the surface IDE co-fired at the same shrinkage rate as the substrate thus ensuring all electrode pattern details. The electrode conductors demonstrated effective line widths of up to 0.21 mm. Microscopic characterisation of the interface between silver and substrate using scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) confirmed the absence of significant elemental diffusion, and X-ray diffraction spectroscopy (XRD) results demonstrate that there is no second-phase generation, thus ensuring the effectiveness of the silver electrode. The ceramic substrates exhibit good thermal stability below 400 ℃ and have a coefficient of thermal expansion (∼ 4.1 ppm/℃) similar to that of silicon, indicating reliability in packaging. A microstrip patch antenna with the design frequency at 9–11 GHz was made through the same MJ procedure, which was experimentally measured to have a resonant frequency of 10.1 GHz, an S11 measurement of −24.6 dB, a simulated radiation efficiency of 88.01 %, and a high gain of up to 7.52 dB. Finally, a curved LTCC substrate with a radius of curvature of 50 mm and curved circuits was successfully fabricated using MJ technology. Interestingly, the curvature of the substrate maintained its original shape both before and after the sintering process, and the serpentine conductor pattern exhibited synchronous contraction, which implies the potential for developing a conformal LTCC utilizing MJ technology.