Prolonged Relaxation Research Articles

Myofibril relaxation with mavacamten is modified by cMyBP-c.

cMyBP-C regulates contractile function through interactions with both thin and thick filaments. Mutations in cMyBP-C are linked to hypertrophic cardiomyopathy (HCM) which is characterized by impaired relaxation. We previously showed that the HCM L348P mutation increased binding affinity of cMyBP-C for actin and significantly prolonged cardiac relaxation in transgenic mice. Here we used single myofibril mechanics and our SpyC “cut and paste” system to study relaxation at high resolution. We first measured relaxation kinetics following ablation of the N-terminal part of cMyBP-C (C0-C7) and its replacement with recombinant C0-C7 domains. We also applied 1 μM mavacamten (Mava), a myosin inhibitor, during relaxation to determine whether effects of Mava depend on cMyBP-C. Results showed that acute ablation of N-terminal C0-C7 of cMyBP-C had no effect on activation kinetics at saturating Ca2+, but slightly increased the fast exponential phase of relaxation. In general, 1 μM Mava slowed the rate of force development and improved relaxation, in particular Mava accelerated the isometric linear phase of myofibril relaxation. Next, we measured effects of the L348P mutation as well as a shorter recombinant protein containing only the C0-C2 domains. Both proteins prolonged the time of isometric linear phase of relaxation. Relaxation in the presence of Mava reduced a new level of passive force relative to baseline in the absence of Mava and the magnitude of the reduction was greater in the presence of the L348P mutation. Interestingly, this effect was blunted in myofibrils in the absence of cMyBP-C or in the presence of C0-C2. We propose that effects of Mava depend on the presence of full-length cMyBP-C and HCM mutations may modulate these effects.

Multivalent Design of Low-Entropy-Penalty Ion–Dipole Interactions for Dynamic Yet Thermostable Supramolecular Networks

Dynamic supramolecular networks are constantly accompanied by thermal instability. The fundamental reason is most reversible noncovalent bonds quickly decay at elevated temperatures and dissociate below 100 °C. Here, in this paper, we realize a reversible ion-dipole interaction with high-temperature stability exceeding 150 °C. The resultant supramolecular network can simultaneously possess mechanical strength of 1.32 MPa (14.8 times that of pristine material), dynamic self-healing capability, and a stable working temperature of up to 200 °C. From the prolonged characteristic relaxation time of 600 s even at 100 °C, our material represents one of the most thermally stable dynamic supramolecular polymers. These remarkable performances are achieved by using a new multivalent yet low-entropy-penalty molecular design. In this way, the noncovalent bond can reach a high enthalpy while minimizing the entropy-dominated thermal dissociations.

Quantitative evaluation of the lumbar ligamentum flavum using MRI T2-mapping: Efficacy of its clinical application in patients with lumbar spinal stenosis

ObejectiveTo perform a magnetic resonance imaging T2-mapping of the ligamentum flavum in healthy individuals and patients with lumbar spinal stenosis scheduled for surgery and compare the T2 relaxation times. Subjects and MethodsThe T2 relaxation time of the ligamentum flavum was compared among 3 groups, healthy young individuals (H group (age< 50)), healthy middle-aged and older individuals (H group (age≥50)), and patients with lumbar spinal stenosis (L group). Additionally, the thickness of the ligament was measured in the axial image plane, and the occupied area ratio of each fiber was measured by staining the surgically obtained ligament, and each was correlated with the T2 relaxation time. We also evaluated the adhesion of the ligamentum flavum with the dura mater during the surgery. ResultsThe T2 relaxation times were significantly prolonged in H group (age ≥50) and L group (P < 0.001) compared to H group (age<50). The relationship between collagen fiber and T2 relaxation times was significantly positive (r = 0.720, P < 0.001). Moreover, the relaxation times were significantly prolonged in those with adhesion of the ligamentum flavum with the dura mater (P < 0.05). The cut-off for the relaxation time was 50 ms (sensitivity: 62.50%, false positive rate: 10.8%). ConclusionHealthy middle-aged and older individuals and patients with lumbar spinal stenosis and adhesion of the ligamentum flavum with the dura mater have prolonged T2 relaxation times. Hence, the adhesion between the ligamentum flavum and dura mater should be considered in cases with a relaxation time ≥50 ms.

TRANSIENT ABSORPTION OF GOLD NANOPARTICLES OF VARIOUS DIAMETERS

excitation by nanosecond laser pulses has been studied. It was shown that the maximum of stationary absorption exhibits as a wide structureless band with a maximum at about 520–540 nm. The transient absorption band of gold nanoparticles with a maximum at about 430 nm has a fine structure with a frequency of maxima of 6–8 nm and it does not depend on the size of the nanoparticles. The absorption duration decreases with a decrease in the average size of nanoparticles. The lifetime of transient absorption is equal to 23±2 and 19.5±2 ns for large and small particles, respectively. The nanosecond lifetime of the transient absorption of Au nanoparticles is the result of a prolonged relaxation process in the “interface of Au nanoparticle–solvent molecule” system as a manifestation of hindered heat exchange with the environment.

Distinct Excitatory and Inhibitory Bump Wandering in a Stochastic Neural Field.

Localized persistent cortical neural activity is a validated neural substrate of parametric working memory. Such activity "bumps" represent the continuous location of a cue over several seconds. Pyramidal (excitatory ()) and interneuronal (inhibitory ()) subpopulations exhibit tuned bumps of activity, linking neural dynamics to behavioral inaccuracies observed in memory recall. However, many bump attractor models collapse these subpopulations into a single joint /(lateral inhibitory) population and do not consider the role of interpopulation neural architecture and noise correlations. Both factors have a high potential to impinge upon the stochastic dynamics of these bumps, ultimately shaping behavioral response variance. In our study, we consider a neural field model with separate / populations and leverage asymptotic analysis to derive a nonlinear Langevin system describing / bump interactions. While the bump attracts the bump, the bump stabilizes but can also repel the bump, which can result in prolonged relaxation dynamics when both bumps are perturbed. Furthermore, the structure of noise correlations within and between subpopulations strongly shapes the variance in bump position. Surprisingly, higher interpopulation correlations reduce variance.

Activin A directly impairs human cardiomyocyte contractile function indicating a potential role in heart failure development.

Activin A has been linked to cardiac dysfunction in aging and disease, with elevated circulating levels found in patients with hypertension, atherosclerosis, and heart failure. Here, we investigated whether Activin A directly impairs cardiomyocyte (CM) contractile function and kinetics utilizing cell, tissue, and animal models. Hydrodynamic gene delivery-mediated overexpression of Activin A in wild-type mice was sufficient to impair cardiac function, and resulted in increased cardiac stress markers (N-terminal pro-atrial natriuretic peptide) and cardiac atrophy. In human-induced pluripotent stem cell-derived (hiPSC) CMs, Activin A caused increased phosphorylation of SMAD2/3 and significantly upregulated SERPINE1 and FSTL3 (markers of SMAD2/3 activation and activin signaling, respectively). Activin A signaling in hiPSC-CMs resulted in impaired contractility, prolonged relaxation kinetics, and spontaneous beating in a dose-dependent manner. To identify the cardiac cellular source of Activin A, inflammatory cytokines were applied to human cardiac fibroblasts. Interleukin -1β induced a strong upregulation of Activin A. Mechanistically, we observed that Activin A-treated hiPSC-CMs exhibited impaired diastolic calcium handling with reduced expression of calcium regulatory genes (SERCA2, RYR2, CACNB2). Importantly, when Activin A was inhibited with an anti-Activin A antibody, maladaptive calcium handling and CM contractile dysfunction were abrogated. Therefore, inflammatory cytokines may play a key role by acting on cardiac fibroblasts, causing local upregulation of Activin A that directly acts on CMs to impair contractility. These findings demonstrate that Activin A acts directly on CMs, which may contribute to the cardiac dysfunction seen in aging populations and in patients with heart failure.

Polymer threadings and rigidity dictate the viscoelasticity of entangled ring-linear blends and their composites with rigid rod microtubules

Mixtures of polymers of varying topologies and stiffnesses display complex emergent rheological properties that often cannot be predicted from their single-component counterparts. For example, entangled blends of ring and linear polymers have been shown to exhibit enhanced shear thinning and viscosity, as well as prolonged relaxation timescales, compared to pure solutions of rings or linear chains. These emergent properties arise in part from the synergistic threading of rings by linear polymers. Topology has also been shown to play an important role in composites of flexible (e.g., DNA) and stiff (e.g., microtubules) polymers, whereby rings promote mixing while linear polymers induce demixing and flocculation of stiff polymers, with these topology-dependent interactions giving rise to highly distinct rheological signatures. To shed light on these intriguing phenomena, we use optical tweezers microrheology to measure the linear and nonlinear rheological properties of entangled ring-linear DNA blends and their composites with rigid microtubules. We show that linear viscoelasticity is primarily dictated by microtubules at lower frequencies, but their contributions become frozen out at frequencies above the DNA entanglement rate. In the nonlinear regime, we reveal that mechanical response features, such as shear thinning and stress softening, are mediated by entropic stretching, threading, and flow alignment of entangled DNA, as well as forced dethreading, disentanglement, and clustering. The contributions of each of these mechanisms depend on the strain rate as well as the entanglement density and stiffness of the polymers, leading to nonmonotonic rate dependences of mechanical properties that are most pronounced for highly concentrated ring-linear blends rather than DNA-microtubule composites.

Abstract 10925: A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Prolonged Relaxation in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases primarily caused by mutations in sarcomeric genes. However, HCM is also associated with mutations in non-sarcomeric proteins and a Finnish founder mutation for HCM in non-sarcomeric protein junctophilin-2 (JPH2) has been identified. MYK-461 is a recently described mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve phenotypic characteristics in human-induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) carrying JPH2 mutation T161K. Hypothesis: Currently all HCM patients are treated the same regardless of the underlying genetic defect. Current medication does not prevent or stop the thickening of the heart muscle; only the symptoms and arrhythmias can be controlled with beta-blockers or calcium blockers. MYK-461 decreases adenosine triphosphatase activity of the cardiac myosin heavy chain to reduce contractility, thus modifying the characteristic pathology of HCM. Methods: Skin fibroblasts from a Finnish patient with HCM causing JPH2 p.(Thr161Lys) were reprogrammed into hiPSCs and further differentiated into CMs. As a control line, an isogenic counterpart was generated using the CRISPR/Cas9 genome editing method. We evaluated the effect of MYK-461 treatment to T161K-hiPSC-CMs by their functional characteristics associated with JPH2 mutation. Results: By video microscopy, we identified increased contractility (BPM; 41±6 SEM, n=9) and prolonged diastolic phase (ms; 394.8±29.7 SEM, n=9) in T161K-hiPSC-CMs. Treatment with MYK-461 reduced contractility (BPM; 36±3 SEM, n=10) and relaxation phase (ms; 293.1±33.6 SEM, n=10) in a dose-dependent manner, displaying functional characteristics closer to isogenic-hiPSC-CMs control group. Conclusions: In conclusion, the results demonstrate that acute reduction in contractility is sufficient to relieve prolonged relaxation. Further, these studies suggest that T161K-hiPSC-CMs provide adequate in vitro platform for modelling the functional effect of MYK-461.

Abstract 15247: A Novel Patient-Derived Stem Cell Model of Restrictive Cardiomyopathy Exhibits Impaired Cardiomyocyte Relaxation Secondary to Increased Myocardial Calcium Sensitivity

Introduction: Restrictive Cardiomyopathy (RCM) is a rare disease characterized by profound, isolated defects in myocardial relaxation, normal or near-normal myocardial wall thickness, and preserved contractile function. Outcomes for patients with RCM are poor, with increased morbidity and mortality compared to other forms of cardiomyopathy. In some patients, RCM can be caused by genetic mutations, notably in genes encoding for components of the sarcomere. While many mutations have been described in RCM patients, the molecular and cellular mechanisms leading from these mutations to the patient’s physiological phenotype are poorly described. Hypothesis: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients will recapitulate the myocardial relaxation defects seen in RCM and provide a novel in vitro model for investigating the molecular mechanisms underpinning this disease. Methods: Induced pluripotent stem cells (iPSCs) were derived from a pediatric patient with RCM caused by a TNNT2 R94C mutation. CRISPR was used to correct the mutation, and cellular mechanics and calcium handling properties were compared to the patient line using a novel high-throughput traction-force imaging platform. Transcriptional profiles were compared using RNA-seq. Results: RCM cells carrying the TNNT2 R94C mutation show increased calcium sensitivity leading to increased resting tension at baseline, as well as prolonged calcium kinetics leading to prolonged relaxation times. Gene expression profiling reveals changes in expression of ECM genes, which may further contribute to the impaired myocardial relaxation seen in RCM. Conclusions: Patient-derived hiPSC-CMs from an RCM patient recapitulate the relaxation defects seen in RCM and highlight the central role of increased calcium sensitivity in impaired myocardial relaxation.

Smoothelin-like 1 knockout mice display sex-dependent alterations in blood flow and cardiac function.

Smoothelin-like 1 (SMTNL1) modulates the contractile performance of smooth muscle and thus has a key role in vascular homeostasis. Elevated vascular tone, recognized as a contributor to the development of progressive cardiac dysfunction, was previously found with SMTNL1 deletion. In this study, we assessed cardiac morphology and function of male and female, wild-type (Smtnl1+/+) and global SMTNL1 knockout (Smtnl1-/-) mice at 10 weeks of age. Gross dissection revealed distinct cardiac morphology only in males; Smtnl1-/- hearts were significantly smaller than Smtnl1+/+, but the left ventricle (LV) proportion of heart mass was greater. Male Smtnl1-/- mice also displayed increased ejection fraction and fractional shortening, as well as elevated aortic and pulmonary flow velocities. The impact of cardiac stress with pressure overload by transverse aortic constriction (TAC) was examined in male mice. With TAC banding, systolic function was preserved, but the LV filling pressure was selectively elevated due to relaxation impairment. Smtnl1-/- mice displayed higher early/passive filling velocity of LV/early mitral annulus velocity ratio (E/E' ratio) and myocardial performance index along with a prolonged isovolumetric relaxation time. Taken together, the findings support a novel, sex-dimorphic role for SMTNL1 in modulating cardiac structure and function of mice.

Cardiac adverse reactions of COVID-19 vaccination: cardiac MRI findings.

The rapid development of COVID-19 vaccines in the wake of the COVID-19 pandemic has led to an equally expediently deployed vaccination campaign with more than 12billion vaccinations administered worldwide. Reports of vaccine-associated adverse reactions (VAARs) have ranged from headaches and pain at the injection site to potentially life-threatening events such as cerebral venous sinus thrombosis. The heart has also not been spared of VAARs, as vaccine-associated myocardial infarction and more commonly, albeit still rare, myocarditis and perimyocarditis have been reported in predominantly young male recipients. Cardiac magnetic resonance imaging findings of vaccine-associated myocarditis such as prolonged T1 and T2 relaxation times, increased T2 signal intensity ratio, and subepicardial late gadolinium enhancement have been demonstrated to be similar to those in virus-induced myocarditis, enabling the use of the modified 2018 Lake Louise Criteria for diagnostic purposes to confirm vaccination-associated myocardial inflammation. Other reported cardiac findings such as cardiomyopathies and arrhythmias were confined to case reports. The incidence of myocardial infarction was not noted to be higher than in the overall population. The overall preliminary prognosis of vaccine- associated myocarditis seems to be good as suggested by initial reports, but long-term follow-up is needed to sufficiently assess possible sequelae and consequences.

Altered contractility in mutation-specific hypertrophic cardiomyopathy: A mechano-energetic in silico study with pharmacological insights.

Introduction: Mavacamten (MAVA), Blebbistatin (BLEB), and Omecamtiv mecarbil (OM) are promising drugs directly targeting sarcomere dynamics, with demonstrated efficacy against hypertrophic cardiomyopathy (HCM) in (pre)clinical trials. However, the molecular mechanism affecting cardiac contractility regulation, and the diseased cell mechano-energetics are not fully understood yet. Methods: We present a new metabolite-sensitive computational model of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) electromechanics to investigate the pathology of R403Q HCM mutation and the effect of MAVA, BLEB, and OM on the cell mechano-energetics. Results: We offer a mechano-energetic HCM calibration of the model, capturing the prolonged contractile relaxation due to R403Q mutation (∼33%), without assuming any further modifications such as an additional Ca2+ flux to the thin filaments. The HCM model variant correctly predicts the negligible alteration in ATPase activity in R403Q HCM condition compared to normal hiPSC-CMs. The simulated inotropic effects of MAVA, OM, and BLEB, along with the ATPase activities in the control and HCM model variant agree with in vitro results from different labs. The proposed model recapitulates the tension-Ca2+ relationship and action potential duration change due to 1µM OM and 5µM BLEB, consistently with in vitro data. Finally, our model replicates the experimental dose-dependent effect of OM and BLEB on the normalized isometric tension. Conclusion: This work is a step toward deep-phenotyping the mutation-specific HCM pathophysiology, manifesting as altered interfilament kinetics. Accordingly, the modeling efforts lend original insights into the MAVA, BLEB, and OM contributions to a new interfilament balance resulting in a cardioprotective effect.

Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy.

Human pluripotent stem cell-derived muscle models show great potential for translational research. Here, we describe developmentally inspired methods for the derivation of skeletal muscle cells and their utility in skeletal muscle tissue engineering with the aim to model skeletal muscle regeneration and dystrophy in vitro. Key steps include the directed differentiation of human pluripotent stem cells to embryonic muscle progenitors followed by primary and secondary foetal myogenesis into three-dimensional muscle. To simulate Duchenne muscular dystrophy (DMD), a patient-specific induced pluripotent stem cell line was compared to a CRISPR/Cas9-edited isogenic control line. The established skeletal muscle differentiation protocol robustly and faithfully recapitulates critical steps of embryonic myogenesis in two-dimensional and three-dimensional cultures, resulting in functional human skeletal muscle organoids (SMOs) and engineered skeletal muscles (ESMs) with a regeneration-competent satellite-like cell pool. Tissue-engineered muscle exhibits organotypic maturation and function (up to 5.7±0.5mN tetanic twitch tension at 100Hz in ESM). Contractile performance could be further enhanced by timed thyroid hormone treatment, increasing the speed of contraction (time to peak contraction) as well as relaxation (time to 50% relaxation) of single twitches from 107±2 to 75±4ms (P<0.05) and from 146±6 to 100±6ms (P<0.05), respectively. Satellite-like cells could be documented as largely quiescent PAX7+ cells (75±6% Ki67- ) located adjacent to muscle fibres confined under a laminin-containing basal membrane. Activation of the engineered satellite-like cell niche was documented in a cardiotoxin injury model with marked recovery of contractility to 57±8% of the pre-injury force 21days post-injury (P<0.05 compared to Day 2 post-injury), which was completely blocked by preceding irradiation. Absence of dystrophin in DMD ESM caused a marked reduction of contractile force (-35±7%, P<0.05) and impaired expression of fast myosin isoforms resulting in prolonged contraction (175±14ms, P<0.05 vs. gene-edited control) and relaxation (238±22ms, P<0.05 vs. gene-edited control) times. Restoration of dystrophin levels by gene editing rescued the DMD phenotype in ESM. We introduce human muscle models with canonical properties of bona fide skeletal muscle in vivo to study muscle development, maturation, disease and repair.

OC-013 INDIVIDUAL STRATEGY FOR PATIENTS WITH ABDOMINAL WALL EVENTRATION – DIFFERENT COMPONENTS SEPARATION TECHNIQUE WITH MESH AUGMENTATION

Abstract Aim To present individual approach for patients with abdominal wall eventration using various anterior component separation techniques (aCST) with mesh augmentation. Materials and Methods Between January 2008 and April 2022, 194 patients with abdominal wall eventration underwent surgery by single surgeon. Surgical treatment consists: a) enlargement of the abdominal cavity using different aCST (Ramirez CST, modified CST in the presence of enterostomies, “open book” modification CST, “method of wide myofascial release” or combination of these techniques); b) mesh augmentation (sublay or onlay hernioplasty); c) prolonged muscle relaxation and mechanical respiratory support in intensive care unit. Results Type of abdominal wall reconstruction: 143 Ramirez CST, 35 modification CST in the presence of enterostomies, 11“open book” CST modification, 5 “method of wide myofascial release”, 159 onlay mesh hernioplasty and 35 sublay mesh hernioplasty. Mean hernia defect size was 255 cm2 (100–750). During the mean follow-up of 31 months, 78 (40%) patients had one or more complications: intraabdominal hypertension 8 (4,1%), seroma 13 (6,7%), hematoma 10 (5,1%), wound/mesh infections 21 (10,8%), skin necrosis 40 (20,6%), pain 3 (1,6%), and recurrence 5 (2,6%). There were 10 (5,1%) postoperative deaths. The cause of dead was significant comorbidity in 8 patients and postoperative compartment syndrome in two. Conclusion Eventration disease is a complex surgical problem and its treatment is associated with significant complications. Individual strategy for each patient based on multidisciplinary approach using different component separation techniques with mesh augmentation may improve postoperative results.

Characteristics and clinical implications of premature summation of early and late diastolic filling in patients without tachycardia

Abstract Backgrounds The summation of early (E) and late diastolic filling (A) on mitral inflow Doppler even in the absence of tachycardia is often found during assessments of left ventricular (LV) diastolic function. We evaluated the echocardiographic characteristics and clinical implications of premature E-A summation. Methods We identified 1,014 subjects who showed E-A summation and normal LV ejection fraction between January 2019 and June 2021 in two tertiary hospitals. Among these, 105 (10.4%) subjects showed premature E-A summation at heart rates less than 100 beats per minute (bpm). The conventional echocardiographic parameters and LV global longitudinal strain (GLS) were compared with 1:1 age, sex, and heart rate matched controls without E-A summation. Results The premature E-A summation group had a heart rate of 96.4±3.7 bpm. Only 4 (3.8%) subjects were classified as having LV diastolic dysfunction according to the current guidelines. That group showed prolonged isovolumic relaxation time (107.2±25.3 vs. 61.6±15.6 msec, p&amp;lt;0.001), increased Tei index (0.76±0.19 vs. 0.48±0.10, p&amp;lt;0.001), lower LVEF (63.8±7.0 vs. 67.3±5.6%, p&amp;lt;0.001) and lower absolute LV GLS (|LV GLS|) (17.0±4.2 vs. 19.7±3.3%, p&amp;lt;0.001) than controls. As the E-A summation occurred at lower heart rate, the |LV GLS| was also lower (p for trend=0.002). Conclusions The premature E-A summation at heart rates less than 100 bpm is associated with subclinical LV dysfunction. Time-based indices and LV GLS are helpful for evaluating this easily overlooked population. Funding Acknowledgement Type of funding sources: None.

Nanoscale Synergetic Effects on Ag-TiO2 Hybrid Substrate for Photoinduced Enhanced Raman Spectroscopy (PIERS) with Ultra-Sensitivity and Reusability.

Here, a 4N-in-1 hybrid substrate concept (nanocolumnar structures, nanocrack network, nanoscale mixed oxide phases, and nanometallic structures) for ultra-sensitive and reliable photo-induced-enhanced Raman spectroscopy (PIERS), is proposed. The use of the 4N-in-1 hybrid substrate leads to an ≈50-fold enhancement over the normal surface-enhanced Raman spectroscopy, which is recorded as the highest PIERS enhancement to date. In addition to an improved Raman signal, the 4N-in-1 hybrid substrate provides a high detection sensitivity which may be attributed to the activation possibility at extremely low UV irradiation dosage and prolonged relaxation time (long measurement time). Moreover, the 4N-in-1 hybrid substrate exhibits a superior photocatalytic degradation performance of analytes, allowing its reuse at least 18 times without any loss of PIERS activity. The use of the 4N-in-1 concept can be adapted to biomedicine, forensic, and security fields easily.

The Variation in the Diastolic Period with Interventricular Septal Displacement and Its Relation to the Right Ventricular Function in Pulmonary Hypertension: A Preliminary Cardiac Magnetic Resonance Study.

Background: Pulmonary hypertension (PH) is known to alter the biventricular shape and temporal phases of the cardiac cycle. The presence of interventricular septal (IVS) displacement has been associated with the severity of PH. There has been limited cardiac magnetic resonance (CMR) data regarding the temporal parameters of the cardiac cycle in PH. This study aimed to quantify the temporal changes in the cardiac cycle derived from CMR in PH patients with and without IVS displacement and sought to understand the mechanism of cardiac dysfunction in the cardiac cycle. Methods: Patients with PH who had CMR and right heart catheterization (RHC) examinations were included retrospectively. Patients were divided into an IVS non-displacement (IVSND) group and an IVS displacement (IVSD) group according to IVS morphology, as observed on short-axis cine CMR images. Additionally, age-matched healthy volunteers were included as the health control (HC). Temporal parameters, IVS displacement, ventricular volume and functional parameters were obtained by CMR, and pulmonary hemodynamics were obtained by RHC. The risk stratification of the PH patients was also graded according to the guidelines. Results: A total of 70 subjects were included, consisting of 33 IVSD patients, 15 IVSND patients, and 22 HC patients. In the IVSND group, only the right ventricle ejection fraction (RVEF) was decreased in the ventricular function, and no temporal change in the cardiac cycle was found. A prolonged isovolumetric relaxation time (IRT) and shortened filling time (FT) in both ventricles, along with biventricular dysfunction, were detected in the IVSD group (p < 0.001). The IRT of the right ventricle (IRTRV) and FT of the right ventricle (FTRV) in the PH patients were associated with pulmonary vascular resistance, right cardiac index, and IVS curvature, and the IRTRV was also associated with the RVEF in a multivariate regression analysis. A total of 90% of the PH patients in the IVSD group were stratified into intermediate- and high-risk categories, and they showed a prolonged IRTRV and a shortened FTRV. The IRTRV was also the predictor of the major cardiovascular events. Conclusions: The temporal changes in the cardiac cycle were related to IVS displacement and mainly impacted the diastolic period of the two ventricles in the PH patients. The IRT and FT changes may provide useful pathophysiological information on the progression of PH.

Abstract P2113: A Novel Patient-derived Stem Cell Model Of Restrictive Cardiomyopathy Exhibits Impaired Cardiomyocyte Relaxation Secondary To Increased Myocardial Calcium Sensitivity

Introduction: Restrictive Cardiomyopathy (RCM) is a rare disease characterized by profound, isolated defects in myocardial relaxation, normal or near-normal myocardial wall thickness, and preserved contractile function. Outcomes for patients with RCM are poor, with increased morbidity and mortality compared to other forms of cardiomyopathy. In some patients, RCM can be caused by genetic mutations, notably in genes encoding for components of the sarcomere. While many mutations have been described in RCM patients, the molecular and cellular mechanisms leading from these mutations to the patient’s physiological phenotype are poorly described. Hypothesis: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients will recapitulate the myocardial relaxation defects seen in RCM and provide a novel in vitro model for investigating the molecular mechanisms underpinning this disease. Methods: Induced pluripotent stem cells (iPSCs) were derived from a pediatric patient with RCM caused by a TNNT2 R94C mutation. CRISPR was used to correct the mutation, and cellular mechanics and calcium handling properties were compared to the patient line using a novel high-throughput traction-force imaging platform. Transcriptional profiles were compared using RNA-seq. Results: RCM cells carrying the TNNT2 R94C mutation show increased calcium sensitivity leading to increased resting tension at baseline, as well as prolonged calcium kinetics leading to prolonged relaxation times. Gene expression profiling reveals changes in expression of ECM genes, which may further contribute to the impaired myocardial relaxation seen in RCM. Conclusions: Patient-derived hiPSC-CMs from an RCM patient recapitulate the relaxation defects seen in RCM and highlight the central role of increased calcium sensitivity in impaired myocardial relaxation.

Suppression of zero-field quantum tunneling of magnetization by a fluorido bridge for a "very hard" 3d-4f single-molecule magnet

<h2>Summary</h2> Single-molecule magnets (SMMs) have been proposed for ultra-high-density information storage due to prolonged relaxation times below blocking temperature (<i>T</i>_B). However, many SMMs suffer from fast magnetization loss at zero-field regime due to the quantum tunneling of magnetization (QTM) effect. Here we show the creation of large ground magnetic momentum is crucial to suppress zero-field QTM for SMMs. The recipe is to use bridging fluoride, which creates ferromagnetic couplings among the lanthanide ions in the complex [Dy₃Cr₃(<i>μ</i>₃-F) (<i>μ</i>₃-OH)₃(mdea)₃(piv)₈DMF]·H₂O·CH₃CN. As such, the molecule owns a large ground magnetic moment of <mml:math><mml:mrow><mml:mn>10.7</mml:mn><mml:mi>μ</mml:mi><mml:mi>B</mml:mi></mml:mrow></mml:math> and is confirmed to be an SMM with <i>T</i>_B of 5 K. More importantly, a "very hard" magnetic hysteresis loop with a coercive field of 1.3 T and more than 97% remanence is observed up to 0.7 K. <i>Ab initio</i> calculations fully support such observations, rendering the importance of fluorido bridge to suppress zero-field QTM for lanthanide-based SMMs.

Polar methylammonium organic cations detune state coupling and extend hot-carrier lifetime in lead halide perovskites

<h2>Summary</h2> The slow hot-carrier relaxation properties of lead halide perovskites show great promise for hot-carrier solar cells. Here, we discover that the hot-carrier relaxation could be prolonged by two orders of magnitude in lead halide perovskites. By ultrafast spectroscopy, we unravel a slow hot-carrier relaxation process mediated by an intermediate state above the conduction band minimum (CBM). This intermediate state is formed by incorporating polar methylammonium (MA) cations. The first-principle calculation further confirms that the incorporation of MA cations introduces a prolonged relaxation process from CBM + 1 to CBM state, which are the split-off states of the CBM due to the strong spin-orbit coupling. The prolonging effect is interpreted that MA cations largely increase the lattice distortions and detune their inter-state coupling. This work reveals a neglected way to prolong the hot-carrier relaxation processes and provides guidance for the hot-carrier photovoltaics to overcome the current Shockley-Queisser limit.