Prolonged Relaxation Research Articles

Prolonged Asynchronous Left Ventricular Isovolumic Relaxation Constant in Ascending Compared to Descending Thoracic Aortic Stenosis for Chronic Early Left Ventricular Afterload and Late Left Ventricular Afterload Increase.

Background: In arterial hypertension, left ventricular relaxation is affected early on in relation to a chronic difference in peak left ventricular afterload with early development of HF. Objective: in ascending compares to descending thoracic aortic stenosis, resulting in chronic late and early LV afterload increase, to assess the left ventricular isovolumic relaxation pressure decay constant through regression analysis, a parameter of left ventricular relaxation on the 4th and 8th week period from invasive left ventricular pressure measurements. Methods: fourteen pigs underwent posterolateral thoracotomy for ascending aortic stenosis, resulting in chronic early left ventricular afterload increase (EL = 6], or descending thoracic aortic stenosis creating chronic late systolic left ventricular load (LL = 8]. Exponential regression with nonzero asymptote for τ assessment, with linear and nonlinear regression were performed on isovolumic relaxation pressure decay from the left ventricular invasive pressure measurements on 4th and 8th week. Two-way repeated measurement ANOVA, post-hoc Tukey test and linear regression were performed for statistical analysis. Results presented are mean ± SEM or median (quartiles], with significance is at p < 0.05. Results: The ascending aortic stenosis associated with prolonged biexponential asynchronous τ, compared to the descending thoracic aorta stenosis, resulted in data that were different at the 8th week in presence of respirations (interaction p < 0.05]. Monoexponential and linear τ were not different in either respiration being preserved or suspended transitionally and in preload reduction. Preload sensitive response of τ was found in ascending compared to descending thoracic aortic banding that reduced in EL and in LL it increased with load reduction (p < 0.05]. These results indicated that τ is not different in and between LV afterloading conditions in a chronic setting, although it indicates that myocardial ischemia is present and that it is greater in ascending aortic banding, compared to descending thoracic aorta banding at the 8th week. Conclusion: In different sequence of the left ventricular afterload, ventricular relaxation is affected early on, having in EL compared to LL prolonged biexponential asynchronous left ventricular relaxation constant, thus indicating the development left ventricular myocardial ischemia and different elastic recoil in an invasive left ventricular hemodynamic assessment.

Unique Random-Block Polymer Architecture for Site-Specific Mitochondrial Sequestration-Aided Effective Chemotherapeutic Delivery and Enhanced Fluorocarbon Segmental Mobility-Facilitated 19F Magnetic Resonance Imaging.

The elevation of the chemotherapeutic efficacy and attenuation of its side effects on healthy cells and tissues become one of the prime targets for the treatment of cancer. Toward this direction, a sequential receptor and mitochondria dual-targeting strategy was implemented in the DX TP PG BN 19F theranostic polymer that was anchored with the chemotherapeutic agent doxorubicin, receptor-targeting biotin, and mitochondria-targeting triphenylphosphonium cations. The polymer was flourished with a unique 19F magnetic resonance imaging (MRI) tracer that exhibited high segmental mobility and eventually led to prolonged T2 relaxation time. Furthermore, for the sake of amphiphilicity, the DX TP PG BN 19F polymer spontaneously aggregated into nano-sphere with positive zeta potential, where the MRI tracer and biotin embedded at the exterior and displayed site-specific targeting and remarkable 19F MRI capability simultaneously. The mitochondria-targeting competency of the DX TP PG BN 19F theranostic polymer was investigated by comparing the non-mitochondrial-targeting DX PG BN 19F polymer using fluorescence microscopic cell imaging in human cervical, HeLa, and breast MCF-7 carcinoma cell lines. Moreover, cytotoxicity experiments of the aforementioned theranostic polymers clarified the enhancement of the chemotherapeutic efficacy of DX TP PG BN 19F theranostic polymers through effective and precise mitochondrial doxorubicin delivery that forced to follow the apoptotic path.

Effect of stimulation frequency on force, power and fatigue of isolated mouse extensor digitorum longus muscle.

This study examined the effect of stimulation frequency (140, 200, 230 and 260 Hz) on isometric force, work loop (WL) power and the fatigue resistance of extensor digitorum longus (EDL) muscle (n=32), isolated from 8- to 10-week-old CD-1 female mice. Stimulation frequency had significant effects on isometric properties of isolated mouse EDL, whereby increasing stimulation frequency evoked increased isometric force, quicker activation and prolonged relaxation (P<0.047) up to 230 Hz and above; thereafter, force and activation did not differ (P>0.137). Increasing stimulation frequency increased maximal WL power output (P<0.001; 140 Hz, 71.3±3.5; 200 Hz, 105.4±4.1; 230 Hz, 115.5±4.1; 260 Hz, 121.1±4.1 W kg-1), but resulted in significantly quicker rates of fatigue during consecutive WLs (P<0.004). WL shapes indicate impaired muscle relaxation at the end of shortening and subsequent increased negative work appeared to contribute to fatigue at 230 and 260 Hz, but not at lower stimulation frequencies. Cumulative work was unaffected by stimulation frequency, except at the start of the fatigue protocol, where 230 and 260 Hz produced more work than 140 Hz (P<0.039). We demonstrate that stimulation frequency affects force, power and fatigue, but these effects are not uniform between different assessments of contractile performance. Therefore, future work examining the contractile properties of isolated skeletal muscle should consider increasing the stimulation frequency beyond that needed for maximal force when examining maximal power but should utilise a sub-maximal stimulation frequency for fatigue assessments to avoid a high degree of negative work atypical of in vivo function.

Do older veterans experience change in posttraumatic cognitions following treatment for posttraumatic stress disorder?

It is unclear whether PTSD treatments improve negative posttraumatic cognitions (NPCs) and if changes in NPCs mediate treatment outcomes in older veterans. The current study examined if prolonged exposure therapy (PE) and relaxation therapy (RT) reduce NPCs over time in older adult veterans with PTSD. This study analyzed data from a randomized controlled trial of 86 older male veterans with PTSD randomized to PE or RT. The Posttraumatic Cognitions Inventory (PTCI; Foa et al., 1999), which includes a total score and three subscales, Negative Cognitions of the Self (Self), Negative Cognitions of the World (World), and Self-Blame (Blame), was used to assess NPCs at pretreatment, posttreatment, and 6-month follow-up. Changes in NPCs differed by treatment condition. Veterans who received PE had significantly reduced overall NPCs and NPCs about the self at posttreatment, but these NPCs were no longer significantly different from baseline at the follow-up assessment. In contrast, NPCs about the world and self-blame did not significantly change following PE. NPCs did not change following RT. Effects of PE on decreased 6-month follow-up clinician-rated PTSD symptoms were conveyed through intervening effects of decreased posttreatment PTCI total scores, suggesting the utility of targeting posttraumatic cognitions as a mechanism of long-term PTSD symptom reduction. Given that reductions in overall negative cognitions are associated with lower clinician-administered PTSD scores 6 months after PE, clinicians could consider monitoring changes in these cognitions over the course of treatment. RT is not a recommended treatment approach to target NPCs in older adults with PTSD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Metabolites Alterations and Liver Injury in Hepatic Encephalopathy Models Evaluated by Use of 7T-MRI.

This study is to observe a thioacetamide (TAA) administered Hepatic encephalopathy (HE) model rats at three and ten days after TAA administration using liver MRI and brain MR Spectroscopy (MRS) by use of 7T-MRI. Forty-two Wistar rats (control group, n = 14) were intraperitoneally administered at 300 mg/kg (low-dose group, n = 14) or 400 mg/kg (high-dose group, n = 14) doses of TAA for induced of HE. At three days after TAA administration, glutamine (Gln) measured by MRS in high-dose and low-dose TAA groups showed significant increases in comparison to those of the control group (p < 0.05). Other metabolites measured by MRS showed no significant changes. Liver T1ρ and T2 relaxation times significantly increased three days after TAA injection compared to pre-injection. There was a correlation between Gln levels in the brain and the relaxation time of the liver. Furthermore, Gln levels and relaxation time changed depending on the TAA dose. The Gln concentration in the brain increased with the deterioration of liver function, as inferred from the prolonged relaxation time of the liver. The prolonged relaxation time of the liver corresponded with the level of Gln in the brain. Gln concentration for the alterations of brain metabolites and T1ρ relaxation time for the assessment of liver damage are useful markers for inter-organ association analysis in the HE model.

Features of nanosecond transient absorption of Ag nanoparticles with manifestations of electron gas degeneracy

The transient absorption of Ag nanoparticles with various sizes under photoexcitation by nanosecond laser pulses was studied. It was found that the transient absorption band of silver nanoparticles with a maximum at 380 nm has a fine structure and does not depend on the nanoparticle size. A theoretical explanation of the observed fine structure of the transient absorption spectrum is proposed based on the hypothesis of the electron gas degeneracy in the metal nanoparticles. The dependencies of the intensity and lifetime of the transient absorption on the average size of nanoparticles, their concentration, and the energy density of laser excitation were investigated. To explain the observed processes, a mathematical model was proposed that considers a prolonged relaxation process in a colloidal system as a manifestation of hindered heat transfer with the environment. It is shown that the absorption kinetics is prolonged up to times of the order of several tens of nanoseconds in the case of the delayed heterophase heat transfer at the “particle–medium” interface.

Embryonic myosin mutations T187I and R672C result in mechanical and structural dysfunction in hiPSC derived skeletal myotubes

Distal arthrogryposis (DA) is a skeletal muscle disorder characterized by joint contractures at various parts of the body, predominantly in the distal extremities. DA is associated with syndromes like Freeman-Sheldon (FSS), caused by mutations in the sarcomeric protein-encoding gene MYH3 responsible for generating embryonic skeletal muscle myosin during development. We previously reported (Racca et al., 2015) that demembranated myofibrils from affected individuals expressing the R672C mutation in MYH3 exhibited lower specific force and prolonged relaxation.

Prevalence of cardiac myosin-binding protein C3 mutations in Maine Coon cats with hypertrophic cardiomyopathy.

Background and Aim:Hypertrophic cardiomyopathy (HCM) is a common heart problem that affects many cats. Although cats with HCM are symptomatic, some die suddenly or develop congestive heart failure. Therefore, this study aimed to estimate the prevalence of myosin-binding protein C3 (MYBPC3), A31P, and A74T polymorphisms in Maine Coon cats to assess risk factors for diagnosing HCM in cats.Materials and Methods:Forty-nine Maine Coon cats of at least 10 months of age were enrolled in this study. First, clinical parameters, such as heart rate, systolic blood pressure, and echocardiography, were evaluated. Then, polymerase chain reaction, followed by DNA sequencing, was conducted using specific primers for amino acid substitutions caused by genetic variants of MYBPC3-A31P and -A74T polymorphisms.Results:Investigations showed that the prevalence of MYBPC3-A31P and -A74T mutations in this study was 16.33% and 24.45%, respectively. Moreover, HCM in cats with MYBPC3-A31P and A74T mutations increased with age, body weight, high heart rate, and prolonged isovolumic relaxation time.Conclusion:Therefore, we propose that Maine Coon cats develop HCM due to multiple genetic factors and underlying clinical characteristics in individual cats. Furthermore, relaxation time assessments can be a sensitive technique for HCM screening during its preclinical phase and can help identify the risk of developing HCM. However, further studies are warranted to evaluate the effect of MYBPC3 mutations on the phenotypic expression of HCM.

History-Dependent Stress Relaxation of Liquids under High-Confinement: A Molecular Dynamics Study

When liquids are confined into a nanometer-scale slit, the induced layering-like film structure allows the liquid to sustain non-isotropic stresses and thus be load-bearing. Such anisotropic characteristics of liquid under confinement arise naturally from the liquids’ wavenumber dependent compressibility, which does not need solidification to take place as a prerequisite. In other words, liquids under confinement can still retain fluidity with molecules being (sub-)diffusive. However, the extensively prolonged structural relaxation times can cause hysteresis of stress relaxation of confined molecules in response to the motions of confining walls and thereby rendering the quasi-static stress tensors history-dependent. In this work, by means of molecular dynamics, stress tensors of a highly confined key base-oil component, i.e., 1-decene trimer, are calculated after its relaxation from being compressed and decompressed. A maximum of 77.1 MPa normal stress discrepancy has been detected within a triple-layer boundary film. Analyses with respect to molecular morphology indicate that among the effects (e.g., confinement, molecular structure, and film density) that can potentially affect confined stresses, the ordering status of the confined molecules plays a predominant role.

Связанное со здоровьем качество жизни при терапевтической коррекции двустороннего паралича гортани

The task of treating any disease is to improve the quality of human life. However, there is no widespread practice in clinical studies to assess the health-related quality of life before and after medical intervention. The aim of the study was to evaluate the health-related quality of life in patients with bilateral laryngeal paralysis and the impact on the quality of life of methods of therapeutic rehabilitation of respiratory function using the international standardized questionnaire SF-36 (Russian version developed and recommended by the Multinational Center for Quality of Life Research (MCQLR)). A survey of 44 patients with bilateral laryngeal paralysis after a strumectomy lasting more than 1 year was conducted twice. The first questionnaire was conducted before the rehabilitation of respiratory function, the second questionnaire was conducted 4–6 months after rehabilitation. The patients underwent rehabilitation as part of two groups: in group 1, respiratory function rehabilitation was carried out by the method of prolonged injectable relaxation of the cricoid muscle with botulinum toxin type A. In group 2, respiratory function rehabilitation was carried out with phonopedic correction by the development of respiratory techniques and drug sedation with benzodiazepine. According to the results obtained, prolonged relaxation of the cricoid muscle by a single injection of botulinum toxin type A into the thickness of the cricoid muscle improves the physical component of the quality of life associated with health by 36%, the mental component, by 50%. Phonopedic correction will improve the physical component of the quality of life by 6%, and the mental component, by 4%. The obtained result can be used in communication between the patient and the doctor at the stage of explaining the effectiveness of available methods of conservative treatment for laryngeal paralysis.

Associations between Subclinical Myocardial Dysfunction and Premature Fusion of Early and Late Diastolic Filling with Uncertain Cause.

PurposeThe fusion of early (E) and late diastolic filling (A) on mitral inflow Doppler, even in the absence of tachycardia, is often found during assessment of left ventricular (LV) diastolic function. We evaluated the echocardiographic characteristics and clinical implications of premature E-A fusion of uncertain cause in the absence of tachycardia.Materials and MethodsWe identified 1014 subjects who showed E-A fusion and normal LV ejection fraction (LVEF) between January 2019 and June 2021 at two tertiary hospitals. Among these, 105 (10.4%) subjects showed premature E-A fusion 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 fusion.ResultsThe premature E-A fusion 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 current guidelines. The group showed prolonged isovolumic relaxation time (107.2±25.3 msec vs. 61.6±15.6 msec, p<0.001), increased Tei index (0.76±0.19 vs. 0.48±0.10, p<0.001), lower LVEF (63.8±7.0% vs. 67.3±5.6%, p<0.001) and lower absolute LV GLS (|LV GLS|) (17.0±4.2% vs. 19.7±3.3%, p<0.001) than controls. As the E-A fusion occurred at lower heart rate, the |LV GLS| was also lower (p for trend=0.002).ConclusionPremature E-A fusion 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.

Abstract 12140: SCN1B Expression Modulates Sodium Influx in Cardiomyocytes and Diastolic Function in the Adult Heart

Voltage-gated sodium channels (VGSCs) are macromolecular complexes composed of a number of proteins regulating channel biophysical properties. VGSCs generate Na + current (I Na ) in myocytes and play fundamental roles in excitability and impulse conduction in the heart. Moreover, VGSCs condition mechanical properties of the myocardium, a process that appears to involve the late component of I Na . Variants in the gene SCN1B , encoding the VGSC β1 and β1B subunits, result in inherited neurological disorders and cardiac arrhythmias. But the precise contributions of β1/β1B subunits and VGSC integrity to the overall function of the adult heart remain to be clarified. For this purpose, adult mice with cardiac-restricted, inducible deletion of Scn1b (conditional knock-out, cKO) were studied. Myocytes from cKO mice had decreased levels of Scn1b transcripts (-85%) and increased densities of fast- (+20%) and slow-inactivating (+140%) components of I Na , with respect to cells from corresponding control (Ctrl) animals. By echocardiography, left ventricular (LV) mass, chamber volume, and systolic function were preserved in both male and female cKO mice, with respect to sex- and age-matched Ctrl animals. However, by transmitral flow Doppler echocardiography, cKO mice presented reduced velocity of the passive filling wave (-~20%), attenuated ratio of the passive-to-active filling velocity waves (-~20%), and prolonged isovolumic relaxation time (+~16%). Moreover, by pressure-volume (PV) loop assessment, cKO mice had steeper slope of the LV end diastolic PV relation and prolonged LV relaxation tau, suggesting impairment of diastolic function. Importantly, inhibition of late I Na with GS967 (0.5 mg/kg body weight) normalized left ventricular filling pattern and isovolumic relaxation time in cKO mice, but had no consequences in Ctrl animals. At the cellular level, cKO myocytes presented delayed kinetics of Ca 2+ transients decay and cell shortening with respect to Ctrl myocytes. These defects were partly corrected by inhibition of the late I Na . Collectively, these results document that VGSC β1/β1B subunits modulate electrical and mechanical function of the heart by regulating, at least in part, Na + influx in cardiomyocytes.

Abstract 12092: IMB-1018792, an Investigational Agent Designed to Augment Cardiac Glucose Utlization and Energetics Reduces Cardiac Remodelling and Preserves Cardiac Function in a Model of Pressure Overload-Induced Heart Failure

Introduction: Energetic impairments play a key role in heart failure (HF). Contributors include reduced pyruvate dehydrogenase activity partially uncoupling glycolysis from glucose oxidation, increased dependence on fatty acid (FA) metabolism yielding less ATP than glucose per O 2 molecule consumed, a lower phosphate-to-O 2 ratio, mitochondrial uncoupling and futile cycling of FA intermediates. IMB-1018972 (IMB-101) is a novel investigational agent designed to increase cardiac glucose uptake to promote glucose oxidation (Randle effect) through partial inhibition of FA oxidation enhancing cardiac energetics and mechanical efficiency. Hypotheses: Administration of IMB-101 will: 1) increase cardiac glucose uptake and 2) attenuate LV hypertrophic remodelling and progression of HF resulting from chronic pressure overload. Methods: 1) Cardiac glucose metabolism was evaluated using dynamic 18 F-FDG PET/CT imaging in vivo in fasted normal rats following a subcutaneous dose of IMB-101 or saline. Each animal had 2 randomized sequenced scan sessions (n=16). 2) Male C57BL/6 mice aged 12 weeks underwent transverse aortic constriction (TAC) or sham surgery (n=15) and were treated with IMB-101 (10 mg/kg/day, n=15) or saline (n=15) from day 1 (D1) for 6 weeks by osmotic minipump. Cardiac function was assessed by conscious echocardiography (D1, week 3 and 6). Cardiac fibrosis was measured by Masson’s Trichrome staining. Results: IMB-101 robustly increased in vivo cardiac 18 F-FDG uptake vs saline in rats. In mice subjected to TAC, compared to saline controls, IMB-101 treatment: preserved LV systolic function (fractional shortening 46%±3% vs 34%±3%, at week 6, p&lt;0.05); improved LV relaxation with less prolonged isovolumic relaxation time (32±1 ms vs 36±1 ms, p&lt;0.05); reduced cardiac hypertrophy (LV mass 156±10 mg vs 195±12 mg, p&lt;0.05; and heart:body weight ratio 7.4±0.3 mg/g vs. 9.1±0.5 mg/g, p&lt;0.05); and attenuated cardiac fibrosis (6.6±0.6% vs 10.7±1%, p&lt;0.01). Conclusions: IMB-101 increases cardiac glucose uptake and protects against LV dysfunction, hypertrophic remodelling and interstitial fibrosis after chronic pressure overload.

Abstract 12635: Mitochondria-Targeted NOX4 Overexpression Causes Restrictive Diastolic Dysfunction in a “Two-Hit” Mouse Model of HFpEF

Heart failure with preserved ejection fraction (HFpEF) prevalence increases with age. However, the pathophysiologic mechanisms of HFpEF are unknown and no specific treatment is available. NOX4 NADPH oxidase levels, particularly in mitochondria, increase with age and induce mitochondrial dysfunction. We previously showed that diastolic dysfunction patients’ hearts had higher NOX4, ROS levels and mitochondrial damage whereas mice with mitochondria-targeted NOX4 overexpression ( Nox4 TG) had impaired mitochondrial function and pronounced diastolic dysfunction. Here we investigated the effects of increased mitochondrial NOX4 levels on the pathophysiology of HFpEF using Nox4 TG mice in a “two-hit” model. The “two-hit” mouse HFpEF model is a combination of metabolic stress from high-fat diet and dysregulation of NO after treatment with L-NAME. Compared to wild-type, Nox4 TG mice had significantly lower ATP-linked and maximal oxygen consumption rates in ventricular cardiomyocytes and showed a trend towards reduced exercise tolerance. Echocardiography analysis showed that both strains in “two-hit” model had increased E/E' versus controls, whereas Nox4 TG mice had significantly prolonged isovolumic relaxation and mitral valve deceleration time. In addition, NOX4 overexpression significantly reduced cardiac output, suggesting restrictive diastolic dysfunction. MCP1 expression was significantly higher in left ventricle (LV) lysates and the percentage of CD11b + cells was higher in LV sections of Nox4 TG mice. Myocardium flow cytometry analysis showed higher percentage of Ly6C hi macrophages with elevated TNFα expression in Nox4 TG mice. TGFβ1 and osteopontin expression was also higher in the LV lysates. Picrosirius red and collagen I staining showed increased interstitial fibrosis in Nox4 TG mice as in LV sections of patients with diastolic dysfunction. Congruently, percentage of periostin + and ACTA2 + cells was significantly higher in Nox4 TG mice, recapitulating findings in human LV sections. Together, our data show that mitochondrial dysfunction leads to restrictive diastolic dysfunction through inflammation and fibrosis, suggesting that preserving mitochondrial function in aging is a potential therapeutic strategy for HFpEF.

Abstract 14365: Interrogating Diastolic Dysfunction Using a Novel Stem Cell Model of Restrictive Cardiomyopathy

Introduction: Diastolic dysfunction is an important cause of morbidity and mortality in both children and adults. Unfortunately, investigation of new therapies is limited by a lack of in vitro models of diastolic dysfunction. Idiopathic Restrictive Cardiomyopathy (RCM) is a serious genetic condition in which children have an isolated defect in myocardial relaxation. Though some of the genetic lesions have been identified, there is still an incomplete understanding of the mechanisms that lead to diastolic dysfunction in this condition. Hypothesis: Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) derived from patients with RCM will provide an in vitro model of diastolic dysfunction and will allow elucidation of cellular and molecular pathways involved in myocardial relaxation. Methods: Patients with RCM and a known pathogenic sarcomeric mutation were identified through speaking with providers in our heart failure and cardiac transplant program. hiPSCs were derived from patient blood samples and differentiated into cardiomyocytes. Isogenic controls were generated using CRISPR-mediated homologous directed repair. Calcium handling, contraction kinetics, and resting tension of RCM hiPSC-CMs were compared to control hiPSC-CMs on substrates with defined stiffness using high-throughput quantitative imaging techniques. Results: hiPSC-CMs derived from a patient with a pathogenic mutation in troponin T (TNNT2) display prolonged calcium kinetics and relaxation times compared to controls, as well as increased resting tension. Conclusions: RCM hiPSC-CMs represent a novel model of diastolic dysfunction that can be interrogated on a high-throughput platform. We plan to use these cells to perform proteome-scale functional screens, providing a novel opportunity to discover previously unknown contributors to diastolic dysfunction.

Abstract 9852: Targeting Mek/Erk Signaling in the Treatment of Mitral Valve Prolapse

Introduction: Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease, affecting 1 in 40 humans and ~70% of small breed dogs. There are no effective nonsurgical treatments for MVP and therapeutic efforts have been hindered due to an incomplete understanding of its fundamental causes. Recent studies by our group have described the genetic basis for non-syndromic MVP and have provided new insights into molecular processes that underlie the disease. We have used this genetic information to identify druggable targets that can provide a non-surgical option for humans. In particular, we have identified the MEK/ERK pathway as the major disease initiating pathway and prolonged hyperactivation of MEK/ERK drives disease progression and severity. Hypothesis: Pharmacological blockade of MEK/ERK activities will sufficiently arrest the disease pathway and maintain the valves in a sub-clinical condition. Methods and Results: The FDA-approved MEK1 inhibitor Trametinib was administered to Dzip1 S24R/+ mice; a disease model that phenocopies human MVP. Preliminary results suggest safety concerns in mice associated with chronic administration of Trametinib (1 mg/kg/day). Animals demonstrated signs of cardiotoxicity on echocardiography, including left atrial enlargement; a reduction in E/A wave intensity; left ventricular wall movement abnormalities; prolonged isovolumetric relaxation time, and a reduced ejection fraction. As such, our lab has focused our efforts on identifying novel MEK1 inhibitors with a favorable safety profile. Utilizing a machine learning based workflow, we have identified highly selective MEK1 inhibitors with retained activity (&lt;100nM IC50 values); high gastrointestinal absorption (&gt;85%); favorable predicted LD50 values (&gt;1,000 mg/kg), and devoid of major cytochrome interactions. Conclusions: MEK1 may serve as a druggable target in the treatment of mitral valve prolapse; however, currently available MEK inhibitors demonstrate limiting toxicities. Future studies will involve in vivo administration of our novel compounds to Dzip1 S24R/+ mice. We envision results from this study will help guide the development of systemic or targeted therapies for the use in human patients with mitral valve prolapse.

Abstract 13995: Proarrhythmic Electromechanical Heterogeneities in Patients With KCNJ2 Mutations

Introduction: Loss-of-function mutations of the KCNJ2 gene encoding the inward-rectifier potassium channel, I K1 , are associated with QT prolongation, prominent U waves, abnormal impulse formation and ventricular tachycardia (VT), besides non-cardiac manifestations. The electromechanical consequences of genetic I K1 dysfunction are unknown. Hypothesis: We hypothesize that I K1 dysfunction leads to increased electrical and mechanical dispersion and electromechanical (EMW) negativity. Dynamic heterogeneity of these functional parameters may conspire to arrhythmia. Methods: High-resolution mapping using ECG imaging, speckle-tracking echocardiography and/or tissue-phase mapping CMR were performed in genotyped KCNJ2 -mutation carriers, besides standard 12-lead and ambulatory recording. Results: Five patients (44±13 years; 2 females) were included; KCNJ2 p.(Val93Ile), p.(Arg218Gln), p.(Thr75Arg), p.(Lys49Arg), p.(Gly144Ala). Three had experienced polymorphic VT/VF. Multifocal ventricular ectopic burden averaged 13%. Mean QTc/QTUc were 446±42/610±78 ms, with U-waves of 149±18 ms and 0.087±0.045 mV. ECG-imaging revealed increased epicardial recovery time gradients (168±58 ms/cm), with LV- and RV-contractile heterogeneities by strain: Delta contraction duration (CD) LV 213±77 ms, standard deviation (SD) 58±14 ms; RV Delta CD 30±22 ms, SD 13±9 ms. Abnormal postsystolic shortenings (Fig.), prolonged isovolumic relaxation times (103±25 ms) and reduced diastolic peak velocities (-7.2±1.7 cm/s) indicated impaired early relaxation. The EMW was -51±35 ms with more pronounced negativity in symptomatic patients (-74 vs. -17 ms). Conclusions: Genetic I K1 dysfunction underlies nonuniform mechanical heterogeneities in contraction and relaxation, besides repolarization and resting membrane-potential instability. Significant EMW negativity further promotes ventricular ectopy, potentially precipitating VT.

Impaired Relaxation and Reduced Lusitropic Reserve in Atrial Myocardium in the Obese Patients.

Background: Obesity can influence the structure and function of the atrium, but most studies focused on the relationship of body mass index (BMI) and overt left atrium (LA) dysfunction as assessed by clinical imaging. We combined the assessment of right atrium (RA) function in vivo and in vitro in obese and non-obese patients scheduled for elective cardiac surgery.Methods: Atrial structure and function were quantified pre-operatively by echocardiography. RA tissue removed for the establishment of extracorporeal support was collected and RA trabeculae function was quantified in vitro at baseline and with adrenergic stimulation (isoproterenol). Fatty acid-binding protein 3 (FABP3) was quantified in RA tissue. Results were stratified according to the BMI of the patients.Results: About 76 patients were included pre-operatively for the echocardiographic analysis. RA trabeculae function at baseline was finally quantified from 46 patients and RA function in 28 patients was also assessed with isoproterenol. There was no significant correlation between BMI and the parameters of atrial function measured by the clinical echocardiography. However, in vitro measurements revealed a significant correlation between BMI and a prolonged relaxation of the atrial myocardium at baseline, which persisted after controlling for the atrial fibrillation and diabetes by the partial correlation analysis. Acceleration of relaxation with isoproterenol was significantly lower in the obese group (BMI ≥ 30 kg/m2). As a result, relaxation with adrenergic stimulation in the obese group remained significantly higher compared to the overweight group (25 kg/m2 ≤ BMI < 30 kg/m2, p = 0.027) and normal group (18.5 kg/m2 ≤ BMI < 25 kg/m2, p = 0.036). There were no differences on impacts of the isoproterenol on (systolic) developed force between groups. The expression of FABP3 in the obese group was significantly higher compared to the normal group (p = 0.049) and the correlation analysis showed the significant correlations between the level of FABP3 in the RA trabeculae function.Conclusion: A higher BMI is associated with the early subclinical changes of RA myocardial function with the slowed relaxation and reduced adrenergic lusitropy.

Effects of Aspiration Prevention Surgery on the Dynamics of the Pharynx and Upper Esophageal Sphincter.

ObjectiveOral intake after aspiration prevention surgery (APS) is influenced by postoperative pharyngeal pressure and the dynamics of the upper esophageal sphincter (UES). We examined the effects of less invasive APS combined with UES relaxation techniques (laryngeal closure with cricopharyngeal myotomy [LC-CPM] and central-part laryngectomy [CPL]) on pharyngeal pressure and UES dynamics.Study DesignRetrospective, observational study.SettingSingle center.MethodsWe assessed the high-resolution pharyngeal manometric parameters of patients who underwent APS from 2018 to 2020. Then, we compared the effects of bilateral cricopharyngeal myotomy (combined with LC: LC-CPM group) and total cricoidectomy (CPL group) on both pharyngeal pressure and UES dynamics pre- and postoperatively.ResultsEighteen patients (median age, 68 years; 17 men [94%]) were enrolled. Primary diseases associated with severe aspiration were neuromuscular disorders in 13, stroke in 3, and others in 2 patients. Pharyngeal swallowing pressure did not significantly change before and after APS. UES resting pressure and UES relaxation duration were significantly reduced (P < .001) and prolonged (P < .001), respectively, after APS. Only the CPL group (8 patients: median 62 years, all men) showed an increase in the velopharyngeal closure integral after APS (P < .05). More prolonged UES relaxation duration was recognized postoperatively in the CPL group (P < .01) than in the LC-CPM group.ConclusionLess invasive APS minimally affects pharyngeal swallowing pressure, decreases UES resting pressure, and prolongs UES relaxation duration. CPL may be more effective for postoperative UES relaxation in patients with a short UES relaxation time.

Cardiac functions in children with growth hormone deficiency: Effects of one year of GH replacement therapy

IntroductionChildren with Growth Hormone deficiency (GHD) are prone to heart dysfunction and, if left untreated, will result in marked cardiac dysfunction in adulthood. The aim was to evaluate the effect of GHD and growth hormone (GH) therapy on cardiac structure in children and adolescents, and to investigate the role of insulin like growth factor-1 (IGF-1) in this. MethodsM-mode, pulse-wave Doppler echocardiography and tissue Doppler imaging (TDI) were performed in 49 children with GHD who were divided into those with a peak GH response < 7 μg/L and 7–10 μg/L after two GH stimulation tests, aged 8–16 years at baseline and at six and 12 months after GH initiation, and 49 healthy peers. IGF-1 concentration was measured. ResultsAlthough the left ventricular end diastolic and systolic diameters in both GH deficient groups were significantly lower than controls (p < 0.01), both diameters increased significantly with one year of treatment and achieved normal values (p > 0.05). Using TDI in both two patients group revealed increased E/A, prolonged isovolumic relaxation time, shortened ejection time, and a significant increase in myocardial performance index compared to controls (p < 0.001). Significant improvement was observed in these parameters from the sixth month of GH treatment (p < 0.001), this improvement does not match parameters measured in healthy peers, even after one year of treatment in both patients group. (p < 0.001). No correlation was found between IGF-1 concentration and any echocardiographic parameter. ConclusionEchocardiographic parameters were similar in children with a GH peak < 7 μg/L and 7–10 μg/L. In TDI, both systolic and diastolic function was impaired in GHD children compared to controls. These parameters improved after one year of GH therapy but did not recover to healthy control levels.