Mechanical Function Of Heart Research Articles

Cardiopreventive effect of Klotho protein on oxidative stress, inflammation and apoptosis during cardiac ischemia/reperfusion injury

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre, Poland. Background The injury of the myocardium during ischemia/reperfusion (IRI) involves metabolic, morphological and contractile disorders [1]. Klotho is a membrane or soluble anti-aging protein. Recent studies have proven the correlation of Klotho deficiency and the occurrence and development of cardiovascular diseases [2]. Purpose This study aimed to evaluate the effect of Klotho protein supply on oxidative stress, inflammation and apoptosis in hearts subjected to IRI. Methods Isolated Wistar rat hearts perfused with the Langendorff method were subjected to ischemia, followed by reperfusion, in the presence or absence of Klotho protein. Hemodynamic parameters, and the levels of nitrate/nitrite (NOX)-, glutathione peroxidase (GPx), superoxide dismutase (SOD), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-Κb), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), interleukin-6 (IL-6), matrix metalloproteinase 2 (MMP-2), cytochrome c (cyt c) and caspase-9 were evaluated. Results Infusion supply of Klotho during IRI resulted in a recovery of contractile function (p=0.031) and heart rate (p=0.02). Klotho protein contributed to increase in the production of GPx (p=0.045) and SOD (p=0.006). The levels of (NOX)- (p=0.022), NF-Κb (p=0.006), NFATc1 (p=0.027), IL-6 (p=0.002), MMP-2 (p=0.008), cyt c (p=0.0002) and caspase-9 (p=0.009) were decreased in the IRI+Klotho group, as compared to the IRI group. Conclusions Klotho protein preserved heart mechanical function, enhanced antioxidant capacity, and reduced inflammation and apoptosis in the injured heart. Thus, Klotho can be recognized as a novel cardiopreventive/cardioprotective agent in ischemic damage.

Silencing RNA for MMPs May Be Utilized for Cardioprotection

Ischemia/reperfusion (I/R) injury is accompanied by an increase of matrix metalloproteinase 2 (MMP-2) activity, which degrades heart contractile proteins. The aim of the study was to investigate the effect of MMP-2 small interfering RNA (MMP-2 siRNA) administration on I/R heart. Isolated rat hearts perfused by the Langendorff method were subjected to I/R in the presence or absence of MMP-2 siRNA. The hemodynamic parameters of heart function were monitored. Lactate dehydrogenase (LDH) activity was measured in coronary effluents. Activity and concentration of MMPs in the hearts were measured. Concentration of troponin I (TnI) in coronary effluents was examined as a target for MMP-2 degradation. Recovery of heart mechanical function was reduced after I/R; however, administration of MMP-2 siRNA resulted in restoration of proper mechanical function (p < 0.001). LDH activity was decreased after the use of MMP-2 siRNA (p = 0.02), providing evidence for reduced cardiac damage. Both MMP-2 and MMP-9 syntheses as well as their activity were inhibited in the I/R hearts after siRNA administration (p < 0.05). MMP-2 siRNA administration inhibited TnI release into the coronary effluents (p < 0.001). The use of MMP-2 siRNA contributed to the improvement of heart mechanical function and reduction of contractile proteins degradation during I/R; therefore, MMP-2 siRNA may be considered a cardioprotective agent.

Biventricular biaxial mechanical testing and constitutive modelling of fetal porcine myocardium passive stiffness

The evaluation of fetal heart mechanical function is becoming increasingly important for determining the prognosis and making subsequent decisions on the treatment and management of congenital heart diseases. Finite Element (FE) modelling can potentially provide detailed information on fetal hearts, and help perform virtual interventions to assist in predicting outcomes and supporting clinical decisions. Previous FE studies have enabled an improved understanding of healthy and diseased fetal heart biomechanics. However, to date, the mechanical properties of the fetal myocardium have not been well characterized which limits the reliability of such modelling. Here, we characterize the passive mechanical properties of late fetal and neonatal porcine hearts via biaxial mechanical testing as a surrogate for human fetal heart mechanical properties. We used samples from both the right and left ventricles over the late gestational period from 85 days of gestation to birth. Constitutive modelling was subsequently performed with a transversely isotropic Fung-type model and a Humphrey-type model, using fiber orientations identified with histology. We found no significant difference in mechanical stiffness across all age groups and between the right and left ventricular samples. This was likely due to the similarity in LV and RV pressures in the fetal heart, and similar gestational maturity across these late gestational ages. We thus recommend using the constitutive model for the average stress-stress behaviour of the tissues in future modelling work. Furthermore, we characterized the variability of the stiffness to inform such work.

Δ9-Tetrahydrocannabinol (Δ9-THC) Improves Ischemia/Reperfusion Heart Dysfunction and Might Serve as a Cardioprotective Agent in the Future Treatment.

Ischemia/reperfusion (I/R) is a pivotal mechanism of organ injury during clinical stetting for example for cardiopulmonary bypasses. The generation of reactive oxygen species (ROS) during I/R induces oxidative stress that promotes endothelial dysfunction, DNA dissociation and local inflammation. In turn, those processes induce cytokine release, resulting in damage to cellular structures and cell death. One of the major psychoactive compounds of Cannabis is delta-9-tetrahydrocannabinol (Δ9-THC), which is known as an anti-inflammatory mediator. Our research aimed to test if Δ9-THC may be protective in the treatment of cardiovascular system dysfunction arising from I/R heart injury. Two experimental models were used: isolated rat hearts perfused with the Langendorff method and human cardiac myocytes (HCM) culture. Rat hearts and HCM underwent ex vivo/chemical in vitro I/R protocol with/without Δ9-THC treatment. The following parameters were measured: cell metabolic activity, morphology changes, cell damage as lactate dehydrogenase (LDH) activity, ceramide kinase (CERK) activity, ROS level, total antioxidant capacity (TAC) and heart hemodynamic parameters. Δ9-THC protected the heart, as evidenced by the improved recovery of cardiac function (p < 0.05, N = 3-6). Cells subjected to I/R showed lower cytoplasmic LDH activity, and 10 μM Δ9-THC treatment reduced cell injury and increased LDH content (p = 0.019, N = 6-9). Morphology changes of HCM-spherical shape, vacuolisation of cytoplasm and swollen mitochondria-were inhibited due to Δ9-THC treatment. I/R condition affected cell viability, but 10 μM Δ9-THC decreased the number of dead cells (p = 0.005, N = 6-9). The total level of CERK was lower in the I/R group, reflecting oxidative/nitrosative stress changes. The administration of Δ9-THC effectively increased the production of CERK to the level of aerobic control (p = 0.028, N = 6-9). ROS level was significantly decreased in I/R cells (p = 0.007, N = 6-8), confirming oxidative stress, while administration of 10 μM Δ9-THC enhanced TAC in cardiomyocytes subjected to I/R (p = 0.010, N = 6-8). Δ9-THC promotes the viability of cardiomyocytes, improves their metabolic activity, decreases cell damage and restores heart mechanical function, serving as a cardioprotective. We proposed the use of Δ9-THC as a cardioprotective drug to be, administered before onset of I/R protocol.

OPTIMIZED CENTRIFUGAL PUMP DIMENSIONS OF SAISPANDAN: HYBRID BSRM TOTAL ARTIFICIAL HEART FOR DESTINATION THERAPY

Optimization of pump characteristics when supporting the mechanical functions of heart as destination therapy is essential because of limitations imposed on design on size and power. Computational uid dynamics assessment with uid bearing similar properties is done. Knowledge of previously designed similar pumps is an 5 added advantage. Pumps supporting heart operate in Reynolds numbers of 10 .Limited data is available on pumps that operate in this range. It is useful to present data using traditional Cordier diagram of nondimensional speed vs diameter. Flow, pressure and rotational speed are the main parametric analytic points. Similitude helps in efcient design concept.

Tissue Expression of Atrial and Ventricular Myosin Light Chains in the Mechanism of Adaptation to Oxidative Stress

Ischemia/reperfusion (I/R) injury induces post-translational modifications of myosin light chains (MLCs), increasing their susceptibility to degradation by matrix metalloproteinase 2 (MMP-2). This results in the degradation of ventricular light chains (VLC1) in heart ventricles. The aim of the study was to investigate changes in MLCs content in the mechanism of adaptation to oxidative stress during I/R. Rat hearts, perfused using the Langendorff method, were subjected to I/R. The control group was maintained in oxygen conditions. Lactate dehydrogenase (LDH) activity and reactive oxygen/nitrogen species (ROS/RNS) content were measured in coronary effluents. Atrial light chains (ALC1) and ventricular light chains (VLC1) gene expression were examined using RQ-PCR. ALC1 and VLC1 protein content were measured using ELISA tests. MMP-2 activity was assessed by zymography. LDH activity as well as ROS/RNS content in coronary effluents was higher in the I/R group (p = 0.01, p = 0.04, respectively), confirming heart injury due to increased oxidative stress. MMP-2 activity in heart homogenates was also higher in the I/R group (p = 0.04). ALC1 gene expression and protein synthesis were significantly increased in I/R ventricles (p < 0.01, 0.04, respectively). VLC1 content in coronary effluents was increased in the I/R group (p = 0.02), confirming the increased degradation of VLC1 by MMP-2 and probably an adaptive production of ALC1 during I/R. This mechanism of adaptation to oxidative stress led to improved heart mechanical function.

Ameliorating Effect of Klotho Protein on Rat Heart during I/R Injury.

An essential procedure for the treatment of myocardial infarction is restoration of blood flow in the obstructed infarct artery, which may cause ischaemia/reperfusion (I/R) injury. Heart I/R injury manifests in oxidative stress, metabolic and morphological disorders, or cardiac contractile dysfunction. Klotho protein was found to be produced in the heart tissue and participate in antioxidation or ion homeostasis. The aim of this study was to examine an influence of Klotho protein on the heart subjected to I/R injury. Wistar rats served as a surrogate heart model ex vivo. Rat hearts perfused using the Langendorff method were subjected to global no-flow ischaemia, and isolated rat cardiomyocytes underwent chemical I/R in vitro, with or without recombinant Klotho protein administration. Haemodynamic parameters of heart function, cell contractility, markers of I/R injury and oxidative stress, and the level of contractile proteins such as myosin light chain 1 (MLC1) and troponin I (TnI) were measured. The treatment of hearts subjected to I/R injury with Klotho protein resulted in a recovery of heart mechanical function and ameliorated myocyte contractility. This improvement was associated with decreased tissue injury, enhanced antioxidant capacity, and reduced release of MLC1 and TnI. The present research showed the contribution of Klotho to cardioprevention during I/R. Thus, Klotho protein may support the protection from I/R injury and prevention of contractile dysfunction in the rat heart.

Mixture of MMP-2, MLC, and NOS Inhibitors Affects NO Metabolism and Protects Heart from Cardiac I/R Injury.

Objectives Coronary reperfusion procedure leads to ischemia/reperfusion injury of the heart (IRI). IRI arises from increased degradation of myosin light chains and increased activity of matrix metalloproteinase 2 (MMP-2). Increased production of toxic peroxynitrite (ONOO−) during oxidative stress is a source of increased nitration/nitrosylation of contractile proteins, which enhance their degradation through MMP-2. Hence, an imbalance in nitric oxide (NO) metabolism along with oxidative stress is an important factor contributing to pathophysiology of cardiovascular disorders, including myocardial infarction. The aim of the current study was to provide an important insight into understanding the interaction of iNOS, eNOS, and ADMA during oxidative stress and to propose the beneficial therapy to modulate this interaction. Material and Methods. Pathogen-free Wistar rats were used in this study as a surrogate heart model ex vivo. Rat hearts perfused using the Langendorff method were subjected to global no-flow ischemia with or without administration of DOXY (1 µM), ML-7 (0.5 µM), and L-NAME (2 µM) mixture. Haemodynamic parameters of heart function, markers of I/R injury, tissue expression of iNOS, eNOS, and phospho-eNOS, asymmetric dimethylarginine, and NO production as well as MMP-2 activity were measured. Results Mechanical heart function and coronary flow (CF) were decreased in the hearts subjected to I/R. Treatment of the hearts with the tested mixture resulted in a recovery of mechanical function due to decreased activity of MMP‐2. An infusion of Doxy, ML-7, and L-NAME mixture into I/R hearts decreased the expression of iNOS, eNOS, and phospho-eNOS and in consequence reduced ADMA expression. Decreased ADMA production led to enhanced NO synthesis and improvement of cardiac function at 85% of aerobic control. Conclusions Synergistic effect of the multidrug therapy with the subthreshold doses allows addressing a few pathways of I/R injury simultaneously to achieve protection of cardiac function during I/R.

Quantifying the Contribution of Cardiomyocyte Metabolic Dysfunction to the Heart Mechanical Function

Hydrolysis of ATP provides the chemical free energy to drive the molecular processes underlying cardiac pumping. Under normal conditions the heart hydrolyzes and resynthesizes the entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the chemical potential (free energy of ATP hydrolysis) at which ATP is synthesized and is made available to drive cellular processes. We hypothesize that this metabolic/energetic dysfunction causes contractile dysfunction of the myocardium in heart failure, contributing to the whole‐body phenotype (venous congestion, exercise intolerance) of heart failure in humans. To test this hypothesis, we used a rat transverse aortic constriction (TAC) model of cardiac decompensation/heart failure to measure the relationships between functional parameters (cardiac output, ejection fraction, etc.) and myocardial energetic state, determined based on measurements of myocardial metabolite pools and mitochondrial oxidative capacity. Cardiac function was measured by echocardiography and hearts were harvested for mitochondrial isolation and phosphate metabolite measurements at the end‐point, either 15 weeks post‐surgery, or 18 weeks post‐surgery. Cardiac phosphate metabolites levels were measured using NADH dependent enzymatic assays and mitochondrial oxidative capacity was measured using an Oroboros O2k Oxygraph. In both cohorts of rats, there was an overall reduction in fatty acid and carbohydrate oxidative capacity, with an increase in the ratio of maximal carbohydrate to fatty acid oxidative capacity in the 18‐week TAC rats compared to sham controls. In addition, we also observed differences in phosphate metabolite levels in both 15‐week TAC and 18‐week TAC rats compared to controls and correlations between metabolite mechanical functional changes. Furthermore, we used multi‐scale computational models of myocardial metabolism and metabolic state‐dependent contractile dynamics to quantify the contribution of reductions in oxidative capacity and metabolite pools levels to heart mechanical function. Our results suggest that there is a causal link between a reduction in free energy of ATP hydrolysis and kinetic impairment of the myosin ATPase cross‐bridge cycle in decompensated hypertrophy/heart failure.Support or Funding InformationFunded by NIH Grants 5T32GM008322‐28 and U01HL122199This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Detection of shockable ventricular arrhythmia using optimal orthogonal wavelet filters

Sudden cardiac death (SCD) is caused by lethal arrhythmia. Ventricular fibrillation (VF) and ventricular tachycardia (VT) are amenable to defibrillation or electrical shock therapy (“shockable” arrhythmia) that can abolish the VF/VT and restore normal electrical and mechanical heart function. The challenge is to differentiate between shockable and non-shockable arrhythmia during the emergency response to SCD. When it comes to saving the life, accurate electrocardiogram (ECG) diagnosis and fast delivery of appropriate treatment is imperative. Automated systems to differentiate shockable from non-shockable arrhythmia have been developed to overcome the difficulty, and possible errors due to the manual inspection. In the present work, we have devised an efficient, effective and robust automated system to detect shockable and non-shockable arrhythmia using an optimal wavelet-based features extracted from ECG epochs of 2 s durations. We employed optimal two-channel frequency selective orthogonal wavelet filter bank to diagnose shockable ventricular arrhythmia. The optimization was carried out by minimizing the stop band ripple energy of the wavelet filter. The optimal orthogonal wavelet filter has been designed using a semi-definite programming (SDP) formulation without the use of any parameterization. The SDP solution gave us the desired optimal orthogonal wavelet filter bank with minimum stop band energy and the desired degree of regularity for the given length of filter. Fuzzy entropy and Renyi entropy features were extracted from the 2-s ECG epochs. These extracted features were then fed into the classifiers for discrimination of shockable arrhythmia rhythms and non-shockable arrhythmia rhythms. The best results were obtained from support vector machine. Accuracy of 97.8%, sensitivity of 93.42%, and specificity of 98.35% were obtained using a tenfold cross validation scheme. The developed automated system is accurate and robust; therefore, it can be integrated in automated external defibrillators that can be deployed for hospitals as well as out-of-hospital emergency resuscitation of SCD.

Cardioprotective effect of MMP-2-inhibitor-NO-donor hybrid against ischaemia/reperfusion injury.

Hypoxic injury of cardiovascular system is one of the most frequent complications following ischaemia. Heart injury arises from increased degradation of contractile proteins, such as myosin light chains (MLCs) and troponin I by matrix metalloproteinase 2 (MMP‐2). The aim of the current research was to study the effects of 5‐phenyloxyphenyl‐5‐aminoalkyl nitrate barbiturate (MMP‐2‐inhibitor‐NO‐donor hybrid) on hearts subjected to ischaemia/reperfusion (I/R) injury. Primary human cardiac myocytes and Wistar rat hearts perfused using Langendorff method have been used. Human cardiomyocytes or rat hearts were subjected to I/R in the presence or absence of tested hybrid. Haemodynamic parameters of heart function, markers of I/R injury, gene and protein expression of MMP‐2, MMP‐9, inducible form of NOS (iNOS), asymmetric dimethylarginine (ADMA), as well as MMP‐2 activity were measured. Mechanical heart function, coronary flow (CF) and heart rate (HR) were decreased in hearts subjected to I/R Treatment of hearts with the hybrid (1‐10 µmol/L) resulted in a concentration‐dependent recovery of mechanical function, improved CF and HR. This improvement was associated with decreased tissue injury and reduction of synthesis and activity of MMP‐2. Decreased activity of intracellular MMP‐2 led to reduced degradation of MLC and improved myocyte contractility in a concentration‐dependent manner. An infusion of a MMP‐2‐inhibitor‐NO‐donor hybrid into I/R hearts decreased the expression of iNOS and reduced the levels of ADMA. Thus, 5‐phenyloxyphenyl‐5‐aminoalkyl nitrate barbiturate protects heart from I/R injury.

Quantifying the Contribution of Cardiomyocyte Metabolic Dysfunction to the Heart Mechanical Function

Quantifying the Contribution of Cardiomyocyte Metabolic Dysfunction to the Heart Mechanical Function

PVA/Dextran hydrogel patches as delivery system of antioxidant astaxanthin: a cardiovascular approach

After myocardial infarction, the heart’s mechanical properties and its intrinsic capability to recover are compromised. To improve this recovery, several groups have developed cardiac patches based on different biomaterials strategies. Here, we developed polyvinylalcohol/dextran (PVA/Dex) elastic hydrogel patches, obtained through the freeze thawing (FT) process, with the aim to deliver locally a potent natural antioxidant molecule, astaxanthin, and to assist the heart’s response against the generated myofibril stress. Extensive rheological and dynamo-mechanical characterization of the effect of the PVA molecular weight, number of freeze-thawing cycles and Dex addition on the mechanical properties of the resulting hydrogels, were carried out. Hydrogel systems based on PVA 145 kDa and PVA 47 kDa blended with Dex 40 kDa, were chosen as the most promising candidates for this application. In order to improve astaxanthin solubility, an inclusion system using hydroxypropyl-β-cyclodextrin was prepared. This system was posteriorly loaded within the PVA/Dex hydrogels. PVA145/Dex 1FT and PVA47/Dex 3FT showed the best rheological and mechanical properties when compared to the other studied systems; environmental scanning electron microscope and confocal imaging evidenced a porous structure of the hydrogels allowing astaxanthin release. In vitro cellular behavior was analyzed after 24 h of contact with astaxanthin-loaded hydrogels. In vivo subcutaneous biocompatibility was performed in rats using PVA145/Dex 1FT, as the best compromise between mechanical support and astaxanthin delivery. Finally, ex vivo and in vivo experiments showed good mechanical and compatibility properties of this hydrogel. The obtained results showed that the studied materials have a potential to be used as myocardial patches to assist infarcted heart mechanical function and to reduce oxidative stress by the in situ release of astaxanthin.

Low Frequency Electromagnetic Field Conditioning Protects against I/R Injury and Contractile Dysfunction in the Isolated Rat Heart

Low frequency electromagnetic field (LF-EMF) decreases the formation of reactive oxygen species, which are key mediators of ischemia/reperfusion (I/R) injury. Therefore, we hypothesized that the LF-EMF protects contractility of hearts subjected to I/R injury. Isolated rat hearts were subjected to 20 min of global no-flow ischemia, followed by 30 min reperfusion, in the presence or absence of LF-EMF. Coronary flow, heart rate, left ventricular developed pressure (LVDP), and rate pressure product (RPP) were determined for evaluation of heart mechanical function. The activity of cardiac matrix metalloproteinase-2 (MMP-2) and the contents of coronary effluent troponin I (TnI) and interleukin-6 (IL-6) were measured as markers of heart injury. LF-EMF prevented decreased RPP in I/R hearts, while having no effect on coronary flow. In addition, hearts subjected to I/R exhibited significantly increased LVDP when subjected to LF-EMF. Although TnI and IL-6 levels were increased in I/R hearts, their levels returned to baseline aerobic levels in I/R hearts subjected to LF-EMF. The reduced activity of MMP-2 in I/R hearts was reversed in hearts subjected to LF-EMF. The data presented here indicate that acute exposure to LF-EMF protects mechanical function of I/R hearts and reduces I/R injury.

A textile-based wearable system for the prolonged assessment of cardiac mechanics in daily life.

Seismocardiogram, SCG, can be detected over the 24 hours in ambulant subjects by a textile-based wearable system together with the electrocardiogram, ECG and respiration. In this pilot study we explored the possibility to derive 24 h profiles of cardiac time intervals, i.e. indexes of heart mechanical function, from the SCG recordings performed in daily life conditions by the above wearable system. Two healthy subjects were recruited for the study. They worn the system for 24 hours during a working day. From each recording, every 30 minutes the following parameters were derived from the ECG and SCG signals: RR interval, RRI, Pre-Ejection Period, PEP, Isovolumic Contraction Time, ICT, Left Ventricular Ejection Time, LVET, Isovolumic Relaxation Time, IRT. From the analysis it appears that 1) all parameters are characterized by a coefficient of variation in the same order of magnitude, and 2) 24 h LVET time profiles mirrors the long term RRI behavior. Common trends in PEP and ICT profiles were observed in one subject. This study indicates that indexes of cardiac mechanics can be derived from SCG recordings performed over the 24 hours. The obtained positive results encourage further studies to refine this methodology and confirm the present findings.

Evidence that 2-aminoethoxydiphenyl borate provokes fibrillation in perfused rat hearts via voltage-independent calcium channels

We tested whether 2-aminoethoxydiphenyl borate (2-APB) induces arrhythmia in perfused rat hearts and whether this arrhythmia might result from the activation of voltage-independent calcium channels. Rat hearts were Langendorff perfused and beat under sinus rhythm. An isovolumic balloon inserted into the left ventricle was used to record mechanical function while bipolar electrograms were recorded from electrodes sutured to the base and the apex of hearts. Western and immunofluorescence analyses were performed on rat left ventricular protein extracts and left ventricular frozen sections, respectively. Rat ventricular myocytes express Orai 1 and Orai 3, and ventricle also contains the Orai regulator Stim1. Rat hearts (n=5) perfused with Krebs–Henseleit (KH) alone maintained sinus rhythm at 4.8±0.1Hz and stable mechanical function. By contrast, perfusing hearts (n=5) with (KH+22μM 2-APB) provoked a period of tachycardic ectopy at rates of up to 10.8±0.2Hz. As perfusion with (KH+22μM 2-APB) continued, the rate of spontaneous ventricular depolarization increased to 21.8±1.2Hz and became disorganized. Heart mechanical function collapsed as developed pressure decreased from 87±8.8 to 3.5±1.9mm Hg. Flow rate did not change between normal (16.6±0.9ml/min) and fibrillating (17.4±0.8ml/min) hearts. The addition of 20μM 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) to (KH+22μM 2-APB) perfusates (n=4) restored sinus rhythm and heart mechanical output. These data indicate that activating myocardial voltage-independent calcium channels, possibly the Orais, may be a novel cause of ventricular arrhythmia.

The effect of K201 on isolated working rabbit heart mechanical function during pharmacologically induced Ca2+ overload

Reduced cardiac contractility has been associated with disrupted myocardial Ca(2+) signalling. The 1,4 benzothiazepine K201 (JTV-519) acts on several Ca(2+) handling proteins and improves cardiac contractility in vivo in a variety of animal models of myocardial dysfunction. However, it is unclear whether this improvement depends on the systemic effects of K201 or if K201 reverses the effects of Ca(2+) dysregulation, regardless of the cause. The effect of K201 on cardiac mechanical function was assessed in isolated working hearts from adult rabbits, using a ventricular pressure-volume catheter. In separate experiments, the effect of K201 was investigated in hearts following pharmacologically induced Ca(2+) overload using elevated extracellular [Ca(2+) ] ([Ca(2+) ](o) ) and β-adrenoceptor stimulation. K201 induced a concentration-dependent decline in systolic function (peak pressure, dP/dt(max) and preload recruitable stroke work), lusitropy (reduced dP/dt(min) and increased end diastolic pressure) and stroke volume, independent of decreased heart rate. In separate experiments, mechanical function in hearts exposed to 4.5 mmol·L(-1) [Ca(2+) ](o) and 150 nmol·L(-1) isoprenaline declined until cessation of aortic flow (in 6 out of 11 hearts). However, all hearts perfused with the addition of 1 µmol·L(-1) K201 maintained aortic flow and demonstrated significantly improved peak systolic pressures, dP/dt(max) and dP/dt(min) . K201 significantly improved mechanical function of the heart during Ca(2+) overload. This suggests that K201 can limit the detrimental effects of elevated intracellular Ca(2+) and exert beneficial effects on cardiac contractile function, independent of systemic effects previously observed in vivo.

E0709 Speckle tracking based circumferential strain analysis to evaluate mechanical function of heart during ventricular pacing: an experimental study on open chest instrumented pigs

AimsThis study aims at assessing ventricular pacing (VP) mechanical change by using global circumferential strain and segmental circumferential strain of speckle tracking imaging.MethodsSeven adult pigs, weighting 30.8±3.6 kg, were sedated,...

Improvement of mechanical heart function by trimetazidine in db/db mice

To investigate the influence of trimetazidine, which is known to be an antioxidant and modulator of metabolism, on cardiac function and the development of diabetic cardiomyopathy in db/db mouse. Trimetazidine was administered to db/db mice for eight weeks. Cardiac function was measured by inserting a Millar catheter into the left ventricle, and oxidative stress and AMP-activated protein kinase (AMPK) activity in the myocardium were evaluated. Untreated db/db mice exhibited a significant decrease in cardiac function compared to normal C57 mice. Oxidative stress and lipid deposition were markedly increased in the myocardium, concomitant with inactivation of AMPK and increased expression of peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1 alpha). Trimetazidine significantly improved systolic and diastolic function in hearts of db/db mice and led to reduced production of reactive oxygen species and deposition of fatty acid in cardiomyocytes. Trimetazidine also caused AMPK activation and reduced PGC-1 alpha expression in the hearts of db/db mice. The data suggest that trimetazidine significantly improves cardiac function in db/db mice by attenuating lipotoxicity and improving the oxidation status of the heart. Activation of AMPK and decreased expression of PGC-1 alpha were involved in this process. Furthermore, our study suggests that trimetazidine suppresses the development of diabetic cardiomyopathy, which warrants further clinical investigation.

Mechanical analysis of congestive heart failure caused by bundle branch block based on an electromechanical canine heart model

Asynchronous electrical activation, induced by bundle branch block (BBB), can cause reduced ventricular function. However, the effects of BBB on the mechanical function of heart are difficult to assess experimentally. Many heart models have been developed to investigate cardiac properties during BBB but have mainly focused on the electrophysiological properties. To date, the mechanical function of BBB has not been well investigated. Based on a three-dimensional electromechanical canine heart model, the mechanical properties of complete left and right bundle branch block (LBBB and RBBB) were simulated. The anatomical model as well as the fiber orientations of a dog heart was reconstructed from magnetic resonance imaging (MRI) and diffusion tensor MRI (DT-MRI). Using the solutions of reaction–diffusion equations and with a strategy of parallel computation, the asynchronous excitation propagation and intraventricular conduction in BBB was simulated. The mechanics of myocardial tissues were computed with time-, sarcomere length-dependent uniaxial active stress initiated at the time of depolarization. The quantification of mechanical intra- and interventricular asynchrony of BBB was then investigated using the finite-element method with an eight-node isoparametric element. The simulation results show that (1) there exists inter- and intraventricular systolic dyssynchrony during BBB; (2) RBBB may have more mechanical synchrony and better systolic function of the left ventricle (LV) than LBBB; (3) the ventricles always move toward the early-activated ventricle; and (4) the septum experiences higher stress than left and right ventricular free walls in BBB. The simulation results validate clinical and experimental recordings of heart deformation and provide regional quantitative estimates of ventricular wall strain and stress. The present work suggests that an electromechanical heart model, incorporating real geometry and fiber orientations, may be helpful for better understanding of the mechanical implications of congestive heart failure (CHF) caused by BBB.