Increase In Left Ventricular Pressure Research Articles

The effects of acute and chronic Red Bull® consumption on cardiodynamics and oxidative stress in coronary effluent of trained rats

Background/Aim. Energy drinks (EDs) are widely used by athletes as ergogenic agents and Red Bull? is one of the most consumed EDs among them. The aim of this study was to determine the acute and chronic effects of Red Bull? on cardiodynamics and parameters of oxidative stress in physically trained rats. Methods. Rats were subjected to a swimming practice (1h a day, 5 days a week, for 4 weeks). They were divided into 4 groups: rats that did not consume ED either before swimming or prior to sacrificing; rats that did not consume ED before swimming but did consume ED 30 min prior to sacrificing; rats that consumed ED 30 min before every swimming training but did not consume ED prior to sacrificing; rats that consumed ED 30 min before every swimming training and 30 min before sacrificing. After sacrificing, the hearts of the rats were isolated and perfused according to the Langendorff technique. The parameters of cardiac function were recorded, and also the levels of prooxidants were measured in the coronary effluent during coronary autoregulation. Results. Acute administration of the ED had a positive inotropic effect (manifested as a significantly higher level of the maximum and minimum rate of pressure development in the left ventricle), while chronic administration affected the isolated increase in systolic left ventricular pressure. The prooxidative effect of the ED was observed, which was more pronounced in chronic consumption. Conclusion. The main conclusion of our study is that chronic consumption of ED changes the cardiovascular response and redox status in acute consumption ED.

The co-treatment of rosuvastatin with dapagliflozin synergistically inhibited apoptosis via activating the PI3K/AKt/mTOR signaling pathway in myocardial ischemia/reperfusion injury rats

ObjectiveThe purpose of the present study was to evaluate the role of co-treatment of rosuvastatin (RSV) and dapagliflozin (DGZ) preconditioning in myocardium ischemia/reperfusion (I/R) injury and to further investigate the underlying mechanism.MethodsSprague-Dawley (SD) rats (n = 25) were divided into five groups randomly: (1) Sham, (2) I/R, (3) I/R + RSV (10 mg/kg), (4) IR + DGZ (1 mg/kg), and (5) I/R + RSV (10 mg/kg) + DGZ (1 mg/kg). The I/R model was induced with 30 min of left anterior descending occlusion followed by 120 min of reperfusion.Results In vivo pretreatment with RSV and DGZ, respectively, showed a significant reduction of infarction size, a significant increase in the levels of left ventricular systolic pressure, and maximal rate increase in left ventricular pressure (+dp/dt max), decrease in the levels of left ventricular end-diastolic pressure (LVEDP), maximal rate of decrease of left ventricular pressure (−dp/dt max) and activity of cardiac enzymes of creatine kinase (CK), creatine kinase MB isoenzymes (CK-MB), and hyper-tensive cardiac troponin I compared with the I/R group. H9C2 cells were exposed to hypoxia/reoxygenation to simulate an I/R model. In vitro administration of 25 µM RSV and 50 µM DGZ significantly enhanced cell viability, upregulated the expression levels of p-PI3K, p-Akt, p-mTOR, and Bcl-2, whereas it downregulated cleaved-caspase3, Bax. TUNEL assay indicated that pretreatment with RSV and DGZ decreased the apoptosis of H9C2 cells.ConclusionThe combination of RSV and DGZ significantly enhances the cardioprotective effects compared with RSV or DGZ alone. RSV and DGZ have the potential cardioprotective effects against I/R injury by activating the PI3K/AKt/mTOR signaling pathway.

Wire Crossing Time Correlate with Left Ventricular End-Diastolic Pressure in Patients with ST Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Backgrounds: Mortality and morbidity in acute myocardial infarction depend on the extent of the infarct area. Rapid recovery of coronary artery blood flow with primary percutaneous coronary intervention (pPCI) can limit the extent of infarction and improve left ventricular function. Acute myocardial infarction reduce diastolic function, which in the early stage of diastolic dysfunction, there is an increase in left ventricular end-diastolic pressure (LVEDP). The non-invasive marker of E/e’ ratio is an accurate parameter of increased LVEDP.Methods: This was a cross-sectional study enrolled consecutive patients with ST Segment Elevation Myocardial Infarction (STEMI) who underwent pPCI at Dr. Sardjito Hospital. The wire crossing time was calculated from the onset of chest pain until the guidewire crossed the infarct-related artery during the pPCI procedure. The E/e’ ratio was determined by transthoracic echocardiography which performed within 48 hours after the primary PCI. Correlation between the wire crossing time and the E/e’ ratio was assessed by the Pearson correlation test. The value of p <0.05 was considered statistically significant.Results: A total of 40 patients were enrolled in this study. The mean wire crossing time was 12.73±5.22 hours. The median value of the E/e’ ratio was 8.36 (range: 4.71-22.00). There was a moderate strength and significant correlation between the wire crossing time and the E/e’ ratio (r = 0.572; p <0.001). Patients with E/e’ ratio >15 had significantly longer wire crossing time than in patient with E/e’ ratio ≤15 (20.21±2.5 hours vs. 11.41±4.39 hours; p <0.001; respectively). The wire crossing time was independently associated the E/e’ ratio (r = 0.463; p = 0.003).Conclusion: There was a moderate strength and significant positive correlation between the wire crossing time and increased LVEDP, an earlier marker of diastolic dysfunction, measured by E/e’ ratio using TTE in patients with STEMI underwent pPCI.

Chronic cardiac structural damage, diastolic and systolic dysfunction following acute myocardial injury due to bromine exposure in rats.

Accidental bromine spills are common and its large industrial stores risk potential terrorist attacks. The mechanisms of bromine toxicity and effective therapeutic strategies are unknown. Our studies demonstrate that inhaled bromine causes deleterious cardiac manifestations. In this manuscript we describe mechanisms of delayed cardiac effects in the survivors of a single bromine exposure. Rats were exposed to bromine (600ppm for 45min) and the survivors were sacrificed at 14 or 28days. Echocardiography, hemodynamic analysis, histology, transmission electron microscopy (TEM) and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects. Increases in right ventricular (RV) and left ventricular (LV) end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis were observed. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. Increases in cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) reflected myofibrillar damage and increased LV wall stress. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased sarcoendoplasmic reticulum calcium ATPase (SERCA) inactivation and a striking dephosphorylation of phospholamban. NADPH oxidase 2 and protein phosphatase 1 were also increased. Increased circulating eosinophils and myocardial 4-hydroxynonenal content suggested increased oxidative stress as a key contributing factor to these effects. Thus, a continuous oxidative stress-induced chronic myocardial damage along with phospholamban dephosphorylation are critical for bromine-induced chronic cardiac dysfunction. These findings in our preclinical model will educate clinicians and public health personnel and provide important endpoints to evaluate therapies.

Treatment of Left Ventricular Circulation Disorder: Application of Echocardiography Information Data Monitoring.

BackgroundCardiac hypertrophy induced by pressure overload is one of the important causes of heart failure and sudden cardiac death. At present, there are few studies on the outcome of left ventricular hypertrophy and left ventricular function after complete pressure load removal.ObjectiveThis study aims to better simulate the changes of left ventricular structure and function during the process of left ventricular pressure overload and deloading, and to explore the application of echocardiography in it.MethodsIn this study, healthy male (BALB/C) mice were used as research objects to establish an ascending aorta constriction model, to carry out echocardiographic and hemodynamic examinations, to establish an ascending aorta deconstriction model in mice, and to carry out echocardiographic and hemodynamic examinations.ResultsCompared with the sham operation group, the left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), interventricular septal (IVS), and left ventricular posterior wall (LVPW) in the constriction operation group were significantly increased (P=.02, P=.02, P=.02, and P=.02, respectively). LVESD, LVEDD, IVS, and LVPW in the early and late constriction groups were significantly decreased, and the degree of decrease in the early group was greater than that in the late group; compared with the sham operation group, left ventricular diastolic pressure in the constriction operation group increased significantly at 9 and 15 weeks after operation (P=.03). Left ventricular systolic pressure at 15 weeks after operation decreased to a certain extent but was higher than that of the sham operation group (P=.02). The maximal rate of the increase of left ventricular pressure at 3 weeks, 9 weeks, and 15 weeks after operation decreased significantly (P=.03, P=.02, and P=.02, respectively).ConclusionsIn this study, the ascending aorta coarctation model and descending aorta coarctation model were successfully established, which verifies the value of echocardiography information data monitoring in the treatment of left ventricular circulation disorders and the evaluation of surgical treatment.

Mangiferin exert cardioprotective and anti-apoptotic effects in heart failure induced rats

Mangiferin is a well-known xanthone extracted from mango leaves (Mangifera indica Linn). Mangiferin is widely distributed in the bark, peel, leaf, seed, stalk, and kernel of mango and higher plants. The pharmacological properties of mangiferin, including its antioxidant, anticancer, antiaging, antiviral, hepatoprotective, analgesic, and immunomodulatory activities, have been described in several studies. We investigated the effect of mangiferin on isoproterenol-induced apoptosis. Experimental heart failure was induced in rats by intraperitoneal administration of isoproterenol (5 mg/kg) for 7 consecutive days. Rats were divided into five groups: group I (sham rats), group II (isoproterenol alone control), group III (isoproterenol + 25 mg/kg mangiferin), group IV (isoproterenol + 50 mg/kg mangiferin), and group V (isoproterenol + 0.0225 mg/kg digitalis as a positive control). Hemodynamic parameters and body weight, heart weight and liver weight, apoptosis induction, and caspase-3, Bax, and Bcl-2 protein levels were measured, and a histopathological analysis of cardiomyocytes was performed. In addition, apoptosis and protein expression of caspase-3, cleaved caspase-3, Bax, and Bcl-2 were measured in cardiac H9c2 cells. Mangiferin supplementation significantly increased heart rate and improved the maximum rate of decrease in left ventricular (LV) pressure, the maximum rate of increase in LV pressure, and LV systolic pressure. Mangiferin reduced inflammatory cell infiltration and the number of broken myocardial fibers, and decreased apoptosis in cardiomyocytes by reducing proteins levels of caspase-3 and Bax and increasing those of Bcl-2. Our findings suggest that mangiferin has a cardioprotective effect against isoproterenol-induced apoptosis in cardiomyocytes.

Impaired Baroreflex Function in an Ovine Model of Chronic Heart Failure Induced by Multiple Coronary Microembolizations.

Testing new therapies in heart failure (HF) requires a chronic stable model of HF in large animals. Microembolization of the coronary arteries has been used to model HF previously; however, neural control has not been previously explored in this model. Thus the aim of this study was to further characterize neural control in this model of HF. HF was induced by infusion of microspheres (45 micron; 1.3 ml) into the proximal left coronary artery or left descending coronary arteries, with three sequential embolizations over 3 weeks. Twelve to 14 weeks after the final embolization, and when ejection fraction had decreased below 45%, animals were instrumented to record blood pressure and heart rate. Baroreflex control of heart rate was investigated in conscious animals. Additionally, pressure-volume loops were constructed under anesthesia. Embolization-induced HF was associated with a decrease in mean arterial pressure (67 ± 2 vs. 85 ± 4 mmHg, p < 0.05), an increase in heart rate (108 ± 4 vs. 94 ± 4 bpm, p < 0.05), and a significant increase in left ventricular end-diastolic pressure (11.4 ± 2 vs. 6.2 ± 1 mmHg, p < 0.01). Under conscious conditions, there was a significant decrease in the gain (−8.2 ± 2 vs. −4.1 ± 1 beats/min/mmHg, p < 0.05) as well as the lower plateau of the baroreflex in HF compared to control animals. HF was also associated with significantly increased respiratory rate (107 ± 4 vs. 87 ± 4 breaths/min, p < 0.01) and incidence of apneas (520 ± 24 vs. 191 ± 8 apnea periods >4 s, p < 0.05), compared to control sheep. The microembolization model of heart failure is associated with an increase in left ventricular end-diastolic pressure, impaired cardiac function, and altered baroreflex control of the heart. These findings suggest this chronic model of HF is appropriate to use for investigating interventions aimed at improving neural control in HF.

Regulation of beta adrenoceptor-mediated myocardial contraction and calcium dynamics by the G protein-coupled estrogen receptor 1

The G protein-coupled estrogen receptor 1 (GPER) produces cardioprotective effects. However, the underlying mechanisms are not well understood. We aimed to investigate the role of GPER in β adrenoceptor-mediated cardiac contraction and myocardial signaling. In anesthetized animals, intrajugular administration of isoproterenol produces a rapid and sustained rise in left ventricular pressure (LVP) and increases ectopic contractions. Administration of the GPER agonist G-1 during the plateau phase of isoproterenol-induced LVP increase rapidly restores LVP to baseline levels and reduces the frequency of ectopic contractions. In freshly isolated cardiomyocytes, isoproterenol potentiates electrically induced peak currents of L-type Ca2+ channels (LTCC) and increases the potential sensitivity of their inactivation. Coadministration of G-1 prevents isoproterenol-induced potentiation of peak LTCC currents and makes channels more sensitive to being inactivated compared to isoproterenol alone. Isoproterenol treatment of cardiomyocytes without electrical stimulation triggers slow-rising Ca2+ signals that are inhibited by the β1AR antagonist metoprolol but not by β2AR antagonist ICI-118551. G-1 pretreatment dose-dependently suppresses isoproterenol-induced total Ca2+ signals and the amplitude and frequency of the intrinsic Ca2+ oscillatory deflections. Pretreatment with the GPER antagonist G-36 produces opposite effects, dose-dependently increasing these signals. ISO promotes robust phosphorylation of Cav1.2 channels at Ser1928. G-1 pretreatment inhibits isoproterenol-stimulated phosphorylation of Cav1.2 at Ser1928, while G-36 pretreatment enhances this signal. Our data indicate that GPER functions as an intrinsic component of β1AR signaling to moderate myocardial Ca2+ dynamics and contraction.

Volume incompliance and transfusion are essential for transfusion-associated circulatory overload: a novel animal model.

BACKGROUNDTransfusion‐associated circulatory overload (TACO) is the predominant complication of transfusion resulting in death. The pathophysiology is poorly understood, but inability to manage volume is associated with TACO, and observational data suggest it is different from simple cardiac overload due to fluids. We developed a two‐hit TACO animal model to assess the role of volume incompliance (“first‐hit”) and studied whether volume overload (“second‐hit”) by red blood cell (RBC) transfusion is different compared to fluids (Ringer's lactate [RL]).MATERIALS AND METHODSMale adult Lewis rats were stratified into a control group (no intervention) or a first hit: either myocardial infarction (MI) or acute kidney injury (AKI). Animals were randomized to a second hit of either RBC transfusion or an equal volume of RL. A clinically relevant difference was defined as an increase in left ventricular end‐diastolic pressure (ΔLVEDP) of +4.0 mm Hg between the RBC and RL groups.RESULTSIn control animals (without first hit) LVEDP was not different between infusion groups (Δ + 1.6 mm Hg). LVEDP increased significantly more after RBCs compared to RL in animals with MI (Δ7.4 mm Hg) and AKI (Δ + 5.4 mm Hg), respectively. Volume‐incompliant rats matched clinical TACO criteria in 92% of transfused versus 25% of RL‐infused animals, with a greater increase in heart rate and significantly higher blood pressure.CONCLUSIONTo our knowledge, this is the first animal model for TACO, showing that a combination of volume incompliance and transfusion is essential for development of circulatory overload. This model allows for further testing of mechanistic factors as well as therapeutic approaches.

Left ventricular retraining in corrected transposition: Relationship between pressure and mass

BackgroundA subset of patients with corrected transposition of the great arteries (CC-TGA) will require left ventricular (LV) retraining before undergoing a double-switch procedure. LV retraining results in an immediate increase in LV pressure but not in LV mass. The purpose of this study was to evaluate the relationship between LV pressure and mass during LV retraining. MethodsThis was a retrospective review of 36 patients with CC-TGA who were enrolled in LV retraining. The median age at enrollment was 12 months. The majority (82%) had an Ebstenoid tricuspid valve or moderate to severe tricuspid valve regurgitation before pulmonary artery banding. ResultsTwenty-seven of the 36 patients underwent LV retraining and a double switch, including 14 patients with a single pulmonary artery band (PAB), 12 patients with 2 PABs, and 1 patient with 3 PABs. There was no early or late mortality associated with these procedures. Ninety percent of the patients demonstrated a linear relationship between LV pressure and mass; however, 3 patients (10%) demonstrated a different LV retraining pattern characterized by excess LV mass compared to LV pressure. Two of these 3 patients are LV retraining failures, whereas the third patient did undergo a double switch. ConclusionsThe data show that the majority of patients enrolled in LV retraining have a predictable relationship between LV mass and pressure. A minority demonstrate an excess accrual of mass with respect to pressure load. These results suggest there may be an important distinction between normal and pathological hypertrophy during the LV retraining process.

Tiotropium bromide, a long acting muscarinic receptor antagonist triggers intracellular calcium signalling in the heart

Background and purposeTiotropium bromide (TB) is a long acting muscarinic receptor antagonist used to manage chronic obstructive pulmonary disease (COPD). Recent meta-analyses suggest an increased risk of cardiovascular events with TB. Ca2+/calmodulin dependent kinase II (CaMKII) and L-type Ca2+ channels regulate Ca2+ concentrations allowing management of Ca2+ across membranes. Pathological increases in Ca2+ are initially slow and progressive, however once the cytosolic concentration rises >1–3 μM from ~100 nM, calcium overload occurs and can lead to cell death. Ipratropium bromide, a short acting muscarinic receptor antagonist has previously been found to induce Ca2+ mediated eryptosis. The aim of this study was to investigate the role of Ca2+ in Tiotropium bromide mediated cardiotoxicity. Experimental approachIsolated Sprague-Dawley rat hearts were perfused with TB (10–0.1 nM) ± KN-93 (400 nM) or nifedipine (1 nM). Hearts were stained to determine infarct size (%) using triphenyltetrazolium chloride (TTC), or snap frozen to determine p-CaMKII (Thr286) expression. Cardiomyocytes were isolated using a modified Langendorff perfusion and enzymatic dissociation before preparation for Fluo 3-AM staining and flow cytometric analysis. Key resultsTB increased infarct size compared to controls by 6.91–8.41%, with no effect on haemodynamic function. KN-93/nifedipine with TB showed a 5.90/7.38% decrease in infarct size compared to TB alone, the combined use of KN-93 with TB also showed a significant increase in left ventricular developed pressure whilst nifedipine with TB showed a significant decrease in coronary flow. TB showed a 42.73% increase in p-CaMKII (Thr286) versus control, and increased Ca2+ fluorescence by 30.63% in cardiomyocytes. Conclusions and implicationsTo our knowledge, this is the first pre-clinical study to show that Tiotropium bromide induces Ca2+ signalling via CaMKII and L-type Ca2+ channels to result in cell damage. This has significant clinical impact due to long term use of TB in COPD patients, and warrants assessment of cardiac drug safety.

Hemodynamic Congestion at Hospital Discharge Predicts Rehospitalization during Short Term Follow Up in Acute Heart Failure Patients

Background: Hemodynamic congestion is an increase in left ventricular diastolic pressure (LVEDP) without clinical symptoms and signs of congestion. Current acute heart failure (AHF) treatment goals only focused on improving clinical congestion. The purpose of this study was to investigate whether hemodynamic congestion measured by NT-proBNP level and ePCWP at hospital discharge could predict short term clinical outcomes in AHF patients.&#x0D; Method: This prospective cohort study was conducted at dr. Saiful Anwar General Hospital Malang from January to July 2018. All patients got AHF treatment according to the 2016 ESC guidelines for heart failure. All patients were discharged without symptoms and signs of clinical congestion. Hemodynamic congestion at hospital discharge was defined as failure of treatment during hospitalization to achieve a reduction in NT-proBNP level &gt;30% and/or ePCWP at hospital discharge &gt;16 mmHg. NT-proBNP level and ePCWP were measured at 0-12 hours after hospital admisssion and at hospital discharge. ePCWP was measured using echocardiography. The clinical outcomes assessed were AHF rehospitalization and cardiovascular mortality within 30 days after hospitral discharge. Subgroup analysis was performed to determine therapeutic regimens that are effective in improving hemodynamic congestion.&#x0D; Result: A total of 33 AHF patients were included in this study. 48% patients were discharged with hemodynamic congestion and 52% patients discharged without hemodynamic congestion. Patients with hemodynamic congestion at hospital discharge showed a higher rehospitalization within 30 days (8 [50%] vs 1 [5.9%]; P = 0.007). Mortality within 30 days in both groups did not show a significant difference (2 [12.5%] vs 0 [0%]; P = 0.277). Treatment regiment of optimal dose of ACEi/ARB, β-blockers, and diuretics was associated with improvement of hemodynamic congestion (P = 0.026; r = 0.454), a decrease in NT-proBNP&gt; 66% (P = 0.02; r = 0,574), and achievement of ePCWP &lt;16 (P = 0,013; r = 0,493) at hospital discharge in HFrEF patients.&#x0D; Conclusion: This study showed that hemodynamic congestion assessed with NT-proBNP level and ePCWP at hospital discharge increased 30 day rehospitalization in AHF patients. In HFrEF, improvements in hemodynamic congestion can be achieved by giving the treatment regiment of optimal dose of ACEi/ARB, β-blockers, and diuretics.&#x0D; Keyword: Acute heart failure, hemodynamic congestion, NT-proBNP, ePCWP

An in silico twin for epicardial augmentation of the failingheart.

Advances in ventricular assist device (VAD) technology for the treatment of end-stage congestive heart failure (CHF) are needed to cope with the increasing numbers of patients that cannot be provided with donor hearts for transplantation. We develop and investigate a novel extravascular VAD technology that provides biventricular, epicardial pressure support for the failing heart. This novel VAD concept avoids blood contact that is accompanied with typical complications such as coagulation and infections. To date, in vivo porcine model results with a prototype of the implant exist, further studies to improve the implant's performance and promote its applicability in humans are needed. In this contribution, we present a personalised functional digital twin of the heart, the vascular system, and the novel VAD technology in terms of a calibrated, customized computational model. The calibration procedure is based on patient-specific measurements and is performed by solving an inverse problem. This in silico model is able to (a) confirm in vivo experimental data, (b) predict healthy and pathologic ventricular function, and (c) assess the beneficial impact of the novel VAD concept to a high level of fidelity. The model shows very good agreement with in vivo data and reliably predicts increases in stroke volume and left ventricular pressure with increasing ventricular support. Furthermore, the digital twin allows insight into quantities that are poorly or not at all amenable in any experimental setup. Conclusively, the model's ability to link integral hemodynamic variables to local tissue mechanical deformation makes it a highly valuable tool for the dimensioning of novel VAD technologies and future treatment strategies in heart failure. The presented in silico twin enhances in vivo studies by facilitating the accessibility and increasing the range of quantities of interest. Because of its flexibility in the assessment of design variants and optimization loops, it may substantially contribute to a reduction of the amount of animal experiments in this and similar settings.

Abstract 500: Progression of Chronic Ischemia-Mediated Arrhythmogenesis in a Rat Model of Heart Failure

Background: Worldwide, the prevalence of heart failure (HF) is increasing and HF patients are living longer. Chronic ischemic HF presents with increased vulnerability to ventricular tachycardia and fibrillation. However, the mechanism of these arrhythmias differ between the acute infarction phase and the chronic, namely via myocyte membrane potential instability in the acute phase versus substrate-mediated reentry in the chronic phase. We propose our chronic heart failure (CHF) model to recapitulate the potentially progressive nature of arrhythmogenesis in the chronic phase. Methods: Adult male Sprague Dawley rats underwent permanent left coronary artery ligation and were maintained for six or ten weeks; SHAM operations were also performed. At each respective endpoint, SHAM and CHF rats underwent transthoracic echocardiography and invasive hemodynamic evaluation. Finally, a median sternotomy was performed for epicardial electrophysiology (EP) assessment. Programmed electrical stimulation was utilized to assess susceptibility to induced ventricular tachycardia (VT) and also to determine effective refractory period (ERP). Results: Six-week CHF (n=50) induction proved successful as evidenced by the decrease in left ventricular ejection fraction (LVEF) (76±3% to 35±2%, p&lt;0.0001) and the increase in left ventricular end-diastolic pressure (LVEDP) (6±1 mmHg to 20±2 mmHg, p=0.0008) compared to SHAM (n=15). Progression to ten-week CHF (n=18) also proved successful via LVEF and LVEDP maintenance (35±2% to 38±3%, p=0.3909) (20±2 mmHg to 15±3 mmHg, p=0.1578). EP studies revealed an increase in the incidence of induced VT between SHAM and six-week CHF (0% to 60%, p&lt;0.0001) and a prolongation of the ERP (54±4 milliseconds to 69±3 ms, p=0.0228). The incidence of induced VT and ERP did not continue to increase between six- and ten-week CHF (60% to 50%, p=0.5804), (69±3 ms to 68±3 ms, p=0.8221). Conclusion: Myocardial infarction-mediated arrhythmogenesis is known to exist in an acute and a chronic phase. Here, we examine the chronic phase of ischemic HF and show evidence to support that once the adverse remodeling-mediated substrate stabilizes, proarrhythmic deterioration ceases.

Effect of phosphoglycogen synthase kinase-3 β induced by low dose of tunicamycin on mitochondrial permeability transition pore in ischemia-reperfusion myocardium

Objective To evaluate the effect of glycogen synthase kinase-3beta (GSK-3β) activity on mitochondrial permeability transition pore (mPTP) in the protective effects of preconditioning with endoplasmic reticulum stress (ERS) induced by low dose of tunicamycin (TM) against myocardial ischemia reperfusion (I/R) injury. Methods Forty adult male sprague-dawley rats were randomly divided into four groups: Sham, TM (Rats were treatmented by TM 0.6 mg/kg at 30 min before model established), I/R, and TM+ LY [Rats were treatmented by TM 0.6 mg/kg and protein kinase B (Akt) inhibitor LY294002 10 mg/kg]. The model of I/R were established by occlusion of left anterior descending coronary artery for 0.5 h followed by reperfusion for 2 h. Hemodynamic parameters were recorded after coronary artery perforation, 1 h and 2 h after reperfusion. After 2 hours of reperfusion, the expression of phosphorylated Akt (p-Akt), p-GSK-3β and the openness of mPTP were detected in the hearts. Results Compared with base line, left ventricular systolic pressure (LVSP), maximum rate of increase or decrease of left ventricular pressure (±dp/dt max) decreased, and left ventricular end-diastolic pressure (LVEDP)increased in I/R group, TM group and TM+ LY group, while the change was more significantly in I/R group. The expression of p-Akt and p-GSK-3 beta protein in TM and TM+ LY group was higher than that in I/R group, and the expression of p-Akt and p-GSK-3β protein in TM+ LY group was lower than that in TM group. At 2 hours after reperfusion, degree of variation of absorbance value (ΔA) of the mPTP of Sham, I/R, TM and TM+ LY group were (78.9±9.2)%, (36.1±4.8)%, (61.4±8.3)% and (46.3 ±5.2)%. The ΔA of TM group was larger than that of I/R group (t=3.280, P<0.01). Compared with TM group, the ΔA of TM+ LY group was relatively small (t=2.720, P<0.01). Conclusion The protective effect of preconditioning with ERS induced by low dose TM is related to the inhibition of mPTP opening by regulating GSK-3β activity. Key words: Myocardial ischemia reperfusion injury; Endoplasmic reticulum stress; Preconditioning; Glycogen synthase kinase-3β; Mitochondrial permeability transition pore

Inhibition of gasotransmitters production and calcium influx affect cardiodynamic variables and cardiac oxidative stress in propofol-anesthetized male Wistar rats 1.

It has been assumed that the cardioprotective effects of propofol are due to its non-anesthetic pleiotropic cardiac and vasodilator effects, in which gasotransmitters (NO, H2S, and CO) as well as calcium influx could be involved. The study on isolated rat heart was performed using 4 experimental groups (n = 7 in each): (1) bolus injection of propofol (100 mg/kg body mass, i.p.); (2) L-NAME (NO synthase inhibitor, 60 mg/kg body mass, i.p.) + propofol; (3) DL-PAG (H2S synthase inhibitor, 50 mg/kg body mass, i.p.) + propofol; (4) ZnPPIX (CO synthase inhibitor, 50 μmol/kg body mass, i.p.) + propofol. Before and after the verapamil (3 μmol/L) administration, cardiodynamic parameters were recorded (dp/dtmax, dp/dtmin, systolic left ventricular pressure, diastolic left ventricular pressure, heart rate, coronary flow), as well as coronary and cardiac oxidative stress parameters. The results showed significant increases of diastolic left ventricular pressure following NO and CO inhibition, but also increases of coronary flow following H2S and CO inhibition. Following verapamil administration, significant decreases of dp/dtmax were noted after NO and CO inhibition, then increase of diastolic left ventricular pressure following CO inhibition, and increase of coronary flow following NO, H2S, or CO inhibition. Oxidative stress markers were increased but catalase activity was significantly decreased in cardiac tissue. Gasotransmitters and calcium influx are involved in pleiotropic cardiovascular effects of propofol in male Wistar rats.

Mechanism of Emulsified Isoflurane Postconditioning-Induced Activation of the Nrf2-Antioxidant Response Element Signaling Pathway During Myocardial Ischemia-Reperfusion: The Relationship With Reactive Oxygen Species.

Emulsified isoflurane (EI) has been shown to alleviate myocardial ischemia-reperfusion (IR) injury. However, previous reports have not been focused on the underlying mechanism. We used models of IR injury in Langendorff-isolated rat hearts to determine the relationship between the mechanism underlying EI postconditioning (EIP)-induced activation of the nuclear factor-E2-related factor 2 (Nrf2)-antioxidant response element signaling pathway during myocardial IR, and its relationship with reactive oxygen species. In comparison with the IR group, the EIP group showed a significant reduction in myocardial ultrastructural damage, significant increase in function [heart rate, left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal rate of the increase in left ventricular pressure (+dp/dtmax)], and upregulated expression of Nrf2, HO-I, NQO1, and SOD1 mRNA and proteins at the end of reperfusion. After treatment with N-(2-mercaptopropionyl)-glycine (MPG), the significant reduction in myocardial ultrastructural damage and significant increases in function, and mRNA and protein expression were no longer evident in the M + EIP group. These results show that EIP can regulate reactive oxygen species levels and activate the Nrf2-antioxidant response element signaling pathway, thereby attenuating myocardial IR injury in rats.

Cardioprotective Effect of Phase 3 Clinical Anticancer Agent, RRx-001, in Doxorubicin-Induced Acute Cardiotoxicity in Mice.

Anthracycline chemotherapy (e.g., doxorubicin or DOX) is associated with a cumulative dose-dependent cardiac dysfunction that may lead to congestive heart failure, which limits both its use and usefulness in the clinic. The cardiotoxicity may manifest acutely and/or months or years after treatment with doxorubicin has ended. Experimental and human data have demonstrated that angiotensin-converting enzyme/angiotensin-receptor antagonists mediate a cardioprotective effect against anthracycline toxicity. In this study, with the angiotensin receptor blocker, candesartan, as a positive control, we evaluated whether pretreatment with the hypoxic nitric oxide generating anticancer agent, RRx-001, could reduce acute DOX-induced cardiotoxicity. A total of 24 BALB/c mice were randomized for prophylactic treatment with vehicle, RRx-001, candesartan, or no-intervention control. Within each of the three intervention arms, mice received treatment with DOX. Murine pressure-volume analysis was performed with microconductance catheters to characterize the degree of cardiovascular dysfunction within each group. The following hemodynamic parameters were monitored: left ventricular systolic pressure (LVSP), heart rate, and maximal rate of increase of left ventricular pressure (±d P/d tmax). Five days after doxorubicin injection, untreated (with RRx-001) mice displayed significantly impaired systolic (LVSP, -27%; d P/d tmax, -25%; left ventricular developed pressure (LVDP), +33%; P < 0.05) and global (stroke volume (SV), -52%; ejection fraction (EF), -20%; stroke work (SW), -62.5%; heart rate (HR), -18%; cardiac output (CO), -57%; mean blood arterial pressure (MAP), -30%; systemic vascular resistance (SVR), +20%; P < 0.05) LV functions when compared with the untreated (with RRx-001) group. In contrast, RRx-001-treated mice showed improved variables of systolic (LVSP, +27%; d P/d tmax, +25%; LVDP, -33%; P < 0.05) and global (SV, +52%; EF, +20%; SW, +62.5%; HR, +18%; CO, +57%; MAP, +30%; SVR, -20%; P < 0.05) LV functions compared with untreated doxorubicin mice. Similar to the positive control, candesartan, the cardiotoxic effects of DOX in mice were partially attenuated by the prophylactic administration of RRx-001. These results suggest that RRx-001 as a multifunctional anticancer agent, which sensitizes cancer cells to the cytotoxic effects of chemotherapy and radiation, may also have beneficial cardioprotective effects.

Regulation of Myocardial Contraction and Ca2+ Dynamics by the G Protein‐Coupled Estrogen Receptor

The G protein‐coupled estrogen receptor (GPER) mediates many cardioprotective effects. However, the underlying mechanisms are not clear.We investigated the role of GPER in cardiac contraction and signaling mediated by the cardiac b1 adrenergic receptor (β1AR). In anesthetized female rats, intrajugular administration of isoproterenol produces rapid and sustained increase in left ventricular systolic pressure (LVSBP) from 100±9 mmHg to 160±12 mmHg and a mild decrease in LV end diastolic pressure (LVEDP) from 10±5 mmHg to 5±5 mmHg. Administration of GPER agonist G‐1 during the plateau phase of the isoproterenol‐induced pressure rise rapidly reduces LVSBP to 90±5 mmHg and LVEDP to 0±5 mmHg. In freshly isolated primary murine cardiomyocytes, isoproterenol triggers oscillatory Ca2+ entry signals that are inhibited by β1AR antagonist metoprolol but not by b2‐AR antagonist ICI‐118551. GPER activation using G‐1 (Kd 11 nM) at 0.01, 0.1 and 1 mM suppresses the total Ca2+ signals by 0.5±0.3, 17.6±2 (p&lt;0.05), and 30±2.1% (p&lt;0.05), the amplitude of oscillations by 12.6±1.2, 36.6±7.1 (p&lt;0.05), and 42.5±5.2% (p&lt;0.05), and the frequency of oscillatory deflections by 0±0.8, 28.6±4.2 (p &lt;0.05), and 30.3±5.4 (p&lt;0.05), respectively. Isoproterenol promotes robust phosphorylation of the CaV1.2 channels at Ser1928 and phospholamban at Ser16/Thr17. G‐1 at 0.01, 0.1 and 1 mM prevents the former by 11.3±1.24, 28.4±2.3 (p&lt;0.05) and 49.3±6.1%, and the latter by 5.3 ± 0.9, 22.3 ± 3.3 (p&lt;0.05) and 42.5 ± 5.2%, respectively. Interestingly, GPER inhibition with G‐36 (IC50 112 nM) at 0.01, 0.1 and 1 mM increases isoproterenol‐induced total Ca2+ signals by 1±0.7, 26±2.5 (p&lt;0.05) and 59.3±3.1% (p&lt;0.05), oscillatory amplitude by 26±5.3, 129±21 (p&lt;0.05) and 294±9.6% (p&lt;0.05), and oscillatory frequency by 22.8±7.6, 59.1±8 (p&lt;0.05) and 92±13% (p&lt;0.05), respectively. G‐36 pretreatment at 0.01, 0.1 and 1 mM enhances isoproterenol‐stimulated Cav1.2 Ser1928 phosphorylation by 1.45±0.93, 27±9.6, and 47.8±7.1% (p&lt;0.05), and phospholamban Ser16/Thr17 phosphorylation by 23.6±5.3, 53.3±17.5, and 32.2±5.6% (p&lt;0.05), respectively.Taken together, the data suggest that GPER activation is an intrinsic component of β1AR‐mediated Ca2+ signaling in the myocardium and plays an important role in β1AR‐mediated cardiac contraction.Support or Funding InformationNational Institutes of Health Grant HL112184 and IOER 091707 to Quang‐Kim Tran; American Heart Association Grant 15SDG25090279 to Eric Wauson; IOER grant to Sarah ClaytonThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Angiotensin (1-7) and Apelin co-therapy: New strategy for heart failure treatment of rats.

Objective:Isoproterenol (ISO)–induced heart failure is a standardized model for the study of beneficial effects of various drugs. Both apelin and angiotensin 1–7 have a cardiac protective effect. We assumed that co–therapy with apelin and angiotensin 1–7 [Ang (1–7)] may have synergistic cardioprotective effects against isoproterenol-induced heart failure.Methods:The rats were randomly assigned to one of eight groups, 7 animals in each, as follows: (1) Control I (saline; IP injection), (2) Control II (saline; via mini-osmotic pump), (3) ISO (5 mg/kg; IP), (4) Apelin (20 μg/kg; IP), (5) Ang (1–7) (30 μg/kg/day; via mini-osmotic pump), (6) Apelin+ISO, (7) Ang (1–7)+ISO, and (8) Apelin+Ang (1–7)+ISO. Rat myocardial injury was induced by intraperitoneal injection of 5 mg/kg of ISO for 10 days. Apelin and Ang (1–7) were administered 30 minutes before the ISO injection.Results:A decrease in the systolic blood pressure [SBP (p<0.001)], diastolic blood pressure [DBP (p=0.024)], left ventricular systolic pressure [LVSP (p<0.001)], left ventricular contractility [dP/dt max. (p<0.001)], relaxation [dP/dt min. (p<0.001)], and an increase in left ventricular end-diastolic pressure [LVEDP, (p<0.001)] were observed in ISO-treated rats. Plasma LDH and myocardial and plasma MDA were higher in the ISO heart than in controls (p<0.001). Histopathological examination of the cardiac tissue showed myocardial fibrosis and leukocyte infiltration in ISO-treated rats as compared to control. Co-therapy with apelin and Ang (1–7) was more effective than either agent used alone in restoring these parameters to that of control rats.Conclusion:The results of this study showed that the combination of apelin and Ang (1–7) had a more cardioprotective effect than either used alone against ISO-induced heart failure, and co–therapy may be a useful treatment option for myocardial injuries and heart failure.