scholarly journals Complex electrophysiological remodeling in postinfarction ischemic heart failure

2018 ◽  
Vol 115 (13) ◽  
pp. E3036-E3044 ◽  
Author(s):  
Bence Hegyi ◽  
Julie Bossuyt ◽  
Leigh G. Griffiths ◽  
Rafael Shimkunas ◽  
Zana Coulibaly ◽  
...  
Keyword(s):  
Heart Failure ◽  
Single Channel ◽  
Ionic Currents ◽  
Border Zone ◽  
Delayed Rectifier ◽  
Large Animal ◽  
Current Profile ◽  
Large Animal Models ◽  
Remote Zone ◽  
Arrhythmogenic Substrate

Heart failure (HF) following myocardial infarction (MI) is associated with high incidence of cardiac arrhythmias. Development of therapeutic strategy requires detailed understanding of electrophysiological remodeling. However, changes of ionic currents in ischemic HF remain incompletely understood, especially in translational large-animal models. Here, we systematically measure the major ionic currents in ventricular myocytes from the infarct border and remote zones in a porcine model of post-MI HF. We recorded eight ionic currents during the cell’s action potential (AP) under physiologically relevant conditions using selfAP-clamp sequential dissection. Compared with healthy controls, HF-remote zone myocytes exhibited increased late Na+ current, Ca2+-activated K+ current, Ca2+-activated Cl− current, decreased rapid delayed rectifier K+ current, and altered Na+/Ca2+ exchange current profile. In HF-border zone myocytes, the above changes also occurred but with additional decrease of L-type Ca2+ current, decrease of inward rectifier K+ current, and Ca2+ release-dependent delayed after-depolarizations. Our data reveal that the changes in any individual current are relatively small, but the integrated impacts shift the balance between the inward and outward currents to shorten AP in the border zone but prolong AP in the remote zone. This differential remodeling in post-MI HF increases the inhomogeneity of AP repolarization, which may enhance the arrhythmogenic substrate. Our comprehensive findings provide a mechanistic framework for understanding why single-channel blockers may fail to suppress arrhythmias, and highlight the need to consider the rich tableau and integration of many ionic currents in designing therapeutic strategies for treating arrhythmias in HF.

Echocardiography Evaluation of a Novel Stable Ovine Heart Failure Model Suitable for Cardiovascular Device Testing

2011 ◽  
Author(s):  
Peter W. Walsh ◽  
Craig S. McLachlan ◽  
Leigh Ladd ◽  
Arie Blitz ◽  
R. Mark Gillies ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Models ◽  
Large Animal ◽  
Failure Model ◽  
Large Animal Models ◽  
Surgical Model ◽  
Coronary Ligation ◽  
Rapid Ventricular Pacing ◽  
Heart Failure Model ◽  
Underlying Pathology

Numerous large animal models of chronic cardiac ischemia have been developed to explore either pathological mechanisms and or device interventions in developed heart failure models. Traditionally chronic heart failure in large animal models such as sheep or pigs has been induced by either coronary ligation with or without reperfusion. Coronary ligation is often attempted in the open chest surgical model or more recently in the closed chest animal via angiography [1]. Both techniques can be challenging and also induce high mortality with the risk of myocardial stunning and resultant shock and or lethal arrhythmias. There is also difficulty in developing stable heart failure across cases where infarct sizes can be variable. One strategy to over come this variability has been via rapid ventricular pacing, however inducing heart failure does not induce sustained heart failure in many cases if the pacing is switched off, and additionally pacing does not induce some of the underlying pathology seen in the development of heart failure [1].

Abstract 13381: hiPSC of CIITA and B2M KO Derived Cardiac Cells Engineered 3D Spheroid Transplantation Induce Tachycardia in Myocardial Infarction in Swine

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Saidulu Mattapally ◽  
Jianyi Zhang
Keyword(s):  
Cardiac Fibroblasts ◽  
Quantitative Polymerase Chain Reaction ◽  
Hla Class I ◽  
Cardiac Cells ◽  
Border Zone ◽  
Large Animal ◽  
Myocardial Repair ◽  
Large Animal Models ◽  
Organ Systems ◽  
Significant Difference

Introduction: Human induced pluripotent stem cells (hiPSCs) are among one the most significant discoveries in life sciences. As a promising —biological drug for cell therapy, multiple lineages of iPSC-derived cardiac cells have been administered in human clinical trials in multiple important organ systems. The potential immunogenicity of hiPSC-derived cardiac cells continues to be one of the concerns in large animal models. Methods: In the present study, WT hiPSCs were generated by transfecting male human cardiac fibroblasts with Sendai viruses coding for OCT4, SOX2, KLF4, and C-MYC.Then hiPSCs carrying knockout mutations for both HLA Class I and Class II (HLAI/II-KOhiPSC) were generated via CRISPR/Cas9 gene-editing technology (Mattapally et al, 2018). hiPSCs were differentiated into cardiomyocytes (CM) endothelial cells (ECs) and spheroid cultured was performed as previously described (Mattapally et al, 2018). We evaluated spheroid transplantation and its potency for myocardial repair in the Swine. Programmed stimulation was used to determine the arrhythmogenic outcome. Results: To determine the engraftment efficacy of HLAI/II KO compared to WT Spheroid, a swine study was performed. After LAD ligation in swine, 800μm spheroid was injected into the border zone of the left ventricle. After transplantation, cell engraftment was monitored by Q-PCR. At week 4, there was a significant difference between the 2 groups. Animal groups included: MI hearts treated with 500 WT Spheroid injection (MI+WT Spheroid, n=5), MI hearts treated with 500 KO Spheroid injection (n=6), MI only hearts (n=6); the fourth group of animals underwent sham surgery (Sham, n=6). Arrhythmia was studied by programmed electrical stimulations (PES) and conduction velocities measured with electrode mapping, and the engraftment rate by calculation of quantitative polymerase chain reaction measurements of expression of the human Y chromosome. Engraftment of iPSC-CMs was found in both treatment groups; however, a significantly higher engraftment rate was found in KO Spheroid. The spheroid treatment is associated with significant changes in arrhythmogenicity. Conclusion: Our study established the improved graft but associated with arrhythmogenicity.

Effect of Prozac on whole cell ionic currents in lens and corneal epithelia

1995 ◽  
Vol 269 (1) ◽  
pp. C250-C256 ◽  
Author(s):  
J. L. Rae ◽  
A. Rich ◽  
A. C. Zamudio ◽  
O. A. Candia
Keyword(s):  
Potassium Channels ◽  
Single Channel ◽  
Ionic Currents ◽  
Current Amplitude ◽  
Human Lens ◽  
Delayed Rectifier ◽  
Open Probability ◽  
Channel Current ◽  
Single Channel Current ◽  
Ionic Conductances

Prozac (fluoxetine), a compound used therapeutically in humans to combat depression, has substantial effects on ionic conductances in rabbit corneal epithelial cells and in cultured human lens epithelium. In corneal epithelium, it reduces the current due to the large-conductance potassium channels that dominate this preparation. Its effects seem largely to decrease the open probability while leaving the single-channel current amplitude unaltered. In cultured human epithelium, currents from calcium-activated potassium channels and inward rectifiers are unaffected by Prozac. Delayed-rectifier potassium currents are reduced by Prozac in a complicated way that involves both gating and single-channel current amplitude. Fast tetrodotoxin-blockable sodium currents are also decreased by Prozac in this preparation. For all of these ion conductance effects, Prozac concentrations of 10(-5) to 10(-4) M are required. Whereas these levels are 10- to 100-fold higher than the plasma levels achieved in therapeutic use in humans, they are comparable to or less than levels needed for many other blockers of the ionic conductances studied here.

scholarly journals A Standardized Approach to Orthotopic (Life-Supporting) Porcine Cardiac Xenotransplantation in a Non-Human Primate Model

2021 ◽  
Author(s):  
Corbin E. Goerlich ◽  
Bartley P. Griffith ◽  
John A. Treffalls ◽  
Tianshu Zhang ◽  
Avneesh K. Singh ◽  
...  
Keyword(s):  
United States ◽  
Heart Failure ◽  
Genetically Modified ◽  
Human Study ◽  
The United States ◽  
Large Animal ◽  
Term Survival ◽  
Human Organ ◽  
Large Animal Models

Abstract There are 5.7 million people in the United States with heart failure, which is life-limiting in 20% of patients.1 While data is most robust in the United States for this cohort, it is known to be a global problem with over 23 million people carrying the diagnosis.1 For end-stage heart failure, many require a heart transplantation, however, there is a shortage in the supply of organ donors. Cardiac xenotransplantation has been proposed to “bridge the gap” in supply for these patients requiring transplantation. Recent pre-clinical success using genetically modified pig donors in baboon recipients has demonstrated survival greater than 6 months.2–5 First-in-human transplantation of a genetically modified pig kidney demonstrated 54 hour rejection-free function when perfused by a deceased human recipient, demonstrating the feasibility of cross-species transplantation and invigorating enthusiasm further to utilize this new organ source for a population that would otherwise die waiting for a human organ.6 While this human study demonstrated proof-of-principle of overcoming hyperacute rejection, further regulatory oversight by Food and Drug Administration (FDA) may be required with pre-clinical trials in large animal models of xenotransplantation with long-term survival. These studies not only require a multi-disciplinary team and expertise in orthotopic transplantation (cardiac surgery, anesthesia and cardiopulmonary bypass), immunology and genetic engineering; but also, specifically handling large animal recipients that cannot communicate their symptoms. Here we detail our approach to pig-to-primate large animal model of orthotopic cardiac xenotransplantation perioperatively and in the months thereafter in long-term surviving animals. We also detail xenograft surveillance methods and common issues that arise in the postoperative period specific to this model and ways to overcome them.

scholarly journals Large Animal Models of Heart Failure

2009 ◽  
Vol 2 (3) ◽  
pp. 262-271 ◽  
Author(s):  
Jennifer A. Dixon ◽  
Francis G. Spinale
Keyword(s):  
Heart Failure ◽  
Animal Models ◽  
Large Animal ◽  
Large Animal Models

scholarly journals Balance Between Rapid Delayed Rectifier K + Current and Late Na + Current on Ventricular Repolarization

2020 ◽  
Vol 13 (4) ◽  
Author(s):  
Bence Hegyi ◽  
Ye Chen-Izu ◽  
Leighton T. Izu ◽  
Sridharan Rajamani ◽  
Luiz Belardinelli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Long Qt Syndrome ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Ionic Currents ◽  
Close Correlation ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Comparable Amount ◽  
Qt Syndrome

Background: Rapid delayed rectifier K + current (I Kr ) and late Na + current (I NaL ) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death. Methods: Physiological self AP-clamp was used to measure I NaL and I Kr during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between I Kr and I NaL affects repolarization stability in health and disease conditions. Results: We found comparable amount of net charge carried by I Kr and I NaL during the physiological AP, suggesting that outward K + current via I Kr and inward Na + current via I NaL are in balance during physiological repolarization. Remarkably, I Kr and I NaL integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block I Kr (mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na + channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit I NaL sufficiently restored APD to control in both cases. Importantly, I NaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, I NaL inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking short QT syndrome), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by I NaL inhibition, increased by I Kr inhibition, and restored by combined I NaL and I Kr inhibitions. Conclusions: Our data demonstrate that I Kr and I NaL are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities. Visual Overview: A visual overview is available for this article.

Voltage-gated currents of rabbit A- and B-type horizontal cells in retinal monolayer cultures

1994 ◽  
Vol 11 (2) ◽  
pp. 369-378 ◽  
Author(s):  
Stefan Löhrke ◽  
Hans-Dieter Hofmann
Keyword(s):  
Single Channel ◽  
Ionic Currents ◽  
Calcium Currents ◽  
Horizontal Cells ◽  
Delayed Rectifier ◽  
Patch Clamp Recording ◽  
Voltage Gated ◽  
Monolayer Cultures ◽  
Inward Currents

AbstractIn monolayer cultures prepared from immature early postnatal rabbit retina, small populations of neurons can be demonstrated to differentiate into apparently mature A- and B-type horizontal cells. Using wholecell, single-channel, patch-clamp recording techniques, we have analyzed the pattern of voltage-gated conductances expressed by mammalian horizontal cells under these conditions. A total of six different voltage-dependent ionic currents were recorded. Tetrodotoxin-sensitive fast sodium inward currents (INa) were found in 81% of the A-type and 90% of the B-type cells. Inward calcium currents could be demonstrated in all cells tested after blockade of other conductances. Two types of outward potassium currents with properties of the 4–aminopyridine-sensitive transient IA and the tetraethylammonium sensitive delayed rectifier IK, respectively, could be characterized in whole-cell recordings. An inward rectifying potassium current (Ianom) typical for horizontal cells was activated in response to hyperpolarizing voltage steps. These types of currents have also been described in dissociated adult horizontal cells from lower vertebrates and cat. With single-channel recordings on inside-out patches excised from B-type cells, an additional Ca2+-dependent current (IK(Ca)) was observed which, so far, has not been described in horizontal cells developing in situ. Our results demonstrate that cultured rabbit horizontal cells express a set of voltage-gated currents which largely, but not completely, corresponds to that described in situ for horizontal cells of other species. The culture system will allow further investigation of developmental and functional aspects of mammalian horizontal cells.

Discrepant effects of heart failure on electrophysiological property in right ventricular outflow tract and left ventricular outflow tract cardiomyocytes

2017 ◽  
Vol 131 (12) ◽  
pp. 1317-1327 ◽  
Author(s):  
Yen-Yu Lu ◽  
Chen-Chuan Cheng ◽  
Chin-Feng Tsai ◽  
Yung-Kuo Lin ◽  
Ting-I Lee ◽  
...  
Keyword(s):  
Heart Failure ◽  
Action Potential ◽  
Ventricular Arrhythmias ◽  
Ionic Currents ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Outflow Tract ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Left Ventricular Outflow

Ventricular arrhythmias commonly arise from the right (RVOT) and left ventricular outflow tracts (LVOT) in patients without structural heart disease. Heart failure (HF) significantly increases the risk of ventricular arrhythmias. The regional differences and how HF affects the electrophysiological characteristics of RVOT and LVOT cardiomyocytes remain unclear. The whole-cell patch-clamp technique was used to investigate the action potentials and ionic currents in isolated single RVOT and LVOT cardiomyocytes from control rabbits and rabbits with HF induced by rapid ventricular pacing. Comparison with control LVOT cardiomyocytes showed that control RVOT cardiomyocytes have a shorter action potential duration (APD), smaller late Na+ currents (INa-late), larger transient outward (Ito) and larger delayed rectifier K+ currents (IKr-tail), but had similar L-type Ca2+ currents (ICa-L) and Na+/Ca2+ exchanger (NCX) current. HF increased APD, INa-late and NCX, but decreased ICa-L and Ito in RVOT cardiomyocytes. In contrast with this, HF decreased APD and ICa-L, but increased Ito and IKr-tail in LVOT cardiomyocytes. In conclusion, RVOT and LVOT cardiomyocytes had distinctive electrophysiological characteristics. HF differentially modulates action potential morphology and ionic currents in RVOT and LVOT cardiomyocytes.

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