scholarly journals R4496C RyR2 mutation impairs atrial and ventricular contractility

2015 ◽  
Vol 147 (1) ◽  
pp. 39-52 ◽  
Author(s):  
Cecilia Ferrantini ◽  
Raffaele Coppini ◽  
Beatrice Scellini ◽  
Claudia Ferrara ◽  
Josè Manuel Pioner ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Contractile Function ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Polymorphic Ventricular Tachycardia ◽  
Ventricular Contractility ◽  
Open Probability ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Baseline Conditions ◽  
Isometric Twitch

Ryanodine receptor (RyR2) is the major Ca2+ channel of the cardiac sarcoplasmic reticulum (SR) and plays a crucial role in the generation of myocardial force. Changes in RyR2 gating properties and resulting increases in its open probability (Po) are associated with Ca2+ leakage from the SR and arrhythmias; however, the effects of RyR2 dysfunction on myocardial contractility are unknown. Here, we investigated the possibility that a RyR2 mutation associated with catecholaminergic polymorphic ventricular tachycardia, R4496C, affects the contractile function of atrial and ventricular myocardium. We measured isometric twitch tension in left ventricular and atrial trabeculae from wild-type mice and heterozygous transgenic mice carrying the R4496C RyR2 mutation and found that twitch force was comparable under baseline conditions (30°C, 2 mM [Ca2+]o, 1 Hz). However, the positive inotropic responses to high stimulation frequency, 0.1 µM isoproterenol, and 5 mM [Ca2+]o were decreased in R4496C trabeculae, as was post-rest potentiation. We investigated the mechanisms underlying inotropic insufficiency in R4496C muscles in single ventricular myocytes. Under baseline conditions, the amplitude of the Ca2+ transient was normal, despite the reduced SR Ca2+ content. Under inotropic challenge, however, R4496C myocytes were unable to boost the amplitude of Ca2+ transients because they are incapable of properly increasing the amount of Ca2+ stored in the SR because of a larger SR Ca2+ leakage. Recovery of force in response to premature stimuli was faster in R4496C myocardium, despite the unchanged rates of recovery of L-type Ca2+ channel current (ICa-L) and SR Ca2+ content in single myocytes. A faster recovery from inactivation of the mutant R4496C channels could explain this behavior. In conclusion, changes in RyR2 channel gating associated with the R4496C mutation could be directly responsible for the alterations in both ventricular and atrial contractility. The increased RyR2 Po and fractional Ca2+ release from the SR induced by the R4496C mutation preserves baseline contractility despite a slight decrease in SR Ca2+ content, but cannot compensate for the inability to increase SR Ca2+ content during inotropic challenge.

Larger late sodium current density as well as greater sensitivities to ATX II and ranolazine in rabbit left atrial than left ventricular myocytes

2014 ◽  
Vol 306 (3) ◽  
pp. H455-H461 ◽  
Author(s):  
Antao Luo ◽  
Jihua Ma ◽  
Yejia Song ◽  
Chunping Qian ◽  
Ying Wu ◽  
...  
Keyword(s):  
Left Atrial ◽  
Ventricular Myocytes ◽  
Sodium Current ◽  
Left Ventricular ◽  
Atrial Myocytes ◽  
Open Probability ◽  
Late Sodium Current ◽  
Ventricular Cells ◽  
Open Time ◽  
Hill Slope

An increase of cardiac late sodium current ( INa.L) is arrhythmogenic in atrial and ventricular tissues, but the densities of INa.L and thus the potential relative contributions of this current to sodium ion (Na+) influx and arrhythmogenesis in atria and ventricles are unclear. In this study, whole-cell and cell-attached patch-clamp techniques were used to measure INa.L in rabbit left atrial and ventricular myocytes under identical conditions. The density of INa.L was 67% greater in left atrial (0.50 ± 0.09 pA/pF, n = 20) than in left ventricular cells (0.30 ± 0.07 pA/pF, n = 27, P < 0.01) when elicited by step pulses from −120 to −20 mV at a rate of 0.2 Hz. Similar results were obtained using step pulses from −90 to −20 mV. Anemone toxin II (ATX II) increased INa.L with an EC50 value of 14 ± 2 nM and a Hill slope of 1.4 ± 0.1 ( n = 9) in atrial myocytes and with an EC50 of 21 ± 5 nM and a Hill slope of 1.2 ± 0.1 ( n = 12) in ventricular myocytes. Na+ channel open probability (but not mean open time) was greater in atrial than in ventricular cells in the absence and presence of ATX II. The INa.L inhibitor ranolazine (3, 6, and 9 μM) reduced INa.L more in atrial than ventricular myocytes in the presence of 40 nM ATX II. In summary, rabbit left atrial myocytes have a greater density of INa.L and higher sensitivities to ATX II and ranolazine than rabbit left ventricular myocytes.

scholarly journals Integrin β1D Deficiency–Mediated RyR2 Dysfunction Contributes to Catecholamine-Sensitive Ventricular Tachycardia in Arrhythmogenic Right Ventricular Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 141 (18) ◽  
pp. 1477-1493 ◽  
Author(s):  
Yihui Wang ◽  
Chunyan Li ◽  
Ling Shi ◽  
Xiuyu Chen ◽  
Chen Cui ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Sudden Cardiac Death ◽  
Right Ventricular ◽  
Cardiac Death ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Left Ventricular ◽  
Polymorphic Ventricular Tachycardia ◽  
Ventricular Cardiomyopathy ◽  
Open Probability ◽  
Increased Risk

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary heart disease characterized by fatty infiltration, life-threatening arrhythmias, and increased risk of sudden cardiac death. The guideline for management of ARVC in patients is to improve quality of life by reducing arrhythmic symptoms and to prevent sudden cardiac death. However, the mechanism underlying ARVC-associated cardiac arrhythmias remains poorly understood. Methods: Using protein mass spectrometry analyses, we identified that integrin β1 is downregulated in ARVC hearts without changes to Ca 2+ -handling proteins. As adult cardiomyocytes express only the β1D isoform, we generated a cardiac specific β1D knockout mouse model and performed functional imaging and biochemical analyses to determine the consequences of integrin β1D loss on function in the heart in vivo and in vitro. Results: Integrin β1D deficiency and RyR2 Ser-2030 hyperphosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. Using lipid bilayer patch clamp single channel recordings, we found that purified integrin β1D protein could stabilize RyR2 function by decreasing RyR2 open probability, mean open time, and increasing mean close time. Also, β1D knockout mice exhibited normal cardiac function and morphology but presented with catecholamine-sensitive polymorphic ventricular tachycardia, consistent with increased RyR2 Ser-2030 phosphorylation and aberrant Ca 2+ handling in β1D knockout cardiomyocytes. Mechanistically, we revealed that loss of DSP (desmoplakin) induces integrin β1D deficiency in ARVC mediated through an ERK1/2 (extracellular signal–regulated kinase 1 and 2)–fibronectin–ubiquitin/lysosome pathway. Conclusions: Our data suggest that integrin β1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.

Shortening and [Ca2+] dynamics of left ventricular myocytes isolated from exercise-trained rats

1998 ◽  
Vol 85 (6) ◽  
pp. 2159-2168 ◽  
Author(s):  
Bradley M. Palmer ◽  
Anne M. Thayer ◽  
Steven M. Snyder ◽  
Russell L. Moore
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Left Ventricular ◽  
Trained Group ◽  
Effective Coupling ◽  
Temporal Characteristics ◽  
Fura 2 ◽  
Intracellular Ca ◽  
Maximal Extent

The effects of run endurance training and fura 2 loading on the contractile function and Ca2+ regulation of rat left ventricular myocytes were examined. In myocytes not loaded with fura 2, the maximal extent of myocyte shortening was reduced with training under our pacing conditions [0.5 Hz at 2.0 and 0.75 mM external Ca2+ concentration ([Ca2+]o)], although training had no effect on the temporal characteristics. The “light” loading of myocytes with fura 2 markedly suppressed (∼50%) maximal shortening in the sedentary and trained groups, although the temporal characteristics of myocyte shortening were significantly prolonged in the trained group. No discernible differences in the dynamic characteristics of the intracellular Ca2+ concentration ([Ca2+]) transient were detected at 2.0 mM [Ca2+]o, although peak [Ca2+] and rate of [Ca2+] rise during caffeine contracture were greater in the trained state at 0.75 mM [Ca2+]o. We conclude that training induced a diminished myocyte contractile function under the conditions studied here and a more effective coupling of inward Ca2+ current to sarcoplasmic reticulum Ca2+ release at low [Ca2+]o, and that fura 2 and its loading vehicle DMSO significantly alter the intrinsic characteristics of myocyte contractile function and Ca2+ regulation.

Chronic ventricular myocyte-specific overexpression of angiotensin II type 2 receptor results in intrinsic myocyte contractile dysfunction

2005 ◽  
Vol 288 (1) ◽  
pp. H317-H327 ◽  
Author(s):  
Masaharu Nakayama ◽  
Xinhua Yan ◽  
Robert L. Price ◽  
Thomas K. Borg ◽  
Kenta Ito ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Left Ventricular ◽  
Contractile Dysfunction ◽  
Inotropic Response ◽  
Ang Ii ◽  
Intracellular Ca ◽  
Depressed Response

ANG II type 2 receptor (AT2) is upregulated in failing hearts, but its effect on myocyte contractile function is not known. We measured fractional cell shortening and intracellular Ca2+ concentration transients in left ventricular myocytes derived from transgenic mice in which ventricle-specific expression of AT2 was driven by the myosin light chain 2v promoter. Confocal microscopy studies confirmed upregulation of AT2 in the ventricular myocytes and partial colocalization of AT2 with AT1. Three components of contractile performance were studied. First, baseline measurements (0.5 Hz, 1.5 mmol/l extracellular Ca2+ concentration, 25°C) and study of contractile reserve at faster pacing rates (1–5 Hz) revealed Ca2+-dependent contractile dysfunction in myocytes from AT2 transgenic mice. Comparison of two transgenic lines suggested a dose-dependent relationship between magnitude of contractile dysfunction and level of AT2 expression. Second, activity of the Na+/H+ exchanger, a dominant transporter that regulates beat-to-beat intracellular pH, was impaired in the transgenic myocytes. Third, the inotropic response to β-adrenergic versus ANG II stimulation differed. Both lines showed impaired contractile response to β-adrenergic stimulation. ANG II elicited an increase in contractility and intracellular Ca2+ in wild-type myocytes but caused a negative inotropic effect in myocytes from AT2 transgenic mice. In contrast with β-adrenergic response, the depressed response to ANG II was related to level of AT2 overexpression. The depressed response to ANG II was also present in myocytes from young transgenic mice before development of heart failure. Thus chronic overexpression of AT2 has the potential to cause Ca2+- and pH-dependent contractile dysfunction in ventricular myocytes, as well as loss of the inotropic response to ANG II.

Short-term in vivo inhibition of nitric oxide synthase with L-NAME influences the contractile function of single left ventricular myocytes in rats

2011 ◽  
Vol 89 (4) ◽  
pp. 305-310 ◽  
Author(s):  
Wellington Lunz ◽  
Antônio José Natali ◽  
Miguel Araújo Carneiro ◽  
Luciano dos Santos Aggum Capettini ◽  
Marcelo Perim Baldo ◽  
...  
Keyword(s):  
Maximum Rate ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Left Ventricular ◽  
Regulatory Proteins ◽  
Hemodynamic Parameters ◽  
Short Term ◽  
Oxide Synthase ◽  
Fractional Shortening

The main purpose of this study was to investigate the effects of short-term L-NAME treatment on the contractile function of left ventricle (LV) myocytes and the expression of proteins related to Ca2+ homeostasis. Data from Wistar rats treated with L-NAME (L group, n = 20; 0.7 g/L in drinking water; 7 days) were compared with results from untreated controls (C group, n = 20). Cardiomyocytes from the L group showed increased (p < 0.05) fractional shortening (23%) and maximum rate of shortening (20%) compared with the C group. LV from the L group also showed increased (p < 0.05) expression of the ryanodine receptor 2 and Na+/Ca2+ exchanger proteins (76% and 83%, respectively; p < 0.05). However, the L and C groups showed similar in vivo hemodynamic parameters of cardiac function. In conclusion, short-term NOS inhibition determines an increased expression of Ca2+ regulatory proteins, which contributes to improving cardiomyocyte contractile function, preserving left ventricular function.

scholarly journals Isolated noncompaction left ventricular myocardium and polymorphic ventricular tachycardia

2003 ◽  
Vol 26 (1) ◽  
pp. 46-48 ◽  
Author(s):  
Luis Serés ◽  
Jorge Lopez ◽  
Eduardo Larrousse ◽  
Angel Moya ◽  
Damian Pereferrer ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Polymorphic Ventricular Tachycardia ◽  
Left Ventricular Myocardium

Different effects of histamine H1 and H2 stimulation on left ventricular contractility in pigs

1995 ◽  
Vol 269 (3) ◽  
pp. H959-H964
Author(s):  
D. J. Cooper ◽  
R. R. Schellenberg ◽  
K. R. Walley
Keyword(s):  
Contractile Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Hill Coefficient ◽  
Maximum Effect ◽  
Low Doses ◽  
Ventricular Contractility ◽  
Left Ventricular Contractility ◽  
Receptor Stimulation ◽  
H2 Antagonist

Histamine decreases ventricular contractility in some settings but increases it in others. To better understand these apparently discrepant results, we measured hemodynamics and left ventricular pressure (Millar catheter) and volume (ultrasonic crystals) in atrially paced, alpha- and beta-antagonist-treated pigs. Histamine was infused (0.5-10 micrograms.kg-1.min-1) before and after H2-antagonist (ranitidine) pretreatment. Changes in left ventricular contractile function were measured as shift of the end-systolic pressure-volume relationship (delta ESPVR) at a pressure of 100 mmHg. We found that at low doses (0.5 and 1 micrograms.kg-1.min-1), histamine significantly decreased delta ESPVR (-1.1 +/- 1.4 ml, P < 0.05) after H2-antagonist pretreatment. At doses above 1 micrograms.kg-1.min-1, histamine increased contractility in a dose-response fashion [maximum effect: 5.1 +/- 3.3 ml, dose resulting in 50% effect (ED50): 0.75 +/- 1.79 micrograms.kg-1.min-1] that was best described using a Hill coefficient of 2. Ranitidine increased the ED50 by approximately one order of magnitude (0.75 +/- 1.79 to 9.50 +/- 2.60 micrograms.kg-1.min-1, P < 0.05). We conclude that in vivo, at higher doses, histamine increases left ventricular contractility via H2-receptor stimulation, whereas at low doses histamine decreases left ventricular contractility, probably via H1-receptor stimulation.

Impaired activation of ATP-sensitive K+channels in endocardial myocytes from left ventricular hypertrophy

2007 ◽  
Vol 293 (6) ◽  
pp. H3643-H3649 ◽  
Author(s):  
Junichi Shimokawa ◽  
Hisashi Yokoshiki ◽  
Hiroyuki Tsutsui
Keyword(s):  
Left Ventricle ◽  
Metabolic Stress ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Response Curves ◽  
Patch Clamp Technique ◽  
Open Probability ◽  
Channel Activation ◽  
Wistar Kyoto ◽  
Channel Currents

ATP-sensitive K+(KATP) channels are essential for maintaining the cellular homeostasis against metabolic stress. Myocardial remodeling in various pathologies may alter this adaptive response to such stress. It was reported that transmural electrophysiological heterogeneity exists in ventricular myocardium. Therefore, we hypothesized that the KATPchannel properties might be altered in hypertrophied myocytes from endocardium. To test this hypothesis, we determined the KATPchannel currents using the perforated patch-clamp technique, open cell-attached patches, and excised inside-out patches in both endocardial and epicardial myocytes isolated from hypertrophied [spontaneous hypertensive rats (SHR)] vs. normal [Wistar-Kyoto rats (WKY)] left ventricle. In endocardial cells, KATPchannel currents ( IK,ATP), produced by 2 mM CN−and no glucose at 0 mV, were significantly smaller ( P < 0.01), and time required to reach peak currents after onset of KATPchannel opening (Timeonset to peak) was significantly longer (319 ± 46 vs. 177 ± 37 s, P = 0.01) in the SHR group ( n = 9) than the WKY group ( n = 13). However, in epicardial cells, there were no differences in IK,ATPand Timeonset to peakbetween the groups (SHR, n = 12; WKY, n = 12). The concentration-open probability-response curves obtained during the exposure of open cells and excised patches to exogenous ATP revealed the impaired KATPchannel activation in endocardial myocytes from SHR. In conclusion, KATPchannel activation under metabolic stress was impaired in endocardial cells from rat hypertrophied left ventricle. The deficit of endocardial KATPchannels to decreased intracellular ATP might contribute to the maladaptive response of hypertrophied hearts to ischemia.

Effects of intrafetal IGF-I on growth of cardiac myocytes in late-gestation fetal sheep

2009 ◽  
Vol 296 (3) ◽  
pp. E513-E519 ◽  
Author(s):  
Eugenie R. Lumbers ◽  
Min young Kim ◽  
Judith H. Burrell ◽  
Vasumathy Kumarasamy ◽  
Amanda C. Boyce ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Left Ventricular ◽  
Late Gestation ◽  
Cycle Phase ◽  
Cell Hyperplasia ◽  
Fetal Sheep ◽  
Igf I

Intrafetal insulin-like growth factor (IGF)-I promotes cardiac hypertrophy in the late-gestation fetal sheep; whether these effects are sustained is unknown. IGF-I was infused for 4 days at 80 μg/h from 121 to 125 days of gestation, and its effects at 128 days, 3 days after the infusion stopped, were determined by comparison with untreated fetal sheep. After IGF-I treatment, fetal weights were similar to those in control fetuses but kidney weights were bigger ( P < 0.05), as were spleen weights of male fetuses ( P < 0.05). Cardiac myocytes were larger in female than male fetal sheep ( P < 0.001). IGF-I increased male ( P < 0.001) but not female myocyte volumes. IGF-I did not alter the proportions of uni- or binucleated right or left ventricular myocytes. Female fetal sheep had a greater proportion of binucleated cardiac myocytes than males ( P < 0.05). IGF-I-treated fetuses had a slightly greater proportion of right ventricular nuclei in cell cycle phase G2/M and a reduced proportion of G0/G1 phase nuclei ( P < 0.1). Therefore, evidence for IGF-I-stimulated cardiac cell hyperplasia in fetal sheep in late gestation was limited. In conclusion, the greater sizes and larger proportion of binucleated cardiac myocytes in female fetal sheep suggest that myocyte maturation may occur earlier in females than in males. This may explain in part the male sex-specific responsiveness of cardiac hypertrophy to IGF-I in late gestation. If IGF-I-stimulated cardiomyocyte growth is accompanied by maturation of contractile function, IGF-I may be a potential therapeutic agent for maintaining cardiac output in preterm males.

Calcium current in rat diabetic ventricular myocytes

1994 ◽  
Vol 267 (6) ◽  
pp. H2280-H2289 ◽  
Author(s):  
K. Tsuchida ◽  
H. Watajima ◽  
S. Otomo
Keyword(s):  
Kinetic Parameters ◽  
Current Density ◽  
Calcium Current ◽  
Matched Control ◽  
Ventricular Myocytes ◽  
Control Cell ◽  
Cell Types ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Ventricular Contractility

The magnitude and kinetics of the L-type calcium current were compared in single left ventricular myocytes isolated from 8-mo-old (8M) and 19-mo-old (19M) genetically diabetic rats (WBN/Kob rats) and age-matched control rats. A diabetic state occurred at 19M but not at 8M. The left ventricular contractility was reduced in 19M WBN/Kob rats compared with age-matched control rats. The duration of the action potential was longer in 19M WBN/Kob rats than in the age-matched control rats. Peak inward current density was similar between diabetic rats and age-matched control rats. In addition, aging did not affect the current density at 8M or 19M. The various kinetic parameters of the L-type calcium current were not different between 19M diabetic and control cell types. The percent increase in the amplitude of the calcium current induced by isoproterenol was less in diabetic cells at the age of 19M, but not at the age of 8M, compared with age-matched control cells. Forskolin (10(-5) M), intracellularly applied adenosine 3',5'-cyclic monophosphate (5 x 10(-5) M), and guanosine 5'-[gamma-thio]triphosphate (10(-4) M) were equally effective in increasing the current in 19M diabetic and age-matched control cell types. The present study demonstrates that the basal calcium current density and kinetic parameters of the current were not altered. However, a decrease in response to beta-stimulation occurred in genetically diabetic rats compared with control rats.

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