Abstract 489: JTV-519 (K201) Reverses Abnormal Ca 2+ Release And Dynamic Ca 2+ Waves In Purkinje Cells From The Infarcted Canine Heart

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Masanori Hirose ◽  
Bruno Stuyvers ◽  
Wen Dun ◽  
Hiroaki Shimokawa ◽  
Henk EDJ ter Keurs ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Ventricular Arrhythmias ◽  
Event Rate ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Core Region ◽  
Canine Heart ◽  
The Core ◽  
Infarcted Heart ◽  
Triggered Arrhythmias

JTV-519 (K201) has been shown to be anti-arrhythmic in the ischemic/reperfusion setting. The mechanism is unknown. Purpose: To investigate the effects of JTV-519(K201) (Aetas Pharm Co.) in Purkinje cells dispersed from the subendocardium of the 48hr infarcted canine heart (IZPCs). IZPCs are the source of the triggered ventricular arrhythmias that occur at this time post coronary artery occlusion. Methods: Ca 2+ release events (elevations of basal [Ca 2+ ] equivalent to F/F 0 3.4 SD over F 0 ) in both intact and permeabilized single IZPCs were imaged using 2DCM with Fluo-4 and analyzed using a custom IDL program. Results: In intact IZPCs, the Ca 2+ release event (ev) rate was increased in the Subsarcolemmal region (SSL, a layer of ∼ 5μm thickness below the membrane; 0.0161±0.0031 ev/μm 2 /sec, n=cells=30, 1198 ev) but not in the Core region, when compared to normal Purkinje cells (NZPCs; SSL, 0.0089±0.0018 ev/μm 2 /sec, n=34, 747 ev, p<0.05). SR Ca 2+ ontent as estimated by rapid caffeine (20mM) application was comparable between NZPCs and IZPCs in both subcellular regions. Superfusion of JTV-519(K201) (1μM) normalized the SSL Ca 2+ event rate in intact IZPCs (to 0.0086±0.0016 ev/μm 2 /sec, n=17, 510ev, p<0.05 vs untreated IZPC value) without a change in SR Ca 2+ content. The incidence of spontaneous Ca 2+ waves is increased in intact IZPCs (0.0016/μm 2 /sec*1000, n=57) and was also normalized by JTV-519(K201)(0.0004/ μm 2 /sec*1000, n=30). In saponin-treated IZPCs ([Ca 2+ ] cyto= 100nM), JTV-519(K201) normalized the enhanced Ca 2+ event rate (from 0.0246±0.0030 ev/μm 2 /sec, n=28 to 0.0110±0.0023 ev/μm 2 /sec, n=7, P<0.05). Conclusion: In Purkinje cells that survive in the infarcted heart, the enhanced subcellular Ca 2+ event rate is due to enhanced Ca 2+ induced Ca 2+ release. This leads to cell wide Ca 2+ waves and arrhythmias. By normalizing Ca 2+ sensitivity of Ca 2+ release channels of IZPCs, JTV519(K201) reduces the spontaneous Ca 2+ event rate, the incidence of Ca 2+ waves and thus the likelihood of infarct Purkinje cell induced triggered arrhythmias.

Tyrosine hydroxylase and choline acetyltransferase activities in ischemic canine heart

1982 ◽  
Vol 243 (5) ◽  
pp. H788-H795 ◽  
Author(s):  
P. G. Schmid ◽  
B. J. Greif ◽  
D. D. Lund ◽  
R. Roskoski
Keyword(s):  
Blood Flow ◽  
Coronary Artery ◽  
Tyrosine Hydroxylase ◽  
Choline Acetyltransferase ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Canine Heart ◽  
Parasympathetic Innervation ◽  
Ischemic Tissue ◽  
Biochemical Indices

After coronary artery occlusion, enzymes involved in the synthesis of sympathetic and parasympathetic neurotransmitters may change disparately. We investigated this in the canine heart by measuring the activity of tyrosine hydroxylase (TH) and choline acetyltransferase (CAT) in normal and ischemic tissue. Myocardial blood flow in selected regions was measured by the microsphere technique. Dogs had either ligation of the anterior descending coronary artery (LAD) or sham ligation (S). In the ischemic zone 5 h after LAD ligation, TH activity was lower than in corresponding anterior apical zones of S dogs (5.1 +/- 1.7 vs. 13.5 +/- 2.3 nmol.g-1.h-1) (P less than 0.05) with a tendency for greater decreases in endocardium than in epicardium. In contrast, there were insignificant changes in CAT activity 2.5 and 5 h after LAD ligation. Thereafter, progressive and significant (P less than 0.05) decreases occurred in CAT activity at 25 and 170 h after LAD ligation. Thus there are early heterogeneous decreases in TH activity that correlate directly with heterogeneous deficits in blood flow. Although decreases in CAT are also heterogeneous and correlate with deficits in perfusion, these changes occur later. These results indicate differences in the effects of infarction on these biochemical indices of sympathetic and parasympathetic innervation in canine heart.

scholarly journals Utility of a Smartphone Based System (cvrPhone) to Predict Short-term Arrhythmia Susceptibility

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kwanghyun Sohn ◽  
Steven P. Dalvin ◽  
Faisal M. Merchant ◽  
Kanchan Kulkarni ◽  
Furrukh Sana ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Arrhythmias ◽  
Smart Phone ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Ecg Signals ◽  
Arrhythmic Event ◽  
User Friendly ◽  
Electrocardiogram Ecg

Abstract Repolarization alternans (RA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death. We developed a 12-lead, blue-tooth/Smart-Phone (Android) based electrocardiogram (ECG) acquisition and monitoring system (cvrPhone), and an application to estimate RA, in real-time. In in-vivo swine studies (N = 17), 12-lead ECG signals were recorded at baseline and following coronary artery occlusion. RA was estimated using the Fast Fourier Transform (FFT) method using a custom developed algorithm in JAVA. Underlying ischemia was detected using a custom developed ischemic index. RA from each lead showed a significant (p < 0.05) increase within 1 min of occlusion compared to baseline (n = 29). Following myocardial infarction, spontaneous ventricular tachycardia episodes (n = 4) were preceded by significant (p < 0.05) increase of RA prior to the onset of the tachy-arrhythmias. Similarly, the ischemic index exhibited a significant increase following myocardial infarction (p < 0.05) and preceding a tachy-arrhythmic event. In conclusion, RA can be effectively estimated using surface lead electrocardiograms by analyzing beat-to-beat variability in ECG morphology using a smartphone based platform. cvrPhone can be used to detect myocardial ischemia and arrhythmia susceptibility using a user-friendly, clinically acceptable, mobile platform.

Stretch-induced ventricular arrhythmias during acute ischemia and reperfusion

2004 ◽  
Vol 97 (1) ◽  
pp. 377-383 ◽  
Author(s):  
Kevin Kit Parker ◽  
James A. Lavelle ◽  
L. Katherine Taylor ◽  
Zifa Wang ◽  
David E. Hansen
Keyword(s):  
Coronary Artery ◽  
Ventricular Arrhythmias ◽  
Mechanical Stretch ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Acute Ischemia ◽  
Ischemia And Reperfusion ◽  
A Value ◽  
Action Potential Waveform ◽  
Electrophysiological Effects

Mechanical stretch has been demonstrated to have electrophysiological effects on cardiac muscle, including alteration of the probability of excitation, alteration of the action potential waveform, and stretch-induced arrhythmia (SIA). We demonstrate that regional ventricular ischemia due to coronary artery occlusion increases arrhythmogenic effects of transient diastolic stretch, whereas globally ischemic hearts showed no such increase. We tested our hypothesis that, during phase Ia ischemia, regionally ischemic hearts may be more susceptible to triggered arrhythmogenesis due to transient diastolic stretch. During the first 20 min of regional ischemia, the probability of eliciting a ventricular SIA ( PSIA) by transient diastolic stretch increased significantly. However, after 30 min, PSIA decreased to a value comparable with baseline measurements, as expected during phase Ib, where most ventricular arrhythmias are of reentrant mechanisms. We also suggest that mechanoelectrical coupling may contribute to the nonreentrant mechanisms underlying reperfusion-induced arrhythmia. When coronary artery occlusion was relieved after 30 min of ischemia, we observed an increase in PSIA and the maintenance of this elevated level throughout 20 min of reperfusion. We conclude that mechanoelectrical coupling may underlie triggered arrhythmogenesis during phase 1a ischemia and reperfusion.

scholarly journals CD36 overexpression predisposes to arrhythmias but reduces infarct size in spontaneously hypertensive rats: gene expression profile analysis

2012 ◽  
Vol 44 (2) ◽  
pp. 173-182 ◽  
Author(s):  
Jan Neckář ◽  
Jan Šilhavý ◽  
Václav Zídek ◽  
Vladimír Landa ◽  
Petr Mlejnek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Coronary Artery ◽  
Circadian Rhythms ◽  
Infarct Size ◽  
Ventricular Arrhythmias ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Transgenic Rats ◽  
Spontaneously Hypertensive ◽  
Long Chain

CD36 fatty acid translocase plays a key role in supplying heart with its major energy substrate, long-chain fatty acids (FA). Previously, we found that the spontaneously hypertensive rat (SHR) harbors a deletion variant of Cd36 gene that results in reduced transport of long-chain FA into cardiomyocytes and predisposes the SHR to cardiac hypertrophy. In the current study, we analyzed the effects of mutant Cd36 on susceptibility to ischemic ventricular arrhythmias and myocardial infarction in adult SHR- Cd36 transgenic rats with wild-type Cd36 compared with age-matched SHR controls. Using an open-chest model of coronary artery occlusion, we found that SHR- Cd36 transgenic rats showed profound arrhythmogenesis resulting in significantly increased duration of tachyarrhythmias (207 ± 48 s vs. 55 ± 21 s, P < 0.05), total number of premature ventricular complexes (2,623 ± 517 vs. 849 ± 250, P < 0.05) and arrhythmia score (3.86 ± 0.18 vs. 3.13 ± 0.13, P < 0.001). On the other hand, transgenic SHR compared with SHR controls showed significantly reduced infarct size (52.6 ± 4.3% vs. 72.4 ± 2.9% of area at risk, P < 0.001). Similar differences were observed in isolated perfused hearts, and the increased susceptibility of transgenic SHR to arrhythmias was abolished by reserpine, suggesting the involvement of catecholamines. To further search for possible molecular mechanisms of altered ischemic tolerance, we compared gene expression profiles in left ventricles dissected from 6-wk-old transgenic SHR vs. age-matched controls using Illumina-based sequencing. Circadian rhythms and oxidative phosphorylation were identified as the top KEGG pathways, while circadian rhythms, VDR/RXR activation, IGF1 signaling, and HMGB1 signaling were the top IPA canonical pathways potentially important for Cd36-mediated effects on ischemic tolerance. It can be concluded that transgenic expression of Cd36 plays an important role in modulating the incidence and severity of ischemic and reperfusion ventricular arrhythmias and myocardial infarct size induced by coronary artery occlusion. The proarrhythmic effect of Cd36 transgene appears to be dependent on adrenergic stimulation.

scholarly journals Acute but not chronic tempol treatment increases ischemic and reperfusion ventricular arrhythmias in open-chest rats

2008 ◽  
pp. 653-656
Author(s):  
J Neckář ◽  
B Ošťádal ◽  
F Kolář
Keyword(s):  
Infarct Size ◽  
Ventricular Arrhythmias ◽  
Coronary Artery Occlusion ◽  
Treated Group ◽  
Artery Occlusion ◽  
Time Profile ◽  
Open Chest ◽  
Male Wistar Rats ◽  
And Control ◽  
Later Phase

The effect of the chronic and acute antioxidant tempol (superoxide dismutase mimetic) treatment on cardiac ischemic tolerance was investigated in adult male Wistar rats. The first experimental group was given tempol (1 mM) in drinking water for three weeks, the second group received tempol (100 mg/kg, i.v.) 10 min before test ischemia, and control rats received the same volume of solvent. Anesthetized open-chest animals (pentobarbitone 60 mg/kg, i.p.) were subjected to 20-min coronary artery occlusion and 3-h reperfusion for infarct size determination. Ventricular arrhythmias were monitored during ischemia and at the beginning (5 min) of reperfusion. Acute tempol administration shifted the time profile of ischemic arrhythmias to the later phase and significantly increased the number of ischemic and reperfusion premature ventricular complexes, respectively (504±127 and 84±21) as compared with the chronically treated group (218±36 and 47±7) or controls (197±26 and 31±7). Acute tempol-treated rats exhibited a tendency to decrease infarct size (P = 0.087). The mechanism of proarrhythmic tempol action during ischemia and reperfusion remains to be elucidated.

Metabolic Consequences of Beta-Adrenergic Receptor Blockade for the Acutely Ischemic Dog Myocardium

1984 ◽  
Vol 22 (01) ◽  
pp. 35-40
Author(s):  
E. E. van der Wall ◽  
M. J. van Eenige ◽  
S. Scholtalbers ◽  
W. den Hollander ◽  
E. C. Visser ◽  
...  
Keyword(s):  
Beta Blockers ◽  
Regional Distribution ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Beta Blockade ◽  
Intrinsic Sympathomimetic Activity ◽  
Canine Heart ◽  
Myocardial Uptake ◽  
Ischemic Tissue ◽  
Additional Influence

SummaryIn an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of 201T1 in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both nonselective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and 201T1, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of 201T1 uptake in non-occluded endocardium. Uptake of 201T1 as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties.

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