scholarly journals Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy

2011 ◽  
Vol 300 (6) ◽  
pp. H2230-H2237 ◽  
Author(s):  
David Benoist ◽  
Rachel Stones ◽  
Mark Drinkhill ◽  
Olivier Bernus ◽  
Ed White
Keyword(s):  
Action Potential ◽  
Right Ventricular ◽  
Action Potential Duration ◽  
Ventricular Hypertrophy ◽  
Pulmonary Artery Hypertension ◽  
Monophasic Action Potential ◽  
Rt Pcr ◽  
Arrhythmogenic Substrate ◽  
Ventricular Tachycardias ◽  
Perfused Hearts

Mechanisms associated with right ventricular (RV) hypertension and arrhythmias are less understood than those in the left ventricle (LV). The aim of our study was to investigate whether and by what mechanisms a proarrhythmic substrate exists in a rat model of RV hypertension and hypertrophy. Rats were injected with monocrotaline (MCT; 60 mg/kg) to induce pulmonary artery hypertension or with saline (CON). Myocardial levels of mRNA for genes expressing ion channels were measured by real-time RT-PCR. Monophasic action potential duration (MAPD) was recorded in isolated Langendorff-perfused hearts. MAPD restitution was measured, and arrhythmias were induced by burst stimulation. Twenty-two to twenty-six days after treatment, MCT animals had RV hypertension, hypertrophy, and decreased ejection fractions compared with CON. A greater proportion of MCT hearts developed sustained ventricular tachycardias/fibrillation (0.83 MCT vs. 0.14 CON). MAPD was prolonged in RV and less so in the LV of MCT hearts. There were decreased levels of mRNA for K+ channels. Restitution curves of MCT RV were steeper than CON RV or either LV. Dispersion of MAPD was greater in MCT hearts and was dependent on stimulation frequency. Computer simulations based on ion channel gene expression closely predicted experimental changes in MAPD and restitution. We have identified a proarrhythmic substrate in the hearts of MCT-treated rats. We conclude that steeper RV electrical restitution and rate-dependant RV-LV action potential duration dispersion may be contributing mechanisms and be implicated in the generation of arrhythmias associated with in RV hypertension and hypertrophy.

Effect of β-adrenergic blockade on dynamic electrical restitution in vivo

2004 ◽  
Vol 287 (1) ◽  
pp. H390-H394 ◽  
Author(s):  
Steven C. Hao ◽  
David J. Christini ◽  
Kenneth M. Stein ◽  
Peter N. Jordan ◽  
Sei Iwai ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Action Potential ◽  
Right Ventricular ◽  
Cardiac Death ◽  
Monophasic Action Potential ◽  
Adrenergic Blockade ◽  
Arrhythmogenic Substrate ◽  
Restitution Curve ◽  
Β Blockers

The slope of the action potential duration (APD) restitution curve may be a significant determinant of the propensity to develop ventricular fibrillation, with steeper slopes associated with a more arrhythmogenic substrate. We hypothesized that one mechanism by which β-blockers reduce sudden cardiac death is by flattening the APD restitution curve. Therefore, we investigated whether infusion of esmolol modulates the APD restitution curve in vivo. In 10 Yorkshire pigs, dynamic APD restitution curves were determined from measurements of APD at 90% repolarization with a monophasic action potential catheter positioned against the right ventricular septum during right ventricular apical pacing in the basal state and during infusion of esmolol. APD restitution curves were fitted to the three-parameter ( a, b, c) exponential equation, APD = a·[1 − e(− b·DI)] + c, where DI is the diastolic interval. Esmolol decreased the maximal APD slope, 0.68 ± 0.14 vs. 0.94 ± 0.24 (baseline), P = 0.002, and flattened the APD restitution curve at shorter DIs, 75 and 100 ms ( P < 0.05). To compare the slopes of the APD restitution curves at similar steady states, slopes were also computed at points of intersection between the restitution curve and the lines representing pacing at a fixed cycle length (CL) of 200, 225, 250, 275, and 300 ms using the relationship CL = APD + DI. Esmolol decreased APD restitution slopes at CLs 200–275 ms ( P < 0.05). Esmolol flattens the cardiac APD restitution curve in vivo, particularly at shorter CLs and DIs. This may represent a novel mechanism by which β-blockers prevent sudden cardiac death.

Abstract 2623: Right Ventricular Hypertrophy in Monocrotaline-induced Pulmonary Hypertension is Associated with Impaired Oxidative Metabolism and Action Potential Prolongation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Lin Piao ◽  
Dalia Urboniene ◽  
Hannah J Zhang ◽  
Peter T Toth ◽  
Jalees Rehman ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Action Potential ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Systolic Pressure ◽  
Right Ventricular Hypertrophy ◽  
Monophasic Action Potential ◽  
Metabolic Shift ◽  
O2 Consumption ◽  
Action Potential Prolongation

Introduction: Right ventricular hypertrophy (RVH) and right ventricular failure are major determinants of prognosis and functional state in pulmonary artery hypertension (PAH). We previously found a mitochondrial metabolic shift in the pulmonary circulation in clinical as well as experimental PAH that includes a shift from oxidation to glycolysis, decreased production of reactive oxygen species (ROS) and normoxic activation of HIF-1α and decreased expression of voltage-gated potassium channels. In this study, we hypothesize that during RVH there is a similar metabolic shift in the RV characterized by impaired mitochondrial respiration and that the resulting electrical remodeling causes action potential prolongation. Methods and Results: PAH was induced in Sprague-Dawley rats by single injection of monocrotaline (60mg/Kg). At 3 weeks, PAH was confirmed by a shortened pulmonary artery acceleration time vs controls (13.8±0.7 vs 36.2±0.2 msec, P < 0.001) as determined by Doppler Echo. RVH was also evident, with a thicker right ventricular free wall in monocrotaline vs control hearts (1.3±0.1 vs 0.9±0.0 mm, P < 0.001 vs control) as assessed by two-dimensional and M-mode Echo. Oxygen consumption of right ventricular tissues (140mg samples) was measured using high-resolution respirometry. In an RV Langendorff model, RV systolic pressure (RVSP) and RV monophasic action potential duration (MAP) were measured. The ratio of RV/LV+S weight increased to 2 fold with monocrotaline (P < 0.001). RVSP in MCT group was increased to 50.9±10.6 vs 21.3±2.7 mmHg, P < 0.05). RV O2-consumption in RVH was significantly reduced vs control [144.1±37.6 vs 277.0±27.4 pmol/(sec*ml), P < 0.05]. The duration of 90% and 75% repolarization of MAP (MAPD90 and MAPD75) was markedly prolonged in RVH (145% and 136% vs controls; P < 0.001, P < 0.05, respectively). Importantly, MAPD90 increased in direct proportion to the severity of PAH, as measured by RVSP. Conclusions: RVH was associated with impaired RV metabolism as evidenced by reduced O2 consumption. This metabolic shift was associated with significant action potential prolongation in the RV. The consequences of this ionic remodeling for arrhythmogenisis and contractility remain to be determined.

Droperidol Inhibits Intracellular Ca2+, Myofilament Ca2+Sensitivity, and Contraction in Rat Ventricular Myocytes

2005 ◽  
Vol 102 (6) ◽  
pp. 1165-1173 ◽  
Author(s):  
Toshiya Shiga ◽  
Sandro Yong ◽  
Joseph Carino ◽  
Paul A. Murray ◽  
Derek S. Damron
Keyword(s):  
Nitric Oxide ◽  
Action Potential ◽  
Action Potential Duration ◽  
Ventricular Myocytes ◽  
Nitric Oxide Production ◽  
Cellular Mechanisms ◽  
Rat Ventricular Myocytes ◽  
Oxide Production ◽  
Perfused Hearts ◽  
Ca Sensitivity

Background Droperidol has recently been associated with cardiac arrhythmias and sudden cardiac death. Changes in action potential duration seem to be the cause of the arrhythmic behavior, which can lead to alterations in intracellular free Ca concentration ([Ca]i). Because [Ca]i and myofilament Ca sensitivity are key regulators of myocardial contractility, the authors' objective was to identify whether droperidol alters [Ca]i or myofilament Ca sensitivity in rat ventricular myocytes and to identify the cellular mechanisms responsible for these effects. Methods Freshly isolated rat ventricular myocytes were obtained from adult rat hearts. Myocyte shortening, [Ca]i, nitric oxide production, intracellular pH, and action potentials were monitored in cardiomyocytes exposed to droperidol. Langendorff perfused hearts were used to assess overall cardiac function. Results Droperidol (0.03-1 mum) caused concentration-dependent decreases in peak [Ca]i and shortening. Droperidol inhibited 35 mm KCl-induced increase in [Ca]i, with little direct effect on sarcoplasmic reticulum Ca stores. Droperidol had no effect on action potential duration but caused a rightward shift in the concentration-response curve to extracellular Ca for shortening, with no concomitant effect on peak [Ca]i. Droperidol decreased pHi and increased nitric oxide production. Droperidol exerted a negative inotropic effect in Langendorff perfused hearts. Conclusion These data demonstrate that droperidol decreases cardiomyocyte function, which is mediated by a decrease in [Ca]i and a decrease in myofilament Ca sensitivity. The decrease in [Ca]i is mediated by decreased sarcolemmal Ca influx. The decrease in myofilament Ca sensitivity is likely mediated by a decrease in pHi and an increase in nitric oxide production.

Effect of sotalol, aprindine and the combination aprindine—sotalol on monophasic action potential duration

1986 ◽  
Vol 7 (1) ◽  
pp. 47-53 ◽  
Author(s):  
R. STROOBANDT ◽  
J. BRACHMANN ◽  
H. KESTELOOT ◽  
W. KÜBLER ◽  
J. SENGES
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Monophasic Action Potential

Hypertensive-diabetic cardiomyopathy in rats

1990 ◽  
Vol 258 (3) ◽  
pp. H793-H805 ◽  
Author(s):  
F. S. Fein ◽  
B. E. Zola ◽  
A. Malhotra ◽  
S. Cho ◽  
S. M. Factor ◽  
...  
Keyword(s):  
Action Potential ◽  
Right Ventricular ◽  
Action Potential Duration ◽  
Stimulus Frequency ◽  
Negative Inotropic Effect ◽  
Left Ventricular ◽  
Resting Membrane Potential ◽  
Contraction And Relaxation ◽  
And Control ◽  
Myocardial Pathology

Left ventricular papillary muscle function, transmembrane action potentials, myosin adenosinetriphosphatase (ATPase) and isoenzyme distribution, and myocardial pathology were studied in hypertensive (H), diabetic (D), hypertensive-diabetic (HD), and control (C) rats. There was approximately 50% relative left ventricular hypertrophy in H and HD rats. Relative lung and liver weights were greater in HD rats. Peak velocity of shortening tended to decrease progressively in H, D, and HD rats. The duration of contraction and relaxation was markedly prolonged in Ds and HDs. The length-developed tension relation was blunted in HDs. The negative inotropic effect of verapamil was similar in all groups. Resting membrane potential and amplitude were decreased in D and HD rats. Action potential duration was increased in H, D, and especially HD rats. The shortening of action potential duration with increased stimulus frequency was greater in H, D, and especially HD rats than in Cs. Left ventricular myosin ATPase and V1 isoenzyme content decreased progressively in H, D, and HD rats. Right ventricular V1 isoenzyme content was not affected in H rats but was markedly decreased in D and HD rats. Left (and right) ventricular pathology was unchanged in rats with diabetes but was increased in rats with hypertension. These data suggest that the combination of myocardial pathology (due to hypertension) and cellular dysfunction (caused mainly by diabetes) may result in cardiomyopathy and congestive heart failure in the HD rat.

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