Simulations of Reduced Conduction Reserve in the Diabetic Rat Heart: Response to Uncoupling and Reduced Excitability

Ghaly, Haisam A.; Boyle, Patrick; Vigmond, Edward J.; Shimoni, Y.; Nygren, Anders

doi:10.1007/s10439-009-9855-2

Cited by 13 publications

(12 citation statements)

References 43 publications

(77 reference statements)

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“…It was also shown that the Cx43 was lateralized in diabetic rat hearts [17]. Further, using computer simulations, these investigators predicted that changes in I Na properties could possibly explain their experimental findings [36]. Indeed, our experiments and simulations confirm an important role for I Na in the impaired propagation in diabetes.…”

Section: Discussionsupporting

confidence: 68%

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

Stables

Musa

Mitra

et al. 2014

Journal of Molecular and Cellular Cardiology

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Diabetes is associated with an increased risk of sudden cardiac death, but the underlying mechanisms remain unclear. Our goal was to investigate changes occurring in the action potential duration (APD) and conduction velocity (CV) in the diabetic rabbit ventricle, and delineate the principal ionic determinants. A rabbit model of alloxan-induced diabetes was utilized. Optical imaging was used to record electrical activity in isolated Langendorff-perfused hearts in normo-, hypo- and hyper-kalemia ([K+]o=4, 2, 12 mM respectively). Patch clamp experiments were conducted to record Na+ current (INa) in isolated ventricular myocytes. The mRNA/protein expression levels for Nav1.5 (the α-subunit of INa) and connexin-43 (Cx43), as well as fibrosis levels were examined. Computer simulations were performed to interpret experimental data. We found that the APD was not different, but that the CV was significantly reduced in diabetic hearts in normo-, hypo-, and, in hyper-kalemic conditions (13%, 17% and 33% reduction in diabetic vs. control, respectively). The cell capacitance (Cm) was increased (by ~14%), and the density of INa was reduced by ~32% in diabetes compared to controls, but the other biophysical properties of INa were unaltered. The mRNA/protein expression levels for Cx43 were unaltered. For Nav1.5, the mRNA expression was not changed, and though the protein level tended to be less in diabetic hearts, this reduction was not statistically significant. Staining showed no difference in fibrosis levels between the control and diabetic ventricles. Computer simulations showed that the reduced magnitude of INa was a key determinant of impaired propagation in the diabetic ventricle, which may have important implications for arrhythmogenesis.

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Section: Discussionsupporting

confidence: 68%

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

Stables

Musa

Mitra

et al. 2014

Journal of Molecular and Cellular Cardiology

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“…However, effects of increased cell size and GJ distribution in hypertrophied hearts are difficult to study experimentally. It is known that cell size can have a strong effect on impulse propagation (12)(13)(14)(15). In a study by Spach et al (13), an increase in cell size resulted in higher conduction velocity (q),in accordance with findings of Ghali et al (15), who showed that decreased cell size can negatively affect q.…”

Section: Introductionsupporting

confidence: 65%

“…It is known that cell size can have a strong effect on impulse propagation (12)(13)(14)(15). In a study by Spach et al (13), an increase in cell size resulted in higher conduction velocity (q),in accordance with findings of Ghali et al (15), who showed that decreased cell size can negatively affect q. In contrast, McIntyre et al (16) found a negative correlation between cell diameter and q in human ventricular tissue, which seems paradoxical, because an increase in cell diameter reduces the intracellular resistance.…”

Section: Introductionmentioning

confidence: 99%

A Simulation Study of Cellular Hypertrophy and Connexin Lateralization in Cardiac Tissue

Seidel

Salameh

Dhein

2010

Biophysical Journal

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Many cardiac diseases coincide with changes in cell size and shape. One example of such a disease is cardiac hypertrophy. It is established that cardiac impulse propagation depends on the cell size, as well as other factors, but interrelations between conduction velocity (CV), cell size, and gap junction (GJ) conductance (g(GJ)) are complex. Furthermore, cardiac diseases are often accompanied by connexin (Cx) lateralization. To analyze the effects of cell size and Cx lateralization in cardiac disease, a two-dimensional computer simulation of ventricular myocytes based on the Luo-Rudy model was used. Control cells (80 μm/20 μm (length/diameter)), long cells (160 μm/20 μm), and wide cells (80 μm/40 μm) were simulated as was a redistribution of lateral GJs (constant lateral g(GJ) and increased lateral g(GJ)). CV in long cells showed high stability, i.e., it declined very slowly when g(GJ) was gradually reduced. Wide cells, however, were more affected by reduced g(GJ), resulting in early transition to discontinuous propagation and low CV. Conduction block occurred earlier in enlarged cells than in control cells due to increased cell capacitance. Increased lateral g(GJ) stabilized longitudinal CV, which was a result of two-dimensional effects during planar wave propagation. Therefore, Cx lateralization may compensate for cardiac inhomogeneities. High lateral g(GJ) and enhanced cell diameter increased the susceptibility to conduction block at tissue expansion, providing a substrate for arrhythmia.

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“…2 demonstrate that the conduction slowing observed in acute ischemia is more pronounced in hearts from STZ-induced diabetic rats than in hearts from healthy controls. This is to be expected, given our previous observations that STZ-induced diabetic hearts suffer from a reduced conduction reserve that is related to the lateralization of Cx43 proteins (18,40,45). Acute ischemia can affect cardiac CV through at least two mechanisms: reduced excitability and reduced coupling.…”

Section: Conduction Slowing During Acute Ischemia In Stz-induced Diabmentioning

confidence: 73%

Reduced conduction reserve in the diabetic rat heart: role of iPLA₂activation in the response to ischemia

Rahnema

Shimoni

Nygren³

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Hearts from streptozotocin (STZ)-induced diabetic rats have previously been shown to have impaired intercellular electrical coupling, due to reorganization (lateralization) of connexin43 proteins. Due to the resulting reduction in conduction reserve, conduction velocity in diabetic hearts is more sensitive to conditions that reduce cellular excitability or intercellular electrical coupling. Diabetes is a known risk factor for cardiac ischemia, a condition associated with both reduced cellular excitability and reduced intercellular coupling. Activation of Ca(2+)-independent phospholipase A(2) (iPLA(2)) is known to be part of the response to acute ischemia and may contribute to the intercellular uncoupling by causing increased levels of arachidonic acid and lysophosphatidyl choline. Normally perfused diabetic hearts are known to exhibit increased iPLA(2) activity and may thus be particularly sensitive to further activation of these enzymes. In this study, we used voltage-sensitive dye mapping to assess changes in conduction velocity in response to acute global ischemia in Langendorff-perfused STZ-induced diabetic hearts. Conduction slowing in response to ischemia was significantly larger in STZ-induced diabetic hearts compared with healthy controls. Similarly, slowing of conduction velocity in response to acidosis was also more pronounced in STZ-induced diabetic hearts. Inhibition of iPLA(2) activity using bromoenol lactone (BEL; 10 μM) had no effect on the response to ischemia in healthy control hearts. However, in STZ-induced diabetic hearts, BEL significantly reduced the amount of conduction slowing observed beginning 5 min after the onset of ischemia. BEL treatment also significantly increased the time to onset of sustained arrhythmias in STZ-induced diabetic hearts but had no effect on the time to arrhythmia in healthy control hearts. Thus, our results suggest that iPLA(2) activation in response to acute ischemia in STZ-induced diabetic hearts is more pronounced than in control hearts and that this response is a significant contributor to arrhythmogenic conduction slowing.

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Simulations of Reduced Conduction Reserve in the Diabetic Rat Heart: Response to Uncoupling and Reduced Excitability

Cited by 13 publications

References 43 publications

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

A Simulation Study of Cellular Hypertrophy and Connexin Lateralization in Cardiac Tissue

Reduced conduction reserve in the diabetic rat heart: role of iPLA₂activation in the response to ischemia

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Simulations of Reduced Conduction Reserve in the Diabetic Rat Heart: Response to Uncoupling and Reduced Excitability

Cited by 13 publications

References 43 publications

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

A Simulation Study of Cellular Hypertrophy and Connexin Lateralization in Cardiac Tissue

Reduced conduction reserve in the diabetic rat heart: role of iPLA2activation in the response to ischemia

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Reduced conduction reserve in the diabetic rat heart: role of iPLA₂activation in the response to ischemia