Kim, Jong
(2012)
MECHANISM UNDERLYING BRADYCARDIA AND LONG QT 2 RELATED ARRHYTHMIAS: INTERPLAY BETWEEN Ca2+ OVERLOAD AND ELECTRICAL DYSFUNCTION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
In numerous pathologies, spontaneous Ca2+ release (SCR) emanating from the sarcoplasmic reticulum and occurring during the action potential (AP) plateau can drive voltage instability that initiates arrhythmias, but the direct interplay between SCRs and arrhythmogeneis has not been fully understood in bradycardia and in long QT type 2 (LQT2) models.
Simultaneous optical measurement of intracellular Ca2+ transient (CaiT) and AP were performed in Langendorff-perfused rabbit hearts following AV node ablation. Bradycardia and/or LQT2 was/were induced and the spatial heterogeneity of intracellular Ca2+ handling and its link to voltage dispersion were investigated.
Upon switching from 120 to 50 beats/min, AP duration (APD) increased gradually with increasing occurrence of SCRs during the AP plateau (p<0.01, n=7). SCR was a) regionally heterogeneous, b) spatially correlated with APD prolongation, c) associated with enhanced dispersion of repolarization (DOR), d) reversed by pacing at 120 beats/min and e) suppressed with K201 (1µM) or flecainide (5µM), inhibitors of cardiac ryanodine receptors (RyR2) which reduced APD (p<0.01, n=5) and DOR (p<0.02, n=5). Western blots of Ca2+ channels/transporters revealed intrinsic spatial distributions of Cav1.2α and NCX (but not RyR2, and SERCA2a) that correlate with the distribution of SCR and underlie the molecular mechanism responsible for SCRs.
In LQT2, lability of Cai, voltage, and ECG signals increased during paced rhythm, before the appearance of early afterdepolarizations (EADs). When EADs appeared, Cai occasionally rose before voltage upstrokes at the origins of propagating EADs. Localized, areas of SCRs appeared in LQT2 and corresponded to areas of prolonged CaiT and APD. Triggered activity appeared after 3-5 min of LQT2 and emanated only at sites with steep membrane potential (Vm) gradients (ΔVm gradient percentile: 94.9 ± 3.2%, n=6). Pre- or post-treatment with K201 suppressed SCRs and decreased DOR, ΔVm and ΔCai. The reduction of ΔVm suppressed triggered activity (n=8/9 hearts).
The results show that bradycardia and LQT2 elicit spatially discordant SCR, which is tightly correlated with AP instability. The SCR mediated-enhancement of repolarization gradients and AP prolongation can promote arrhythmogenesis. These findings underscore the importance of a detailed understanding of Ca2+-dependent arrhythmogenic mechanisms for the development of rational treatment strategies.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Kim, Jong | J | | |
|
| ETD Committee: |
|
| Date: |
2 February 2012 |
| Date Type: |
Publication |
| Defense Date: |
22 November 2011 |
| Approval Date: |
2 February 2012 |
| Submission Date: |
2 December 2011 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
130 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Bradycardia;cardiac arrhythmia;long QT syndrome;torsade de pointe;optical mapping;afterdepolarization;triggered activity;dispersion of repolarization;action potential;calcium abnormality |
| Date Deposited: |
02 Feb 2012 15:17 |
| Last Modified: |
19 Dec 2016 14:38 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10649 |
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