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Myocardial Electrotonic Coupling Modulates Repolarization Heterogeneities in vivo: Implications for the Assessment of Pro‐Arrhythmic Liabilities in vitro and in silico
Author(s) -
Rio Carlos L,
Hamlin Robert L,
Billman George E
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1274.7
Subject(s) - repolarization , in vivo , coupling (piping) , cardiology , medicine , qt interval , ischemia , electrophysiology , chemistry , biophysics , neuroscience , biology , materials science , microbiology and biotechnology , metallurgy
Passive electrical properties determining electrotonic cell‐to‐cell coupling in the myocardium can modulate repolarization disturbances/heterogeneities; in short, poorly‐coupled cells exert limited electrotonic influence(s) over their neighbors (i.e., lower space constant) facilitating induced/acquired heterogeneities, and therefore, pro‐arrhythmic potential/behaviors. This study investigated, both in vivo and in silico , the effects of changes in myocardial electrotonic coupling on clinically‐relevant indices of arrhythmic liabilities. Electrotonic coupling in vivo , both at rest and/or during acute ischemia, was modulated by interventions affecting autonomic balance/β‐adrenoceptor (β‐AR) signaling. At rest, acute ischemia induced marked electrotonic uncoupling but β‐AR activation enhanced it; ischemic passive electrical derangements were blunted by vagal‐nerve stimulation and complete/partial β‐AR blockade but were enhanced by exercise. Overall, electrotonic derangements were well correlated with changes in the rate‐corrected QT‐interval (QTc, R 2 =0.89, P<0.05) and/or the with duration (terminal‐portion) of the T‐wave (TPEc, R 2 = 0.81, P < 0.05); these responses were well‐modeled in silico by introducing (only) aspatially heterogeneous coupling resistance in a one dimensional structure of propagating cardiac action potentials following the Luo‐Rudy formulation. Electrotonic uncoupling also predicted ischemic T‐wave alternans (TWA, R 2 = 0.82, P<0.05), a known risk‐marker for malignant arrhythmias in the clinic. Taken together, these data demonstrate that the degree of ventricular electrotonic uncoupling can explain, at least partially, pro‐arrhythmic electrocardiographic changes reflective of myocardial repolarization abnormalities in vivo , and therefore, it must be considered when examining pro‐arrhythmic liabilities in vitro and/or in silico .