%0 Journal Article %1 Pogw_2001_1159 %A Pogwizd, S. M. %A Schlotthauer, K. %A Li, L. %A Yuan, W. %A Bers, D. M. %D 2001 %J Circ. Res. %K 11397771 A, Adrenergic Animal, Animals, Arrhythmia, Caffeine, Calcium, Cells, Channels, Congestive, Contraction, Cultured, Disease Down-Regulation, Dysfunction, Exchanger, Failure, Gov't, Heart Inwardly Isoproterenol, Left, Membrane Models, Myocardial P.H.S., Patch-Clamp Potassium Potassium, Potentials, Propranolol, Rabbits, Receptors, Rectifying, Research Reticulum, Sarcoplasmic Sodium, Sodium-Calcium Support, Techniques, U.S. Up-Regulation, Ventricular beta, beta-Agonists, beta-Antagonists, drenergic, %N 11 %P 1159--1167 %R 10.1161/hh1101.091193 %T Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. %U http://dx.doi.org/10.1161/hh1101.091193 %V 88 %X Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of Na$^+$-Ca$^2+$ exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca$^2+$ stores, reducing Ca$^2+$ transients and contractile function. Whereas beta-adrenergic receptors (beta-ARs) are progressively downregulated in HF, residual beta-AR responsiveness at this critical HF stage allows SR Ca$^2+$ load to increase, causing spontaneous SR Ca$^2+$ release and transient inward current carried by NaCaX. A given Ca$^2+$ release produces greater arrhythmogenic inward current in HF (as a result of NaCaX upregulation), and approximately 50\% less Ca$^2+$ release is required to trigger an action potential in HF. The inward rectifier potassium current (I(K1)) is reduced by 49\% in HF, and this allows greater depolarization for a given NaCaX current. Partially blocking I(K1) in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a novel paradigm in which changes in NaCaX and I(K1), and residual beta-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.

@article{Pogw_2001_1159, abstract = {Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of {N}a$^{+}$-{C}a$^{2+}$ exchange (NaCaX) unloads sarcoplasmic reticulum (SR) {C}a$^{2+}$ stores, reducing {C}a$^{2+}$ transients and contractile function. Whereas beta-adrenergic receptors (beta-ARs) are progressively downregulated in HF, residual beta-AR responsiveness at this critical HF stage allows SR {C}a$^{2+}$ load to increase, causing spontaneous SR {C}a$^{2+}$ release and transient inward current carried by NaCaX. A given {C}a$^{2+}$ release produces greater arrhythmogenic inward current in HF (as a result of NaCaX upregulation), and approximately 50\% less {C}a$^{2+}$ release is required to trigger an action potential in HF. The inward rectifier potassium current (I(K1)) is reduced by 49\% in HF, and this allows greater depolarization for a given NaCaX current. Partially blocking I(K1) in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a novel paradigm in which changes in NaCaX and I(K1), and residual beta-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Pogwizd, S. M. and Schlotthauer, K. and Li, L. and Yuan, W. and Bers, D. M.}, biburl = {https://www.bibsonomy.org/bibtex/2564e54e52e82bbd0f3e527093f9ab10e/hake}, description = {The whole bibliography file I use.}, doi = {10.1161/hh1101.091193}, file = {Pogw_2001_1159.pdf:Pogw_2001_1159.pdf:PDF}, interhash = {3673032049a1d48d0bdc2b19b3aff4f7}, intrahash = {564e54e52e82bbd0f3e527093f9ab10e}, journal = {Circ. Res.}, key = 278, keywords = {11397771 A, Adrenergic Animal, Animals, Arrhythmia, Caffeine, Calcium, Cells, Channels, Congestive, Contraction, Cultured, Disease Down-Regulation, Dysfunction, Exchanger, Failure, Gov't, Heart Inwardly Isoproterenol, Left, Membrane Models, Myocardial P.H.S., Patch-Clamp Potassium Potassium, Potentials, Propranolol, Rabbits, Receptors, Rectifying, Research Reticulum, Sarcoplasmic Sodium, Sodium-Calcium Support, Techniques, U.S. Up-Regulation, Ventricular beta, beta-Agonists, beta-Antagonists, drenergic,}, month = Jun, number = 11, pages = {1159--1167}, pmid = {11397771}, timestamp = {2009-06-03T11:21:26.000+0200}, title = {Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness.}, url = {http://dx.doi.org/10.1161/hh1101.091193}, volume = 88, year = 2001 }