Richard C Wu

Johns Hopkins University, Baltimore, MD, United States

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Publications (6)29.27 Total impact

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    ABSTRACT: Heart failure (HF) is characterized by marked prolongation of action potential duration and reduction in cellular repolarization reserve. These changes are caused in large part by HF-induced K(+) current downregulation. Molecular mechanisms underlying these changes remain unclear. We determined whether downregulation of K(+) currents in a canine model of tachycardia-induced HF is caused by altered expression of underlying K(+) channel alpha- and beta-subunits encoding these currents. K(+) channel subunit expression was quantified in normal and failing dogs at the mRNA and protein levels in epicardial (Epi), midmyocardial (Mid), and endocardial (Endo) layers of left ventricle. Analysis of mRNA and protein levels of candidate genes encoding the transient outward K(+) current (I(to)) revealed marked reductions in canine cKv4.3 expression in HF in Epi (44% mRNA, 39% protein), Mid (52% mRNA, 34% protein), and Endo (49% mRNA, 73% protein) layers and a paradoxical enhancement (41% Epi, 97% Mid, 113% Endo) in cKv1.4 protein levels, without significant changes in Kv channel-interacting protein cKChIP2 expression. Expression of cKir2.1, the gene underlying inward rectifier K(+) current (I(K1)), was unaffected by HF at mRNA and protein levels despite significant reduction in I(K1), whereas canine ether-a-go-go-related gene (cERG), which encodes the rapidly activating component of the delayed rectifier current (I(K)), exhibited increased protein expression. HF was not accompanied by significant changes in cKvLQT1 or cMinK mRNA and protein levels. These data indicate that 1) downregulation of I(to) in HF is associated with decreased cKv4.3 and not cKv1.4 or cKChIP2, and 2) alterations in both the rapidly activating and slowly activating components of I(K) as well as I(K1) in nonischemic dilated cardiomyopathy are not caused by changes in either transcript or immunoreactive protein levels of relevant channel subunits, which suggests posttranslational modification of these currents by HF.
    AJP Heart and Circulatory Physiology 07/2005; 288(6):H2887-96. · 4.01 Impact Factor
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    ABSTRACT: The Ca(2+)-independent transient outward K(+) current (I(to)) plays an important electrophysiological role in normal and diseased hearts. However, its contribution to ventricular repolarization remains controversial because of differences in its phenotypic expression and function across species. The dog, a frequently used model of human cardiac disease, exhibits altered functional expression of I(to). To better understand the relevance of electrical remodeling in dogs to humans, we studied the phenotypic differences in ventricular I(to) of both species with electrophysiological, pharmacological, and protein-chemical techniques. Several notable distinctions were elucidated, including slower current decay, more rapid recovery from inactivation, and a depolarizing shift of steady-state inactivation in human vs. canine I(to). Whereas recovery from inactivation of human I(to) followed a monoexponential time course, canine I(to) recovered with biexponential kinetics. Pharmacological sensitivity to flecainide was markedly greater in human than canine I(to), and exposure to oxidative stress did not alter the inactivation kinetics of I(to) in either species. Western blot analysis revealed immunoreactive bands specific for Kv4.3, Kv1.4, and Kv channel-interacting protein (KChIP)2 in dog and human, but with notable differences in band sizes across species. We report for the first time major variations in phenotypic properties of human and canine ventricular I(to) despite the presence of the same subunit proteins in both species. These data suggest that differences in electrophysiological and pharmacological properties of I(to) between humans and dogs are not caused by differential expression of the K channel subunit genes thought to encode I(to), but rather may arise from differences in molecular structure and/or posttranslational modification of these subunits.
    AJP Heart and Circulatory Physiology 03/2004; 286(2):H602-9. · 4.01 Impact Factor
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    ABSTRACT: Radiofrequency catheter ablation of focal atrial fibrillation triggers within the pulmonary veins is a rapidly developing therapy that relies on both recent technologies and evolving techniques. We describe the entrapment of a circular mapping catheter within the mitral valve apparatus after transseptal catheterization and mapping of the left atrium and pulmonary veins. The occurrence of this previously unreported complication stresses the need for continual monitoring and reporting of adverse effects from new devices and procedures to better inform patients and physicians of the benefits and risks of electrophysiologic interventions.
    Journal of Cardiovascular Electrophysiology 09/2002; 13(8):819-21. · 3.48 Impact Factor
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    ABSTRACT: The transient outward potassium current (I(to)) encoded by the Kv4 family of potassium channels is important in the repolarization of cardiac myocytes. KChIPs are a recently identified group of Ca2+-binding accessory subunits that modulate Kv4-encoded currents. KChIP2 is the only family member expressed in the heart. We previously cloned 2 novel splice variants of KChIP2 from human heart, named KChIP2S and KChIP2T. The transmural distribution of KChIP2 mRNA and protein in human and canine left ventricle was examined using kinetic RT-PCR and Western blots in the same tissues. A steep gradient of mRNA with greater KChIP2 expression in the epicardium was observed. However, no gradient of immunoreactive protein was observed. Immunocytochemistry reveals KChIP2 expression in the t-tubules and the nucleus. The predominant effects of all 3 KChIP2 splice variants on hKv4.3-encoded current are to increase the density, slow the current decay in a Ca2+-dependent manner, and hasten recovery from inactivation in a splice variant-specific fashion. A family of KChIP2 proteins is expressed in human hearts that exhibits differential modulation of hKv4.3 current in a Ca2+-dependent fashion. The effect of KChIP2 on the biophysical properties of expressed Kv4.3 current and the absence of a gradient of protein across the ventricular wall suggest that KChIP2 is either not a requisite component of human or canine ventricular I(to) or that its functional effect is being affected or additionally modified by other factors present in myocardial cells.
    Circulation 08/2002; 106(4):423-9. · 15.20 Impact Factor
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    Richard C Wu, Ronald Berger, Hugh Calkins
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    ABSTRACT: Catheter ablation has evolved from an experimental technique to first-line therapy for the treatment of atrial flutter. Atrial flutter is characterized by a macroreentrant atrial tachycardia circuit. Successful ablation of atrial flutter involves (1) mapping the atrial flutter to define the conduction zones within the re-entrant circuit to determine whether the atrial flutter is isthmus-dependent, non-isthmus-dependent, or atypical; (2) interrupting the atrial flutter macroreentrant circuit with an ablation catheter by creating either focal or linear lesions within a critical zone of slow conduction that extends to anatomical borders; and (3) terminating the tachycardia and demonstrating conduction block within the atrial flutter circuit after ablation. This update discusses the classification schemes of atrial flutter and macroreentrant atrial tachycardias, reviews the technique of radiofrequency catheter ablation, and highlights recent ablation approaches for atrial flutters and macroreentrant atrial tachycardias.
    Current Opinion in Cardiology 02/2002; 17(1):58-64. · 2.56 Impact Factor
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    ABSTRACT: ABSTRACT Heart failure (HF) is characterized, by ,marked ,prolongation ,of the ,action ,potential