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Fabry disease is an important secondary cardiomyopathy characterized by the accumulation of glycosphingolipids due to a pathogenic mutation in the GLA gene. Lethal ventricular arrhythmia is the most common cause of sudden death in patients with Fabry disease. We herein report a case of a man in his 40s with late-onset Fabry disease who had polymorphic ventricular tachycardia and fibrillation during enzyme replacement therapy. After recovery from successful cardiopulmonary resuscitation, we recommended implantation of an implantable cardioverter-defibrillator; however, the patient refused to undergo implantation at that time. We administered a wearable cardioverter-defibrillator at his discharge, and he was successfully rescued from polymorphic ventricular tachycardia and fibrillation. He was finally given an implantable cardioverter-defibrillator. In Fabry disease, lethal ventricular arrhythmia is an important cause of sudden death. Ventricular tachycardia and fibrillation during enzyme replacement therapy have not been reported. Furthermore, secondary prevention of lethal ventricular arrhythmia using a wearable cardioverter-defibrillator has not been reported in Fabry disease. Therefore, this case report has implications for the possible incidence and prevention of lethal ventricular arrhythmias in patients with Fabry disease. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) shows a positive inotropic effect on cardiac muscle. Although the L-type [Ca.sup.2+] current ([I.sub.ca]) is one of the important determinants of cardiac excitation-contraction coupling, the effect of ET-1 on the [I.sub.ca] is not always clear. The controversial results appear to be due to different patchclamp methods. The present study measured the effect of ET- 1 on the [I.sub.Ca] of rat ventficular myocytes using the perforated patch-clamp technique. The holding potential was set to -40 mV, and depolarization was applied every 10 s. ET-1 (10 nM) increased the [I.sub.ca] in a monophasic manner. The current reached a steady state 15 min after the application of ET-1, when the measurement was done. Endothelin receptor subtype expression was also investigated using Western immunoblotting. [ET.sub.A]-receptor protein was expressed, but [ET.sub.B]-receptor protein was not expressed, in the cell membranes of rat ventricular myocytes. The effect of ET-1 on the[I.sub.Ca] was inhibited by a selective [ET.sub.A]-receptor antagonist, BQ-123, but not by a selective [ET.sub.B]-receptor antagonist, BQ-788. The effect was inhibited by protein kinase C (PKC) inhibitor chelerythrine and [Ca.sup.2+]/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93, but not by its inactive analog KN-92. The effect of ET-1 was also blocked by another CaMKII inhibitor, autocamtide-2-related inhibitory peptide. These results suggest that ET-1 increases the [I.sub.ca] via the [ET.sub.A]-receptor-PKC-CaMKII pathway. perforated patch clamp; endothelin A receptor; KN-93; BQ-123 doi: 10.1152/aioheart.01141.2009.

[alpha]1-Adrenoceptor stimulation ([[alpha].sub.1]ARS) modulates cardiac muscle contraction under physiological conditions by means of changes in [Ca.sup.2+] current through L-type channels ([I.sub.Ca,L]) and [Ca.sup.2+] sensitivity of the myofilaments. However, the cellular mechanisms of [[alpha].sub.1]ARS are not fully clarified. In this study, we investigated the role of [Ca.sup.2+]/calmodulin- dependent PK II (CaMKII) in the regulation of [I.sub.Ca,L] during [[alpha].sub.1]ARS in isolated adult rat ventricular myocytes by using the perforated patch--clamp technique. CaMKII inhibition with 0.5 [micro]M KN-93 abolished the potentiation in [I.sub.Ca,L] observed during [[alpha].sub.1]ARS by 10 [micro]M phenylephrine. In the presence of PKC inhibitor (10 [micro]M chelerythrine), the potentiation of [I.sub.Ca,L] by phenylephrine also disappeared. In Western immunoblotting analysis, phenylephrine ([greater than or equal to] [micro]M) increased the amount of autophosphorylated CaMKII (active CaMKII) significantly, and this increase was abolished by CaMKII inhibition or PKC inhibition. Also, we investigated changes in the subcellular localization of active CaMKII by using immunofluorescence microscopy and immunoelectron microscopy. Before [[alpha].sub.1]ARS, active CaMKII was exclusively located just beneath the plasmalemma. However, after [[alpha].sub.1]ARS, active CaMKII was localized close to transverse tubules, where most of L-type [Ca.sup.2+] channels are located. From these results, we propose that CaMKII, which exists near transverse tubules, is activated and phosphorylated by [[alpha].sub.1]ARS and that CaMKII activation directly potentiates [I.sub.Ca,L] in rat ventricular myocytes. cardiac muscle | perforated patch-clamp | PKC | phenylephrine

Sarcolipin (SLN) inhibits the cardiac sarco(endo)plasmic reticulum [Ca.sup.2+] ATPase (SERCA2a) by direct binding and is superinhibitory if it binds through phospholamban (PLN). To determine whether overexpression of SLN in the heart might impair cardiac function, transgenic (TG) mice were generated with cardiac-specific overexpression of NF-SLN (SLN tagged at its N terminus with the FLAG epitope). The level of NF-SLN expression (the NF-SLN/PLN expression ratio) was equivalent to that which induces profound superinhibition when coexpressed with PLN and SERCA2a in HEK-293 cells. In TG hearts, the apparent affinity of SERCA2a for [Ca.sup.2+] was decreased compared with non-TG littermate control hearts. Invasive hemodynamic and echocardiographic analyses revealed impaired cardiac contractility and ventricular hypertrophy in TG mice. Basal PLN phosphorylation was reduced. In isolated papillary muscle subjected to isometric tension, peak amplitudes of [Ca.sup.2+] transients and peak tensions were reduced, whereas decay times of [Ca.sup.2+] transients and relaxation times of tension were increased in TG mice. Isoproterenol largely restored contractility in papillary muscle and stimulated PLN phosphorylation to wild-type levels in intact hearts. No compensatory changes in expression of SERCA2a, PLN, ryanodine receptor, and calsequestrin were observed in TG hearts. Coimmunoprecipitation indicated that overexpressed NF-SLN was bound to both SERCA2a and PLN, forming a ternary complex. These data suggest that NF-SLN overexpression inhibits SERCA2a through stabilization of SERCA2a-PLN interaction in the absence of PLN phosphorylation and through the inhibition of PLN phosphorylation. Inhibition of SERCA2a impairs contractility and calcium cycling, but responsiveness to [beta]-adrenergic agonists may prevent progression to heart failure.