Inhibition of Cardiac Ca2+ Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia
BACKGROUND—Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is...
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| Veröffentlicht in: | Circulation. Arrhythmia and electrophysiology 2011-04, Vol.4 (2), p.128-135 |
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| creator | Hwang, Hyun Seok Hasdemir, Can Laver, Derek Mehra, Divya Turhan, Kutsal Faggioni, Michela Yin, Huiyong Knollmann, Björn C |
| description | BACKGROUND—Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT.
METHODS AND RESULTS—We first measured the effect of all class I antiarrhythmic drugs marketed in the United States (quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2 myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca waves at clinically relevant concentrations, whereas Na channel inhibitors without RyR2 blocking properties did not. In Casq2 mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P |
| doi_str_mv | 10.1161/CIRCEP.110.959916 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_wolte</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3667204</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>21270101</sourcerecordid><originalsourceid>FETCH-LOGICAL-j3076-b80e2591bb88e93b4951a55823ea23740aff8327422f13b5715b42a7741829de3</originalsourceid><addsrcrecordid>eNpVUduKFDEUDKK4F_0AXySPisyak6RvL8LSO-rAgsuw-hpOZ9KTrOn0kPS49Nf4q5vZcUWfTsGpKooqQt4AuwAo4WO7WrfLm4zZRVM0DZTPyCk0EhaC1fL5EwbZnJCzlO4YK6GG8iU54cArBgxOye9VsK5zkxsDHXvaYtw41PnyD3RtvMFkaGsxBOMTfbee1_w9vTKTiYMLJtFl3zuNen7UekyJruhlmBzGaOfJDk7Tq7jfJupC9pyMtqPHgzRu8-tm9PMwxp3N-IcJU3R67zHSW9R21o9RXpEXPfpkXv-55-T75-Vt-3Vx_e3Lqr28XtwJVpWLrmaGFw10XV2bRnSyKQCLoubCIBeVZNj3teCV5LwH0RUVFJ3kWFUSat5sjDgnn46-u303mI0-pEGvdtENGGc1olP_f4Kzajv-UqIsK85kNnj7r8Ff5VPVmVAcCfejz_2ln35_b6KyBv1kFTB1mFQdJ82YqeOk4gEUUJRY</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Inhibition of Cardiac Ca2+ Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia</title><source>MEDLINE</source><source>EZB Electronic Journals Library</source><source>American Heart Association</source><creator>Hwang, Hyun Seok ; Hasdemir, Can ; Laver, Derek ; Mehra, Divya ; Turhan, Kutsal ; Faggioni, Michela ; Yin, Huiyong ; Knollmann, Björn C</creator><creatorcontrib>Hwang, Hyun Seok ; Hasdemir, Can ; Laver, Derek ; Mehra, Divya ; Turhan, Kutsal ; Faggioni, Michela ; Yin, Huiyong ; Knollmann, Björn C</creatorcontrib><description>BACKGROUND—Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT.
METHODS AND RESULTS—We first measured the effect of all class I antiarrhythmic drugs marketed in the United States (quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2 myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca waves at clinically relevant concentrations, whereas Na channel inhibitors without RyR2 blocking properties did not. In Casq2 mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P<0.05). QRS duration was not significantly different, indicating a similar degree of Na channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy.
CONCLUSIONS—RyR2 cardiac Ca release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2 mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on β-blockers.</description><identifier>ISSN: 1941-3149</identifier><identifier>EISSN: 1941-3084</identifier><identifier>DOI: 10.1161/CIRCEP.110.959916</identifier><identifier>PMID: 21270101</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Analysis of Variance ; Animals ; Anti-Arrhythmia Agents - pharmacology ; Calcium Channel Blockers - pharmacology ; Calsequestrin - deficiency ; Calsequestrin - genetics ; Defibrillators, Implantable ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Electric Countershock - instrumentation ; Electrocardiography ; Flecainide - pharmacology ; Humans ; Ion Channel Gating - drug effects ; Lidocaine - pharmacology ; Male ; Mice ; Mice, Knockout ; Mutation, Missense ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Procainamide - pharmacology ; Propafenone - pharmacology ; Ryanodine Receptor Calcium Release Channel - drug effects ; Ryanodine Receptor Calcium Release Channel - genetics ; Ryanodine Receptor Calcium Release Channel - metabolism ; Sodium Channel Blockers - pharmacology ; Tachycardia, Ventricular - drug therapy ; Tachycardia, Ventricular - genetics ; Tachycardia, Ventricular - metabolism ; Tachycardia, Ventricular - physiopathology ; Time Factors ; Young Adult</subject><ispartof>Circulation. Arrhythmia and electrophysiology, 2011-04, Vol.4 (2), p.128-135</ispartof><rights>2011 American Heart Association, Inc.</rights><rights>Copyright © 2011 American Heart Association. All rights reserved. 2011</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27915,27916</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21270101$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hwang, Hyun Seok</creatorcontrib><creatorcontrib>Hasdemir, Can</creatorcontrib><creatorcontrib>Laver, Derek</creatorcontrib><creatorcontrib>Mehra, Divya</creatorcontrib><creatorcontrib>Turhan, Kutsal</creatorcontrib><creatorcontrib>Faggioni, Michela</creatorcontrib><creatorcontrib>Yin, Huiyong</creatorcontrib><creatorcontrib>Knollmann, Björn C</creatorcontrib><title>Inhibition of Cardiac Ca2+ Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia</title><title>Circulation. Arrhythmia and electrophysiology</title><addtitle>Circ Arrhythm Electrophysiol</addtitle><description>BACKGROUND—Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT.
METHODS AND RESULTS—We first measured the effect of all class I antiarrhythmic drugs marketed in the United States (quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2 myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca waves at clinically relevant concentrations, whereas Na channel inhibitors without RyR2 blocking properties did not. In Casq2 mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P<0.05). QRS duration was not significantly different, indicating a similar degree of Na channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy.
CONCLUSIONS—RyR2 cardiac Ca release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2 mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on β-blockers.</description><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Anti-Arrhythmia Agents - pharmacology</subject><subject>Calcium Channel Blockers - pharmacology</subject><subject>Calsequestrin - deficiency</subject><subject>Calsequestrin - genetics</subject><subject>Defibrillators, Implantable</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Electric Countershock - instrumentation</subject><subject>Electrocardiography</subject><subject>Flecainide - pharmacology</subject><subject>Humans</subject><subject>Ion Channel Gating - drug effects</subject><subject>Lidocaine - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mutation, Missense</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Procainamide - pharmacology</subject><subject>Propafenone - pharmacology</subject><subject>Ryanodine Receptor Calcium Release Channel - drug effects</subject><subject>Ryanodine Receptor Calcium Release Channel - genetics</subject><subject>Ryanodine Receptor Calcium Release Channel - metabolism</subject><subject>Sodium Channel Blockers - pharmacology</subject><subject>Tachycardia, Ventricular - drug therapy</subject><subject>Tachycardia, Ventricular - genetics</subject><subject>Tachycardia, Ventricular - metabolism</subject><subject>Tachycardia, Ventricular - physiopathology</subject><subject>Time Factors</subject><subject>Young Adult</subject><issn>1941-3149</issn><issn>1941-3084</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUduKFDEUDKK4F_0AXySPisyak6RvL8LSO-rAgsuw-hpOZ9KTrOn0kPS49Nf4q5vZcUWfTsGpKooqQt4AuwAo4WO7WrfLm4zZRVM0DZTPyCk0EhaC1fL5EwbZnJCzlO4YK6GG8iU54cArBgxOye9VsK5zkxsDHXvaYtw41PnyD3RtvMFkaGsxBOMTfbee1_w9vTKTiYMLJtFl3zuNen7UekyJruhlmBzGaOfJDk7Tq7jfJupC9pyMtqPHgzRu8-tm9PMwxp3N-IcJU3R67zHSW9R21o9RXpEXPfpkXv-55-T75-Vt-3Vx_e3Lqr28XtwJVpWLrmaGFw10XV2bRnSyKQCLoubCIBeVZNj3teCV5LwH0RUVFJ3kWFUSat5sjDgnn46-u303mI0-pEGvdtENGGc1olP_f4Kzajv-UqIsK85kNnj7r8Ff5VPVmVAcCfejz_2ln35_b6KyBv1kFTB1mFQdJ82YqeOk4gEUUJRY</recordid><startdate>201104</startdate><enddate>201104</enddate><creator>Hwang, Hyun Seok</creator><creator>Hasdemir, Can</creator><creator>Laver, Derek</creator><creator>Mehra, Divya</creator><creator>Turhan, Kutsal</creator><creator>Faggioni, Michela</creator><creator>Yin, Huiyong</creator><creator>Knollmann, Björn C</creator><general>American Heart Association, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>5PM</scope></search><sort><creationdate>201104</creationdate><title>Inhibition of Cardiac Ca2+ Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia</title><author>Hwang, Hyun Seok ; Hasdemir, Can ; Laver, Derek ; Mehra, Divya ; Turhan, Kutsal ; Faggioni, Michela ; Yin, Huiyong ; Knollmann, Björn C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j3076-b80e2591bb88e93b4951a55823ea23740aff8327422f13b5715b42a7741829de3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Anti-Arrhythmia Agents - pharmacology</topic><topic>Calcium Channel Blockers - pharmacology</topic><topic>Calsequestrin - deficiency</topic><topic>Calsequestrin - genetics</topic><topic>Defibrillators, Implantable</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Electric Countershock - instrumentation</topic><topic>Electrocardiography</topic><topic>Flecainide - pharmacology</topic><topic>Humans</topic><topic>Ion Channel Gating - drug effects</topic><topic>Lidocaine - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mutation, Missense</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Procainamide - pharmacology</topic><topic>Propafenone - pharmacology</topic><topic>Ryanodine Receptor Calcium Release Channel - drug effects</topic><topic>Ryanodine Receptor Calcium Release Channel - genetics</topic><topic>Ryanodine Receptor Calcium Release Channel - metabolism</topic><topic>Sodium Channel Blockers - pharmacology</topic><topic>Tachycardia, Ventricular - drug therapy</topic><topic>Tachycardia, Ventricular - genetics</topic><topic>Tachycardia, Ventricular - metabolism</topic><topic>Tachycardia, Ventricular - physiopathology</topic><topic>Time Factors</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hwang, Hyun Seok</creatorcontrib><creatorcontrib>Hasdemir, Can</creatorcontrib><creatorcontrib>Laver, Derek</creatorcontrib><creatorcontrib>Mehra, Divya</creatorcontrib><creatorcontrib>Turhan, Kutsal</creatorcontrib><creatorcontrib>Faggioni, Michela</creatorcontrib><creatorcontrib>Yin, Huiyong</creatorcontrib><creatorcontrib>Knollmann, Björn C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Circulation. Arrhythmia and electrophysiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hwang, Hyun Seok</au><au>Hasdemir, Can</au><au>Laver, Derek</au><au>Mehra, Divya</au><au>Turhan, Kutsal</au><au>Faggioni, Michela</au><au>Yin, Huiyong</au><au>Knollmann, Björn C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Cardiac Ca2+ Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia</atitle><jtitle>Circulation. Arrhythmia and electrophysiology</jtitle><addtitle>Circ Arrhythm Electrophysiol</addtitle><date>2011-04</date><risdate>2011</risdate><volume>4</volume><issue>2</issue><spage>128</spage><epage>135</epage><pages>128-135</pages><issn>1941-3149</issn><eissn>1941-3084</eissn><abstract>BACKGROUND—Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT.
METHODS AND RESULTS—We first measured the effect of all class I antiarrhythmic drugs marketed in the United States (quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2 myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca waves at clinically relevant concentrations, whereas Na channel inhibitors without RyR2 blocking properties did not. In Casq2 mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P<0.05). QRS duration was not significantly different, indicating a similar degree of Na channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy.
CONCLUSIONS—RyR2 cardiac Ca release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2 mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on β-blockers.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>21270101</pmid><doi>10.1161/CIRCEP.110.959916</doi><tpages>8</tpages></addata></record> |
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| ispartof | Circulation. Arrhythmia and electrophysiology, 2011-04, Vol.4 (2), p.128-135 |
| issn | 1941-3149 1941-3084 |
| language | eng |
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| source | MEDLINE; EZB Electronic Journals Library; American Heart Association |
| subjects | Analysis of Variance Animals Anti-Arrhythmia Agents - pharmacology Calcium Channel Blockers - pharmacology Calsequestrin - deficiency Calsequestrin - genetics Defibrillators, Implantable Disease Models, Animal Dose-Response Relationship, Drug Electric Countershock - instrumentation Electrocardiography Flecainide - pharmacology Humans Ion Channel Gating - drug effects Lidocaine - pharmacology Male Mice Mice, Knockout Mutation, Missense Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Procainamide - pharmacology Propafenone - pharmacology Ryanodine Receptor Calcium Release Channel - drug effects Ryanodine Receptor Calcium Release Channel - genetics Ryanodine Receptor Calcium Release Channel - metabolism Sodium Channel Blockers - pharmacology Tachycardia, Ventricular - drug therapy Tachycardia, Ventricular - genetics Tachycardia, Ventricular - metabolism Tachycardia, Ventricular - physiopathology Time Factors Young Adult |
| title | Inhibition of Cardiac Ca2+ Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia |
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