Inhibition of the Na+ /Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3
Background Long QT syndrome (LQTS) is associated with sudden cardiac death resulting from torsades de pointes (TdP), which are triggered by early afterdepolarizations (EADs). The cardiac Na+ /Ca2+ exchanger (NCX) has been suggested to work as a trigger for EADs. Objective The purpose of this study w...
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| creator | Milberg, Peter, MD Pott, Christian, MD Fink, Martin, PhD Frommeyer, Gerrit, MS Matsuda, Toshio, PhD Baba, Akemichi, PhD Osada, Nani, PhD Breithardt, Günter, MD, FESC, FACC, FHRS Noble, Denis, PhD, CBE, FRS, FRCP (Hon) Eckardt, Lars, MD |
| description | Background Long QT syndrome (LQTS) is associated with sudden cardiac death resulting from torsades de pointes (TdP), which are triggered by early afterdepolarizations (EADs). The cardiac Na+ /Ca2+ exchanger (NCX) has been suggested to work as a trigger for EADs. Objective The purpose of this study was to test the hypothesis that inhibition of NCX with a newly developed selective NCX inhibitor (SEA0400) reduces TdP. Methods and Results In 34 Langendorff-perfused rabbit hearts, the IKr -blocker sotalol (100 μM; n = 18) as well as veratridine (0.5 μM; n = 16), an inhibitor of sodium channel inactivation, led to a significant increase in monophasic action potential (MAP) duration thereby mimicking LQTS2 and LQTS3. In bradycardic hearts, recordings of eight MAPs demonstrated an increased dispersion of repolarization (sotalol: 67%; veratridine: 89%; P |
| doi_str_mv | 10.1016/j.hrthm.2008.06.017 |
| format | Article |
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The cardiac Na+ /Ca2+ exchanger (NCX) has been suggested to work as a trigger for EADs. Objective The purpose of this study was to test the hypothesis that inhibition of NCX with a newly developed selective NCX inhibitor (SEA0400) reduces TdP. Methods and Results In 34 Langendorff-perfused rabbit hearts, the IKr -blocker sotalol (100 μM; n = 18) as well as veratridine (0.5 μM; n = 16), an inhibitor of sodium channel inactivation, led to a significant increase in monophasic action potential (MAP) duration thereby mimicking LQTS2 and LQTS3. In bradycardic hearts, recordings of eight MAPs demonstrated an increased dispersion of repolarization (sotalol: 67%; veratridine: 89%; P <.05). After lowering of potassium concentration, sotalol (56%) and veratridine (63%) induced TdP. Perfusion with SEA0400 (1 μM) suppressed EADs in 15 of 16 sotalol hearts and in seven of 13 veratridine hearts. SEA0400 significantly shortened MAP duration and reduced dispersion of repolarization in both groups ( P <.05). This reduced TdP incidence in the sotalol group (100%) and in the veratridine group (77%). To investigate the effects of NCX inhibition on the cellular level, we used a computer model of the rabbit ventricular myocyte. INa and IKr were modified to mimic the effects of veratridine and sotalol, respectively. Consistent with our in vitro experiments, reduction of NCX activity accelerated repolarization of the cellular action potential and prevented EADs. Conclusion In an intact rabbit heart model of LQT2 and LQT3 as well as in a computer model of the rabbit cardiac myocyte, inhibition of NCX is effective in preventing TdP due to a suppression of EADs, a reversion of action potential prolongation, and a reduction of dispersion of repolarization. Our observations suggest a therapeutic benefit of selective NCX inhibition in LQTS.</description><identifier>ISSN: 1547-5271</identifier><identifier>EISSN: 1556-3871</identifier><identifier>DOI: 10.1016/j.hrthm.2008.06.017</identifier><identifier>PMID: 18929333</identifier><language>eng</language><publisher>United States</publisher><subject>Aniline Compounds - pharmacology ; Animals ; Cardiovascular ; Disease Models, Animal ; Female ; Long QT Syndrome - classification ; Long QT Syndrome - prevention & control ; Muscle Cells - drug effects ; Phenyl Ethers - pharmacology ; Rabbits ; Sodium-Calcium Exchanger - metabolism ; Torsades de Pointes - prevention & control</subject><ispartof>Heart rhythm, 2008-10, Vol.5 (10), p.1444-1452</ispartof><rights>Heart Rhythm Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-b3620e795f669ef449a54717a45b443b57b9b4d4756c3c25e8712819edc54c8e3</citedby><cites>FETCH-LOGICAL-c354t-b3620e795f669ef449a54717a45b443b57b9b4d4756c3c25e8712819edc54c8e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27907,27908</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18929333$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Milberg, Peter, MD</creatorcontrib><creatorcontrib>Pott, Christian, MD</creatorcontrib><creatorcontrib>Fink, Martin, PhD</creatorcontrib><creatorcontrib>Frommeyer, Gerrit, MS</creatorcontrib><creatorcontrib>Matsuda, Toshio, PhD</creatorcontrib><creatorcontrib>Baba, Akemichi, PhD</creatorcontrib><creatorcontrib>Osada, Nani, PhD</creatorcontrib><creatorcontrib>Breithardt, Günter, MD, FESC, FACC, FHRS</creatorcontrib><creatorcontrib>Noble, Denis, PhD, CBE, FRS, FRCP (Hon)</creatorcontrib><creatorcontrib>Eckardt, Lars, MD</creatorcontrib><title>Inhibition of the Na+ /Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3</title><title>Heart rhythm</title><addtitle>Heart Rhythm</addtitle><description>Background Long QT syndrome (LQTS) is associated with sudden cardiac death resulting from torsades de pointes (TdP), which are triggered by early afterdepolarizations (EADs). The cardiac Na+ /Ca2+ exchanger (NCX) has been suggested to work as a trigger for EADs. Objective The purpose of this study was to test the hypothesis that inhibition of NCX with a newly developed selective NCX inhibitor (SEA0400) reduces TdP. Methods and Results In 34 Langendorff-perfused rabbit hearts, the IKr -blocker sotalol (100 μM; n = 18) as well as veratridine (0.5 μM; n = 16), an inhibitor of sodium channel inactivation, led to a significant increase in monophasic action potential (MAP) duration thereby mimicking LQTS2 and LQTS3. In bradycardic hearts, recordings of eight MAPs demonstrated an increased dispersion of repolarization (sotalol: 67%; veratridine: 89%; P <.05). After lowering of potassium concentration, sotalol (56%) and veratridine (63%) induced TdP. Perfusion with SEA0400 (1 μM) suppressed EADs in 15 of 16 sotalol hearts and in seven of 13 veratridine hearts. SEA0400 significantly shortened MAP duration and reduced dispersion of repolarization in both groups ( P <.05). This reduced TdP incidence in the sotalol group (100%) and in the veratridine group (77%). To investigate the effects of NCX inhibition on the cellular level, we used a computer model of the rabbit ventricular myocyte. INa and IKr were modified to mimic the effects of veratridine and sotalol, respectively. Consistent with our in vitro experiments, reduction of NCX activity accelerated repolarization of the cellular action potential and prevented EADs. Conclusion In an intact rabbit heart model of LQT2 and LQT3 as well as in a computer model of the rabbit cardiac myocyte, inhibition of NCX is effective in preventing TdP due to a suppression of EADs, a reversion of action potential prolongation, and a reduction of dispersion of repolarization. Our observations suggest a therapeutic benefit of selective NCX inhibition in LQTS.</description><subject>Aniline Compounds - pharmacology</subject><subject>Animals</subject><subject>Cardiovascular</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Long QT Syndrome - classification</subject><subject>Long QT Syndrome - prevention & control</subject><subject>Muscle Cells - drug effects</subject><subject>Phenyl Ethers - pharmacology</subject><subject>Rabbits</subject><subject>Sodium-Calcium Exchanger - metabolism</subject><subject>Torsades de Pointes - prevention & control</subject><issn>1547-5271</issn><issn>1556-3871</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNplkd2K1TAUhYsozjj6BILkypuhnfy3uRHk4M_AoIjjdUjT3WmObXJMUvG8gk9t6jnghTfJYrP2grW_qnpJcEMwkTf7Zop5WhqKcddg2WDSPqouiRCyZl1LHm-at7WgLbmonqW0x5gqidnT6oJ0iirG2GX1-9ZPrnfZBY_CiPIE6JO5Rjc7Q68R_LKT8Q8QUVoPhwgpQUI5xGSGIgZAh-B8LtJ5ZHx5s7EZTWBiRksYYN4i5-Af0Jd7lI5-iGGBmhbv8P-YPa-ejGZO8OL8X1Xf3r-7332s7z5_uN29vastEzzXPZMUQ6vEKKWCkXNlSk3SGi56zlkv2l71fOCtkJZZKqDcgnZEwWAFtx2wq-r1KfcQw48VUtaLSxbm2XgIa9JSyQ53ihQjOxltDClFGPUhusXEoyZYbwj0Xv9FoDcEGktdEJStV-f4tV9g-LdzvnkxvDkZoJT86SBqOzvvrJm_wxHSPqzRl_6a6EQ11l83ihtE3GEspezYH-6RmCk</recordid><startdate>20081001</startdate><enddate>20081001</enddate><creator>Milberg, Peter, MD</creator><creator>Pott, Christian, MD</creator><creator>Fink, Martin, PhD</creator><creator>Frommeyer, Gerrit, MS</creator><creator>Matsuda, Toshio, PhD</creator><creator>Baba, Akemichi, PhD</creator><creator>Osada, Nani, PhD</creator><creator>Breithardt, Günter, MD, FESC, FACC, FHRS</creator><creator>Noble, Denis, PhD, CBE, FRS, FRCP (Hon)</creator><creator>Eckardt, Lars, MD</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20081001</creationdate><title>Inhibition of the Na+ /Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3</title><author>Milberg, Peter, MD ; Pott, Christian, MD ; Fink, Martin, PhD ; Frommeyer, Gerrit, MS ; Matsuda, Toshio, PhD ; Baba, Akemichi, PhD ; Osada, Nani, PhD ; Breithardt, Günter, MD, FESC, FACC, FHRS ; Noble, Denis, PhD, CBE, FRS, FRCP (Hon) ; Eckardt, Lars, MD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-b3620e795f669ef449a54717a45b443b57b9b4d4756c3c25e8712819edc54c8e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Aniline Compounds - pharmacology</topic><topic>Animals</topic><topic>Cardiovascular</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Long QT Syndrome - classification</topic><topic>Long QT Syndrome - prevention & control</topic><topic>Muscle Cells - drug effects</topic><topic>Phenyl Ethers - pharmacology</topic><topic>Rabbits</topic><topic>Sodium-Calcium Exchanger - metabolism</topic><topic>Torsades de Pointes - prevention & control</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Milberg, Peter, MD</creatorcontrib><creatorcontrib>Pott, Christian, MD</creatorcontrib><creatorcontrib>Fink, Martin, PhD</creatorcontrib><creatorcontrib>Frommeyer, Gerrit, MS</creatorcontrib><creatorcontrib>Matsuda, Toshio, PhD</creatorcontrib><creatorcontrib>Baba, Akemichi, PhD</creatorcontrib><creatorcontrib>Osada, Nani, PhD</creatorcontrib><creatorcontrib>Breithardt, Günter, MD, FESC, FACC, FHRS</creatorcontrib><creatorcontrib>Noble, Denis, PhD, CBE, FRS, FRCP (Hon)</creatorcontrib><creatorcontrib>Eckardt, Lars, MD</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Heart rhythm</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Milberg, Peter, MD</au><au>Pott, Christian, MD</au><au>Fink, Martin, PhD</au><au>Frommeyer, Gerrit, MS</au><au>Matsuda, Toshio, PhD</au><au>Baba, Akemichi, PhD</au><au>Osada, Nani, PhD</au><au>Breithardt, Günter, MD, FESC, FACC, FHRS</au><au>Noble, Denis, PhD, CBE, FRS, FRCP (Hon)</au><au>Eckardt, Lars, MD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the Na+ /Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3</atitle><jtitle>Heart rhythm</jtitle><addtitle>Heart Rhythm</addtitle><date>2008-10-01</date><risdate>2008</risdate><volume>5</volume><issue>10</issue><spage>1444</spage><epage>1452</epage><pages>1444-1452</pages><issn>1547-5271</issn><eissn>1556-3871</eissn><abstract>Background Long QT syndrome (LQTS) is associated with sudden cardiac death resulting from torsades de pointes (TdP), which are triggered by early afterdepolarizations (EADs). The cardiac Na+ /Ca2+ exchanger (NCX) has been suggested to work as a trigger for EADs. Objective The purpose of this study was to test the hypothesis that inhibition of NCX with a newly developed selective NCX inhibitor (SEA0400) reduces TdP. Methods and Results In 34 Langendorff-perfused rabbit hearts, the IKr -blocker sotalol (100 μM; n = 18) as well as veratridine (0.5 μM; n = 16), an inhibitor of sodium channel inactivation, led to a significant increase in monophasic action potential (MAP) duration thereby mimicking LQTS2 and LQTS3. In bradycardic hearts, recordings of eight MAPs demonstrated an increased dispersion of repolarization (sotalol: 67%; veratridine: 89%; P <.05). After lowering of potassium concentration, sotalol (56%) and veratridine (63%) induced TdP. Perfusion with SEA0400 (1 μM) suppressed EADs in 15 of 16 sotalol hearts and in seven of 13 veratridine hearts. SEA0400 significantly shortened MAP duration and reduced dispersion of repolarization in both groups ( P <.05). This reduced TdP incidence in the sotalol group (100%) and in the veratridine group (77%). To investigate the effects of NCX inhibition on the cellular level, we used a computer model of the rabbit ventricular myocyte. INa and IKr were modified to mimic the effects of veratridine and sotalol, respectively. Consistent with our in vitro experiments, reduction of NCX activity accelerated repolarization of the cellular action potential and prevented EADs. Conclusion In an intact rabbit heart model of LQT2 and LQT3 as well as in a computer model of the rabbit cardiac myocyte, inhibition of NCX is effective in preventing TdP due to a suppression of EADs, a reversion of action potential prolongation, and a reduction of dispersion of repolarization. Our observations suggest a therapeutic benefit of selective NCX inhibition in LQTS.</abstract><cop>United States</cop><pmid>18929333</pmid><doi>10.1016/j.hrthm.2008.06.017</doi><tpages>9</tpages></addata></record> |
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| subjects | Aniline Compounds - pharmacology Animals Cardiovascular Disease Models, Animal Female Long QT Syndrome - classification Long QT Syndrome - prevention & control Muscle Cells - drug effects Phenyl Ethers - pharmacology Rabbits Sodium-Calcium Exchanger - metabolism Torsades de Pointes - prevention & control |
| title | Inhibition of the Na+ /Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3 |
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