Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry
Abstract Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to un...
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| Veröffentlicht in: | European heart journal 2019-09, Vol.40 (35), p.2964-2975 |
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| creator | Crotti, Lia Spazzolini, Carla Tester, David J Ghidoni, Alice Baruteau, Alban-Elouen Beckmann, Britt-Maria Behr, Elijah R Bennett, Jeffrey S Bezzina, Connie R Bhuiyan, Zahurul A Celiker, Alpay Cerrone, Marina Dagradi, Federica De Ferrari, Gaetano M Etheridge, Susan P Fatah, Meena Garcia-Pavia, Pablo Al-Ghamdi, Saleh Hamilton, Robert M Al-Hassnan, Zuhair N Horie, Minoru Jimenez-Jaimez, Juan Kanter, Ronald J Kaski, Juan P Kotta, Maria-Christina Lahrouchi, Najim Makita, Naomasa Norrish, Gabrielle Odland, Hans H Ohno, Seiko Papagiannis, John Parati, Gianfranco Sekarski, Nicole Tveten, Kristian Vatta, Matteo Webster, Gregory Wilde, Arthur A M Wojciak, Julianne George, Alfred L Ackerman, Michael J Schwartz, Peter J |
| description | Abstract
Aims
Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.
Methods and results
A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.
Conclusion
Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered. |
| doi_str_mv | 10.1093/eurheartj/ehz311 |
| format | Article |
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Aims
Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.
Methods and results
A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.
Conclusion
Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.</description><identifier>ISSN: 0195-668X</identifier><identifier>EISSN: 1522-9645</identifier><identifier>DOI: 10.1093/eurheartj/ehz311</identifier><identifier>PMID: 31170290</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Age of Onset ; Arrhythmias, Cardiac - genetics ; Arrhythmias, Cardiac - mortality ; Calmodulin - genetics ; Child ; Child, Preschool ; Clinical Research ; Death, Sudden, Cardiac - etiology ; DNA Mutational Analysis ; Female ; Genetic Variation - genetics ; Humans ; Long QT Syndrome - genetics ; Phenotype ; Registries ; Survival Rate ; Tachycardia, Ventricular - genetics</subject><ispartof>European heart journal, 2019-09, Vol.40 (35), p.2964-2975</ispartof><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com. 2019</rights><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-daea46771bc1b672fc46d9f9a9d5e6d73f764d0683daade7286a42185abff5443</citedby><cites>FETCH-LOGICAL-c498t-daea46771bc1b672fc46d9f9a9d5e6d73f764d0683daade7286a42185abff5443</cites><orcidid>0000-0002-9029-2339 ; 0000-0002-3665-5661 ; 0000-0003-0367-1048</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31170290$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Crotti, Lia</creatorcontrib><creatorcontrib>Spazzolini, Carla</creatorcontrib><creatorcontrib>Tester, David J</creatorcontrib><creatorcontrib>Ghidoni, Alice</creatorcontrib><creatorcontrib>Baruteau, Alban-Elouen</creatorcontrib><creatorcontrib>Beckmann, Britt-Maria</creatorcontrib><creatorcontrib>Behr, Elijah R</creatorcontrib><creatorcontrib>Bennett, Jeffrey S</creatorcontrib><creatorcontrib>Bezzina, Connie R</creatorcontrib><creatorcontrib>Bhuiyan, Zahurul A</creatorcontrib><creatorcontrib>Celiker, Alpay</creatorcontrib><creatorcontrib>Cerrone, Marina</creatorcontrib><creatorcontrib>Dagradi, Federica</creatorcontrib><creatorcontrib>De Ferrari, Gaetano M</creatorcontrib><creatorcontrib>Etheridge, Susan P</creatorcontrib><creatorcontrib>Fatah, Meena</creatorcontrib><creatorcontrib>Garcia-Pavia, Pablo</creatorcontrib><creatorcontrib>Al-Ghamdi, Saleh</creatorcontrib><creatorcontrib>Hamilton, Robert M</creatorcontrib><creatorcontrib>Al-Hassnan, Zuhair N</creatorcontrib><creatorcontrib>Horie, Minoru</creatorcontrib><creatorcontrib>Jimenez-Jaimez, Juan</creatorcontrib><creatorcontrib>Kanter, Ronald J</creatorcontrib><creatorcontrib>Kaski, Juan P</creatorcontrib><creatorcontrib>Kotta, Maria-Christina</creatorcontrib><creatorcontrib>Lahrouchi, Najim</creatorcontrib><creatorcontrib>Makita, Naomasa</creatorcontrib><creatorcontrib>Norrish, Gabrielle</creatorcontrib><creatorcontrib>Odland, Hans H</creatorcontrib><creatorcontrib>Ohno, Seiko</creatorcontrib><creatorcontrib>Papagiannis, John</creatorcontrib><creatorcontrib>Parati, Gianfranco</creatorcontrib><creatorcontrib>Sekarski, Nicole</creatorcontrib><creatorcontrib>Tveten, Kristian</creatorcontrib><creatorcontrib>Vatta, Matteo</creatorcontrib><creatorcontrib>Webster, Gregory</creatorcontrib><creatorcontrib>Wilde, Arthur A M</creatorcontrib><creatorcontrib>Wojciak, Julianne</creatorcontrib><creatorcontrib>George, Alfred L</creatorcontrib><creatorcontrib>Ackerman, Michael J</creatorcontrib><creatorcontrib>Schwartz, Peter J</creatorcontrib><title>Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry</title><title>European heart journal</title><addtitle>Eur Heart J</addtitle><description>Abstract
Aims
Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.
Methods and results
A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.
Conclusion
Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.</description><subject>Age of Onset</subject><subject>Arrhythmias, Cardiac - genetics</subject><subject>Arrhythmias, Cardiac - mortality</subject><subject>Calmodulin - genetics</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Clinical Research</subject><subject>Death, Sudden, Cardiac - etiology</subject><subject>DNA Mutational Analysis</subject><subject>Female</subject><subject>Genetic Variation - genetics</subject><subject>Humans</subject><subject>Long QT Syndrome - genetics</subject><subject>Phenotype</subject><subject>Registries</subject><subject>Survival Rate</subject><subject>Tachycardia, Ventricular - genetics</subject><issn>0195-668X</issn><issn>1522-9645</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFrFTEQh4Mo9rV69yQ5CrI22c0mux4EeVgtFApFwVuYt5m8pOwmzyQrPv96t331qSdPc5hvvhnmR8gLzt5w1jfnOCeHkMrtObqfDeePyIq3dV31UrSPyYrxvq2k7L6ekNOcbxljneTyKTlZUMXqnq3IjzWMUzTz6AOd5gLFx5ApBENHb7EqLiEUDD5s6QDJeBgopOT2xU0e8lvqQ_ZbVzK1KU60OKSXoWAK9yIY6R993EFxe3qDW59L2j8jTyyMGZ8_1DPy5eLD5_Wn6ur64-X6_VU1iL4rlQEEIZXim4FvpKrtIKTpbQ-9aVEa1VglhWGyawyAQVV3EkTNuxY21rZCNGfk3cG7mzcTmgFDSTDqXfITpL2O4PW_neCd3sbvWirRKaEWwasHQYrfZsxFTz4POI4QMM5Z18sfeyaWzQvKDuiQYs4J7XENZ_ouMH0MTB8CW0Ze_n3eceB3Qgvw-gDEefd_3S9smqnp</recordid><startdate>20190914</startdate><enddate>20190914</enddate><creator>Crotti, Lia</creator><creator>Spazzolini, Carla</creator><creator>Tester, David J</creator><creator>Ghidoni, Alice</creator><creator>Baruteau, Alban-Elouen</creator><creator>Beckmann, Britt-Maria</creator><creator>Behr, Elijah R</creator><creator>Bennett, Jeffrey S</creator><creator>Bezzina, Connie R</creator><creator>Bhuiyan, Zahurul A</creator><creator>Celiker, Alpay</creator><creator>Cerrone, Marina</creator><creator>Dagradi, Federica</creator><creator>De Ferrari, Gaetano M</creator><creator>Etheridge, Susan P</creator><creator>Fatah, Meena</creator><creator>Garcia-Pavia, Pablo</creator><creator>Al-Ghamdi, Saleh</creator><creator>Hamilton, Robert M</creator><creator>Al-Hassnan, Zuhair N</creator><creator>Horie, Minoru</creator><creator>Jimenez-Jaimez, Juan</creator><creator>Kanter, Ronald J</creator><creator>Kaski, Juan P</creator><creator>Kotta, Maria-Christina</creator><creator>Lahrouchi, Najim</creator><creator>Makita, Naomasa</creator><creator>Norrish, Gabrielle</creator><creator>Odland, Hans H</creator><creator>Ohno, Seiko</creator><creator>Papagiannis, John</creator><creator>Parati, Gianfranco</creator><creator>Sekarski, Nicole</creator><creator>Tveten, Kristian</creator><creator>Vatta, Matteo</creator><creator>Webster, Gregory</creator><creator>Wilde, Arthur A M</creator><creator>Wojciak, Julianne</creator><creator>George, Alfred L</creator><creator>Ackerman, Michael J</creator><creator>Schwartz, Peter J</creator><general>Oxford University Press</general><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><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9029-2339</orcidid><orcidid>https://orcid.org/0000-0002-3665-5661</orcidid><orcidid>https://orcid.org/0000-0003-0367-1048</orcidid></search><sort><creationdate>20190914</creationdate><title>Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry</title><author>Crotti, Lia ; Spazzolini, Carla ; Tester, David J ; Ghidoni, Alice ; Baruteau, Alban-Elouen ; Beckmann, Britt-Maria ; Behr, Elijah R ; Bennett, Jeffrey S ; Bezzina, Connie R ; Bhuiyan, Zahurul A ; Celiker, Alpay ; Cerrone, Marina ; Dagradi, Federica ; De Ferrari, Gaetano M ; Etheridge, Susan P ; Fatah, Meena ; Garcia-Pavia, Pablo ; Al-Ghamdi, Saleh ; Hamilton, Robert M ; Al-Hassnan, Zuhair N ; Horie, Minoru ; Jimenez-Jaimez, Juan ; Kanter, Ronald J ; Kaski, Juan P ; Kotta, Maria-Christina ; Lahrouchi, Najim ; Makita, Naomasa ; Norrish, Gabrielle ; Odland, Hans H ; Ohno, Seiko ; Papagiannis, John ; Parati, Gianfranco ; Sekarski, Nicole ; Tveten, Kristian ; Vatta, Matteo ; Webster, Gregory ; Wilde, Arthur A M ; Wojciak, Julianne ; George, Alfred L ; Ackerman, Michael J ; Schwartz, Peter J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-daea46771bc1b672fc46d9f9a9d5e6d73f764d0683daade7286a42185abff5443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Age of Onset</topic><topic>Arrhythmias, Cardiac - genetics</topic><topic>Arrhythmias, Cardiac - mortality</topic><topic>Calmodulin - genetics</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Clinical Research</topic><topic>Death, Sudden, Cardiac - etiology</topic><topic>DNA Mutational Analysis</topic><topic>Female</topic><topic>Genetic Variation - genetics</topic><topic>Humans</topic><topic>Long QT Syndrome - genetics</topic><topic>Phenotype</topic><topic>Registries</topic><topic>Survival Rate</topic><topic>Tachycardia, Ventricular - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Crotti, Lia</creatorcontrib><creatorcontrib>Spazzolini, Carla</creatorcontrib><creatorcontrib>Tester, David J</creatorcontrib><creatorcontrib>Ghidoni, Alice</creatorcontrib><creatorcontrib>Baruteau, Alban-Elouen</creatorcontrib><creatorcontrib>Beckmann, Britt-Maria</creatorcontrib><creatorcontrib>Behr, Elijah R</creatorcontrib><creatorcontrib>Bennett, Jeffrey S</creatorcontrib><creatorcontrib>Bezzina, Connie R</creatorcontrib><creatorcontrib>Bhuiyan, Zahurul A</creatorcontrib><creatorcontrib>Celiker, Alpay</creatorcontrib><creatorcontrib>Cerrone, Marina</creatorcontrib><creatorcontrib>Dagradi, Federica</creatorcontrib><creatorcontrib>De Ferrari, Gaetano M</creatorcontrib><creatorcontrib>Etheridge, Susan P</creatorcontrib><creatorcontrib>Fatah, Meena</creatorcontrib><creatorcontrib>Garcia-Pavia, Pablo</creatorcontrib><creatorcontrib>Al-Ghamdi, Saleh</creatorcontrib><creatorcontrib>Hamilton, Robert M</creatorcontrib><creatorcontrib>Al-Hassnan, Zuhair N</creatorcontrib><creatorcontrib>Horie, Minoru</creatorcontrib><creatorcontrib>Jimenez-Jaimez, Juan</creatorcontrib><creatorcontrib>Kanter, Ronald J</creatorcontrib><creatorcontrib>Kaski, Juan P</creatorcontrib><creatorcontrib>Kotta, Maria-Christina</creatorcontrib><creatorcontrib>Lahrouchi, Najim</creatorcontrib><creatorcontrib>Makita, Naomasa</creatorcontrib><creatorcontrib>Norrish, Gabrielle</creatorcontrib><creatorcontrib>Odland, Hans H</creatorcontrib><creatorcontrib>Ohno, Seiko</creatorcontrib><creatorcontrib>Papagiannis, John</creatorcontrib><creatorcontrib>Parati, Gianfranco</creatorcontrib><creatorcontrib>Sekarski, Nicole</creatorcontrib><creatorcontrib>Tveten, Kristian</creatorcontrib><creatorcontrib>Vatta, Matteo</creatorcontrib><creatorcontrib>Webster, Gregory</creatorcontrib><creatorcontrib>Wilde, Arthur A M</creatorcontrib><creatorcontrib>Wojciak, Julianne</creatorcontrib><creatorcontrib>George, Alfred L</creatorcontrib><creatorcontrib>Ackerman, Michael J</creatorcontrib><creatorcontrib>Schwartz, Peter J</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>European heart journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Crotti, Lia</au><au>Spazzolini, Carla</au><au>Tester, David J</au><au>Ghidoni, Alice</au><au>Baruteau, Alban-Elouen</au><au>Beckmann, Britt-Maria</au><au>Behr, Elijah R</au><au>Bennett, Jeffrey S</au><au>Bezzina, Connie R</au><au>Bhuiyan, Zahurul A</au><au>Celiker, Alpay</au><au>Cerrone, Marina</au><au>Dagradi, Federica</au><au>De Ferrari, Gaetano M</au><au>Etheridge, Susan P</au><au>Fatah, Meena</au><au>Garcia-Pavia, Pablo</au><au>Al-Ghamdi, Saleh</au><au>Hamilton, Robert M</au><au>Al-Hassnan, Zuhair N</au><au>Horie, Minoru</au><au>Jimenez-Jaimez, Juan</au><au>Kanter, Ronald J</au><au>Kaski, Juan P</au><au>Kotta, Maria-Christina</au><au>Lahrouchi, Najim</au><au>Makita, Naomasa</au><au>Norrish, Gabrielle</au><au>Odland, Hans H</au><au>Ohno, Seiko</au><au>Papagiannis, John</au><au>Parati, Gianfranco</au><au>Sekarski, Nicole</au><au>Tveten, Kristian</au><au>Vatta, Matteo</au><au>Webster, Gregory</au><au>Wilde, Arthur A M</au><au>Wojciak, Julianne</au><au>George, Alfred L</au><au>Ackerman, Michael J</au><au>Schwartz, Peter J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry</atitle><jtitle>European heart journal</jtitle><addtitle>Eur Heart J</addtitle><date>2019-09-14</date><risdate>2019</risdate><volume>40</volume><issue>35</issue><spage>2964</spage><epage>2975</epage><pages>2964-2975</pages><issn>0195-668X</issn><eissn>1522-9645</eissn><abstract>Abstract
Aims
Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.
Methods and results
A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.
Conclusion
Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>31170290</pmid><doi>10.1093/eurheartj/ehz311</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-9029-2339</orcidid><orcidid>https://orcid.org/0000-0002-3665-5661</orcidid><orcidid>https://orcid.org/0000-0003-0367-1048</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0195-668X |
| ispartof | European heart journal, 2019-09, Vol.40 (35), p.2964-2975 |
| issn | 0195-668X 1522-9645 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6748747 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Age of Onset Arrhythmias, Cardiac - genetics Arrhythmias, Cardiac - mortality Calmodulin - genetics Child Child, Preschool Clinical Research Death, Sudden, Cardiac - etiology DNA Mutational Analysis Female Genetic Variation - genetics Humans Long QT Syndrome - genetics Phenotype Registries Survival Rate Tachycardia, Ventricular - genetics |
| title | Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T01%3A25%3A39IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Calmodulin%20mutations%20and%20life-threatening%20cardiac%20arrhythmias:%20insights%20from%20the%20International%20Calmodulinopathy%20Registry&rft.jtitle=European%20heart%20journal&rft.au=Crotti,%20Lia&rft.date=2019-09-14&rft.volume=40&rft.issue=35&rft.spage=2964&rft.epage=2975&rft.pages=2964-2975&rft.issn=0195-668X&rft.eissn=1522-9645&rft_id=info:doi/10.1093/eurheartj/ehz311&rft_dat=%3Cproquest_pubme%3E2290904728%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2290904728&rft_id=info:pmid/31170290&rft_oup_id=10.1093/eurheartj/ehz311&rfr_iscdi=true |