Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy
Abstract Aims The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. Methods and results...
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| Veröffentlicht in: | European heart journal 2021-08, Vol.42 (32), p.3063-3073 |
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| creator | Lopes, Luis R Garcia-Hernández, Soledad Lorenzini, Massimiliano Futema, Marta Chumakova, Olga Zateyshchikov, Dmitry Isidoro-Garcia, Maria Villacorta, Eduardo Escobar-Lopez, Luis Garcia-Pavia, Pablo Bilbao, Raquel Dobarro, David Sandin-Fuentes, Maria Catalli, Claudio Gener Querol, Blanca Mezcua, Ainhoa Garcia Pinilla, Jose Bloch Rasmussen, Torsten Ferreira-Aguar, Ana Revilla-Martí, Pablo Basurte Elorz, Maria Teresa Bautista Paves, Alicia Ramon Gimeno, Juan Figueroa, Ana Virginia Franco-Gutierrez, Raul Fuentes-Cañamero, Maria Eugenia Martinez Moreno, Marina Ortiz-Genga, Martin Piqueras-Flores, Jesus Analia Ramos, Karina Rudzitis, Ainars Ruiz-Guerrero, Luis Stein, Ricardo Triguero-Bocharán, Mayte de la Higuera, Luis Ochoa, Juan Pablo Abu-Bonsrah, Dad Kwok, Cecilia Y T Smith, Jacob B Porrello, Enzo R Akhtar, Mohammed M Jager, Joanna Ashworth, Michael Syrris, Petros Elliott, David A Monserrat, Lorenzo Elliott, Perry M |
| description | Abstract
Aims
The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.
Methods and results
In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P |
| doi_str_mv | 10.1093/eurheartj/ehab424 |
| format | Article |
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Aims
The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.
Methods and results
In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.
Conclusions
Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
Graphical Abstract
Truncating variants in ALPK3 are a cause of 1–2% of autosomal dominant hypertrophic cardiomyopathy and are associated with a phenotype characterized by extensive fibrosis and a predominantly concentric or apical pattern of left ventricular hypertrophy without left ventricular outflow tract obstruction. (A) Main phenotype characteristics and outcomes. ALPK3tv, alpha-protein kinase 3-truncating variants; CK, creatine kinase; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter–defibrillator; LVH, left ventricular hypertrophy; LVSD, left ventricular systolic dysfunction; SCD, sudden cardiac death. (B) Cardiac magnetic resonance imaging showing the prevalent phenotype of severe mid to apical hypertrophy and extensive late gadolinium enhancement in three patients. Left to right: 4-chamber view end-diastole cine image, 4-chamber view late gadolinium enhancement image, short axis late gadolinium enhancement image. (C) Kaplan–Meier analysis comparing incidence of an outcome of heart failure death and transplant between ALP3tv patients, sarcomere positive and sarcomere negative. SARC+: sarcomere positive; SARC−: sarcomere negative.</description><identifier>ISSN: 0195-668X</identifier><identifier>EISSN: 1522-9645</identifier><identifier>DOI: 10.1093/eurheartj/ehab424</identifier><identifier>PMID: 34263907</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Cardiomyopathy, Hypertrophic - genetics ; Clinical Research ; Heterozygote ; Humans ; Muscle Proteins - genetics ; Mutation ; Protein Kinases - genetics ; Sarcomeres</subject><ispartof>European heart journal, 2021-08, Vol.42 (32), p.3063-3073</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-30df286920ca09f8d97b85240b63faf2d85fe70f5bde022e737c10d549bd364d3</citedby><cites>FETCH-LOGICAL-c436t-30df286920ca09f8d97b85240b63faf2d85fe70f5bde022e737c10d549bd364d3</cites><orcidid>0000-0003-2517-7227 ; 0000-0003-2290-0838 ; 0000-0002-1831-7853 ; 0000-0001-7453-7896 ; 0000-0002-1419-0779 ; 0000-0002-6408-4667 ; 0000-0002-6272-2717 ; 0000-0002-2363-8758 ; 0000-0003-3383-3984 ; 0000-0001-7065-2045 ; 0000-0002-4354-7263 ; 0000-0001-5776-0623 ; 0000-0002-2687-3526 ; 0000-0001-6105-7463 ; 0000-0003-0486-1740 ; 0000-0003-1468-7248 ; 0000-0001-6212-9959 ; 0000-0003-3447-6376</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34263907$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lopes, Luis R</creatorcontrib><creatorcontrib>Garcia-Hernández, Soledad</creatorcontrib><creatorcontrib>Lorenzini, Massimiliano</creatorcontrib><creatorcontrib>Futema, Marta</creatorcontrib><creatorcontrib>Chumakova, Olga</creatorcontrib><creatorcontrib>Zateyshchikov, Dmitry</creatorcontrib><creatorcontrib>Isidoro-Garcia, Maria</creatorcontrib><creatorcontrib>Villacorta, Eduardo</creatorcontrib><creatorcontrib>Escobar-Lopez, Luis</creatorcontrib><creatorcontrib>Garcia-Pavia, Pablo</creatorcontrib><creatorcontrib>Bilbao, Raquel</creatorcontrib><creatorcontrib>Dobarro, David</creatorcontrib><creatorcontrib>Sandin-Fuentes, Maria</creatorcontrib><creatorcontrib>Catalli, Claudio</creatorcontrib><creatorcontrib>Gener Querol, Blanca</creatorcontrib><creatorcontrib>Mezcua, Ainhoa</creatorcontrib><creatorcontrib>Garcia Pinilla, Jose</creatorcontrib><creatorcontrib>Bloch Rasmussen, Torsten</creatorcontrib><creatorcontrib>Ferreira-Aguar, Ana</creatorcontrib><creatorcontrib>Revilla-Martí, Pablo</creatorcontrib><creatorcontrib>Basurte Elorz, Maria Teresa</creatorcontrib><creatorcontrib>Bautista Paves, Alicia</creatorcontrib><creatorcontrib>Ramon Gimeno, Juan</creatorcontrib><creatorcontrib>Figueroa, Ana Virginia</creatorcontrib><creatorcontrib>Franco-Gutierrez, Raul</creatorcontrib><creatorcontrib>Fuentes-Cañamero, Maria Eugenia</creatorcontrib><creatorcontrib>Martinez Moreno, Marina</creatorcontrib><creatorcontrib>Ortiz-Genga, Martin</creatorcontrib><creatorcontrib>Piqueras-Flores, Jesus</creatorcontrib><creatorcontrib>Analia Ramos, Karina</creatorcontrib><creatorcontrib>Rudzitis, Ainars</creatorcontrib><creatorcontrib>Ruiz-Guerrero, Luis</creatorcontrib><creatorcontrib>Stein, Ricardo</creatorcontrib><creatorcontrib>Triguero-Bocharán, Mayte</creatorcontrib><creatorcontrib>de la Higuera, Luis</creatorcontrib><creatorcontrib>Ochoa, Juan Pablo</creatorcontrib><creatorcontrib>Abu-Bonsrah, Dad</creatorcontrib><creatorcontrib>Kwok, Cecilia Y T</creatorcontrib><creatorcontrib>Smith, Jacob B</creatorcontrib><creatorcontrib>Porrello, Enzo R</creatorcontrib><creatorcontrib>Akhtar, Mohammed M</creatorcontrib><creatorcontrib>Jager, Joanna</creatorcontrib><creatorcontrib>Ashworth, Michael</creatorcontrib><creatorcontrib>Syrris, Petros</creatorcontrib><creatorcontrib>Elliott, David A</creatorcontrib><creatorcontrib>Monserrat, Lorenzo</creatorcontrib><creatorcontrib>Elliott, Perry M</creatorcontrib><title>Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy</title><title>European heart journal</title><addtitle>Eur Heart J</addtitle><description>Abstract
Aims
The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.
Methods and results
In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.
Conclusions
Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
Graphical Abstract
Truncating variants in ALPK3 are a cause of 1–2% of autosomal dominant hypertrophic cardiomyopathy and are associated with a phenotype characterized by extensive fibrosis and a predominantly concentric or apical pattern of left ventricular hypertrophy without left ventricular outflow tract obstruction. (A) Main phenotype characteristics and outcomes. ALPK3tv, alpha-protein kinase 3-truncating variants; CK, creatine kinase; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter–defibrillator; LVH, left ventricular hypertrophy; LVSD, left ventricular systolic dysfunction; SCD, sudden cardiac death. (B) Cardiac magnetic resonance imaging showing the prevalent phenotype of severe mid to apical hypertrophy and extensive late gadolinium enhancement in three patients. Left to right: 4-chamber view end-diastole cine image, 4-chamber view late gadolinium enhancement image, short axis late gadolinium enhancement image. (C) Kaplan–Meier analysis comparing incidence of an outcome of heart failure death and transplant between ALP3tv patients, sarcomere positive and sarcomere negative. 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kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy</title><author>Lopes, Luis R ; Garcia-Hernández, Soledad ; Lorenzini, Massimiliano ; Futema, Marta ; Chumakova, Olga ; Zateyshchikov, Dmitry ; Isidoro-Garcia, Maria ; Villacorta, Eduardo ; Escobar-Lopez, Luis ; Garcia-Pavia, Pablo ; Bilbao, Raquel ; Dobarro, David ; Sandin-Fuentes, Maria ; Catalli, Claudio ; Gener Querol, Blanca ; Mezcua, Ainhoa ; Garcia Pinilla, Jose ; Bloch Rasmussen, Torsten ; Ferreira-Aguar, Ana ; Revilla-Martí, Pablo ; Basurte Elorz, Maria Teresa ; Bautista Paves, Alicia ; Ramon Gimeno, Juan ; Figueroa, Ana Virginia ; Franco-Gutierrez, Raul ; Fuentes-Cañamero, Maria Eugenia ; Martinez Moreno, Marina ; Ortiz-Genga, Martin ; Piqueras-Flores, Jesus ; Analia Ramos, Karina ; Rudzitis, Ainars ; Ruiz-Guerrero, Luis ; Stein, Ricardo ; Triguero-Bocharán, Mayte ; de la Higuera, Luis ; Ochoa, Juan Pablo ; Abu-Bonsrah, Dad ; Kwok, Cecilia Y T ; Smith, Jacob B ; Porrello, Enzo R ; Akhtar, Mohammed M ; Jager, Joanna ; Ashworth, Michael ; Syrris, Petros ; Elliott, David A ; Monserrat, Lorenzo ; Elliott, Perry M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c436t-30df286920ca09f8d97b85240b63faf2d85fe70f5bde022e737c10d549bd364d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Cardiomyopathy, Hypertrophic - genetics</topic><topic>Clinical Research</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Muscle Proteins - genetics</topic><topic>Mutation</topic><topic>Protein Kinases - genetics</topic><topic>Sarcomeres</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lopes, Luis R</creatorcontrib><creatorcontrib>Garcia-Hernández, Soledad</creatorcontrib><creatorcontrib>Lorenzini, Massimiliano</creatorcontrib><creatorcontrib>Futema, Marta</creatorcontrib><creatorcontrib>Chumakova, Olga</creatorcontrib><creatorcontrib>Zateyshchikov, Dmitry</creatorcontrib><creatorcontrib>Isidoro-Garcia, Maria</creatorcontrib><creatorcontrib>Villacorta, Eduardo</creatorcontrib><creatorcontrib>Escobar-Lopez, Luis</creatorcontrib><creatorcontrib>Garcia-Pavia, Pablo</creatorcontrib><creatorcontrib>Bilbao, Raquel</creatorcontrib><creatorcontrib>Dobarro, David</creatorcontrib><creatorcontrib>Sandin-Fuentes, Maria</creatorcontrib><creatorcontrib>Catalli, Claudio</creatorcontrib><creatorcontrib>Gener Querol, Blanca</creatorcontrib><creatorcontrib>Mezcua, Ainhoa</creatorcontrib><creatorcontrib>Garcia Pinilla, Jose</creatorcontrib><creatorcontrib>Bloch Rasmussen, Torsten</creatorcontrib><creatorcontrib>Ferreira-Aguar, Ana</creatorcontrib><creatorcontrib>Revilla-Martí, Pablo</creatorcontrib><creatorcontrib>Basurte Elorz, Maria Teresa</creatorcontrib><creatorcontrib>Bautista Paves, Alicia</creatorcontrib><creatorcontrib>Ramon Gimeno, Juan</creatorcontrib><creatorcontrib>Figueroa, Ana Virginia</creatorcontrib><creatorcontrib>Franco-Gutierrez, Raul</creatorcontrib><creatorcontrib>Fuentes-Cañamero, Maria Eugenia</creatorcontrib><creatorcontrib>Martinez Moreno, Marina</creatorcontrib><creatorcontrib>Ortiz-Genga, Martin</creatorcontrib><creatorcontrib>Piqueras-Flores, Jesus</creatorcontrib><creatorcontrib>Analia Ramos, Karina</creatorcontrib><creatorcontrib>Rudzitis, Ainars</creatorcontrib><creatorcontrib>Ruiz-Guerrero, Luis</creatorcontrib><creatorcontrib>Stein, Ricardo</creatorcontrib><creatorcontrib>Triguero-Bocharán, Mayte</creatorcontrib><creatorcontrib>de la Higuera, Luis</creatorcontrib><creatorcontrib>Ochoa, Juan Pablo</creatorcontrib><creatorcontrib>Abu-Bonsrah, Dad</creatorcontrib><creatorcontrib>Kwok, Cecilia Y T</creatorcontrib><creatorcontrib>Smith, Jacob B</creatorcontrib><creatorcontrib>Porrello, Enzo R</creatorcontrib><creatorcontrib>Akhtar, Mohammed M</creatorcontrib><creatorcontrib>Jager, Joanna</creatorcontrib><creatorcontrib>Ashworth, Michael</creatorcontrib><creatorcontrib>Syrris, Petros</creatorcontrib><creatorcontrib>Elliott, David A</creatorcontrib><creatorcontrib>Monserrat, Lorenzo</creatorcontrib><creatorcontrib>Elliott, Perry M</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><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>Lopes, Luis R</au><au>Garcia-Hernández, Soledad</au><au>Lorenzini, Massimiliano</au><au>Futema, Marta</au><au>Chumakova, Olga</au><au>Zateyshchikov, Dmitry</au><au>Isidoro-Garcia, Maria</au><au>Villacorta, Eduardo</au><au>Escobar-Lopez, Luis</au><au>Garcia-Pavia, Pablo</au><au>Bilbao, Raquel</au><au>Dobarro, David</au><au>Sandin-Fuentes, Maria</au><au>Catalli, Claudio</au><au>Gener Querol, Blanca</au><au>Mezcua, Ainhoa</au><au>Garcia Pinilla, Jose</au><au>Bloch Rasmussen, Torsten</au><au>Ferreira-Aguar, Ana</au><au>Revilla-Martí, Pablo</au><au>Basurte Elorz, Maria Teresa</au><au>Bautista Paves, Alicia</au><au>Ramon Gimeno, Juan</au><au>Figueroa, Ana Virginia</au><au>Franco-Gutierrez, Raul</au><au>Fuentes-Cañamero, Maria Eugenia</au><au>Martinez Moreno, Marina</au><au>Ortiz-Genga, Martin</au><au>Piqueras-Flores, Jesus</au><au>Analia Ramos, Karina</au><au>Rudzitis, Ainars</au><au>Ruiz-Guerrero, Luis</au><au>Stein, Ricardo</au><au>Triguero-Bocharán, Mayte</au><au>de la Higuera, Luis</au><au>Ochoa, Juan Pablo</au><au>Abu-Bonsrah, Dad</au><au>Kwok, Cecilia Y T</au><au>Smith, Jacob B</au><au>Porrello, Enzo R</au><au>Akhtar, Mohammed M</au><au>Jager, Joanna</au><au>Ashworth, Michael</au><au>Syrris, Petros</au><au>Elliott, David A</au><au>Monserrat, Lorenzo</au><au>Elliott, Perry M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy</atitle><jtitle>European heart journal</jtitle><addtitle>Eur Heart J</addtitle><date>2021-08-21</date><risdate>2021</risdate><volume>42</volume><issue>32</issue><spage>3063</spage><epage>3073</epage><pages>3063-3073</pages><issn>0195-668X</issn><eissn>1522-9645</eissn><abstract>Abstract
Aims
The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.
Methods and results
In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.
Conclusions
Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
Graphical Abstract
Truncating variants in ALPK3 are a cause of 1–2% of autosomal dominant hypertrophic cardiomyopathy and are associated with a phenotype characterized by extensive fibrosis and a predominantly concentric or apical pattern of left ventricular hypertrophy without left ventricular outflow tract obstruction. (A) Main phenotype characteristics and outcomes. ALPK3tv, alpha-protein kinase 3-truncating variants; CK, creatine kinase; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter–defibrillator; LVH, left ventricular hypertrophy; LVSD, left ventricular systolic dysfunction; SCD, sudden cardiac death. (B) Cardiac magnetic resonance imaging showing the prevalent phenotype of severe mid to apical hypertrophy and extensive late gadolinium enhancement in three patients. Left to right: 4-chamber view end-diastole cine image, 4-chamber view late gadolinium enhancement image, short axis late gadolinium enhancement image. (C) Kaplan–Meier analysis comparing incidence of an outcome of heart failure death and transplant between ALP3tv patients, sarcomere positive and sarcomere negative. SARC+: sarcomere positive; SARC−: sarcomere negative.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>34263907</pmid><doi>10.1093/eurheartj/ehab424</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-2517-7227</orcidid><orcidid>https://orcid.org/0000-0003-2290-0838</orcidid><orcidid>https://orcid.org/0000-0002-1831-7853</orcidid><orcidid>https://orcid.org/0000-0001-7453-7896</orcidid><orcidid>https://orcid.org/0000-0002-1419-0779</orcidid><orcidid>https://orcid.org/0000-0002-6408-4667</orcidid><orcidid>https://orcid.org/0000-0002-6272-2717</orcidid><orcidid>https://orcid.org/0000-0002-2363-8758</orcidid><orcidid>https://orcid.org/0000-0003-3383-3984</orcidid><orcidid>https://orcid.org/0000-0001-7065-2045</orcidid><orcidid>https://orcid.org/0000-0002-4354-7263</orcidid><orcidid>https://orcid.org/0000-0001-5776-0623</orcidid><orcidid>https://orcid.org/0000-0002-2687-3526</orcidid><orcidid>https://orcid.org/0000-0001-6105-7463</orcidid><orcidid>https://orcid.org/0000-0003-0486-1740</orcidid><orcidid>https://orcid.org/0000-0003-1468-7248</orcidid><orcidid>https://orcid.org/0000-0001-6212-9959</orcidid><orcidid>https://orcid.org/0000-0003-3447-6376</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0195-668X |
| ispartof | European heart journal, 2021-08, Vol.42 (32), p.3063-3073 |
| issn | 0195-668X 1522-9645 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8380059 |
| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Cardiomyopathy, Hypertrophic - genetics Clinical Research Heterozygote Humans Muscle Proteins - genetics Mutation Protein Kinases - genetics Sarcomeres |
| title | Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy |
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