Assessment of the causal relevance of ECG parameters for risk of atrial fibrillation: A mendelian randomisation study
Background Atrial electrical and structural remodelling in older individuals with cardiovascular risk factors has been associated with changes in surface electrocardiographic (ECG) parameters (e.g., prolongation of the PR interval) and higher risks of atrial fibrillation (AF). However, it has been d...
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| Veröffentlicht in: | PLoS medicine 2021-05, Vol.18 (5), p.e1003572-e1003572, Article 1003572 |
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| creator | Gajendragadkar, Parag Ravindra Von Ende, Adam Ibrahim, Maysson Valdes-Marquez, Elsa Camm, Christian Fielder Murgia, Federico Stiby, Alexander Casadei, Barbara Hopewell, Jemma C. |
| description | Background Atrial electrical and structural remodelling in older individuals with cardiovascular risk factors has been associated with changes in surface electrocardiographic (ECG) parameters (e.g., prolongation of the PR interval) and higher risks of atrial fibrillation (AF). However, it has been difficult to establish whether altered ECG parameters are the cause or a consequence of the myocardial substrate leading to AF. This study aimed to examine the potential causal relevance of ECG parameters on risk of AF using mendelian randomisation (MR).
Methods and findings Weighted genetic scores explaining lifelong differences in P-wave duration, PR interval, and QT interval were constructed, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases). The independent genetic variants contributing to each of the separate ECG scores, and their corresponding weights, were based on published genome-wide association studies. In UK Biobank, genetic scores representing a 5 ms longer P-wave duration or PR interval were significantly associated with lower risks of AF (odds ratio [OR] 0.91; 95% confidence interval [CI]: 0.87-0.96, P = 2 x 10(-4) and OR 0.94; 95% CI: 0.93-0.96, P = 2 x 10(-19), respectively), while longer QT interval was not significantly associated with AF. These effects were independently replicated among a further 17,931 AF cases from the AFGen Consortium. Investigation of potential mechanistic pathways showed that differences in ECG parameters associated with specific ion channel genes had effects on risk of AF consistent with the overall scores, while the overall scores were not associated with changes in left atrial size. Limitations of the study included the inherent assumptions of MR, restriction to individuals of European ancestry, and possible restriction of results to the normal ECG ranges represented in UK Biobank.
Conclusions In UK Biobank, we observed evidence suggesting a causal relationship between lifelong differences in ECG parameters (particularly PR interval) that reflect longer atrial conduction times and a lower risk of AF. These findings, which appear to be independent of atrial size and concomitant cardiovascular comorbidity, support the relevance of varying mechanisms underpinning AF and indicate that more individualised treatment strategies warrant consideration.
Author summary
Why was this study done?
Atrial fibrillation (AF) |
| doi_str_mv | 10.1371/journal.pmed.1003572 |
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Methods and findings Weighted genetic scores explaining lifelong differences in P-wave duration, PR interval, and QT interval were constructed, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases). The independent genetic variants contributing to each of the separate ECG scores, and their corresponding weights, were based on published genome-wide association studies. In UK Biobank, genetic scores representing a 5 ms longer P-wave duration or PR interval were significantly associated with lower risks of AF (odds ratio [OR] 0.91; 95% confidence interval [CI]: 0.87-0.96, P = 2 x 10(-4) and OR 0.94; 95% CI: 0.93-0.96, P = 2 x 10(-19), respectively), while longer QT interval was not significantly associated with AF. These effects were independently replicated among a further 17,931 AF cases from the AFGen Consortium. Investigation of potential mechanistic pathways showed that differences in ECG parameters associated with specific ion channel genes had effects on risk of AF consistent with the overall scores, while the overall scores were not associated with changes in left atrial size. Limitations of the study included the inherent assumptions of MR, restriction to individuals of European ancestry, and possible restriction of results to the normal ECG ranges represented in UK Biobank.
Conclusions In UK Biobank, we observed evidence suggesting a causal relationship between lifelong differences in ECG parameters (particularly PR interval) that reflect longer atrial conduction times and a lower risk of AF. These findings, which appear to be independent of atrial size and concomitant cardiovascular comorbidity, support the relevance of varying mechanisms underpinning AF and indicate that more individualised treatment strategies warrant consideration.
Author summary
Why was this study done?
Atrial fibrillation (AF) is the most common arrhythmia worldwide and associated with higher risk of stroke, dementia, heart failure, and death. Incomplete understanding of the underlying substrates for AF has hampered therapeutic advances and effective risk stratification, with current anti-arrhythmic drug therapy and a variety of catheter ablation strategies for AF still showing high medium-term failure rates and no material effects on the risk of stroke. Observational studies have suggested associations between electrocardiographic (ECG) parameters and risk of AF, but these associations may be subject to confounding and reverse causality, and thus the causal relevance of ECG parameters for AF remains unclear.
What did the researchers do and find?
We used a mendelian randomisation (MR) approach to examine the potential causal relevance of lifelong differences in ECG parameters for AF among approximately 300,000 individuals in UK Biobank. Unexpectedly, we found evidence supporting a causal association between lifelong differences in ECG parameters representing longer atrial conduction times within the normal range and a lower risk of AF. The relationship between ECG parameters and AF appeared to be independent of atrial size and cardiovascular comorbidities.
What do these findings mean?
These findings further emphasise that substantial variation in the mechanisms underpinning AF exists and warrants the consideration of more individualised treatment strategies.</description><identifier>ISSN: 1549-1277</identifier><identifier>ISSN: 1549-1676</identifier><identifier>EISSN: 1549-1676</identifier><identifier>DOI: 10.1371/journal.pmed.1003572</identifier><identifier>PMID: 33983917</identifier><language>eng</language><publisher>SAN FRANCISCO: Public Library Science</publisher><subject>Aged ; Alleles ; Atrial fibrillation ; Atrial Fibrillation - epidemiology ; Atrial Fibrillation - genetics ; Biobanks ; Biology and Life Sciences ; Cardiac arrhythmia ; Cardiovascular disease ; Catheters ; Codes ; Congestive heart failure ; Coronary artery disease ; Diabetes mellitus ; Diagnosis ; Drug therapy ; EKG ; Electrocardiogram ; Electrocardiography ; Electrocardiography - statistics & numerical data ; Female ; Fibrillation ; General & Internal Medicine ; Genomes ; Heart failure ; Humans ; Hypertension ; Life Sciences & Biomedicine ; Magnetic resonance imaging ; Male ; Medicine and Health Sciences ; Medicine, General & Internal ; Mendelian Randomization Analysis ; Methods ; Middle Aged ; Observational studies ; Physical Sciences ; Prevalence ; Research and Analysis Methods ; Risk Assessment - methods ; Risk factors ; Science & Technology ; Statistics ; United Kingdom - epidemiology</subject><ispartof>PLoS medicine, 2021-05, Vol.18 (5), p.e1003572-e1003572, Article 1003572</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Gajendragadkar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Gajendragadkar et al 2021 Gajendragadkar et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>6</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000664389400001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c815t-445a48a32f036badf259a482d345363f7a214fc3db40fd68d0149e898d46be793</citedby><cites>FETCH-LOGICAL-c815t-445a48a32f036badf259a482d345363f7a214fc3db40fd68d0149e898d46be793</cites><orcidid>0000-0002-3870-8018 ; 0000-0003-0000-5664 ; 0000-0002-6801-1617 ; 0000-0002-3608-845X ; 0000-0003-2122-4225 ; 0000-0003-3312-0183 ; 0000-0003-0570-6750</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118296/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118296/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2108,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33983917$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ma, Ronald C. W.</contributor><creatorcontrib>Gajendragadkar, Parag Ravindra</creatorcontrib><creatorcontrib>Von Ende, Adam</creatorcontrib><creatorcontrib>Ibrahim, Maysson</creatorcontrib><creatorcontrib>Valdes-Marquez, Elsa</creatorcontrib><creatorcontrib>Camm, Christian Fielder</creatorcontrib><creatorcontrib>Murgia, Federico</creatorcontrib><creatorcontrib>Stiby, Alexander</creatorcontrib><creatorcontrib>Casadei, Barbara</creatorcontrib><creatorcontrib>Hopewell, Jemma C.</creatorcontrib><title>Assessment of the causal relevance of ECG parameters for risk of atrial fibrillation: A mendelian randomisation study</title><title>PLoS medicine</title><addtitle>PLOS MED</addtitle><addtitle>PLoS Med</addtitle><description>Background Atrial electrical and structural remodelling in older individuals with cardiovascular risk factors has been associated with changes in surface electrocardiographic (ECG) parameters (e.g., prolongation of the PR interval) and higher risks of atrial fibrillation (AF). However, it has been difficult to establish whether altered ECG parameters are the cause or a consequence of the myocardial substrate leading to AF. This study aimed to examine the potential causal relevance of ECG parameters on risk of AF using mendelian randomisation (MR).
Methods and findings Weighted genetic scores explaining lifelong differences in P-wave duration, PR interval, and QT interval were constructed, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases). The independent genetic variants contributing to each of the separate ECG scores, and their corresponding weights, were based on published genome-wide association studies. In UK Biobank, genetic scores representing a 5 ms longer P-wave duration or PR interval were significantly associated with lower risks of AF (odds ratio [OR] 0.91; 95% confidence interval [CI]: 0.87-0.96, P = 2 x 10(-4) and OR 0.94; 95% CI: 0.93-0.96, P = 2 x 10(-19), respectively), while longer QT interval was not significantly associated with AF. These effects were independently replicated among a further 17,931 AF cases from the AFGen Consortium. Investigation of potential mechanistic pathways showed that differences in ECG parameters associated with specific ion channel genes had effects on risk of AF consistent with the overall scores, while the overall scores were not associated with changes in left atrial size. Limitations of the study included the inherent assumptions of MR, restriction to individuals of European ancestry, and possible restriction of results to the normal ECG ranges represented in UK Biobank.
Conclusions In UK Biobank, we observed evidence suggesting a causal relationship between lifelong differences in ECG parameters (particularly PR interval) that reflect longer atrial conduction times and a lower risk of AF. These findings, which appear to be independent of atrial size and concomitant cardiovascular comorbidity, support the relevance of varying mechanisms underpinning AF and indicate that more individualised treatment strategies warrant consideration.
Author summary
Why was this study done?
Atrial fibrillation (AF) is the most common arrhythmia worldwide and associated with higher risk of stroke, dementia, heart failure, and death. Incomplete understanding of the underlying substrates for AF has hampered therapeutic advances and effective risk stratification, with current anti-arrhythmic drug therapy and a variety of catheter ablation strategies for AF still showing high medium-term failure rates and no material effects on the risk of stroke. Observational studies have suggested associations between electrocardiographic (ECG) parameters and risk of AF, but these associations may be subject to confounding and reverse causality, and thus the causal relevance of ECG parameters for AF remains unclear.
What did the researchers do and find?
We used a mendelian randomisation (MR) approach to examine the potential causal relevance of lifelong differences in ECG parameters for AF among approximately 300,000 individuals in UK Biobank. Unexpectedly, we found evidence supporting a causal association between lifelong differences in ECG parameters representing longer atrial conduction times within the normal range and a lower risk of AF. The relationship between ECG parameters and AF appeared to be independent of atrial size and cardiovascular comorbidities.
What do these findings mean?
These findings further emphasise that substantial variation in the mechanisms underpinning AF exists and warrants the consideration of more individualised treatment strategies.</description><subject>Aged</subject><subject>Alleles</subject><subject>Atrial fibrillation</subject><subject>Atrial Fibrillation - epidemiology</subject><subject>Atrial Fibrillation - genetics</subject><subject>Biobanks</subject><subject>Biology and Life Sciences</subject><subject>Cardiac arrhythmia</subject><subject>Cardiovascular disease</subject><subject>Catheters</subject><subject>Codes</subject><subject>Congestive heart failure</subject><subject>Coronary artery disease</subject><subject>Diabetes mellitus</subject><subject>Diagnosis</subject><subject>Drug therapy</subject><subject>EKG</subject><subject>Electrocardiogram</subject><subject>Electrocardiography</subject><subject>Electrocardiography - statistics & numerical data</subject><subject>Female</subject><subject>Fibrillation</subject><subject>General & Internal Medicine</subject><subject>Genomes</subject><subject>Heart failure</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Life Sciences & Biomedicine</subject><subject>Magnetic resonance imaging</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Medicine, General & Internal</subject><subject>Mendelian Randomization Analysis</subject><subject>Methods</subject><subject>Middle Aged</subject><subject>Observational studies</subject><subject>Physical Sciences</subject><subject>Prevalence</subject><subject>Research and Analysis Methods</subject><subject>Risk Assessment - methods</subject><subject>Risk factors</subject><subject>Science & Technology</subject><subject>Statistics</subject><subject>United Kingdom - epidemiology</subject><issn>1549-1277</issn><issn>1549-1676</issn><issn>1549-1676</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNqVk29v0zAQxiMEYmPwDRBEmoRAqMWOncTmBVJVjTFpYhL_3lpufG490rjYzmDfnsvaTivqi6G8iHX3u8fns58se07JmLKavrv0feh0O14twYwpIaysiwfZIS25HNGqrh5u10VdH2RPYrwkpJBEksfZAWNSMEnrw6yfxAgxLqFLubd5WkDe6D7qNg_QwpXuGhjiJ9PTfKWDXkKCEHPrQx5c_DmkdAoOcetmwbWtTs537_NJjooGWqe7POjO-KWLN6k8pt5cP80eWd1GeLb5H2XfP558m34anV-cnk0n56NG0DKNOC81F5oVlrBqpo0tSomBwjBesorZWheU24aZGSfWVMIQyiUIKQyvZlBLdpS9XOuuWh_VZmJRFSWnomSEMyTO1oTx-lKtglvqcK28duom4MNc6ZBc04LijRBlgcJE1NySWhYARFa2prWhRANqfdjs1s_wUhqcadDtjuhupnMLNfdXSlAqClmhwOuNQPC_eohJ4dgawKl24Puh70JIKnhFET3-B91_ug0113gA11mP-zaDqJpUFa8Io0QgNdpDzaEDbNJ3YB2Gd_jxHh4_A0vX7C14s1OATII_aY4PLaqzr1_-g_18f_bixy776g67AN2mRfRtPzzKuAvyNdgEH2MAe3uBlKjBedtJq8F5auM8LHtx9_Jvi7ZWQ0Csgd8w8zY2DtBbtxghBFtgQnJcETp16cYuU993CUvf3r-U_QXVKEeU</recordid><startdate>20210513</startdate><enddate>20210513</enddate><creator>Gajendragadkar, Parag Ravindra</creator><creator>Von Ende, Adam</creator><creator>Ibrahim, Maysson</creator><creator>Valdes-Marquez, Elsa</creator><creator>Camm, Christian Fielder</creator><creator>Murgia, Federico</creator><creator>Stiby, Alexander</creator><creator>Casadei, Barbara</creator><creator>Hopewell, Jemma C.</creator><general>Public Library Science</general><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><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>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><scope>CZK</scope><orcidid>https://orcid.org/0000-0002-3870-8018</orcidid><orcidid>https://orcid.org/0000-0003-0000-5664</orcidid><orcidid>https://orcid.org/0000-0002-6801-1617</orcidid><orcidid>https://orcid.org/0000-0002-3608-845X</orcidid><orcidid>https://orcid.org/0000-0003-2122-4225</orcidid><orcidid>https://orcid.org/0000-0003-3312-0183</orcidid><orcidid>https://orcid.org/0000-0003-0570-6750</orcidid></search><sort><creationdate>20210513</creationdate><title>Assessment of the causal relevance of ECG parameters for risk of atrial fibrillation: A mendelian randomisation study</title><author>Gajendragadkar, Parag Ravindra ; Von Ende, Adam ; Ibrahim, Maysson ; Valdes-Marquez, Elsa ; Camm, Christian Fielder ; Murgia, Federico ; Stiby, Alexander ; Casadei, Barbara ; Hopewell, Jemma C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c815t-445a48a32f036badf259a482d345363f7a214fc3db40fd68d0149e898d46be793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Aged</topic><topic>Alleles</topic><topic>Atrial fibrillation</topic><topic>Atrial Fibrillation - epidemiology</topic><topic>Atrial Fibrillation - genetics</topic><topic>Biobanks</topic><topic>Biology and Life Sciences</topic><topic>Cardiac arrhythmia</topic><topic>Cardiovascular disease</topic><topic>Catheters</topic><topic>Codes</topic><topic>Congestive heart failure</topic><topic>Coronary artery disease</topic><topic>Diabetes mellitus</topic><topic>Diagnosis</topic><topic>Drug therapy</topic><topic>EKG</topic><topic>Electrocardiogram</topic><topic>Electrocardiography</topic><topic>Electrocardiography - statistics & numerical data</topic><topic>Female</topic><topic>Fibrillation</topic><topic>General & Internal Medicine</topic><topic>Genomes</topic><topic>Heart failure</topic><topic>Humans</topic><topic>Hypertension</topic><topic>Life Sciences & Biomedicine</topic><topic>Magnetic resonance imaging</topic><topic>Male</topic><topic>Medicine and Health Sciences</topic><topic>Medicine, General & Internal</topic><topic>Mendelian Randomization Analysis</topic><topic>Methods</topic><topic>Middle Aged</topic><topic>Observational studies</topic><topic>Physical Sciences</topic><topic>Prevalence</topic><topic>Research and Analysis Methods</topic><topic>Risk Assessment - methods</topic><topic>Risk factors</topic><topic>Science & Technology</topic><topic>Statistics</topic><topic>United Kingdom - epidemiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gajendragadkar, Parag Ravindra</creatorcontrib><creatorcontrib>Von Ende, Adam</creatorcontrib><creatorcontrib>Ibrahim, Maysson</creatorcontrib><creatorcontrib>Valdes-Marquez, Elsa</creatorcontrib><creatorcontrib>Camm, Christian Fielder</creatorcontrib><creatorcontrib>Murgia, Federico</creatorcontrib><creatorcontrib>Stiby, Alexander</creatorcontrib><creatorcontrib>Casadei, Barbara</creatorcontrib><creatorcontrib>Hopewell, Jemma C.</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><collection>PLoS Medicine</collection><jtitle>PLoS medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gajendragadkar, Parag Ravindra</au><au>Von Ende, Adam</au><au>Ibrahim, Maysson</au><au>Valdes-Marquez, Elsa</au><au>Camm, Christian Fielder</au><au>Murgia, Federico</au><au>Stiby, Alexander</au><au>Casadei, Barbara</au><au>Hopewell, Jemma C.</au><au>Ma, Ronald C. W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Assessment of the causal relevance of ECG parameters for risk of atrial fibrillation: A mendelian randomisation study</atitle><jtitle>PLoS medicine</jtitle><stitle>PLOS MED</stitle><addtitle>PLoS Med</addtitle><date>2021-05-13</date><risdate>2021</risdate><volume>18</volume><issue>5</issue><spage>e1003572</spage><epage>e1003572</epage><pages>e1003572-e1003572</pages><artnum>1003572</artnum><issn>1549-1277</issn><issn>1549-1676</issn><eissn>1549-1676</eissn><abstract>Background Atrial electrical and structural remodelling in older individuals with cardiovascular risk factors has been associated with changes in surface electrocardiographic (ECG) parameters (e.g., prolongation of the PR interval) and higher risks of atrial fibrillation (AF). However, it has been difficult to establish whether altered ECG parameters are the cause or a consequence of the myocardial substrate leading to AF. This study aimed to examine the potential causal relevance of ECG parameters on risk of AF using mendelian randomisation (MR).
Methods and findings Weighted genetic scores explaining lifelong differences in P-wave duration, PR interval, and QT interval were constructed, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases). The independent genetic variants contributing to each of the separate ECG scores, and their corresponding weights, were based on published genome-wide association studies. In UK Biobank, genetic scores representing a 5 ms longer P-wave duration or PR interval were significantly associated with lower risks of AF (odds ratio [OR] 0.91; 95% confidence interval [CI]: 0.87-0.96, P = 2 x 10(-4) and OR 0.94; 95% CI: 0.93-0.96, P = 2 x 10(-19), respectively), while longer QT interval was not significantly associated with AF. These effects were independently replicated among a further 17,931 AF cases from the AFGen Consortium. Investigation of potential mechanistic pathways showed that differences in ECG parameters associated with specific ion channel genes had effects on risk of AF consistent with the overall scores, while the overall scores were not associated with changes in left atrial size. Limitations of the study included the inherent assumptions of MR, restriction to individuals of European ancestry, and possible restriction of results to the normal ECG ranges represented in UK Biobank.
Conclusions In UK Biobank, we observed evidence suggesting a causal relationship between lifelong differences in ECG parameters (particularly PR interval) that reflect longer atrial conduction times and a lower risk of AF. These findings, which appear to be independent of atrial size and concomitant cardiovascular comorbidity, support the relevance of varying mechanisms underpinning AF and indicate that more individualised treatment strategies warrant consideration.
Author summary
Why was this study done?
Atrial fibrillation (AF) is the most common arrhythmia worldwide and associated with higher risk of stroke, dementia, heart failure, and death. Incomplete understanding of the underlying substrates for AF has hampered therapeutic advances and effective risk stratification, with current anti-arrhythmic drug therapy and a variety of catheter ablation strategies for AF still showing high medium-term failure rates and no material effects on the risk of stroke. Observational studies have suggested associations between electrocardiographic (ECG) parameters and risk of AF, but these associations may be subject to confounding and reverse causality, and thus the causal relevance of ECG parameters for AF remains unclear.
What did the researchers do and find?
We used a mendelian randomisation (MR) approach to examine the potential causal relevance of lifelong differences in ECG parameters for AF among approximately 300,000 individuals in UK Biobank. Unexpectedly, we found evidence supporting a causal association between lifelong differences in ECG parameters representing longer atrial conduction times within the normal range and a lower risk of AF. The relationship between ECG parameters and AF appeared to be independent of atrial size and cardiovascular comorbidities.
What do these findings mean?
These findings further emphasise that substantial variation in the mechanisms underpinning AF exists and warrants the consideration of more individualised treatment strategies.</abstract><cop>SAN FRANCISCO</cop><pub>Public Library Science</pub><pmid>33983917</pmid><doi>10.1371/journal.pmed.1003572</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-3870-8018</orcidid><orcidid>https://orcid.org/0000-0003-0000-5664</orcidid><orcidid>https://orcid.org/0000-0002-6801-1617</orcidid><orcidid>https://orcid.org/0000-0002-3608-845X</orcidid><orcidid>https://orcid.org/0000-0003-2122-4225</orcidid><orcidid>https://orcid.org/0000-0003-3312-0183</orcidid><orcidid>https://orcid.org/0000-0003-0570-6750</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1549-1277 |
| ispartof | PLoS medicine, 2021-05, Vol.18 (5), p.e1003572-e1003572, Article 1003572 |
| issn | 1549-1277 1549-1676 1549-1676 |
| language | eng |
| recordid | cdi_plos_journals_2541853043 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central |
| subjects | Aged Alleles Atrial fibrillation Atrial Fibrillation - epidemiology Atrial Fibrillation - genetics Biobanks Biology and Life Sciences Cardiac arrhythmia Cardiovascular disease Catheters Codes Congestive heart failure Coronary artery disease Diabetes mellitus Diagnosis Drug therapy EKG Electrocardiogram Electrocardiography Electrocardiography - statistics & numerical data Female Fibrillation General & Internal Medicine Genomes Heart failure Humans Hypertension Life Sciences & Biomedicine Magnetic resonance imaging Male Medicine and Health Sciences Medicine, General & Internal Mendelian Randomization Analysis Methods Middle Aged Observational studies Physical Sciences Prevalence Research and Analysis Methods Risk Assessment - methods Risk factors Science & Technology Statistics United Kingdom - epidemiology |
| title | Assessment of the causal relevance of ECG parameters for risk of atrial fibrillation: A mendelian randomisation study |
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