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1. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Author

Joglar, José, Joglar, José, Chung, Mina, Armbruster, Anastasia, Benjamin, Emelia, Chyou, Janice, Cronin, Edmond, Deswal, Anita, Eckhardt, Lee, Goldberger, Zachary, Gopinathannair, Rakesh, Gorenek, Bulent, Hess, Paul, Hlatky, Mark, Hogan, Gail, Ibeh, Chinwe, Indik, Julia, Kido, Kazuhiko, Kusumoto, Fred, Link, Mark, Linta, Kathleen, McCarthy, Patrick, Patel, Nimesh, Patton, Kristen, Perez, Marco, Piccini, Jonathan, Russo, Andrea, Sanders, Prashanthan, Streur, Megan, Thomas, Kevin, Times, Sabrina, Tisdale, James, Valente, Anne, Van Wagoner, David, Marcus, Gregory, Joglar, José, Joglar, José, Chung, Mina, Armbruster, Anastasia, Benjamin, Emelia, Chyou, Janice, Cronin, Edmond, Deswal, Anita, Eckhardt, Lee, Goldberger, Zachary, Gopinathannair, Rakesh, Gorenek, Bulent, Hess, Paul, Hlatky, Mark, Hogan, Gail, Ibeh, Chinwe, Indik, Julia, Kido, Kazuhiko, Kusumoto, Fred, Link, Mark, Linta, Kathleen, McCarthy, Patrick, Patel, Nimesh, Patton, Kristen, Perez, Marco, Piccini, Jonathan, Russo, Andrea, Sanders, Prashanthan, Streur, Megan, Thomas, Kevin, Times, Sabrina, Tisdale, James, Valente, Anne, Van Wagoner, David, and Marcus, Gregory

Abstract

AIM: The 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation and the 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Published
2024

2. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Author

Joglar, José, Joglar, José, Chung, Mina, Armbruster, Anastasia, Benjamin, Emelia, Chyou, Janice, Cronin, Edmond, Deswal, Anita, Eckhardt, Lee, Goldberger, Zachary, Gopinathannair, Rakesh, Gorenek, Bulent, Hess, Paul, Hlatky, Mark, Hogan, Gail, Ibeh, Chinwe, Indik, Julia, Kido, Kazuhiko, Kusumoto, Fred, Link, Mark, Linta, Kathleen, McCarthy, Patrick, Patel, Nimesh, Patton, Kristen, Perez, Marco, Piccini, Jonathan, Russo, Andrea, Sanders, Prashanthan, Streur, Megan, Thomas, Kevin, Times, Sabrina, Tisdale, James, Valente, Anne, Van Wagoner, David, Marcus, Gregory, Joglar, José, Joglar, José, Chung, Mina, Armbruster, Anastasia, Benjamin, Emelia, Chyou, Janice, Cronin, Edmond, Deswal, Anita, Eckhardt, Lee, Goldberger, Zachary, Gopinathannair, Rakesh, Gorenek, Bulent, Hess, Paul, Hlatky, Mark, Hogan, Gail, Ibeh, Chinwe, Indik, Julia, Kido, Kazuhiko, Kusumoto, Fred, Link, Mark, Linta, Kathleen, McCarthy, Patrick, Patel, Nimesh, Patton, Kristen, Perez, Marco, Piccini, Jonathan, Russo, Andrea, Sanders, Prashanthan, Streur, Megan, Thomas, Kevin, Times, Sabrina, Tisdale, James, Valente, Anne, Van Wagoner, David, and Marcus, Gregory

Abstract

AIM: The 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation and the 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Published
2024

3. An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.

Author

Ng, Kevin, Ng, Kevin, Titus, Erron W, Lieve, Krystien V, Roston, Thomas M, Mazzanti, Andrea, Deiter, Frederick H, Denjoy, Isabelle, Ingles, Jodie, Till, Jan, Robyns, Tomas, Connors, Sean P, Steinberg, Christian, Abrams, Dominic J, Pang, Benjamin, Scheinman, Melvin M, Bos, J Martijn, Duffett, Stephen A, van der Werf, Christian, Maltret, Alice, Green, Martin S, Rutberg, Julie, Balaji, Seshadri, Cadrin-Tourigny, Julia, Orland, Kate M, Knight, Linda M, Brateng, Caitlin, Wu, Jeremy, Tang, Anthony S, Skanes, Allan C, Manlucu, Jaimie, Healey, Jeff S, January, Craig T, Krahn, Andrew D, Collins, Kathryn K, Maginot, Kathleen R, Fischbach, Peter, Etheridge, Susan P, Eckhardt, Lee L, Hamilton, Robert M, Ackerman, Michael J, Noguer, Ferran Rosés I, Semsarian, Christopher, Jura, Natalia, Leenhardt, Antoine, Gollob, Michael H, Priori, Silvia G, Sanatani, Shubhayan, Wilde, Arthur AM, Deo, Rahul C, Roberts, Jason D, Ng, Kevin, Ng, Kevin, Titus, Erron W, Lieve, Krystien V, Roston, Thomas M, Mazzanti, Andrea, Deiter, Frederick H, Denjoy, Isabelle, Ingles, Jodie, Till, Jan, Robyns, Tomas, Connors, Sean P, Steinberg, Christian, Abrams, Dominic J, Pang, Benjamin, Scheinman, Melvin M, Bos, J Martijn, Duffett, Stephen A, van der Werf, Christian, Maltret, Alice, Green, Martin S, Rutberg, Julie, Balaji, Seshadri, Cadrin-Tourigny, Julia, Orland, Kate M, Knight, Linda M, Brateng, Caitlin, Wu, Jeremy, Tang, Anthony S, Skanes, Allan C, Manlucu, Jaimie, Healey, Jeff S, January, Craig T, Krahn, Andrew D, Collins, Kathryn K, Maginot, Kathleen R, Fischbach, Peter, Etheridge, Susan P, Eckhardt, Lee L, Hamilton, Robert M, Ackerman, Michael J, Noguer, Ferran Rosés I, Semsarian, Christopher, Jura, Natalia, Leenhardt, Antoine, Gollob, Michael H, Priori, Silvia G, Sanatani, Shubhayan, Wilde, Arthur AM, Deo, Rahul C, and Roberts, Jason D

Abstract

BackgroundGenetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter collaboration.MethodsGenotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.ResultsA total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P<0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants loc

Published
2020

4. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias:Use the right tool for the right outcome, in the right population

Author

Nielsen, Jens Cosedis, Lin, Yenn Jiang, de Oliveira Figueiredo, Marcio Jansen, Shamloo, Alireza Sepehri, Alfie, Alberto, Boveda, Serge, Dagres, Nikolaos, Di Toro, Dario, Eckhardt, Lee L., Ellenbogen, Kenneth, Hardy, Carina, Ikeda, Takanori, Jaswal, Aparna, Kaufman, Elizabeth, Krahn, Andrew, Kusano, Kengo, Kutyifa, Valentina, Lim, Han S., Lip, Gregory Y.H., Nava-Townsend, Santiago, Pak, Hui Nam, Diez, Gerardo Rodríguez, Sauer, William, Saxena, Anil, Svendsen, Jesper Hastrup, Vanegas, Diego, Vaseghi, Marmar, Wilde, Arthur, Jared Bunch, T., Buxton, Alfred E., Calvimontes, Gonzalo, Chao, Tze Fan, Eckardt, Lars, Estner, Heidi, Gillis, Anne M., Isa, Rodrigo, Kautzner, Josef, Maury, Philippe, Moss, Joshua D., Nam, Gi Byung, Olshansky, Brian, Pava Molano, Luis Fernando, Pimentel, Mauricio, Prabhu, Mukund, Tzou, Wendy S., Sommer, Philipp, Swampillai, Janice, Vidal, Alejandro, Deneke, Thomas, Hindricks, Gerhard, Leclercq, Christophe, Nielsen, Jens Cosedis, Lin, Yenn Jiang, de Oliveira Figueiredo, Marcio Jansen, Shamloo, Alireza Sepehri, Alfie, Alberto, Boveda, Serge, Dagres, Nikolaos, Di Toro, Dario, Eckhardt, Lee L., Ellenbogen, Kenneth, Hardy, Carina, Ikeda, Takanori, Jaswal, Aparna, Kaufman, Elizabeth, Krahn, Andrew, Kusano, Kengo, Kutyifa, Valentina, Lim, Han S., Lip, Gregory Y.H., Nava-Townsend, Santiago, Pak, Hui Nam, Diez, Gerardo Rodríguez, Sauer, William, Saxena, Anil, Svendsen, Jesper Hastrup, Vanegas, Diego, Vaseghi, Marmar, Wilde, Arthur, Jared Bunch, T., Buxton, Alfred E., Calvimontes, Gonzalo, Chao, Tze Fan, Eckardt, Lars, Estner, Heidi, Gillis, Anne M., Isa, Rodrigo, Kautzner, Josef, Maury, Philippe, Moss, Joshua D., Nam, Gi Byung, Olshansky, Brian, Pava Molano, Luis Fernando, Pimentel, Mauricio, Prabhu, Mukund, Tzou, Wendy S., Sommer, Philipp, Swampillai, Janice, Vidal, Alejandro, Deneke, Thomas, Hindricks, Gerhard, and Leclercq, Christophe

Abstract

In clinical practice and for scientific purposes, cardiologists and primary care physicians perform risk assessment in patients with cardiac diseases or conditions with high risk of developing such. The European Heart Rhythm Association (EHRA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) set down this expert consensus statement task force to summarize the consensus regarding risk assessment in cardiac arrhythmias. Objectives were to raise awareness of using the right risk assessment tool for a given outcome in a given population, and to provide physicians with practical proposals that may lead to rational and evidence-based risk assessment and improvement of patient care in this regard. A large variety of methods are used for risk assessment and choosing the best methods and tools hereof in a given situation is not simple. Even though parameters and test results found associated with increased risk of one outcome (e.g. death) may also be associated with higher risk of other adverse outcomes, specific risk assessment strategies should be used only for the purposes for which they are validated. The work of this task force is summarized in a row of consensus statement tables.

Published
2020

5. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias:use the right tool for the right outcome, in the right population

Author

Nielsen, Jens Cosedis, Lin, Yenn Jiang, de Oliveira Figueiredo, Marcio Jansen, Sepehri Shamloo, Alireza, Alfie, Alberto, Boveda, Serge, Dagres, Nikolaos, Di Toro, Dario, Eckhardt, Lee L., Ellenbogen, Kenneth, Hardy, Carina, Ikeda, Takanori, Jaswal, Aparna, Kaufman, Elizabeth, Krahn, Andrew, Kusano, Kengo, Kutyifa, Valentina, Lim, Han S., Lip, Gregory Y.H., Nava-Townsend, Santiago, Pak, Hui Nam, Diez, Gerardo Rodríguez, Sauer, William, Saxena, Anil, Svendsen, Jesper Hastrup, Vanegas, Diego, Vaseghi, Marmar, Wilde, Arthur, Bunch, T. Jared, Buxton, Alfred E., Calvimontes, Gonzalo, Chao, Tze Fan, Eckardt, Lars, Estner, Heidi, Gillis, Anne M., Isa, Rodrigo, Kautzner, Josef, Maury, Philippe, Moss, Joshua D., Nam, Gi Byung, Olshansky, Brian, Pava Molano, Luis Fernando, Pimentel, Mauricio, Prabhu, Mukund, Tzou, Wendy S., Sommer, Philipp, Swampillai, Janice, Vidal, Alejandro, Deneke, Thomas, Hindricks, Gerhard, Nielsen, Jens Cosedis, Lin, Yenn Jiang, de Oliveira Figueiredo, Marcio Jansen, Sepehri Shamloo, Alireza, Alfie, Alberto, Boveda, Serge, Dagres, Nikolaos, Di Toro, Dario, Eckhardt, Lee L., Ellenbogen, Kenneth, Hardy, Carina, Ikeda, Takanori, Jaswal, Aparna, Kaufman, Elizabeth, Krahn, Andrew, Kusano, Kengo, Kutyifa, Valentina, Lim, Han S., Lip, Gregory Y.H., Nava-Townsend, Santiago, Pak, Hui Nam, Diez, Gerardo Rodríguez, Sauer, William, Saxena, Anil, Svendsen, Jesper Hastrup, Vanegas, Diego, Vaseghi, Marmar, Wilde, Arthur, Bunch, T. Jared, Buxton, Alfred E., Calvimontes, Gonzalo, Chao, Tze Fan, Eckardt, Lars, Estner, Heidi, Gillis, Anne M., Isa, Rodrigo, Kautzner, Josef, Maury, Philippe, Moss, Joshua D., Nam, Gi Byung, Olshansky, Brian, Pava Molano, Luis Fernando, Pimentel, Mauricio, Prabhu, Mukund, Tzou, Wendy S., Sommer, Philipp, Swampillai, Janice, Vidal, Alejandro, Deneke, Thomas, and Hindricks, Gerhard

Published
2020

6. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias:Use the right tool for the right outcome, in the right population

Author

Nielsen, Jens Cosedis, Lin, Yenn Jiang, de Oliveira Figueiredo, Marcio Jansen, Shamloo, Alireza Sepehri, Alfie, Alberto, Boveda, Serge, Dagres, Nikolaos, Di Toro, Dario, Eckhardt, Lee L., Ellenbogen, Kenneth, Hardy, Carina, Ikeda, Takanori, Jaswal, Aparna, Kaufman, Elizabeth, Krahn, Andrew, Kusano, Kengo, Kutyifa, Valentina, Lim, Han S., Lip, Gregory Y.H., Nava-Townsend, Santiago, Pak, Hui Nam, Diez, Gerardo Rodríguez, Sauer, William, Saxena, Anil, Svendsen, Jesper Hastrup, Vanegas, Diego, Vaseghi, Marmar, Wilde, Arthur, Jared Bunch, T., Buxton, Alfred E., Calvimontes, Gonzalo, Chao, Tze Fan, Eckardt, Lars, Estner, Heidi, Gillis, Anne M., Isa, Rodrigo, Kautzner, Josef, Maury, Philippe, Moss, Joshua D., Nam, Gi Byung, Olshansky, Brian, Pava Molano, Luis Fernando, Pimentel, Mauricio, Prabhu, Mukund, Tzou, Wendy S., Sommer, Philipp, Swampillai, Janice, Vidal, Alejandro, Deneke, Thomas, Hindricks, Gerhard, Leclercq, Christophe, Nielsen, Jens Cosedis, Lin, Yenn Jiang, de Oliveira Figueiredo, Marcio Jansen, Shamloo, Alireza Sepehri, Alfie, Alberto, Boveda, Serge, Dagres, Nikolaos, Di Toro, Dario, Eckhardt, Lee L., Ellenbogen, Kenneth, Hardy, Carina, Ikeda, Takanori, Jaswal, Aparna, Kaufman, Elizabeth, Krahn, Andrew, Kusano, Kengo, Kutyifa, Valentina, Lim, Han S., Lip, Gregory Y.H., Nava-Townsend, Santiago, Pak, Hui Nam, Diez, Gerardo Rodríguez, Sauer, William, Saxena, Anil, Svendsen, Jesper Hastrup, Vanegas, Diego, Vaseghi, Marmar, Wilde, Arthur, Jared Bunch, T., Buxton, Alfred E., Calvimontes, Gonzalo, Chao, Tze Fan, Eckardt, Lars, Estner, Heidi, Gillis, Anne M., Isa, Rodrigo, Kautzner, Josef, Maury, Philippe, Moss, Joshua D., Nam, Gi Byung, Olshansky, Brian, Pava Molano, Luis Fernando, Pimentel, Mauricio, Prabhu, Mukund, Tzou, Wendy S., Sommer, Philipp, Swampillai, Janice, Vidal, Alejandro, Deneke, Thomas, Hindricks, Gerhard, and Leclercq, Christophe

Abstract

In clinical practice and for scientific purposes, cardiologists and primary care physicians perform risk assessment in patients with cardiac diseases or conditions with high risk of developing such. The European Heart Rhythm Association (EHRA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) set down this expert consensus statement task force to summarize the consensus regarding risk assessment in cardiac arrhythmias. Objectives were to raise awareness of using the right risk assessment tool for a given outcome in a given population, and to provide physicians with practical proposals that may lead to rational and evidence-based risk assessment and improvement of patient care in this regard. A large variety of methods are used for risk assessment and choosing the best methods and tools hereof in a given situation is not simple. Even though parameters and test results found associated with increased risk of one outcome (e.g. death) may also be associated with higher risk of other adverse outcomes, specific risk assessment strategies should be used only for the purposes for which they are validated. The work of this task force is summarized in a row of consensus statement tables.

Published
2020

7. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias:use the right tool for the right outcome, in the right population

Author

Nielsen, Jens Cosedis, Lin, Yenn Jiang, de Oliveira Figueiredo, Marcio Jansen, Sepehri Shamloo, Alireza, Alfie, Alberto, Boveda, Serge, Dagres, Nikolaos, Di Toro, Dario, Eckhardt, Lee L., Ellenbogen, Kenneth, Hardy, Carina, Ikeda, Takanori, Jaswal, Aparna, Kaufman, Elizabeth, Krahn, Andrew, Kusano, Kengo, Kutyifa, Valentina, Lim, Han S., Lip, Gregory Y.H., Nava-Townsend, Santiago, Pak, Hui Nam, Diez, Gerardo Rodríguez, Sauer, William, Saxena, Anil, Svendsen, Jesper Hastrup, Vanegas, Diego, Vaseghi, Marmar, Wilde, Arthur, Bunch, T. Jared, Buxton, Alfred E., Calvimontes, Gonzalo, Chao, Tze Fan, Eckardt, Lars, Estner, Heidi, Gillis, Anne M., Isa, Rodrigo, Kautzner, Josef, Maury, Philippe, Moss, Joshua D., Nam, Gi Byung, Olshansky, Brian, Pava Molano, Luis Fernando, Pimentel, Mauricio, Prabhu, Mukund, Tzou, Wendy S., Sommer, Philipp, Swampillai, Janice, Vidal, Alejandro, Deneke, Thomas, Hindricks, Gerhard, Nielsen, Jens Cosedis, Lin, Yenn Jiang, de Oliveira Figueiredo, Marcio Jansen, Sepehri Shamloo, Alireza, Alfie, Alberto, Boveda, Serge, Dagres, Nikolaos, Di Toro, Dario, Eckhardt, Lee L., Ellenbogen, Kenneth, Hardy, Carina, Ikeda, Takanori, Jaswal, Aparna, Kaufman, Elizabeth, Krahn, Andrew, Kusano, Kengo, Kutyifa, Valentina, Lim, Han S., Lip, Gregory Y.H., Nava-Townsend, Santiago, Pak, Hui Nam, Diez, Gerardo Rodríguez, Sauer, William, Saxena, Anil, Svendsen, Jesper Hastrup, Vanegas, Diego, Vaseghi, Marmar, Wilde, Arthur, Bunch, T. Jared, Buxton, Alfred E., Calvimontes, Gonzalo, Chao, Tze Fan, Eckardt, Lars, Estner, Heidi, Gillis, Anne M., Isa, Rodrigo, Kautzner, Josef, Maury, Philippe, Moss, Joshua D., Nam, Gi Byung, Olshansky, Brian, Pava Molano, Luis Fernando, Pimentel, Mauricio, Prabhu, Mukund, Tzou, Wendy S., Sommer, Philipp, Swampillai, Janice, Vidal, Alejandro, Deneke, Thomas, and Hindricks, Gerhard

Published
2020

8. Inward Rectifier Potassium Channels (Kir2.x) and Caveolin-3 Domain-Specific Interaction: Implications for Purkinje Cell-Dependent Ventricular Arrhythmias.

Author

Vaidyanathan, Ravi, Vaidyanathan, Ravi, Van Ert, Hanora, Haq, Kazi T, Morotti, Stefano, Esch, Samuel, McCune, Elise C, Grandi, Eleonora, Eckhardt, Lee L, Vaidyanathan, Ravi, Vaidyanathan, Ravi, Van Ert, Hanora, Haq, Kazi T, Morotti, Stefano, Esch, Samuel, McCune, Elise C, Grandi, Eleonora, and Eckhardt, Lee L

Abstract

BACKGROUND:In human cardiac ventricle, IK1 is mainly comprised Kir2.1, but Kir2.2 and Kir2.3 heterotetramers occur and modulate IK1. Long-QT syndrome-9-associated CAV3 mutations cause decreased Kir2.1 current density, but Kir2.x heterotetramers have not been studied. Here, we determine the effect of long-QT syndrome-9-CAV3 mutation F97C on Kir2.x homo- and heterotetramers and model-associated arrhythmia mechanisms. METHODS AND RESULTS:Super-resolution microscopy, co-immunoprecipitation, cellular electrophysiology, on-cell Western blotting, and simulation of Purkinje and ventricular myocyte mathematical models were used. Kir2.x isoforms have unique subcellular colocalization in human cardiomyocytes and coimmunoprecipitate with Cav3. F97C-Cav3 decreased peak inward Kir2.2 current density by 50% (-120 mV; P=0.019) and peak outward by 75% (-40 mV; P<0.05) but did not affect Kir2.3 current density. FRET (Förster resonance energy transfer) efficiency for Kir2.2 with Cav3 is high, and on-cell Western blotting demonstrates decreased Kir2.2 membrane expression with F97C-Cav3. Cav3-F97C reduced peak inward and outward current density of Kir2.2/Kir2.1 or Kir2.2/Kir2.3 heterotetramers (P<0.05). Only Cav3 scaffolding and membrane domains co-immunoprecipitation with Kir2.1 and Kir2.2 and Kir2.x-N-terminal Cav3 binding motifs are required for interaction. Mathematical Purkinje, but not ventricular, myocyte model incorporating simulated current reductions, predicts spontaneous delayed after-depolarization-mediated triggered activity. CONCLUSIONS:Kir2.x isoforms have a unique intracellular pattern of distribution in association with specific Cav3 domains and that critically depends on interaction with N-terminal Kir2.x Cav3-binding motifs. Long-QT syndrome-9-CAV3 mutation differentially regulates current density and cell surface expression of Kir2.x homomeric and heteromeric channels. Mathematical Purkinje cell model incorporating experimental findings suggests delayed after-d

Published
2018

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