Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart
Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells in...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2023-05-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/84088 |
| _version_ | 1827761662799642624 |
|---|---|
| author | Brett C Baggett Kevin R Murphy Elif Sengun Eric Mi Yueming Cao Nilufer N Turan Yichun Lu Lorraine Schofield Tae Yun Kim Anatoli Y Kabakov Peter Bronk Zhilin Qu Patrizia Camelliti Patrycja Dubielecka Dmitry Terentyev Federica del Monte Bum-Rak Choi John Sedivy Gideon Koren |
| author_facet | Brett C Baggett Kevin R Murphy Elif Sengun Eric Mi Yueming Cao Nilufer N Turan Yichun Lu Lorraine Schofield Tae Yun Kim Anatoli Y Kabakov Peter Bronk Zhilin Qu Patrizia Camelliti Patrycja Dubielecka Dmitry Terentyev Federica del Monte Bum-Rak Choi John Sedivy Gideon Koren |
| author_sort | Brett C Baggett |
| collection | DOAJ |
| description | Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in larger animals, and the mechanisms are unknown. Specifically, age-associated changes in timecourse of senescence and related changes in inflammation and fibrosis are not well understood. Additionally, the cellular and systemic role of senescence and its inflammatory milieu in influencing arrhythmogenesis with age is not clear, particularly in large animal models with cardiac electrophysiology more similar to humans than previously studied animal models. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a 12-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that therapeutic interventions targeting senescent cells may mitigate arrhythmias post-MI with age. |
| first_indexed | 2024-03-11T10:16:09Z |
| format | Article |
| id | doaj.art-d202d60827684d86801b098db8759f70 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T10:16:09Z |
| publishDate | 2023-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d202d60827684d86801b098db8759f702023-11-16T09:16:03ZengeLife Sciences Publications LtdeLife2050-084X2023-05-011210.7554/eLife.84088Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heartBrett C Baggett0https://orcid.org/0000-0003-2227-0004Kevin R Murphy1Elif Sengun2Eric Mi3Yueming Cao4Nilufer N Turan5Yichun Lu6Lorraine Schofield7Tae Yun Kim8Anatoli Y Kabakov9Peter Bronk10https://orcid.org/0000-0002-9067-2016Zhilin Qu11Patrizia Camelliti12Patrycja Dubielecka13https://orcid.org/0000-0003-3987-0647Dmitry Terentyev14Federica del Monte15Bum-Rak Choi16John Sedivy17Gideon Koren18https://orcid.org/0000-0002-6211-5837Brown University, Providence, United States; Cardiovascular Research Center, Rhode Island Hospital, Providence, United StatesBrown University, Providence, United States; Cardiovascular Research Center, Rhode Island Hospital, Providence, United StatesBrown University, Providence, United States; Cardiovascular Research Center, Rhode Island Hospital, Providence, United States; Department of Pharmacology, Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, TurkeyBrown University, Providence, United States; Cardiovascular Research Center, Rhode Island Hospital, Providence, United StatesBrown University, Providence, United States; Cardiovascular Research Center, Rhode Island Hospital, Providence, United StatesCardiovascular Research Center, Rhode Island Hospital, Providence, United StatesCardiovascular Research Center, Rhode Island Hospital, Providence, United StatesCardiovascular Research Center, Rhode Island Hospital, Providence, United StatesCardiovascular Research Center, Rhode Island Hospital, Providence, United StatesBrown University, Providence, United States; Cardiovascular Research Center, Rhode Island Hospital, Providence, United StatesCardiovascular Research Center, Rhode Island Hospital, Providence, United StatesSchool of Medicine, University of California, Los Angeles, Los Angeles, United StatesSchool of Biosciences and Medicine, University of Surrey, Guildford, United KingdomBrown University, Providence, United States; Department of Hematology, Rhode Island Hospital, Providence, United StatesCardiovascular Research Center, Rhode Island Hospital, Providence, United StatesMedical University of South Carolina, Charleston, United StatesCardiovascular Research Center, Rhode Island Hospital, Providence, United StatesBrown University, Providence, United StatesBrown University, Providence, United States; Cardiovascular Research Center, Rhode Island Hospital, Providence, United StatesProgressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in larger animals, and the mechanisms are unknown. Specifically, age-associated changes in timecourse of senescence and related changes in inflammation and fibrosis are not well understood. Additionally, the cellular and systemic role of senescence and its inflammatory milieu in influencing arrhythmogenesis with age is not clear, particularly in large animal models with cardiac electrophysiology more similar to humans than previously studied animal models. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a 12-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that therapeutic interventions targeting senescent cells may mitigate arrhythmias post-MI with age.https://elifesciences.org/articles/84088cardiac arrhythmiasudden cardiac deathmyocardial infarctionsenescence |
| spellingShingle | Brett C Baggett Kevin R Murphy Elif Sengun Eric Mi Yueming Cao Nilufer N Turan Yichun Lu Lorraine Schofield Tae Yun Kim Anatoli Y Kabakov Peter Bronk Zhilin Qu Patrizia Camelliti Patrycja Dubielecka Dmitry Terentyev Federica del Monte Bum-Rak Choi John Sedivy Gideon Koren Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart eLife cardiac arrhythmia sudden cardiac death myocardial infarction senescence |
| title | Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart |
| title_full | Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart |
| title_fullStr | Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart |
| title_full_unstemmed | Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart |
| title_short | Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart |
| title_sort | myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart |
| topic | cardiac arrhythmia sudden cardiac death myocardial infarction senescence |
| url | https://elifesciences.org/articles/84088 |
| work_keys_str_mv | AT brettcbaggett myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT kevinrmurphy myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT elifsengun myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT ericmi myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT yuemingcao myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT nilufernturan myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT yichunlu myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT lorraineschofield myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT taeyunkim myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT anatoliykabakov myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT peterbronk myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT zhilinqu myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT patriziacamelliti myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT patrycjadubielecka myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT dmitryterentyev myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT federicadelmonte myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT bumrakchoi myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT johnsedivy myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart AT gideonkoren myofibroblastsenescencepromotesarrhythmogenicremodelingintheagedinfarctedrabbitheart |