- Title Information
- Title
- Age-Associated Arrhythmogenic Substrate and Trigger in a Rabbit Model of Cardiac Aging
- Name:
Personal
- Name Part
- Cooper, Leroy Leon
- Role
- Role Term:
Text
- creator
- Origin Information
- Copyright Date
- 2013
- Physical Description
- Extent
- 19, 205 p.
- digitalOrigin
- born digital
- Note
- Thesis (Ph.D. -- Brown University (2013)
- Name:
Personal
- Name Part
- Koren, g
- Role
- Role Term:
Text
- Director
- Name:
Personal
- Name Part
- Koren, Gideon
- Role
- Role Term:
Text
- Director
- Name:
Personal
- Name Part
- Mende, Ulrike
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Harrington, Elizabeth
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Sedivy, John
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Lakatta, Edward
- Role
- Role Term:
Text
- Reader
- Name:
Corporate
- Name Part
- Brown University. BIOMED: Molecular Pharmacology, Physiology, and Biotechnology
- Role
- Role Term:
Text
- sponsor
- Genre (aat)
- theses
- Abstract
- Aging is associated with an increased risk of arrhythmias and sudden cardiac death (SCD). Yet, much remains unknown about the mechanisms that underlie the age-related, pro-arrhythmic changes in the mammalian heart at the cellular and molecular levels and how they manifest as increased incidence of cardiac arrhythmia. Here, we used a physiologically-relevant aging rabbit model to test the hypothesis that the consequences of cellular aging contribute to in vivo dysfunction that enhances substrate and trigger for arrhythmias in the aging heart. In vivo and ex vivo studies showed that aging rabbits have reduced aortic and diastolic and systolic myocardial compliances. In addition, we observed an age-related slowing of ventricular and His-Purkinje conduction, altered conduction anisotropy, and greater ventricular fibrillation (VF) inducibility in old rabbits. Old rabbit hearts were physiologically hypertrophied (increased wall thickness) and absent of pathological hypertrophy markers. Aging was also associated with an increase in myocardial fibrosis, which along with an alteration to myofibrillar orientation and myocardial sheet structure, created anatomical substrates important to maintain VF. Aberrant calcium (Ca2+) handling has been shown to be an important contributor to the electrical and contractile dysfunction that may provide triggers for arrhythmic activity. However, the molecular mechanisms underlying abnormal Ca2+ handling in the aging heart remain poorly understood. We found that cardiomyocytes from old rabbit hearts were characterized by an increased rate of reactive oxygen species production by mildly depolarized mitochondria leading to the thiol-oxidation of RyRs, which underlies the hyperactivity of RyRs and thereby shortened refractoriness of Ca2+ release in cardiomyocytes from the aging heart. The major age-related changes in Ca2+ homeostasis manifested at the sarcolemma as potentially malignant spontaneous calcium waves under β-adrenergic stimulation, which could trigger extrasystolic activity that would lead to initiation of arrhythmias. This novel finding demonstrates a mechanism that is involved with age progression and its relation to alterations in Ca2+ cycling as it pertains to increased arrhythmogenic potential in the aging heart. Thus, aging enhances the development of arrhythmogenic triggers and substrate to maintain arrhythmias in the heart, promoting a higher incidence of age-associated SCD.
- Subject
- Topic
- senescence
- Subject
- Topic
- calcium dynamics
- Subject
- Topic
- ryanodine receptor
- Subject (FAST)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/953493")
- Topic
- Heart
- Subject (FAST)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/815084")
- Topic
- Arrhythmia
- Subject (FAST)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/800293")
- Topic
- Aging
- Subject (FAST)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/844035")
- Topic
- Calcium
- Subject (FAST)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/1102626")
- Topic
- Ryanodine--Receptors
- Record Information
- Record Content Source (marcorg)
- RPB
- Record Creation Date
(encoding="iso8601")
- 20131219
- Language
- Language Term:
Code (ISO639-2B)
- eng
- Language Term:
Text
- English
- Identifier:
DOI
- 10.7301/Z0D21VX9
- Access Condition:
rights statement
(href="http://rightsstatements.org/vocab/InC/1.0/")
- In Copyright
- Access Condition:
restriction on access
- Collection is open for research.
- Type of Resource (primo)
- dissertations