Abstract

Postoperative atrial fibrillation (poAF) is a common complication of cardiothoracic surgery with an incidence between 10 and 50%. This condition typically peaks on day 2-3 following surgery, and is associated with excessive hospitalization time, increased risk of stroke, and an increase in patient morbidity. Whereas progress has been made towards understanding the pathogenesis of AF in general, very little remains known about the molecular mechanisms underlying poAF. Our preliminary data reveal perturbed intracellular Ca handling in atrial biopsies from patients with poAF. Increased activity of the ryanodine receptor Ca release channel was found in atrial myocytes of patients with poAF and a novel mouse model of poAF. Our data suggest that enhanced RyR2 activity is caused by altered levels of `Striated Muscle Preferentially Expressed Protein Kinase' (SPEG) in atria of patients and mice with poAF. The long-term goal of this project is to elucidate the molecular and cellular mechanisms underlying poAF development. We will test the hypothesis that abnormal Ca release via RyR2 due to altered SPEG phosphorylation causes enhanced susceptibility to poAF.

Public Health Relevance

The proposed work will elucidate the molecular basis of altered intracellular calcium handling in patients and mice with postoperative atrial fibrillation. In particular, the cellular mechanisms underlying aberrant sarcoplasmic reticulum calcium handling will be studies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089598-11
Application #
9969534
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Balijepalli, Ravi C
Project Start
2007-08-01
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
11
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Lezcano, N; Mariángelo, J I E; Vittone, L et al. (2018) Early effects of Epac depend on the fine-tuning of the sarcoplasmic reticulum Ca2+ handling in cardiomyocytes. J Mol Cell Cardiol 114:1-9
Yao, Chunxia; Veleva, Tina; Scott Jr, Larry et al. (2018) Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation. Circulation 138:2227-2242
Ni, Li; Scott Jr, Larry; Campbell, Hannah M et al. (2018) Atrial-Specific Gene Delivery Using an Adeno-Associated Viral Vector. Circ Res :
Auguste, Gaelle; Gurha, Priyatansh; Lombardi, Raffaella et al. (2018) Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies. Circ Res 122:678-692
Dobrev, Dobromir; Wehrens, Xander H T (2018) Mouse Models of Cardiac Arrhythmias. Circ Res 123:332-334
Wang, Qiongling; Quick, Ann P; Cao, Shuyi et al. (2018) Oxidized CaMKII (Ca2+/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy. Circ Arrhythm Electrophysiol 11:e005682
Wehrens, Xander H T (2018) Unraveling the Mechanisms by Which Calpain Inhibition Prevents Heart Failure Development. JACC Basic Transl Sci 3:518-520
Chiang, David Y; Alsina, Katherina M; Corradini, Eleonora et al. (2018) Rearrangement of the Protein Phosphatase 1 Interactome During Heart Failure Progression. Circulation 138:1569-1581
Klipp, Robert C; Li, Na; Wang, Qiongling et al. (2018) EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2. Heart Rhythm 15:578-586
Pan, Xiaolu; Philippen, Leonne; Lahiri, Satadru K et al. (2018) In Vivo Ryr2 Editing Corrects Catecholaminergic Polymorphic Ventricular Tachycardia. Circ Res 123:953-963

Showing the most recent 10 out of 130 publications