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American Heart Association

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Final ID: Tu107

Decreased Mitochondrial Protein Expression Accompanies Atrial Hypertrophy but Precedes Atrial Fibrillation Onset in a Mouse Model of Spontaneous Atrial Fibrillation

Abstract Body: Introduction: Atrial fibrillation (AF), characterized by episodes of rapid and irregular heart rate, increases left atrial (LA) demand for ATP. While the heart is metabolically flexible, able to use fatty acids, lactate, glucose, ketones, and amino acids to generate ATP, fatty acids are the primary fuel source. AF is associated with altered mitochondrial structure and function, but the role of energetic pathways in early stages of AF progression is not clear.
Hypothesis: Decreased expression of mitochondrial proteins contributes to AF progression.
Aim: Evaluate expression of proteins that influence mitochondrial structure and energetic capacity in AF onset and progression.
Methods: AF burden was assessed weekly by electrocardiography (ECG) in male wild-type (WT) and cAMP responsive element modulator IbΔC-X heterozygous mice (CREM) (n=3). LA (4 - 9 mg) was obtained at 7 weeks and 16 weeks. Global proteomics was conducted, and 139,316 peptides were identified that mapped to 6000 robustly quantified proteins.
Results: LA hypertrophy was evident in 7-week and 16-week CREM mice (Figure 1). We detected 2408 proteins differentially expressed in CREM compared to WT. At 7 weeks, Hallmark pathways adipogenesis, fatty acid metabolism, oxidative phosphorylation, and myogenesis were decreased in CREM (Table 1). These changes persisted at 16 weeks. We identified 740 differentially expressed mitochondrial proteins using MitoCarta 3.0 (552 decreased, 188 increased). Mitochondrial pathways associated with energy production, including branched chain amino acid metabolism, fatty acid transport and oxidation, carbohydrate metabolism, and tricarboxylic acid cycle were decreased (Table 1). Mitochondrial cristae organizing system (MICOS) and mitophagy, pathways that influence mitochondrial structure and content, were decreased. Terminal ECGs confirmed AF in 16-week CREM mice only. The coefficient of variation of RR intervals (CVRR), a measure of heart rate variability, was increased in 16-week CREM (Figure 2). These data suggest that decreased expression of mitochondrial proteins accompanies LA hypertrophy but precedes onset of AF.
Conclusions: Decreased expression of proteins that regulate mitochondrial structure and energy production prior to AF onset suggests that these proteins play an important role in early LA changes that promote AF onset and progression. Future studies will examine how these changes in protein expression relate to alterations in atrial energy homeostasis.
  • Li, Ling  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Rennison, Julie  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Hanmer, Shannon  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Willard, Belinda  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Smith, Jonathan  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Laurita, Kenneth  ( MetroHealth Campus Case Western Reserve University , Cleveland , Ohio , United States )
  • Chung, Mina  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Schumacher, Sarah  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Barnard, John  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Van Wagoner, David  ( Cleveland Clinic , Cleveland , Ohio , United States )
  • Author Disclosures:
    Ling Li: DO NOT have relevant financial relationships | Julie Rennison: DO NOT have relevant financial relationships | Shannon Hanmer: DO NOT have relevant financial relationships | Belinda Willard: No Answer | Jonathan Smith: DO have relevant financial relationships ; Other (please indicate in the box next to the company name):Ionis, gift of research reagent not relevant to current abstract:Active (exists now) | Kenneth Laurita: No Answer | Mina Chung: DO NOT have relevant financial relationships | Sarah Schumacher: DO NOT have relevant financial relationships | John Barnard: DO NOT have relevant financial relationships | David Van Wagoner: DO NOT have relevant financial relationships
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Poster Session and Reception 2

Tuesday, 07/23/2024 , 04:30PM - 07:00PM

Poster Session and Reception

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