March 16, 2015PLoS ONEOpen Access

Atrial Fibrillation Complicated by Heart Failure Induces Distinct Remodeling of Calcium Cycling Proteins

Q: What is the clinical evidence from this study?

Population: Atrial Fibrillation and Heart Failure (n=10). Intervention: Atrial burst pacing-induced atrial fibrillation vs. Sinus rhythm controls. Primary outcome: Na+-Ca2+ exchanger (NCX) 1 expression (p=<0.0001).

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Key result

Atrial fibrillation complicated by mild heart failure in a porcine model induced distinct arrhythmogenic remodeling of calcium handling, including a 473% upregulation of Na+-Ca2+ exchanger levels.

Why the study?

Does atrial fibrillation complicated by mild heart failure induce distinct remodeling of calcium cycling proteins in a porcine model?

Structured PICO

Does atrial fibrillation complicated by mild heart failure induce distinct remodeling of calcium cycling proteins in a porcine model?

Population

Domestic swine (<6 months of age; body weight 25 to 30 kg), n=10 (5 subjected to atrial fibrillation induction, 5 sinus rhythm controls).

Intervention

Atrial fibrillation induced by rapid atrial burst pacing (42 Hz for 2 seconds followed by 2 second intervals) via a pacemaker for 7 days, resulting in tachycardia-induced mild heart failure.

Comparator

Healthy domestic swine during sinus rhythm (SR) with similar weight and age, not subjected to functional evaluation or pacing.

Outcome

Expression and phosphorylation status of Ca2+ cycling proteins (including CaMKII, PKA, LTCC, NCX1, Serca2a, PLN, and RyR2) in right atrial tissue samples at day 7.surrogate

Main Result

p-value: p=<0.0001

Atrial fibrillation complicated by mild heart failure in a porcine model induces a distinct arrhythmogenic remodeling pattern of calcium handling proteins that differs from isolated AF or HF, suggesting a need for tailored therapeutic approaches.

Limitations

Experimental large animal models do not show spontaneous AF occurrence.
Functional analyses were limited to in vivo studies, precluding experimental confirmation of cellular mechanisms.
The 7-day follow-up period only reflects short-term remodeling processes.
Experimental large animal models do not show spontaneous AF occurrence
Functional analyses were limited to in vivo studies, precluding experimental confirmation of proposed arrhythmogenic mechanisms at the cellular level
The 7 day follow-up period reflects only short-term remodeling processes
Requires additional studies in AF patients with concomitant HF to validate data

Implication

Should not yet change AF-HF management; hypothesis-generating for distinct calcium remodeling in combined disease.

Abstract

Atrial fibrillation (AF) and heart failure (HF) are two of the most common cardiovascular diseases. They often coexist and account for significant morbidity and mortality. Alterations in cellular Ca2+ homeostasis play a critical role in AF initiation and maintenance. This study was designed to specifically elucidate AF-associated remodeling of atrial Ca2+ cycling in the presence of mild HF. AF was induced in domestic pigs by atrial burst pacing. The animals underwent electrophysiologic and echocardiographic examinations. Ca2+ handling proteins were analyzed in right atrial tissue obtained from pigs with AF (day 7; n = 5) and compared to sinus rhythm (SR) controls (n = 5). During AF, animals exhibited reduction of left ventricular ejection fraction (from 73% to 58%) and prolonged atrial refractory periods. AF and HF were associated with suppression of protein kinase A (PKA)RII (-62%) and Ca2+-calmodulin-dependent kinase II (CaMKII) δ by 37%, without changes in CaMKIIδ autophosphorylation. We further detected downregulation of L-type calcium channel (LTCC) subunit α2 (-75%), sarcoplasmic reticulum Ca2+-ATPase (Serca) 2a (-29%), phosphorylated phospholamban (Ser16, -92%; Thr17, -70%), and phospho-ryanodine receptor 2 (RyR2) (Ser2808, -62%). Na+-Ca2+ exchanger (NCX) levels were upregulated (+473%), whereas expression of Ser2814-phosphorylated RyR2 and LTCCα1c subunits was not significantly altered. In conclusion, AF produced distinct arrhythmogenic remodeling of Ca2+ handling in the presence of tachycardia-induced mild HF that is different from AF without structural alterations. The changes may provide a starting point for personalized approaches to AF treatment.

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Cite This Study

Lugenbiel et al. (2015) studied Atrial Fibrillation and Heart Failure (n=10). Atrial burst pacing-induced atrial fibrillation vs. Sinus rhythm controls was evaluated on Na+-Ca2+ exchanger (NCX) 1 expression (p=<0.0001). Atrial fibrillation complicated by mild heart failure in a porcine model induced distinct arrhythmogenic remodeling of calcium handling, including a 473% upregulation of Na+-Ca2+ exchanger levels.

synapsesocial.com/papers/6a11dce75a604c357c21b15c https://doi.org/10.1371/journal.pone.0116395