Atrial fibrillation is associated with cardiac hypoxia.
BACKGROUND
Atrial fibrillation (AF), the most common human arrhythmia, is responsible for substantial morbidity and mortality and may be promoted by selective atrial ischemia and atrial fibrosis. Consequently, we investigated markers for hypoxia and angiogenesis in AF.


METHODS
Right atrial appendages (n=158) were grouped according to heart rhythm [sinus rhythm (SR) or AF]. The degree of fibrosis and microvessel density of all patients were determined morphometrically using Sirius-Red- and CD34/CD105-stained sections, respectively. Next, sections (n=77) underwent immunostaining to detect hypoxia- and angiogenesis-related proteins [hypoxia-inducible factor (HIF)1 alpha, HIF2 alpha, vascular endothelial growth factor (VEGF), VEGF receptor 2 (KDR), phosphorylated KDR (pKDR), carboanhydrase IX, platelet-derived growth factor] and the apoptosis-related B-cell lymphoma 2 protein.


RESULTS
Fibrosis progressed significantly from 14.7+/-0.8% (SR) to 22.3+/-1.4% (AF). While the positive cytoplasmic staining of HIF1 alpha, HIF2 alpha, VEGF, KDR, and pKDR rose significantly from SR to AF, their nuclear fractions fell (only pKDR significantly). The median CD34/CD105-positive microvessel size increased significantly from SR to AF.


CONCLUSIONS
AF is closely associated with an atrial up-regulation of hypoxic and angiogenic markers. Whether this is cause, effect, or co-phenomenon of fibrosis remains to be investigated. It is conceivable that fibrosis might lead to an increased O(2) diffusion distance and thus induce ischemic signaling, which, in turn, leads to angiogenesis.
Gramley
Felix
F
Department of Cardiology and Vascular Medicine, Mainz University, Mainz, Germany. gramley@hotmail.com
Lorenzen
Johann
J
Jedamzik
Britta
B
Gatter
Kevin
K
Koellensperger
Eva
E
Munzel
Thomas
T
Pezzella
Francesco
F
D000368:Aged; D020517:Atrial Appendage / Q000378:metabolism / Q000473:pathology*; D001281:Atrial Fibrillation / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C467484:VEGFA protein, human