| KATP channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response. | |
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MedLine Citation:
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PMID: 19685080 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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ATP-sensitive K+ (K(ATP)) channels maintain cardiac homeostasis under stress, as revealed by murine gene knockout models of the KCNJ11-encoded Kir6.2 pore. However, the translational significance of K(ATP) channels in human cardiac physiology remains largely unknown. Here, the frequency of the minor K23 allele of the common functional Kir6.2 E23K polymorphism was found overrepresented in 115 subjects with congestive heart failure compared to 2,031 community-based controls (69 vs. 56%, P < 0.001). Moreover, the KK genotype, present in 18% of heart failure patients, was associated with abnormal cardiopulmonary exercise stress testing. In spite of similar baseline heart rates at rest among genotypic subgroups (EE: 72.2 ± 2.3, EK: 75.0 ± 1.8 and KK:77.1 ± 3.0 bpm), subjects with the KK genotype had a significantly reduced heart rate increase at matched workload (EE: 32.8 ± 2.7%, EK: 28.8 ± 2.1%, KK: 21.7 ± 2.6%, P < 0.05), at 75% of maximum oxygen consumption (EE: 53.9 ± 3.9%, EK: 49.9 ± 3.1%, KK: 36.8 ± 5.3%, P < 0.05), and at peak V(O2) (EE: 82.8 ± 6.0%, EK: 80.5 ± 4.7%, KK: 59.7 ± 8.1%, P < 0.05). Molecular modeling of the tetrameric Kir6.2 pore structure revealed the E23 residue within the functionally relevant intracellular slide helix region. Substitution of the wild-type E residue with an oppositely charged, bulkier K residue would potentially result in a significant structural rearrangement and disrupted interactions with neighboring Kir6.2 subunits, providing a basis for altered high-fidelity K(ATP) channel gating, particularly in the homozygous state. Blunted heart rate response during exercise is a risk factor for mortality in patients with heart failure, establishing the clinical relevance of Kir6.2 E23K as a biomarker for impaired stress performance and underscoring the essential role of K(ATP) channels in human cardiac physiology. |
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Authors:
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Santiago Reyes; Sungjo Park; Bruce D Johnson; Andre Terzic; Timothy M Olson |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Human genetics Volume: 126 ISSN: 1432-1203 ISO Abbreviation: Hum. Genet. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2011-04-08 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7613873 Medline TA: Hum Genet Country: Germany |
Other Details:
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Languages: eng Pagination: 779-89 Citation Subset: IM |
Affiliation:
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Marriott Heart Disease Research Program, Mayo Clinic, Rochester, MN 55905, USA. |
Export Citation:
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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HL064822/HL/NHLBI NIH HHS; HL071225/HL/NHLBI NIH HHS; HL071478/HL/NHLBI NIH HHS |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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