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KATP channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response

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Abstract

ATP-sensitive K+ (KATP) 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 KATP 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 VO2 (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 KATP 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 KATP channels in human cardiac physiology.

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Acknowledgments

This work was supported by the National Institutes of Health (HL071225, HL071478, HL064822), Marriott Heart Disease Research Program, and Mayo Graduate School.

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Authors and Affiliations

  1. Marriott Heart Disease Research Program, Mayo Clinic, Stabile 5, 200 First Street SW, Rochester, MN, 55905, USA

    Santiago Reyes, Sungjo Park, Andre Terzic & Timothy M. Olson

  2. Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Stabile 5, 200 First Street SW, Rochester, MN, 55905, USA

    Santiago Reyes, Sungjo Park, Bruce D. Johnson, Andre Terzic & Timothy M. Olson

  3. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Stabile 5, 200 First Street SW, Rochester, MN, 55905, USA

    Santiago Reyes, Sungjo Park, Andre Terzic & Timothy M. Olson

  4. Department of Medical Genetics, Mayo Clinic, Stabile 5, 200 First Street SW, Rochester, MN, 55905, USA

    Santiago Reyes, Sungjo Park, Andre Terzic & Timothy M. Olson

  5. Department of Physiology and Biomedical Engineering, Mayo Clinic, Stabile 5, 200 First Street SW, Rochester, MN, 55905, USA

    Bruce D. Johnson

  6. Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Stabile 5, 200 First Street SW, Rochester, MN, 55905, USA

    Timothy M. Olson

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Correspondence to Andre Terzic or Timothy M. Olson.

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Reyes, S., Park, S., Johnson, B.D. et al. KATP channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response. Hum Genet 126, 779–789 (2009). https://doi.org/10.1007/s00439-009-0731-9

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