Allelic variant of NOS1AP effects on cardiac alternans of repolarization during exercise testing

Abstract

Introduction. A repolarization abnormality manifested as T-wave alternans (TWA) in electrocardiogram (ECG) predicts cardiovascular mortality. A common variant in the NOS1AP gene is associated with mortality and QT interval duration, possibly in a gender-specific manner, but data is lacking on potential association with TWA. This study tested association between rs10494366 in NOS1AP and both TWA and 4-year mortality. Material and methods. A total of 1963 Finnish Cardiovascular Study participants (36.6% female, 57.1 ± 13.0 years) were genotyped and their maximal TWA values were measured from continuous ECG recordings during clinical exercise test at rest, exercise and recovery. Results. We observed a significant gender-specific effect of NOS1AP genotype on TWA. In all subjects, there was no statistically significant difference between the three genotypes (TT, TG, GG) in the responses of TWA over the entire exercise test (time-by-genotype interaction p = 0.057). In women, after adjustment for age, coronary heart disease and β-blocker medication status, changes of TWA over different phases of exercise test were significantly associated with NOS1AP genotype (time-by-genotype interaction p = 0.001). In men, NOS1AP rs10494366 was not associated with TWA. During follow-up (mean 47 months), 113 patients died. NOS1AP rs10494366 was not a statistically significant predictor of mortality. Conclusion. The NOSIAP variant rs10494366 influences TWA and TWA response during clinical exercise test in females. Gender-specific effects have also been previously reported for the influence of the variant on QT interval. If replicated, these findings should prompt studies to further elucidate the mechanisms underlying the gender differences in NOS1AP effects on repolarization.

Key Words::

• Cardiac electrophysiology
• exercise test
• mortality
• polymorphism

Acknowledgements

The authors wish to thank the staff of the Department of Clinical Physiology for collecting the exercise test data. This work was supported by the Medical Research Fund of Tampere University Hospital (grant 9M048), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research (T.L., I.P.), the Tampere Tuberculosis Foundation, the Emil Aaltonen Foundation, and MRC Clinician Scientist Fellowship (G0501942 to M.D.T.). N.J.S. holds a chair funded by the British Heart Foundation.

Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the article.