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HEART FAILURE AND PHARMACOGENETICS

Interaction between cardiac sympathetic drive and heart rate in heart failure

Modulation by adrenergic receptor genotype

David M. Kaye, MD, PhD, FRACP, FACC^*,*, Belinda Smirk, BSc^*, Samara Finch, BSc^*, Carolyn Williams, PhD and Murray D. Esler, MD, PhD, FRACP

^* Wynn Department of Metabolic Cardiology
Alfred Baker Genebank, Melbourne, Australia
Human Neurotransmitter Laboratory, Baker Heart Research Institute, Melbourne, Australia

Manuscript received April 28, 2004; revised manuscript received June 23, 2004, accepted July 12, 2004.

^* Reprint requests and correspondence: Dr. David M. Kaye, Wynn Dept. of Metabolic Cardiology, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road, Melbourne, VIC 8008, Australia (Email: david.kaye{at}baker.edu.au).

OBJECTIVES: In the present study, we aimed to evaluate the effect of adrenergic receptor polymorphisms on the response of myocardium to measured levels of cardiac adrenergic drive, and to evaluate whether polymorphisms of presynaptic adrenoceptors modified the rate of cardiac and systemic release of norepinephrine.

BACKGROUND: Heightened sympathetic activity plays an important pathophysiologic role in congestive heart failure (CHF). Recently several functionally relevant polymorphisms of the ₂-, ß₁-, and ß₂-adrenoceptors have been identified, and specific genotypes have been associated with the incidence or clinical severity of CHF. These adrenoceptors are known to be located both pre-synaptically (₂ and ß₂) and post-synaptically (ß₁ and ß₂), raising the possibility that their association with clinical measures in CHF could be mediated either by modulation of the cardiac response to a given level of adrenergic drive or by altering norepinephrine release from sympathetic nerve terminals.

METHODS: We determined the ß₁-, ß₂-, and _2C-adrenoceptor genotype in 60 patients with severe CHF in conjunction with measurement of cardiac and systemic sympathetic activity using the radiotracer norepinephrine spillover method.

RESULTS: We showed a strong relationship (r = 0.67, p < 0.001) between heart rate and the level of cardiac adrenergic drive, and heart rate for a given level of cardiac adrenergic drive was substantially greater in patients with the Arg/Arg16 ß₂-adrenoceptor polymorphism (p = 0.02), whereas no such relationship existed for polymorphisms of the ß₁-adrenoceptor. The genotype of the _2C- and ß₂-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves.

CONCLUSIONS: For the first time, we show that ß₂-adrenoceptor polymorphisms significantly influence the relationship between heart rate and cardiac adrenergic drive in CHF, but do not affect the rate of norepinephrine release from sympathetic nerve terminals.

Abbreviations and Acronyms   CHF = congestive heart failure   HF = heart failure   PCR = polymerase chain reaction

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