Interaction between cardiac sympathetic drive and heart rate in heart failure: modulation by adrenergic receptor genotype.
OBJECTIVE
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 alpha(2)-, beta(1)-, and beta(2)-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 (alpha(2) and beta(2)) and post-synaptically (beta(1) and beta(2)), 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 beta(1)-, beta(2)-, and alpha(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 beta(2)-adrenoceptor polymorphism (p = 0.02), whereas no such relationship existed for polymorphisms of the beta(1)-adrenoceptor. The genotype of the alpha(2C)- and beta(2)-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves.


CONCLUSIONS
For the first time, we show that beta(2)-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.
Kaye
David M
DM
Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, Melbourne, VIC, Australia. david.kaye@baker.edu.au <david.kaye@baker.edu.au>
Smirk
Belinda
B
Finch
Samara
S
Williams
Carolyn
C
Esler
Murray D
MD
D000328:Adult; D000368:Aged; D017931:DNA Primers; D005260:Female; D005838:Genotype; D006329:Heart Conduction System; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology*; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012720:Severity of Illness Index
D017931:DNA Primers; D018343:Receptors, Adrenergic, beta-2