Modulation by adrenergic receptor genotype Interaction between cardiac sympathetic drive and heart rate in heart failure (original) (raw)
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Interaction between cardiac sympathetic drive and heart rate in heart failure
Journal of the American College of Cardiology, 2004
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-,  1-, and  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 (␣ 2 and  2) and post-synaptically ( 1 and  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  1-,  2-, 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 ϭ 0.67, p Ͻ 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  2-adrenoceptor polymorphism (p ϭ 0.02), whereas no such relationship existed for polymorphisms of the  1-adrenoceptor. The genotype of the ␣ 2C-and  2-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves. CONCLUSIONS For the first time, we show that  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.
Role of ?1- and ?2-adrenoceptor polymorphisms in heart failure: a case-control study
European Heart Journal, 2004
Background We hypothesised that the polymorphisms of the genes encoding for b1and the b2-adrenoceptors may have a role in the pathogenesis of heart failure (HF). We therefore compared the polymorphisms of the b1-adrenoceptor gene (Arg389Gly), the b2-adrenoceptor gene (Arg16Gly, Gln27Glu) and their combinations in patients with HF and normal subjects living in the same area. Methods and results A total of 256 cases with HF (left ventricular ejection fraction 6 40%) and 230 normal subjects were enrolled. The b1-and b2-adrenoceptor gene polymorphisms were assessed by PCR, followed by restriction enzyme digestion. No differences were observed in the distribution of any of the three genotypes studied in patients with HF and normal subjects. An analysis of the genotype combinations showed a non-significant increase in the risk of HF associated with the Arg389-Gly16Gln27 (odds ratio = 1.4; 95%CI 0.5-3.6) and Arg389Gly16 Glu27 (odds ratio = 1.2; 95%CI, 0.5-2.8) homozygous allele combinations. Conclusion None of the three most common polymorphisms of b-adrenoreceptors are associated with an increased risk of HF.
Journal of the American College of Cardiology, 2004
Plasma norepinephrine (NE), a prognostic marker for congestive heart failure (HF), is elevated as a consequence of increased release and decreased clearance (measured as "NE spillover") from the heart and kidney (1,2). Cardiac NE spillover is five times higher in the failing heart, and the degree of elevation of plasma NE is associated with decreased survival (3). The beneficial use of beta-adrenergic receptor (AR) antagonists provides evidence that response to, as well as elevation in, NE levels is part of a vicious cycle that leads to worsening cardiac function and, ultimately, death (4). Whether elevated NE contributes to or compensates for ventricular failure is controversial, but it probably does both. See page 2008 Norepinephrine and epinephrine, the major catecholamines of the sympathoadrenal system, alter function via AR, of which three major types (␣ 1 , ␣ 2 , and ), each with three subtypes (␣ 1a,b,d , ␣ 2a,b,c , and  1,2,3) are found in the human genome (5). Studies initiated two decades ago showed that downregulation (decreased number) of  1-AR and uncoupling (decreased functionality) of  2-AR contribute to the pathophysiology and progression of HF (6). Such changes presumably result from the enhanced levels of catecholamines, especially NE, that occur with worsening HF (1-3). An important question is whether all patients (and their receptors) are equally susceptible to such changes. Most AR subtypes show genetic variations that include deletions and coding and non-coding single nucleotide polymorphisms (SNPs) (5,7). High-efficiency sequencing techniques have made SNP discovery feasible and analysis of large clinical datasets for "SNP hits" fashionable. When such studies are "positive," they provide a priori evidence that the SNP is detrimental even in the absence of supporting mechanistic data. Several recent reviews summarize the results of such studies and of in vitro experiments with AR variants; thus far the assay for variants has not reached the stage of clinical utility (5,7-9).
The American Journal of Cardiology, 2008
Beta1-adrenergic receptor polymorphisms have been implicated with inconsistent results in the pathogenesis, clinical presentation, and prognosis of patients with heart failure (HF). The impact of 2 functional polymorphisms (1-Arg389Gly and 1-Ser49Gly) on HF susceptibility, arrhythmogenesis, and prognosis was evaluated in Brazilian outpatients. Genotyping at codons 389 and 49 was performed using polymerase chain reaction with restriction fragment length polymorphism analysis in 201 outpatients with systolic HF and 141 apparently healthy controls. Enrolled patients were followed up at the HF clinic, and vital status was evaluated using electronic hospital records, telephone contact, and a local death certificate database. Allele frequencies were similar between patients with HF and controls, with neither polymorphism related to HF susceptibility. The 1-389Gly homozygotes had significantly less nonsustained ventricular tachycardia on Holter monitoring (17% vs 48% for Arg/Arg patients; p ؍ 0.015) and improved HF-related survival, with no events after a median follow-up of 40 months (log-rank statistics ؍ 0.025). The negative impact of 1-389Arg allele on HF-related survival was substantially reduced using highdose -blocker therapy (80% survival for high-dose vs 42% for low-dose  blockers or nonusers; log-rank statistics ؍ 0.0003). The 1-Ser49Gly polymorphism was not associated with nonsustained ventricular tachycardia or HF prognosis. In conclusion, 1-Arg389Gly and 1-Ser49Gly polymorphisms had no influence on HF susceptibility. However, the Gly389 allele was associated with a lower prevalence of ventricular arrhythmias and better HF-related survival. A pharmacogenetic interaction is suggested because  blockers were more effective in 1-389Arg allele carriers.
A Polymorphism in the β1 Adrenergic Receptor Is Associated with Resting Heart Rate
The American Journal of Human Genetics, 2002
Resting heart rate is significantly associated with cardiovascular morbidity and mortality. However, the extent to which resting heart rate is genetically determined is poorly understood, and no genes have been found that contribute to variation in resting heart rate. Because signaling through the b1 adrenergic receptor is a key determinant of cardiac function, we tested whether polymorphisms in this receptor are associated with resting heart rate. A cohort of 11,000 individuals of Chinese and Japanese descent, from nuclear families, was genotyped for two polymorphisms, resulting in a serine/glycine substitution at amino acid 49 (Ser49Gly) and an arginine/glycine substitution at residue 389 (Arg389Gly), in the b1 adrenergic receptor. For comparison, polymorphisms in the b2 and b3 adrenergic receptors were also evaluated. The Ser49Gly polymorphism was significantly associated ( ) with resting P p .0004 heart rate, independent of other variables, such as body-mass index, age, sex, ethnicity, exercise, smoking, alcohol intake, hypertension status, and treatment with beta blockers. The data support an additive model in which individuals heterozygous for the Ser49Gly polymorphism had mean heart rates intermediate to those of either type of homozygote, with Ser homozygotes having the highest mean heart rate and with Gly homozygotes having the lowest. Neither the Arg389Gly polymorphism in the b1 adrenergic receptor nor polymorphisms in the b2 and b3 adrenergic receptors were associated with resting heart rate. The heritability of heart rate was 39.7% ע 7.1% ( ) .
β 1 and β 2 -Adrenergic Receptor Polymorphisms and Idiopathic Ventricular Arrhythmias
Journal of Cardiovascular Electrophysiology, 2008
Genetics and Idiopathic Ventricular Arrhythmias. Introduction: Idiopathic ventricular arrhythmias commonly refer to ventricular tachycardia (VT) and/or frequent/monomorphic premature ventricular contractions (PVC) in patients with structurally normal heart. Activation of sympathetic tone has been shown to play an important role in the provocation and maintenance of these arrhythmias. We investigated whether common single nucleotide polymorphisms in the β 1 and β 2 -adrenergic receptors are associated with idiopathic ventricular arrhythmias.
The American Journal of Medicine, 2004
PURPOSE. Increased sympathetic nervous system activation via the -adrenergic pathway influences the evolution of idiopathic dilated cardiomyopathy. We assessed the effects of -adrenergic receptor variants on heart failure in idiopathic dilated cardiomyopathy. METHODS. We prospectively analyzed 171 consecutive patients (mean [Ϯ SD] age, 49 Ϯ 14 years; 129 men) with idiopathic dilated cardiomyopathy who were receiving conventional treatment. All were characterized by polymerase chain reaction-restriction fragment length polymorphism analysis for Ser49Gly and Arg389Gly in the  1 -adrenergic receptor; the 5= leader cistron (LC) Arg19Cys, Arg16Gly, Gln27Glu, and Thr164Ile in the  2 -adrenergic receptor; and Arg64Trp in the  3 -adrenergic receptor. The endpoint was heart failure, defined as a worsening of clinical condition leading to hospitalization for heart failure, cardiac transplantation, or death from heart failure.
Proceedings of the National Academy of Sciences, 2004
The presynaptic ␣2C adrenergic receptors (AR) act to inhibit norepinephrine release in cardiac and other presynaptic nerves. We have recently shown that a genetic variant in the ␣2CAR coding region (Del322-325), which renders the receptor partially uncoupled from G i, is a risk factor for heart failure. However, variability of heart failure phenotypes and a dominance of Del322-325 in those of African descent led us to hypothesize that other regions of this gene have functional polymorphisms. In a multiethnic population, we found 20 polymorphisms within 4,625 bp of contiguous sequence of this intronless gene encompassing the promoter, 5 UTR, coding, and 3 UTR. These polymorphisms occur in 24 distinct haplotypes with complex organizations, including multiple 5-upstream polymorphisms in regions known to direct expression, a 3 UTR substitution polymorphism within an insertion͞ deletion sequence, and the radical coding polymorphism that deletes four amino acids. Relatively low linkage disequilibrium between many polymorphisms, few cosmopolitan haplotypes, prevalent ethnic-specific haplotypes, and substantial genetic divergence among haplotypes was noted. The dysfunctional Del322-325 allele was partitioned into multiple haplotypes, with frequencies of 48% to 2%. The functional implications of the haplotypes were ascertained by whole-gene transfections of human neuronal cells, where haplotype was significantly related (P < 0.001) to expression levels of receptor transcript and protein. Expression varied by as much as Ϸ50% by haplotype, and such studies enabled haplotype clustering by phenotypic, rather than genotypic, similarities. Thus, depending on phenotype, expression-specific haplotypes may amplify, attenuate, or dominate the cardiomyopathic effect attributed to the ␣2CDel322-325 marker.