2 -ADRENERGIC RECEPTOR AND THE CIRCULATION Niels V. Olsen, MD, - PowerPoint PPT Presentation

GENETIC VARIATION IN THE β 2 -ADRENERGIC RECEPTOR AND THE CIRCULATION Niels V. Olsen, MD, DMSc Department of Biomedicine University of Copenhagen

Single nucleotide polymorphism (SNP)

Single nucleotide polymorphisms (SNPs) in β -adrenergic receptors ADRB1 ADRB2

How does ADRB2 variation influence circulation i n ’normal’ subjects

The Gly16Arg SNP seems to have an independent effect on haemodymics in humans

Effects of the Gly16Arg SNP in ADRB2 and the ACE I/D polymorphism on resting Q and Q during submaximal exercise Rokamp et al 2013

Presence of the Gly16 allele in healthy subjects is associated with greater cardiac output and β 2 -mediated vasodilation

Dose-dependent effect of the Gly16 allele on cardiac output Snyder et al 2006

The Gly16 allele enhances β 2 -mediated vasodilatation after baroreflex ablation with Trimethaphan Hesse et al 2010

Anesth Analg 2016; 122: 1385-93

Gly16Arg SNP in ADRB2 and perioperative haemodynamics N = 564 Caucasians Neurosurgery Gly16 homozygote subjects received 32% more ephedrine than Arg16 homozygotes (p = 0.0068, 95% CI: 8%-63%). Nielsen et al 2014

Gly16Arg SNP in ADRB2 and perioperative haemodynamics N = 168 AAA patients Staalsoe et al 2014

Gly16 homozygotes have higher ScO 2 perioperatively compared with Arg16 carriers This association seems to rely on the effect of Gly16 on Q Staalsoe et al 2014

Effects of the Gly16Arg SNP in ADRB2 on relation between Q and age N = 168 AAA patients Staalsoe et al 2014

N = 40 healthy Caucasians During infusion of epinephrine plasma glucose was 1.9 mM higher in the Gly / Gly compared with Arg / Arg homozygotes (p = 0.0001) A genotype specific modulation of epinephrine-induced glycolysis?

ADVANCE ARTICLE 60% 50% Prevalence of severe hypoglycemia (%) 40% * ** 30% 20% 10% 0% GG GA AA GG GA AA GG GA AA Total Normal awareness Impaired awareness

ADVANCE ARTICLE 7 6 Relative Risk of severe hypoglycemia (CI 95 ) 5 * ** 4 3 2 1 0 GG GA AA GG GA AA GG GA AA Total Normal awareness Impaired awareness

How does ADRB2 polymorphism affect the receptor function? Agonist-mediated desensitization Receptor density Degradation

ADRB2 genetic variation and cardiovascular health • In heart failure, Arg16 increases risk of adverse outcome (Shin et al 2007, de Groote et al 2005) • Survival after acute coronary syndrome better with Gly16 in African-Americans (Cresci et al 2012) • No influence on survival in heart failure patients (Sehnert et al 2008)

Conclusions 1. Presence of the Gly16 allele is linked with greater cardiac output and β 2 -mediated vasodilation 2. Genetic variation in the gene encoding the β 2 -adrenergic receptor (ADRB2) has a role in regulation of perioperative haemodynamics in general anaesthesia 3. ADRB2 variation may predict cardiovascular health