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Pharmacogenetics in the Treatment of Heart Failure

Morten Pedersen

English summary

Beta-blockers are used as first-line treatment of chronic heart failure (HF). Despite a documented survival effect, some HF patients do not have the expected benefit from beta-blocker treatment. Pharmacogenetics might be a means to identify the group of poor responders. Mainly, two functional SNPs from ADRB1 and two functional SNPs from ADRB2 have been the subject of interest, when trying to document a consistent genotype-dependent betablocker response, i.e. drug-genotype interaction. Studies indicate that metoprolol might interact with the ADRB1 Arg389Gly polymorphism, and that carvedilol might interact with the ADRB2 Gln27Glu polymorphism, but this has only been shown for clinical markers and biomarkers in HF. In survival association studies, these genotype-dependent responses have not been replicated. It was the aim of the present PhD-project to investigate, whether combining functional SNPs from ADRB1 and ADRB2 could prove more valuable in identifying groups of poor beta-blocker responders. In addition to this strategy, we suspected that an important interplay between beta-blockers and the renin-angiotensin-aldosterone system (RAAS) have largely been overlooked. Two SNPs from AGT have shown clinical relevant functionalities, and we hypothesized that adding these SNPs to combinations of ADRB1 and ADRB2 genotypes could improve the identification of poor responders.

Blood samples from 618 HF patients from the EchoCardiography and Heart Outcome Study (ECHOS) were used for the ADRB1ADRB2, AGT genotyping. Also other candidate genes were genotyped. The outcome was all-cause mortality, and the primary results are presented in two papers. With these two papers we were able to identify a group of poor carvedilol responders based on their ADRB1, ADRB2, AGT genotypes. By combining these geno types specifically we identified a group of HF patients with a doubled hazard of mortality compared to any other HF patients when treated with carvedilol. The specific combinations were based of the known functionalities of the individual SNPs and made up 37–46 percent of the entire cohort depending on which stratification was superior. This, we were not able to determine. With the ECHOS sub-study we were not able to identify a group of poor metoprolol responders. 

Paper III in the present PhD-project presents a clinical study of 29 healthy, subjects treated with metoprolol. This study verified the findings of other studies, showing that the response to metoprolol might be dependent on the ADRB1 Arg389Gly polymorphism. Unlike all other studies, we found that the concentration of metoprolol was essential for this genotype-dependent response. We found a strong association between metoprolol concentration and plasma renin activity (PRA) in Gly/Gly subjects that was different to the non-significant associations in Arg/Gly and Arg/Arg subjects. Based on these findings, we speculated that there might be different dose-response curves for metoprolol between the Arg389Gly genotypes. This might be relevant in optimizing and individualizing the metoprolol up-titration in HF patients. The significance of accounting for metoprolol concentration when investigating the drug-genotype interaction between metoprolol and Arg389Gly, might explain why several studies have failed to determine a genotype-dependent survival response to metoprolol. 

Our findings need replication, before any definite conclusions on the genotype-dependent responses to metoprolol and carvedilol can be done. Hopefully, two ongoing studies (DANISH, MOCADICHO) will show the reproducibility of the present findings.