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European Heart Journal
Article . 2021 . Peer-reviewed
License: OUP Standard Publication Reuse
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Pharmacogenetics of therapy effectiveness for anthracycline-induced cardiotoxicity

Authors: A.A Popova; SN Shilov; E T Ratushniak; K. V. Kopeva; A T Teplyakov; M N Neupokoeva; E V Grakova; +1 Authors

Pharmacogenetics of therapy effectiveness for anthracycline-induced cardiotoxicity

Abstract

Abstract Objective To evaluate role of genetic factors (polymorphisms of ADRB1 gene (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) for effectiveness assessment of β-blocker (carvedilol) and angiotensin-converting enzyme inhibitor (enalapril) therapy in women with anthracycline- induced cardiotoxicity during 12-month follow-up period. Methods A total of 82 women, median age of 45.0 (42.0; 50.0) years with anthracycline-induced cardiotoxicity and without prior cardiovascular diseases were enrolled in the study. All patients received chemotherapy for the treatment of breast cancer included a combination of doxorubicin and cyclophosphamide, or combination of doxorubicin, cyclophosphamide and docetaxel. The cumulative dose of doxorubicin was 300–360 mg/m2. Criteria for the development of cardiotoxicity were a decrease in the left ventricle ejection fraction (LVEF) at the 12 months after chemotherapy completion by >10%, the development of heart failure (HF) with symptoms and clinical signs, and NT-proBNP levels ≥125 pg/mL. Echocardiography and serum levels of NT-proBNP were performed at baseline and at 12 months after enrollment. Average up-titrated dosage of carvedilol was 50 (25; 50) mg per day and enalapril was 10 (10; 20) mg per day. Evaluation of gene polymorphisms of ADRB1 gene and ACE gene were carried out by polymerase chain reaction at baseline before treatment initiation. Results The baseline LVEF, end-systolic and end-diastolic dimension indexes, NT-proBNP levels, 6-minute walk test distance did not differ among patients with different genotypes of ADRB1 and ACE genes. However, carriers of T/T genotype of ADRB1 gene had a significant increasing in LVEF (<0.001) by 11% from 50.0 (48.0; 51.0) to 56.0 (53.0; 57.0)% and decreasing in end-systolic dimension index (p<0.001) by 27.7% and end-systolic dimension index (p<0.001) by 6% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.001) by 34.2% from 327.5 (260.1; 381.8) to 213.5 (195.3; 256.7) pg/mL and 6-minute walk test distance increased (0.008) by 10%. Carriers of G/G genotype of ACE gene had the same benefits from this therapy: LVEF (<0.001) increased by 6.5% from 50.5 (47.0; 51.0) to 54.0 (50.0; 57.0)%, end-systolic dimension index (p<0.001) decreased by 5.3% and end-systolic dimension index (p<0.001) by 3% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.005) by 20.3 from 314.1 (279.6; 372.9) to 249.9 (197.3; 267.8) pg/mL and 6-minute walk test distance increased (0.008) by 5%. Carriers of other genotypes had decreasing in LVEF, increasing in LV dimensions and NT-proBNP, and further progression of HF. Conclusion Our data suggest that evaluation of gene polymorphisms of ADRB1 (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) can be recommended before treatment initiation of anthracycline- induced cardiotoxicity in women without prior cardiovascular diseases to determine who will benefit of carvedilol and enalapril therapy. Funding Acknowledgement Type of funding sources: None.

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
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Average
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