Pharmacogenomics of heart failure -- focus on drug disposition and action.
Heart failure represents the composite endpoint of various cardiovascular disorders. Advanced pharmacotherapy resulted in significant improvement of overall survival, however with highly variable outcome, possibly due to genetic modification of drug disposition and action. This review highlights the role of genetic polymorphisms in systems responsible for disposition of drugs, used in heart failure patients (e.g. the polymorphic drug metabolizing enzymes such as cytochrome P450 enzymes, as well as polymorphic ATP-membrane transporters like P-glycoprotein (P-gp)). In addition, genetic variants in physiological systems, being target of drug action, particularly beta-adrenergic receptors, the renin-angiotensin-aldosterone system (RAAS)- and endothelin system, and the endothelial nitrogene monoxide (NO) synthase are reviewed. The current situation in pharmacogenomics of heart failure with respect to drug disposition and action is characterized by multiple studies investigating single components of a complex system. Therefore, overall conclusions regarding treatment and/or outcome of heart failure patients based on individual genetic traits require large prospective trials allowing for simultaneous assessment of multiple genetic variants in different systems. Using advanced screening technologies, such trials can be carried out in the near future.
Cascorbi
Ingolf
I
Department of Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt University, Greifswald, Germany.
Paul
Martin
M
Kroemer
Heyo K
HK
D000450:Aldosterone / Q000235:genetics; D002317:Cardiovascular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology
D002317:Cardiovascular Agents; D044140:Receptor, Angiotensin, Type 1; D000450:Aldosterone; D003577:Cytochrome P-450 Enzyme System; D007703:Peptidyl-Dipeptidase A