Genomic variation and neurohormonal intervention in heart failure.
Neurohormonal activation is an important driver of heart-failure progression, and all pharmacologic interventions that improve heart-failure survival inhibit this systemic response to myocardial injury. Adrenergic stimulation of beta(1) receptors in the kidney results in the release of plasma renin, the conversion of peptide precursors to angiotensin II (a2), and ultimately the production of aldosterone. beta(1)-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone receptor antagonists all act by inhibiting the activity of critical protein of this core pathway: the beta(1) receptor, ACE, the a2 receptor, and aldosterone synthase. Investigation of the pharmacogenetic interactions of the ACE D/I polymorphism and heart-failure therapy demonstrates the power of genomics to target therapeutics. This review explores how genetic variation in genes involved in neurohormonal activation influences heart-failure outcomes and the impact of pharmacotherapy.
McNamara
Dennis M
DM
Heart Failure/Transplantation Program, Cardiovascular Institute, University of Pittsburgh Medical Center, S566 Scaife Hall, 200 Lothrop Street, Pittsburgh, PA 15213, USA. mcnamaradm@upmc.edu
D000110:Acetylcholinesterase / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D018377:Neurotransmitter Agents / Q000627:therapeutic use*; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000235:genetics; D011110:Polymorphism, Genetic; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D018570:Risk Assessment
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D018377:Neurotransmitter Agents; D011943:Receptors, Adrenergic, beta; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019405:Cytochrome P-450 CYP11B2; D000110:Acetylcholinesterase