Receptor Polymorphisms and Predisposition to Heart Failure
Stephen Liggett, M.D.
University of Cincinnati College of Medicine
P30ES06096
Background: Despite advances in treating heart disease, mortality from heart failure is approximately 50% within 5 years. Beta adrenergic receptors are the predominant cardiac receptors for the catecholamines norepinephrine and epinephrine. These receptors represent the major mechanism whereby cardiac output is increased by the sympathetic nervous system. However, prolonged activation of the receptors ultimately worsens heart function regardless of the initial cause of failure. This is the basis for the therapeutic efficacy of beta-blockers in heart failure.
Advance: Beta-1 adrenergic receptors have been shown to be polymorphic, or to have genetic variants that affect the heart's contractility. This team of investigators created a transgenic mouse model of the human heart failure genotype thus enabling controlled laboratory studies that mimic the human condition. Their studies found that the hearts from the transgenic mice behaved similarly to human hearts.
Implication: These studies show that the human variant genotype predisposes individuals for heart failure by causing hyperactive signaling programs leading to depressed receptor binding and ventricular dysfunction. It also influences the response to therapeutic beta-receptor blockers. The authors conclude that if these phenotypic associations are confirmed in additional studies, early genotyping of all heart failure patients could be indicated for assessing risk or prognosis, or for tailoring therapy for individual patients.
Citation: Citation: Mialet Perez J, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, Schwartz A, Dorn GW, Liggett SB. Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med. 2003 Oct;9(10):1300-5. Epub 2003 Sep 14.
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