491nervous system and that patients with the D allele may thus derive greater benefi ts
from pharmacologic interventions to decrease sympathetic nervous system activity
(e.g., β-blocker therapy).
Despite the proven effi cacy of β-blockers, there are many reasons why so many
patients with congestive heart failure are not treated with these medications. One
important reason is concern for adverse reactions, which occur in 25–43 % of
patients. Discontinuation of therapy is frequent due to hypotension, bradycardia and
worsening of heart failure. This has led to the study of genetic variants that determine
response to β-blockers. Polymorphisms in the gene coding for the CYP2D6 isoen-
zyme, which catalyzes the metabolism of β-blockers such as metoprolol, carvedilol,
timolol, and propranolol, may also affect β-blocker response. It is possible that the
CYP2D6-related genotype interacts with drug target polymorphisms (e.g., β-receptor
polymorphisms) and polymorphisms in genes involved in pathophysiology (e.g., the
ACE I/D polymorphism) to infl uence the overall response to β-blockers.
In addition to genetic variants that affect plasma concentrations of a drug, vari-
ants in drug target, the β 1 -receptor could also alter responses to β-blockers. A clini-
cal study of titration of metoprolol controlled release/extended release in heart
failure revealed that patients with the Gly389 variant and Ser49Ser genotype of β 1 -
receptor are signifi cantly more likely to require increases in heart failure medica-
tions during β-blocker titration and thus may require more frequent follow-up
during titration (Terra et al. 2005 ).
Bucindolol
Bucindolol’s unique pharmacology in advanced heart failure patients is to produce
either a hyper-response (a β1 receptor polymorphism) or avoid an adverse effect (an
α2c receptor polymorphism). These dual gene loci create a set of diplotypes charac-
terizing the population. By identifying important genetic factors underlying heart
failure and the response to bucindolol, Arca Discovery Inc has identifi ed those
patients who will benefi t most from bucindolol treatment. A polymorphism within a
conserved beta(1)-adrenergic receptor motif alters cardiac function and β-blocker
response in human heart failure. A study concluded that beta(1)AR-389 variation
alters signaling in multiple models and affects the β-blocker therapeutic response in
heart failure and, thus, might be used to individualize treatment of the syndrome
(Liggett et al. 2006 ).
When prescribed genetically, bucindolol will be the state of the art in heart fail-
ure treatment for a majority of the of the US heart failure population. Bucindolol’s
unique pharmacology gives it other advantages as well, such as superior myocardial
infarction clinical endpoints and tolerability.
BiDil
Enalapril therapy is associated with a signifi cant reduction in the risk of hospitaliza-
tion for heart failure among white patients with left ventricular dysfunction, but not
among similar black patients. This fi nding underscores the need for additional
Role of Diagnostics in Personalized Management of Cardiovascular Disease