480
It is estimated that ~12,000 genes are expressed in the cardiovascular system
assuming that the total number of genes in the human genome is ~19,000. Reported
polymorphisms relevant to cardiovascular disease management are shown in
Table 14.1. Genotyping for cardiovascular disorders polymorphisms enables per-
sonalization in management.
In patients with systolic dysfunction, the ACE D allele is associated with a sig-
nifi cantly poorer transplant-free survival. This effect is primarily evident in patients
not treated with β-blockers and is not seen in patients receiving therapy implying
that β-blocker therapy can negate this effect. These fi ndings suggest a potential
pharmacogenetic interaction between the ACE D/I polymorphism and therapy with
β-blockers in the determination of heart failure survival. Further information on this
point will be available when a pharmacogenetic substudy of the β-blocker Evaluation
of the Survival Trial (BEST) is unblinded. BEST is a randomized, placebo- controlled
joint study by the US Veterans Administration and National Heart Lung & Blood
Institute that looks at polymorphisms in the genes for ACE, angiotensinogen, angio-
tensin receptor, β 1 and β 2 receptors, and endothelin in over 1,000 patients.
In the familial type of heart failure called dilated cardiomyopathy (DCM), addi-
tional mutations have been reported in SCN5A, a gene on chromosome 3. SCN5A
encodes the Na ion channel in the heart, which helps regulate transport of positively
charged Na ions, and therefore the heart’s electrical patterns. This fi nding broadens
the indications for genetic screening of SCN5A beyond isolated rhythm disorders.
Since these variations hinder Na transport, it is advisable to avoid using Na channel-
blocking drugs in heart failure patients with SCN5A mutations, because those drugs
may make the problem worse.
Despite the enormous progress in sequencing the human genome and in molecu-
lar genetic and bioinformatic techniques during the past decade, the progress in
mapping and identifying genes responsible for complex traits such as coronary
heart disease and myocardial infarction has been modest and presents a formidable
challenge to medical research in the twenty-fi rst century. One example is the study
of why hypertension is more frequent and more severe in Afro-Americans. Although
many studies have focused on hypertension in black people in an attempt to under-
stand the genetic and environmental factors that regulate blood pressure, this
approach has not been productive. Study of the relationship between specifi c phe-
notypes and genotypes, both within and across ethnic groups, is more likely to
advance our understanding of the regulation of blood pressure than studies focused
on race and blood pressure.
Despite the limitation, impact of genomic analysis on cardiovascular research is
already visible. New genes of cardiovascular interest have been discovered, while a
number of known genes have been found to be changed in unexpected contexts. The
patterns in the variation of expression of many genes correlate well with the models
currently used to explain the pathogenesis of cardiovascular diseases. Much more
work has yet to be done, however, for the full exploitation of the immense informa-
tive potential of cardiovascular genomics. Meanwhile, cardiovascular system is
receiving its due share of interest in genomics-based drug discovery and develop-
ment in the commercial sector.
14 Personalized Management of Cardiovascular Disorders