Pharmacogenomics of congestive heart failure

The future of pharmacogenomic therapy for CHF will require the determination of key genes that are critical in mediating cardiac remodeling [28]. Cardiac remodeling includes several processes including cardiac myocyte hypertrophy and apoptosis. Determination of genes that turn on and off the processes of hypertrophy and apoptosis may allow the future clinician to determine which patients with dilated cardiomyopathy would require antiapoptotic therapy, therapy directed to reducing cardiac myocyte hypertrophy, therapy directed to influencing cell survival, or a combination of such therapies. One strategy for identifying culprit heart failure genes is to compare expression profiles and cellular responses in human and mouse models of disease (Figs. 1 and 2). A high-throughput screen using common transcripts in the mouse and human models of heart failure is the initial step. This is followed by evaluation of the function of these novel genes by using the genes in mouse culture with the gain of function assay or the loss of function assay (antisense nucleotides). Other steps in the confirmation of the culprit gene include the use of transgenic animals to verify their individual contribution to the pathogenesis of CHF [29]. One group of investigators [30] using some of these techniques, particularly large-scale automated DNA sequencing, generated over 40,000 expressed sequence tags (ESTs) from human heart cDNA libraries. In addition, they retrieved over 40,000 ESTs from public databases. They found that, from the total of 84,904 ESTs, about 55% matched known genes, or approximately one third, matched other ESTs, and approximately 12% did not match any known sequences. Many of the latter are novel genes, and further efforts have to be made to verify their contribution to the pathogenesis of heart failure. Using high-density oligonucleotide arrays, one group of investigators found that several genes were altered in the failing heart, and they grouped these into five clusters. The clusters included (1) genes that encode contractile and cytoskeletal proteins (ie, SLIM1, β-acting, and myomesin MLC2); (2) genes encoding proteins that influence the disassembly and degradation of myocardial proteins (ie, ubiquitin, gelsolin, and α1-antichymotrypsin); (3) genes encoding proteins of the mitochondria (ie, aldose reductase, ATP synthase α-subunit, and TIM17 preprotein translocase); (4) genes encoding stress proteins (ie, αβ-crystallin and μ-crystallin); and (5) genes encoding proteins that influence protein synthesis including EF-2 and transcription factor homologue-HBZ17. Although the precise role of these proteins in CHF remains to be characterized, these genes should enhance our understanding of signaling pathways in the cardiac myocyte and, consequently, promote the development of newer therapies for CHF including gene delivery depending on pharmacogenomic profile (see the article by Dr. Hajjar et al elsewhere in this issue). Fast forward to the year 2010. A typical patient with CHF will require a blood test to determine his or her gene profile for the management of the disease. A deletion/insertion of the polymorphism in the ACE gene indicating that the patient is salt-sensitive suggests that salt restriction and diuretic therapy are more important in such a patient than in one who is not salt-sensitive [31-33]. A bradykinin-receptor polymorphism suggesting that the patient may develop a cough with ACE-inhibitor therapy means the clinician will have to avoid an ACE inhibitor. If the patient has beta-receptor polymorphisms suggesting that he or she will respond to beta-blocker therapy, then the patient may have only beta-blocker and diuretic therapy rather than the whole complement of ACE-I, digoxin, and diuretics. Depending on the genetic variant of CYP2D6, the clinician can decide whether the patient requires only β-1 blockade with metoprolol XL or requires α1/β blockade with carvedilol. In a different scenario, if the patient has pulmonary hypertension and a receptor polymorphism of the endothelin receptor, then the clinician may decide on an endothelin-receptor antagonist as first-line therapy (although, at this point of time, endothelin receptor antagonists have not been shown to be beneficial when added to standard therapy). Therefore, tailored therapy will not only allow a choice of which drug is more effective, but it will also allow the physician to withhold drugs that may cause side effects and to determine optimal dosages. These examples represent our incomplete understanding of the genetic modifiers of CHF and host sensitivity to therapy; ongoing studies should substantially enhance the use of such pharmacogenomic strategies. The rapid growth of ESTs and single-nucleotide polymorphism (SNP) databases coupled with advances in genomic technology should make pharmacogenomic therapy a reality in the not-too-distant future. Although the SNP profiles will provide information concerning a patient's response to medicine, it is important to reassure patients that the profiles will not determine precisely the presence of a disease-specific genetic mutation or any other disease-specific information about the patient or family members. Information on the drug's probable efficacy and safety for an individualized patient should change both the economics and the management of CHF. The rapid profiling of patients should allow more streamlined drug development and enhance the development of "designer" drugs for different patients with similar disease phenotypes. Another potential advantage of pharmacogenomics is that it may resurrect promising drugs that were discarded because they did not show benefit when previously added to standard therapy. The promise of pharmacogenomics has to be tempered, however, by the sensitivity to concerns regarding potential misuse of genomic information; these include loss of confidentiality for the patient, as well as possible stigmatization of groups. Such difficult genoethical issues must be addressed in order to reap the full benefits of this rapidly evolving and exciting field.