ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Feldman, A. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Feldman, A. M.
Related Collections
Right arrow History

Ann Thorac Surg 2003;76:S2246-S2253
© 2003 The Society of Thoracic Surgeons

Supplement: Gibbon & His Heart-Lung Machine

The emerging role of pharmacogenomics in the treatment of patients with heart failure

Arthur M. Feldman, MD, PhDa*

a Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, USA

* Address reprint requests to Dr Feldman, Department of Medicine, Jefferson Medical College, 1025 Walnut St, Room 822, Philadelphia, PA 19107-5083, USA
e-mail: Arthur.feldman{at}mail.tju.edu

Presented at the symposium, "Gibbon & His Heart-Lung Machine: 50 Years & Beyond," Philadelphia, PA, May 2, 2003.

Heart failure is a disease of epidemic proportions effecting more than 5 million people in the United States. It accounts for more than 1 million hospitalizations, represents the most common discharge diagnosis of patients over the age of 65, and is one of only a handful of human diseases that are increasing in frequency. The increase in frequency of heart failure is due at least in part to the aging of the US population. It is expected that more than 450,000 new cases will be recognized in the coming year and nearly an equal number of deaths will occur that are directly attributable to heart failure. Inclusive of both inpatient and outpatient costs, the care for heart failure will cost the US economy nearly 30 billion dollars in 2003.

Over the past 2 decades seminal information regarding the pathophysiology of heart failure has come from evaluation of the results of large multicenter, randomized, placebo-controlled clinical trials. These studies have validated the use of both angiotensin-converting enzyme (ACE) inhibitors and beta adrenergic-receptor blockers (ß-blockers) in the therapy of heart failure, findings that have resulted in improvements in both morbidity and mortality. However two fundamental observations have come from heart failure clinical trials: only some patients respond to a given drug; and different patients respond differently to the same drug. This variability in pharmacologic response provides important relevance to heart failure patients, many of whom take as many as nine medications. Identifying which drugs benefit selected patients can obviate adverse drug effects; decrease the total number of medications consumed by individual patients; decrease pharmaceutical costs; improve compliances; and provide an opportunity to optimize the dosing of those drugs that will be most effective.

The fact that selective patient groups respond differently to a pharmacologic agent could be explained by either their phenotype or their genotype. In patients with heart failure, phenotype is relatively easy to assess and can include measures such as ejection fraction, functional capacity (MVO2, 6-minute walk time), heart failure symptoms (New York Heart Association classification, Global Assessment scoring), quality of life (Minnesota Living with Heart Failure, Kansas City Questionnaire), or ventricular morphology (left ventricular volume, left ventricular mass, or left ventricular diameter). In addition historical information can also be important in patient phenotyping including the number of hospitalizations. By contrast identifying a patient's genotype has been far more challenging. However recent breakthroughs in molecular technology now provide the opportunity to identify both mutations and single nucleotide polymorphisms with a high degree of accuracy. These new techniques have resulted in the advancement of pharmacogenomics and functional genomics and their application to the treatment of patients with heart failure.

Effect of phenotype on heart failure outcomes

Several recent clinical trials clearly illustrate selective response in patients with different phenotypes. For example in an early trial involving 477 patients, the oral inotropic agent vesnarinone effected a 61% reduction in the risk of a patient dying during a 6-month period [1]. By contrast in a second study involving a total of 3,833 patients, an identical dose of vesnarinone was associated with an increased number of deaths [2]. While these differences might be attributed to the size of the two studies there were important phenotypic differences between the two study populations. For example in the initial study patients were required to have serum digoxin levels less than 1.8 ug/L, serum creatinine less than 2.4 mg/dL, and the ability to perform upright-bicycle exercise. Nearly 20% of enrolled patients had NYHA class II symptoms. By contrast there were no exercise criteria for entry into the Vesnarinone Trial, digoxin levels were not assessed, and patients were required to have NYHA class III or IV heart failure symptoms. Similar differences in drug response can be identified in recent studies assessing the efficacy of anticytokine therapy with the tumor necrosis factor (TNF) soluble receptor etanercept (Enbrel). In early studies assessing efficacy of etanercept in patients who were able to exercise, the recombinant protein effected improvements in cardiac size and function [3]. By contrast etanercept showed no benefit in patients who were unable to exercise (D. Mann, unpublished data). Perhaps exercise served as a surrogate marker of functional reserve and fibrosis in these patients.

Evaluation of genotype in patients with heart failure

Recent clinical trials have also suggested the possibility that genotypic differences rather than simply phenotypic differences might also result in different outcomes in various patient groups. For example the ACE inhibitor enalapril was more effective in white patients with heart failure than in black patients [4] whereas the combination of hydralazine and isosorbide appeared to be more effective in black patients [5]. Furthermore the ß1 selective ß-blocker bucindolol appears less effective in black patients whereas the nonselective ß-blocker carvedilol appears to be equally effective in black and white patients [6, 7] Figures 1–7 .



View larger version (13K):
[in this window]
[in a new window]
  		Fig 1. Effects of the wild-type genotype (n = 247 patients) or Ile164 (n = 10) polymorphism in the adrenergic receptor gene on transplant-free survival in patients with heart failure. (Reprinted with permission from Liggett SB, et al. J Clin Invest 1998;102:1534–9.)

 


View larger version (10K):
[in this window]
[in a new window]
  		Fig 2. Effect of a bi-allelic polymorphism in intron 16 of the angiotensin-converting enzyme gene on angiotensin II levels.

 


View larger version (14K):
[in this window]
[in a new window]
  		Fig 3. Transplant-free survival compared by angiotensin-converting enzyme (ACE) genotype. Overall cohort, n = 328. Ordered log-rank test, p = 0.044. (Light line = ACE II; dashed line = ACE ID; heavy line = ACE DD.) (Reprinted with permission from McNamara DM, et al. Circulation 2001;103:1644–8.)

 


View larger version (20K):
[in this window]
[in a new window]
  		Fig 4. (A) Transplant-free survival by angiotensin-converting enzyme (ACE) genotype. Patients not treated with ß-blockers at time of study entry (n = 208). (Light line = ACE II; dashed line = ACE ID; heavy line = ACE DD.) (B) Transplant-free survival compared by ß-blocker use for patients with ACE DD genotype only (n = 105). Event-free survival was significantly better for patients treated with ß-blockers (n = 43) compared with those not receiving therapy (n = 62; p = 0.007 by log-rank test). (Solid line = no beta blocker; dashed line = beta blocker.) (Reprinted with permission from McNamara DM, et al. Circulation 2001;103:1644–8.)

 


View larger version (18K):
[in this window]
[in a new window]
  		Fig 5. The effects of mutations in the adenosine monophosphate (AMP) deaminase gene.

 


View larger version (16K):
[in this window]
[in a new window]
  		Fig 6. Event-free survival by endothelial nitric oxide synthase (NOS3) codon 298 polymorphism in a population of heart failure patients (n = 469). (Solid line = Asp298; dashed line = Glu-Glu.) (Reprinted with permission from McNamara DM, et al. Circulation 2003;107:1598–602.)

 


View larger version (13K):
[in this window]
[in a new window]
  		Fig 7. Effects of adenosine monophosphate (AMP) genotype on the probability of survival without transplantation in patients with heart failure. (Reprinted with permission from Loh E, et al. Circulation 1999;99:1422–5.)

 
Over the past decade a small number of genetic mutations have been identified that are associated with development of a familial form of idiopathic dilated cardiomyopathy. More recently in light of clinical studies suggesting an influence of genotype in disease response scientific interest has focused on the role of a patient's genotype in predicting their likelihood of developing disease in response to stress or injury (functional genomics) or the response to pharmacologic therapy (pharmacogenomics) in patients who already have heart failure. The human genome project, which provided the nucleotide sequence of the human genome, has provided many of the scientific underpinnings of functional genomics; however new technology has also been important for providing the tools necessary to evaluate the importance of genetics in the development of heart failure. For example it has become increasingly easy to identify the occurrence of polymorphisms, nonlethal mutations that alter protein function (eg, enzyme function). Polymorphisms may alter an individual's response to environmental factors including drugs, stress or disease, or may have no functional significance. Technologic breakthroughs have also provided the capabilities necessary to accurately and efficiently identify the presence of single nucleotide polymorphisms (SNPs) in genetic material obtained from DNA. Estimated to exist in the thousands in any individual's gene pool, SNPs may or may not have functional significance. Thus their recognition requires a close linkage of genomics and translational medicine: genomics being the science that identifies the structure of the human gene and translational medicine (or functional genomics) being the science that evaluates the functional significance of changes in genetic structure.

In cardiovascular disease these tools have been used to identify the role of gene structure in predicting the risk of developing heart failure as well as for determining an individual patient's response to pharmacologic therapy. To date this research has focused largely on the presence of polymorphisms in genes that are important in the pathophysiology of heart failure—most notably genes encoding proteins important in neurohormonal and cytokine activation. In each case the overexpression of various neurohormones, cytokines, and endogenous peptides have been shown to play some role in the pathogenesis of heart failure. In addition these proteins and peptides have also served as therapeutic targets. Thus the presence of polymorphisms that effect either an increase or a decrease in neurohormone/cytokine production or responsiveness would be predicted to modify either outcome or therapeutic response in a heart failure population.

Polymorphisms in adrenergic receptors

In response to diminished cardiac output the failing heart is characterized by increased adrenergic drive and the release of norepinephrine. This increased adrenergic drive is maladaptive as it leads to adrenergic receptor pathway desensitization and cardiotoxic effects on the ventricular myocardium [8, 9]. Indeed in animal models, cardiac targeted overexpression of either the ß1 or the ß2 adrenergic receptor lead to the development of cardiac dilatation and failure in a dose-responsive manner [10]. These findings led investigators to assess whether the presence of polymorphisms or mutations in the genes encoding the ß-adrenergic receptors might have import in determining either drug response or outcome in patients with heart failure or alternatively the risk of developing heart failure in patients without obvious cardiac disease.

Several relatively common polymorphisms have been identified in the ß1-AR gene [11, 12]. An A to G substitution at nucleotide position 145 results in either a Ser or Gly at amino acid position 49. A G to A substitution at nucleotide 1165 results in an Arg instead of a Gly at amino acid position 389—although it should be noted that the Gly is actually the minor allele (the original report of the cloning of the receptor having cloned the less common allele). When studied in kidney cells, the Gly 49 receptor underwent a 25% loss of receptor density after exposure to isoproterenol for 18 hours; however the Ser 49 receptor did not undergo receptor downregulation [13]. Thus the Gly49 receptor exhibits wild-type coupling with enhanced agonist-promoted downregulation.

When expressed in vitro, receptors having a Gly at amino acid position 389 were less able to effect an increase in adenlyl cyclase activity in the presence of agonist than were receptors having an Arg. Thus it was not surprising that patients homozygous for Arg 389 had a more robust exercise response when compared with patients homozygous for Gly 389 [14]. However because of the limited size of these studies, they were unable to provide information as to how ß1/ß2AR genotypic combinations might influence exercise capacity. Furthermore these studies raised the possibility that while patients having decreased adrenergic coupling due to a Gly at position 389 had a less robust exercise response, they might have improved survival because of diminished adrenergic receptor-adenlyl cyclase coupling. Interestingly the Arg 389 genotype alone was not associated with an increased risk for the development of heart failure [15]. However there was a 10-fold increased risk of the development of heart failure in black subjects who were homozygous for ß1Arg389 and a common coding polymorphism of the gene for the {alpha}2c-AR—the deletion of four amino acids (Del322-325).

Found at an allele frequency of 0.411 in black subjects but only at an allele frequency of 0.038 in white subjects, {alpha}2c Del322-326 effects a substantial loss of synaptic autoinhibitory feedback resulting in enhanced presynaptic release of norepinephrine [16, 17]. Taken alone it results in a 5.65 odds ratio for heart failure. By contrast black subjects have an allele frequency for the ß1Arg389 of 0.560 while white subjects have an allele frequency of 0.762. Thus individuals harboring homozygous alleles for both variants would have enhanced receptor activation secondary to higher extracellular levels of norepinephrine and heightened responsiveness due to more effective receptor-effector coupling. Taken together these two changes would likely magnify any cardiotoxic effects of adrenergic drive. Furthermore these studies suggest that the presence of this two-locus genotype may be effectively treated with tailored therapy that combines a ß-adrenergic receptor antagonist and an {alpha}2-adrenergic receptor agonist. Studies to test this hypothesis are ongoing.

At least four polymorphic loci have been identified in the coding region of the ß2AR gene and several have also been identified in the five upstream regions [18–21]. The most common polymorphisms are an A to G substitution at nucleotide 46 resulting in an Arg or Gly being encoded at amino acid 16; a C or a G at nucleotide 79 resulting in a Gln or Glu at amino acid 27; and a C or a T at nucleotide 492 resulting in a Thr or Ile at amino acid position 164 in the fourth transmembrane spanning domain of the receptor (homozygous Ile being extremely rare). Because of their location in the amino-terminal end of the receptor, polymorphisms at amino acids 16 and 27 did not influence agonist or antagonist binding or coupling to G proteins [22]. However polymorphisms in these two regions (namely amino acids 16 and 27) did alter downregulation in response to chronic agonist exposure. For example wild-type (Arg-16/Glyn 27) receptors downregulated 26%, Gly-16/Glyn27 receptors downregulated 41%, and the Arg16/Glu27 receptor failed to downregulate when exposed long-term to isoproterenol; Ile164 has decreased binding affinity for ßAR agonists resulting in decreased basal and agonist-stimulated adenylyl cyclase activities when compared with Thr ßAR [23].

Evaluation of the influence of selected polymorphisms in patients with heart failure was consistent with studies in vitro (Fig 1). For example patients with Ile164, Gly 16, and the combination of Gly16 and Gln27 had diminished functional capacity when compared with Thr164, Arg16, and Gly16/Gln27 respectively [24]. Thus patients having a genotype in which both loci were homozygous for receptors resistant to downregulation (namely Arg16/Glu27) had higher functional capacity on exercise as measured by a higher oxygen consumption than did patients in whom both receptor polymorphisms favored susceptibility to downregulation (namely Gly16/Gln27) [24]. By contrast when comparing patients with Ile64 or Thr164 the lower functional capacity in patients with Ile164 was likely secondary to decreased ability of adrenergic drive to effect increased adenylyl cyclase and subsequent improvements in myocardial contractility due to decreased coupling of the Ile64 receptor. The Gly-16 ß2AR polymorphism has also been associated with attenuated vasodilatory response to catecholamines in normal individuals and thus might influence peripheral blood flow and vascular resistance in patients with heart failure. Thus assessment of ßAR genotype might have important implications in both prognosis and treatment of patients with heart failure. However identification of the response to ß-blockade or long-term outcomes in heart failure patients with varying ßAR genotypes has not yet been thoroughly evaluated.

Polymorphisms in the angiotensin-converting enzyme gene

Like adrenergic drive, increased levels of angiotensin II have also been associated with a worse outcome and higher mortality in patients with heart failure [25]. Angiotensin II is produced in the heart, upregulated by hypertrophic signals and mechanical load, and effects changes in both myocyte structure and the extracellular matrix [26]. However whether it is the AT1 or AT2 receptor that initiates deleterious myocardial or myocyte events is unclear [27] despite recent studies using genetic over-expression and knock-out models. However inhibition of the angiotensin-converting enzyme has become a mainstay in the therapy of patients with heart failure as ACE inhibition improves survival in patients with NYHA class II to IV symptoms and decreases the combined endpoint of all cause mortality and hospitalizations in patients with assymptomatic left ventricular dysfunction [28, 29]. Like ß-blockade, ACE inhibition appears to benefit some but not all patients with heart failure. This finding is most notable in the differential effect of ACE inhibitors in black patients and white patients with heart failure described earlier. In addition both normal patients and those with heart failure have great variability in circulating levels of ACE.

The variability in serum levels of ACE is due at least in part to genetics [30]. A common biallelic polymorphism is found in intron 16 of the ACE gene [31]. The two alleles differ in the presence or absence of a 287-base pair insertion (I, insertion; D, deletion) (Fig 2). Thus individuals can present with one of three genotypes: DD, ID, and II. The D allele has been consistently associated with higher ACE activity or angiotensin II levels in a variety of populations including normal persons [32], hypertensive subjects [33], and patients with heart failure after a myocardial infarction [34]. Those homozygous for the D allele have the highest levels of angiotensin II, those homozygous for the I allele have the lowest levels, and heterozygous individuals have intermediate levels. However despite the obvious pathophysiologic relevance and early observational studies the relevance of the ACE polymorphism to clinical risk remains somewhat controversial [35–38].

There is less controversy regarding the influence of ACE genotype in patients with heart muscle disease. For example patients with the D/D genotype have decreased exercise tolerance [39]. In addition patients in the Captopril and Thrombolysis study (CATS) with two D alleles had significantly more left ventricular dilatation one year after a myocardial infarction [40]. However both of these studies were relatively small.

Recently we investigated whether the ACE deletion allele was associated with an adverse outcome in 328 patients with heart failure who were either treated or not treated with ß-blockade [41]. Transplant-free survival was compared by genotype for the whole cohort and separately in patients with (n = 120) or without (n = 208) ß-blocker therapy (Fig 3). Transplant-free survival was significantly worse in patients with the D allele—a finding that was consistent with an earlier study [42]. This genetic heterogeneity did not seem to be influenced by ACE inhibitor therapy. Also consistent with earlier studies, the ACE D allele did not appear to increase the risk of myocardial injury and the development of heart failure but rather appeared to act as a disease modifier, altering the rate of disease progression [43]. Importantly in patients not treated with ß-blockers the adverse impact of the ACE D allele was dramatically increased. By contrast in patients receiving ß-blocker therapy the influence of ACE genotype on transplant-free survival was not evident. Furthermore ß-blocker therapy appeared to have its most marked effect in patients with the DD genotype. Thus these results suggested important pharmacogenetic interactions between the ACE D/I polymorphism and therapy with ß-blockers in the determination of heart failure survival (Fig 4). Furthermore they suggested that in patients with the DD genotype, treatment with optimal doses of ß-blockade might be started before optimization of therapy with an ACE inhibitor—in contrast to common therapeutic algorithms.

Influence of a polymorphism in the endothelial nitric oxide synthase gene

Another neurohormone that is expressed at high levels in patients with heart failure is nitric oxide (NO) [44]. Nitric oxide is synthesized from L-arginine by a family of three enzymes, the nitric oxide synthases (NOS) [45]. Endothelial nitric oxide synthase (NOS3) and the neuronal isoform (NOS1) are constitutive enzymes that produce low levels of basal NO production. By contrast inducible nitric oxide synthase (NOS2) produces high levels of NO in the presence of physiologic stimuli most notably tumor necrosis factor (TNF). Nitric oxide plays an important role in the pathophysiology of heart failure through relaxation of smooth muscle cells in the peripheral vasculature (although effects appear to be blunted in heart failure patients secondary to a decrease in the L-arginine-NO metabolic pathway and impairment of NOS activity) [46] and inhibition of adrenergic-activated myocyte toxicity [47]. Thus pharmacologic or genetic reductions in NOS activity would be predicted to have an adverse impact on heart failure progression.

In NOS3 a common polymorphism switch from G to T in nucleotide 894 results in the conversion of glutamate to aspartate at codon 298. The Asp298 variant has a shorter half-life in endothelial cell cultures as the result of increased enzymatic cleavage [48]. Thus it is not surprising that patients with Asp298 have an increased vasoconstrictive response to vasoconstrictors consistent with decreased NOS activity. Consistent with this finding patients with heart failure who harbored the Asp298 polymorphism had a significantly poorer event-free survival when compared with those having the wild-type genotype [49]. That these interactions are complex was shown by the fact that the impact of the Asp298 variant was seen predominantly in patients with nonischemic cardiomyopathy and not in those with heart failure secondary to ischemic heart disease. While studies assessing the relevance of polymorphisms in the NOS2 gene will also be of importance, these early association studies suggest that polymorphisms in the NOS genes might be important in prognostic predictions as well as in the evaluation of the success of potential NO donors in the therapy of heart failure (Fig 6).

Aldosterone synthase and heart failure

Like angiotensin II and NO, an increase in aldosterone is also associated with heart failure. Similar to other neurohormones a direct relationship has been identified between aldosterone and mortality in this group of patients [50, 51]. Aldosterone has a variety of effects on both the heart and the vasculature. For example aldosterone induces rapid increases in intracellular calcium and thus may potentiate the effects of other vasoconstrictors and might also exert important effects on nitric oxide pathways in the endothelium. Fibroblasts residing in the interstitial spaces of the adventitia also respond to aldosterone and this peptide may be an important determinant of vessel and heart muscle remodeling [52, 53]. That inhibition of aldosterone can provide salutary benefits in patients with heart failure was first observed by the Randomized Aldactone Evaluation Study (RALES) [54]. In patients with NYHA class III/IV heart failure symptoms treated with standard therapy including an ACE inhibitor, a diuretic, and a ß-blocker, aldosterone effected a 30% reduction in mortality that was the result of a decrease in progressive heart failure-related deaths as well as sudden cardiac death.

Interestingly a single nucleotide polymorphism has been recognized in the promoter of the aldosterone synthase gene. Located at position -344, this T to C transition results in a significant increase in aldosterone levels in patients harboring either one or two copies of the effected allele. Recently we found that survival was not adversely effected by the presence of patients having one allele containing the polymorphism. However when linked with the DD ACE genotype, patients who were homozygous for the DD ACE allele and who had one copy of the aldosterone synthase -344 single nucleotide polymorphism had a markedly worse transplant free survival than those having the ACE DD genotype alone [49]. However additional studies will be needed to fully understand the relevance of this polymorphism to disease prognosis as well as to therapy with aldosterone inhibitors.

Cardioprotection effects of adenosine

Heart failure in humans is also characterized by an increase in plasma concentrations of adenosine, possibly through norepinephrine and angiotensin II-induced activation of ecto-5'nucleotidease [55, 56]. Produced by both cardiomyocytes and endothelial cells, adenosine effects salutary benefits on the heart through a variety of mechanisms including attenuation of release of catecholamine, increase in coronary blood flow, inhibition of platelet and leukocyte activation, and inhibition of rennin release and TNF{alpha} expression [57–59]. In addition adenosine is a critically important mediator of the cardioprotection afforded by ischemic preconditioning [60].

The enzyme adenosine monophosphate (AMP) deaminase is the rate-limiting step for entry into the purine nucleotide cycle and catalyzes the conversion of AMP to inosine monophosphate (Fig 5). Alternatively AMP is converted to adenosine by nucleotidase [61]. In the presence of decreased activity of AMP deaminase, the stoichiometry of the reaction shifts toward increased production of adenosine. Thus patients with AMP deaminase deficiency have increased adenosine production. A relatively common mutation is found in at least 1 allele of the AMP deaminase 1 gene. This nonsense mutation results in diminished (heterozygous) or absent activity of AMP deaminase resulting in increased expression of adenosine. Putatively the presence of the AMPD1 mutation would be expected to have a better outcome in the presence of heart muscle dysfunction because endogenous muscle adenosine levels would be higher. Indeed Loh and colleagues [62] found that patients having at least one allele harboring the AMPD1 mutation experienced significantly longer duration of heart failure symptoms before referral for transplantation evaluation and had a greater chance of surviving without a cardiac transplant when compared with patients homozygous for the wild-type allele (Fig 7).

Another tumor necrosis factor-{alpha} peptide that is expressed by the heart is tumor necrosis factor-{alpha} (TNF{alpha}). Expressed by failing heart but not by nonfailing myocardium, investigators have identified a direct relationship between levels of circulating TNF{alpha} and both functional symptoms and mortality in patients with heart failure [63, 64]. That TNF{alpha} participates in the development of dilated cardiomyopathy is evidenced by the fact that cardiac-specific overexpression of TNF{alpha} in transgenic mice elicits the development of heart failure that recapitulates that seen in humans. Mice develop cardiac hypertrophy, dilation, interstitial infiltrates, fibrosis, ventricular dysrhythmias, reexpression of fetal genes, and early death [65].

The genes encoding both TNF{alpha} and TNFß are located in tandem on the short arm of chromosome 6. Two biallelic polymorphisms have been identified: a G to A transition at position -308 in the promoter region of the TNF{alpha} gene (G = TNF{alpha}1, A = TNF{alpha}2) and a G to A transition at position +252 in the first intron of the TNFß gene (G = TNFß1, A = TNFß2) [66, 67]. Both TNF{alpha}2 and TNFß2 are associated with high TNF{alpha} production [68, 69]. Furthermore, rheumatoid arthritis and systemic lupus erythematosus are associated with increased frequency of the TNF{alpha}2 allele and patients homozygous for the TNF{alpha}2 allele have a higher risk for death due to cerebral malaria [70, 71]. However we were not able to identify a relationship between either TNF{alpha} or TNFß polymorphisms and the presence of either heart failure or circulating levels of TNF in a relatively large cohort of patients with chronic heart failure [72]. However these studies were limited by the fact that all patients had class III heart failure symptoms and we did not assess the relevance of the genotype to long-term prognosis in this patient population. Furthermore because the causes of TNF{alpha} elevation are multifactorial, genotype alone might not predict circulating TNF levels.

Conclusions

In conclusion a variety of recent clinical studies suggest that the presence of selected polymorphisms and mutations can in different situations predict the occurrence of disease, a patient's response to pharmacologic therapy, or an individual's long-term prognosis. These studies are facilitated by the accomplishments of the human genome project as well as by technologic breakthroughs including silicon-based techniques and high-throughput genotyping that is rapid and cost effective. It is believed that more than 100,000 functional polymorphisms and mutations exist in the more than 30,000 human genes and an increasing array of studies suggest that the overall response of any given person is probably predicated on the combination of more than one genotype. Thus not only is technology required but also sophisticated computational analysis will eventually be necessary to utilize the information now being gleaned from focused association studies in the actual treatment of patients with heart failure and other cardiac diseases. Nonetheless we should expect that in the not too distant future clinicians will choose their therapeutic drugs and devices not just based on patient phenotype but also on genotype. Perhaps one good example might be the treatment of heart failure. Physicians now choose between starting an ACE inhibitor and a ß-blocker based on their own experience and intuition and up-titrate that agent before adding a second drug. One can easily imagine a time in the future when such decisions will be based on genotype, allowing each patient to receive that specific agent (and have that agent up-titrated to appropriate levels) that will best facilitate improvements in their heart muscle performance. Of even greater importance will be the opportunity to identify patients at risk of developing heart failure and begin treatment before the onset of symptoms.[73]

Acknowledgments

The author thanks Michele Breccia for preparation of the manuscript. This work was supported by NHLBI Grant UO1HL69009–02.

References

  1. Feldman A.M., Bristow M.R., Parmley W.W., et al. Effects of vesnarinone on morbidity and mortality in patients with heart failure. Vesnarinone Study Group. N Engl J Med 1993;329:149-155.[Abstract/Free Full Text]
  2. Cohn J.N., Goldstein S.O., Greenberg B.H., et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. N Engl J Med 1998;339:1810-1816.[Abstract/Free Full Text]
  3. Bozkurt B, Torre-Amione G, Soran O, et al. Results of targeted anti-tumor necrosis factor therapy with Etanercept in patients with advanced heart failure. Circulation 2001;103:1044–7
  4. Cohn J.N., Johnson G., Ziesche S., et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310.[Abstract]
  5. Carson P., Ziesche S., Johnson G., Cohn J.N. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail 1999;5:178-187.[Medline]
  6. Beta-Blocker Evaluation of Survival Trial Investigatiors. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659–67
  7. Yancy C.W., Fowler M.B., Colucci W.S., et al. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med 2001;344:1358-1365.[Abstract/Free Full Text]
  8. Bristow M.R., Minobe W.A., Raynolds M.V., et al. Reduced beta 1 receptor messenger RNA abundance in the failing human heart. J Clin Invest 1993;92:2737-2745.
  9. Bristow M.R., Kantrowitz N.E., Ginsburg R., Fowler M.B. Beta-adrenergic function in heart muscle disease and heart failure. J Mol Cell Cardiol 1985;17(Suppl 2):41-52.
  10. Koch W.J., Lefkowitz R.J., Rockman H.A. Functional consequences of altering myocardial adrenergic receptor signaling. Annu Rev Physiol 2000;62:237-260.[Medline]
  11. Moore J.D., Mason D.A., Green S.A., Hsu J., Liggett S.B. Racial differences in the frequencies of cardiac beta(1)-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C. Hum Mutat 1999;14:271.[Medline]
  12. Mason D.A., Moore J.D., Green S.A., Liggett S.B. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 1999;274:12670-12674.[Abstract/Free Full Text]
  13. Rathz D.A., Brown K.M., Kramer L.A., Liggett S.B. Amino acid 49 polymorphisms of the human beta1-adrenergic receptor affect agonist-promoted trafficking. J Cardiovasc Pharmacol 2002;39:155-160.[Medline]
  14. Wagoner L.E., Craft L.L., Zengel P., et al. Polymorphisms of the beta1-adrenergic receptor predict exercise capacity in heart failure. Am Heart J 2002;144:840-846.[Medline]
  15. Small K.M., Wagoner L.E., Levin A.M., Kardia S.L., Liggett S.B. Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 2002;347:1135-1142.[Abstract/Free Full Text]
  16. Hein L., Altman J.D., Kobilka B.K. Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature 1999;402:181-184.[Medline]
  17. Small K.M., Forbes S.L., Rahman F.F., Bridges K.M., Liggett S.B. A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem 2000;275:23059-23064.[Abstract/Free Full Text]
  18. McGraw D.W., Forbes S.L., Kramer L.A., Liggett S.B. Polymorphisms of the 5' leader cistron of the human beta2-adrenergic receptor regulate receptor expression. J Clin Invest 1998;102:1927-1932.[Medline]
  19. Scott M.G., Swan C., Wheatley A.P., Hall I.P. Identification of novel polymorphisms within the promoter region of the human beta2 adrenergic receptor gene. Br J Pharmacol 1999;126:841-844.[Medline]
  20. Drysdale C.M., McGraw D.W., Stack C.B., et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000;97:10483-10488.[Abstract/Free Full Text]
  21. Liggett S.B. Pharmacogenetics of beta-1- and beta-2-adrenergic receptors. Pharmacology 2000;61:167-173.[Medline]
  22. Green S.A., Turki J., Innis M., Liggett S.B. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994;33:9414-9419.[Medline]
  23. Green S.A., Cole G., Jacinto M., Innis M., Liggett S.B. A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem 1993;268:23116-23121.[Abstract/Free Full Text]
  24. Wagoner L.E., Craft L.L., Singh B., et al. Polymorphisms of the beta(2)-adrenergic receptor determine exercise capacity in patients with heart failure. Circ Res 2000;86:834-840.[Abstract/Free Full Text]
  25. Swedberg K., Eneroth P., Kjekshus J., Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 1990;82:1730-1736.[Abstract/Free Full Text]
  26. Gaussin V., Schneider M.D. Surviving infarction one gene at a time: decreased remodeling and mortality in engineered mice lacking the angiotensin II type 1A receptor. Circulation 1999;100:2043-2044.[Free Full Text]
  27. Schneider M.D., Lorell B.H. AT(2), judgment day: which angiotensin receptor is the culprit in cardiac hypertrophy?. Circulation 2001;104:247-248.[Free Full Text]
  28. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435.[Abstract]
  29. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.[Abstract]
  30. Rigat B., Hubert C., Alhenc-Gelas F., Cambien F., Corvol P., Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-1346.
  31. Rigat B., Hubert C., Corvol P., Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res 1992;20:1433.[Free Full Text]
  32. Tiret L., Rigat B., Visvikis S., et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992;51:197-205.[Medline]
  33. Danser A.H., Derkx F.H., Hense H.W., Jeunemaitre X., Riegger G.A., Schunkert H. Angiotensinogen (M235T) and angiotensin-converting enzyme (I/D) polymorphisms in association with plasma renin and prorenin levels. J Hypertens 1998;16:1879-1883.[Medline]
  34. Bryne J., Robb S.D., Morton I.J., Cooke A., McMurray J.J., Dargie H.J. The insertion/deletion polymorphism of the angiotensin-converting enzyme gene and indices of left ventricular function following myocardial infarction. J Am Coll Cardiol 1998;31:491A.
  35. Cambien F., Poirier O., Lecerf L., et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-644.[Medline]
  36. Winkelmann B.R., Nauck M., Klein B., et al. Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with increased plasma angiotensin-converting enzyme activity but not with increased risk for myocardial infarction and coronary artery disease. Ann Intern Med 1996;125:19-25.[Abstract/Free Full Text]
  37. Nagashima J., Musha H., So T., Kunishima T., Nobuoka S., Murayama M. Effect of angiotensin-converting enzyme gene polymorphism on left ventricular remodeling after anteroseptal infarction. Clin Cardiol 1999;22:587-590.[Medline]
  38. Ledru F., Blanchard D., Battaglia S., et al. Relation between severity of coronary artery disease, left ventricular function and myocardial infarction, and influence of the ACE I/D gene polymorphism. Am J Cardiol 1998;82:160-165.[Medline]
  39. Abraham M.R., Olson L.J., Joyner M.J., Turner S.T., Beck K.C., Johnson B.D. Angiotensin-converting enzyme genotype modulates pulmonary function and exercise capacity in treated patients with congestive stable heart failure. Circulation 2002;106:1794-1799.[Abstract/Free Full Text]
  40. Pinto Y.M., van Gilst W.H., Kingma J.H., Schunkert H. Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilation after anterior myocardial infarction. Captopril and Thrombolysis Study investigators. J Am Coll Cardiol 1995;25:1622-1626.[Abstract]
  41. McNamara D.M., Holubkov R., Janosko K., et al. Pharmacogenetic interactions between beta-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Circulation 2001;103:1644-1648.[Abstract/Free Full Text]
  42. Andersson B., Sylven C. The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure. J Am Coll Cardiol 1996;28:162-167.[Abstract]
  43. Montgomery H.E., Keeling P.J., Goldman J.H., Humphries S.E., Talmud P.J., McKenna W.J. Lack of association between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1995;25:1627-1631.[Abstract]
  44. Haywood G.A., Tsao P.S., von der Leyen H.E., et al. Expression of inducible nitric oxide synthase in human heart failure. Circulation 1996;93:1087-1094.[Abstract/Free Full Text]
  45. Kelly R.A., Balligand J.L., Smith T.W. Nitric oxide and cardiac function. Circ Res 1996;79:363-380.[Free Full Text]
  46. Maguire S.M., Nugent A.G., McGurk C., Johnston G.D., Nicholls D.P. Abnormal vascular responses in human chronic cardiac failure are both endothelium dependent and endothelium independent. Heart 1998;80:141-145.[Abstract/Free Full Text]
  47. Shinke T., Takaoka H., Takeuchi M., et al. Nitric oxide spares myocardial oxygen consumption through attenuation of contractile response to beta-adrenergic stimulation in patients with idiopathic dilated cardiomyopathy. Circulation 2000;101:1925-1930.[Abstract/Free Full Text]
  48. Tesauro M., Thompson W.C., Rogliani P., Qi L., Chaudhary P.P., Moss J. Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA 2000;97:2832-2835.[Abstract/Free Full Text]
  49. McNamara D.M., Holubkov R., Postava L., et al. Effect of the Asp298 variant of endothelial nitric oxide synthase on survival for patients with congestive heart failure. Circulation 2003;107:1598-1602.[Abstract/Free Full Text]
  50. Dzau V.J., Colucci W.S., Hollenberg N.K., Williams G.H. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation 1981;63:645-651.[Free Full Text]
  51. Schrier R.W., Abraham W.T. Hormones and hemodynamics in heart failure. N Engl J Med 1999;341:577-585.[Free Full Text]
  52. Lombes M., Oblin M.E., Gasc J.M., Baulieu E.E., Farman N., Bonvalet J.P. Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ Res 1992;71:503-510.[Abstract/Free Full Text]
  53. Zhou G., Kandala J.C., Tyagi S.C., Katwa L.C., Weber K.T. Effects of angiotensin II and aldosterone on collagen gene expression and protein turnover in cardiac fibroblasts. Mol Cell Biochem 1996;154:171-178.[Medline]
  54. Pitt B., Zannad F., Remme W.J., et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study investigators. N Engl J Med 1999;341:709-717.[Abstract/Free Full Text]
  55. Funaya H., Kitakaze M., Node K., Minamino T., Komamura K., Hori M. Plasma adenosine levels increase in patients with chronic heart failure. Circulation 1997;95:1363-1365.[Abstract/Free Full Text]
  56. Savic V., Stefanovic V., Ardaillou N., Ardaillou R. Induction of ecto-5'-nucleotidase of rat cultured mesangial cells by interleukin-1 beta and tumour necrosis factor-alpha. Immunology 1990;70:321-326.[Medline]
  57. Kitakaze M., Hori M., Kamada T. Role of adenosine and its interaction with alpha adrenoceptor activity in ischaemic and reperfusion injury of the myocardium. Cardiovasc Res 1993;27:18-27.[Medline]
  58. Wagner D.R., McTiernan C., Sanders V.J., Feldman A.M. Adenosine inhibits lipopolysaccharide-induced secretion of tumor necrosis factor-alpha in the failing human heart. Circulation 1998;97:521-524.[Abstract/Free Full Text]
  59. Wagner D.R., Combes A., McTiernan C., Sanders V.J., Lemster B., Feldman A.M. Adenosine inhibits lipopolysaccharide-induced cardiac expression of tumor necrosis factor-alpha. Circ Res 1998;82:47-56.[Abstract/Free Full Text]
  60. Sommerschild H.T., Kirkeboen K.A. Adenosine and cardioprotection during ischaemia and reperfusion—an overview. Acta Anaesthesiol Scand 2000;44:1038-1055.[Medline]
  61. Sabina RL, Holmes EW. Myoadenylate deaminase deficiency. In: The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 1995:1769–80
  62. Loh E., Rebbeck T.R., Mahoney P.D., DeNofrio D., Swain J.L., Holmes E.W. Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure. Circulation 1999;99:1422-1425.[Abstract/Free Full Text]
  63. Torre-Amione G., Kapadia S., Lee J., et al. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93:704-711.[Abstract/Free Full Text]
  64. Torre-Amione G., Kapadia S., Benedict C., Oral H., Young J.B., Mann D.L. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1201-1206.[Abstract]
  65. Kubota T., McTiernan C.F., Frye C.S., et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 1997;81:627-635.[Abstract/Free Full Text]
  66. Wilson A.G., di Giovine F.S., Blakemore A.I., Duff G.W. Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genet 1992;1:353.[Free Full Text]
  67. Wilson A.G., di Giovine F.S., Duff G.W. Genetics of tumour necrosis factor-alpha in autoimmune, infectious, and neoplastic diseases. J Inflamm 1995;45:1-12.[Medline]
  68. Wilson A.G., Symons J.A., McDowell T.L., McDevitt H.O., Duff G.W. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997;94:3195-3199.[Abstract/Free Full Text]
  69. Stuber F., Petersen M., Bokelmann F., Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 1996;24:381-384.[Medline]
  70. Danis V.A., Millington M., Hyland V., Lawford R., Huang Q., Grennan D. Increased frequency of the uncommon allele of a tumour necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus. Dis Markers 1995;12:127-133.[Medline]
  71. McGuire W., Hill A.V., Allsopp C.E., Greenwood B.M., Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 1994;371:508-510.[Medline]
  72. Kubota T., McNamara D.M., Wang J.J., et al. Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. Circulation 1998;97:2499-2501.[Abstract/Free Full Text]
  73. Liggett S.B.W.L., Craft L.L., Hornung R.W., Hoit B.D., McIntosh T.C., Walsh R.A. The IIe164 ß2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 1998;102:1534-1539.[Medline]



This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
I. Cascorbi, M. Paul, and H. K. Kroemer
Pharmacogenomics of heart failure - focus on drug disposition and action
Cardiovasc Res, October 1, 2004; 64(1): 32 - 39.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Feldman, A. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Feldman, A. M.
Related Collections
Right arrow History

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS