Markers For Heart Failure

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6.1. ANGIOTENSIN-CONVERTING ENZYME The angiotensin-converting enzyme (ACE) is a critical enzyme in the rennin-angiotensin-aldosterone (RAA) axis. Under the action of renin, angiotensinogen is first degraded to the decapeptide angiotensinI and then to the octapeptide angiotensinII by ACE. Angiotensin II is further degraded into a heptapeptide angiotensin III by angiotensinase. When there are periods of blood and fluid loss, the RAA axis is essential in maintaining blood pressure by stimulating vasoconstriction (via angiotensinII), sodium plasma volume retention and potassium loss, and inactivating bradykinin (vasodilator). Prolonged stimulation of the RAA axis leads to cardiovascular remodeling and has been implicated in the pathogenesis of neointimal hyperplasia. The use of ACE inhibitors has been shown to reduce atherosclerosis in animal models (88).

There is acommon polymorphism in the angiotensin-converting enzyme gene in intron 16 involving the insertion (I) or deletion (D) of a 287-bp alu repeat sequence. The allele frequency for the insertion is 45%. The concentration of plasma ACE is increased in patients with the DD vs the II genotypes (e.g., 494 vs 299 ng/mL, respectively) (89). The first study that correlated the presence of the DD genotype to ACS was published in 1992 on 1343 cases and controls (90). Subsequently, a metaanalysis was conducted combining the results of 15 studies on 8873 cases and control (91). The cumulative meta-analysis produced an odds ratio of 1.26 (95% CI: 1.15-1.39) for the DD allele.

The accuracy of these early studies was questioned by Shanmugan et al., who showed that the D allele is preferentially amplified in heterozygote subjects (92). These investigators suggested the use of primers that specifically recognizes the insertion-specific sequence. More recent articles that have used the preferred primers have not demonstrated a relationship between ACE polymorphism and presence of CAD (93).

Given the role of the RAA axis on stimulating the growth of smooth muscles, ACE polymorphisms have been examined as a contributor to restenosis after angioplasty (94). These authors suggest that the pathophysiology of post-PTCA restenosis is related to smooth muscle cell migration and remodeling rather than proliferation. In contrast, stent placement might be more related to the growth effects of ACE. The study of Amant et al.

showed an inverse relationship between the number of D alleles present and the minimum lumen diameter (MLD) at 6 mo after successful stent implantation (95). These observations would be significant if the MDL can be modified by use of ACE inhibitors such as quinapril. Unfortunately, the trials conducted to date have produced widely conflicting results. Although one trial showed beneficial effects of this drug in increasing MLD (96), another showed no effect (97). Still another found that the D allele produced a detrimental effect (98), whereas a fourth study suggested that the ACE I homozygotes and not the D genotype exhibited beneficial effects on MLD (99). Thus, the role of ACE inhibition and ACE polymorphism after stent placement remains unclear at this time.

Because the RAA system is important in the pathophysiology of CHF, the effect of ACE polymorphisms has also been studied to determine if there is a correlation to CHF. Like results for CAD, the studies conducted to date are conflicting. Candy et al. correlated ACE genotypes with left ventricular systolic performance as measured by ejection fraction using both echocardiography and radionuclide ventriculography (100). McNamara reported higher survival rates for CHF patients who were not treated with P-blockers (101). However, Montgomery was unable to find an association of ACE polymorphism in 99 patients with idiopathic dilated cariomyopathy (102). One explanation for the lack of an association between the DD polymorphism was suggested by Spruth et al. (103), who found no difference in mRNA expression among the DD, ID, and II genotypes. Finding genetic markers for patients with CHF might be more difficult than for patients with ACS because there might be more heterogeniety in the pathophysi-ology of CHF.

The ACE D/I polymorphism has also been examined in patients with atrial fibrillation. In a pilot study, the II genotype was a significant risk factor for atrial fibrillation (OR: 3.2; 95% CI: 1.3-7.8) among 138 patients with dilated cardiomyopathy (104). This interesting observation needs to be confirmed with larger clinical trials.

Given the importance of ACE inhibitors for the treatment of patients with essential hypertension, there have been a number of clinical studies conducted to determine if the D/I polymorphism in the ACE gene correlates to susceptibility to antihyper-tensive therapy. Such a finding could pave the way for the determination of genotypes on an individual basis prior to the selection of a particular drug regimen. A review of studies was recently conducted by Niu et al. (105). In some studies, there was no significant differences in genotypes and clinical measures such as left ventricular modeling (106). It is possible that these studies were underpowered to find a significant difference (107). In other studies, favorable outcomes (e.g., reduction in left ventricular hypertrophy) were found for individuals with the DD genotype (108), whereas other studies suggested more favorable outcomes (e.g., reduction in diastolic blood pressure) for the II genotype (109). As essential hypertension is a multifactorial disease, more careful selection of hypertensive subjects will be necessary to sort out the discordances that currently exist in the literature. In patients suffering AMI, the success of post-AMI treatment with ACE inhibitors was evaluated according to ACE D/I polymorphism, using a reduction in left ventricular size or function as the outcome measures. Unfortunately, there was no association between genotype and outcomes among 265 patients to suggest a pharcogenomic role in improving clinical efficacy (110).

A polymorphism also exists in the gene for angiotensin receptor type 1, where there is a change from an A^T substitution in nucleotide 1166. This mutation might be linked to increased prevalence of hypertension and coronary vasoconstriction. A early study suggested that this polymorphism was linked to the ACE D/I polymorphism; that is, the combination of the DD and 1166CC phenotype produced a significant association for AMI (OR: 3.95; 95% CI: 1.26-12.4) (111). This association has not been confirmed in more recent studies (112). In a study in which angiotensin II was given to volunteers, investigators concluded that the A1166C polymorphism does not have an effect on the actions of angiotensin II (113).

6.2 a- AND P-ADRENERGIC RECEPTORS Cardiac inotropy and chronotropy are modulated in part by a- and ยก3-adrenergic receptors expressed in the human heart. Both a and P receptors are subdivided into subtypes. The a1 subtypes are localized in the postsynaptic junctions regulating catecholamine uptake, whereas the a2 subtypes are found in presynaptic junctions and regulating catecholamine release (114). There are four a:- (a1A-D), and three a2- (a2A-C) subtypes. Although several polymorphisms have been described in these subtypes, only a few have been examined in conjunction with CAD. A polymorphism in the a1A subtype has been described where a cysteine is substituted for arginine in position 492. Although there are differences in the frequency of this mutation among Caucasians and African-Americans, there was no association of this polymorphism with essential hypertension (115). There are two nucleotide substitution polymorphisms in the a1B adrenergic receptor at nucleotide positions 534 and 549 (but do not result in an amino acid substitution) and a C^G substitution in the promoter region of a2A, but none of these polymorphisms were associated with resting and challenged blood pressures (116).

A three-amino-acid deletion polymorphism in the a2B receptor within a 12 glutamic acid repeat segment (positions 297-309) has been linked to a reduced basal metabolic rate and obesity (117) and flow-mediated dilatation of the brachial artery (118). Both obesity and defects in endothelial function are known risk factors for CAD. There has been one study to date that attempted to link this polymorphism to cardiovascular disease. In 912 Finnish men, the homozygous deletion genotype was associated with an odds ratio of 2.2 (95% CI: 1.1-4.4) for development of an ACS compared to the heterozygote and wild-type genotypes (119). There was no association in this study between these genotypes and hypertension.

A four-amino-acid deletion polymorphism exists in the a2C receptor located at positions 322-325, resulting in the loss of agonist-mediated receptor function in transfected cells (120). The loss of inhibitory function results in the release of epineph-rine and overstimulation of the cardiovasculature (121).

More research in the role of polymorphism in hypertension and heart disease has been conducted with the P-adrenergic receptors. These receptors are important in activating adenylate cyclase to produce cyclic AMP (second messenger) that augment myocardial contractility. Patients with heart failure have an

Fig. 3. Putative mechanism for the role of a- and P- adrenergic receptor polymorphisms as risk factors for heart failure. The a2c-adrenergic receptor inhibits norepinephrine release. A deletion of amino acids 322-325 results in a loss of receptor function and overstimulation of catecholamines at synpaptic junctions. Epinephrine activates Pj-adrenergic receptors via adnenylate cylase within myocytes resulting in increased heart rate and force. The Arg389 polymorphism in the Pj-adrenergic gene results in increased coupling to adenylyl cylase and enhanced function. (Used with permission from ref. 125.)

Fig. 3. Putative mechanism for the role of a- and P- adrenergic receptor polymorphisms as risk factors for heart failure. The a2c-adrenergic receptor inhibits norepinephrine release. A deletion of amino acids 322-325 results in a loss of receptor function and overstimulation of catecholamines at synpaptic junctions. Epinephrine activates Pj-adrenergic receptors via adnenylate cylase within myocytes resulting in increased heart rate and force. The Arg389 polymorphism in the Pj-adrenergic gene results in increased coupling to adenylyl cylase and enhanced function. (Used with permission from ref. 125.)

overstimulation of epinephrine, resulting in a downregulation of the P receptors. The use of P-blocker therapy improves clinical symptoms and cardiac output by slowing the heart rate and improving the rhythm. Under a situation of increased RAA axis stimulation, polymorphisms in the P receptors might predispose an individual to the development of heart failure.

There are many polymorphisms in the Pj-receptor gene that encode for a 478-amino-acid protein. Many of the polymorphisms, however, are silent and, thus, their significance toward development of CHF can be questioned (122). Two of these polymorphisms have been studied with regard to idiopathic dilated cardiomyopathy. One involves nucleotide 145, where there is a change from an A^G resulting in the substitution of serine for a glycine. The other is at nucleotide 1165, where there is a change from a C^G resulting in an arginine to a glycine substitution. The allele frequencies for the 145G and 1165C are 15% and 25%, respectively. These polymorphisms were studied in a cohort of patients with CHF. In two studies totaling 1063 cases and 1660 controls, the 1165G polymorphism was not associated with idiopathic dilated cardiomy-opathy (123-125). In another study, Borjesson et al. found the 49G allele frequency was higher than for the 49S allele (126). These investigators also reported significant differences in survival rates with the mutation (OR: 2.34; 95% CI: 1.30-4.20). The N-terminal sequence where the 49S mutation resides might be important to fold the receptor within the membrane while not being the target for receptor activation. These observations may help explain why some individuals respond to P-blockade while others do not. Prospective pharmacogenomic trials for different P1- and P2-blockers will be the next logical step in this field.

Three common polymorphism in the P2 receptor in amino acid position 16 substituting an arginine for a glycine, position 27 substituting a glutamine for a glutamic acid, and 164

substituting an arginine for an isoleucine. The allele frequencies for the respective polymorphisms are 61%, 43%, and 2%. The polymorphism in positions 16 and 27 have different susceptibility to agonist-induced downregulation. The 164 polymorphism exhibits a decreased affinity for P2-adrenogeric angonists, and an uncoupling of receptors from the Gs protein. In volunteer subjects, the increase in heart rate and systolic blood pressure among those with the Thr164Ile polymorphism was less than for the wild type (127). In a study of 471 case and controls, Liggett et al. found no difference in the allele frequencies for CHF patients and controls (128). However, when the 1-yr outcomes were compared, patients with the 164 ile genotype had a higher death risk rate and need for cardiac transplantation than CHF patients with the wild-type mutation. In 140 cases and controls, Wieczorek et al. was able to find an increased incidence of the 164 ile genotype with CHF (129).

Recently, Small et al. correlated the combination of the adrenergic receptor polymorphism of a2C-322-325 deletion and Pj-arg389gly substitution to risk of CHF in black subjects (125). The basis of their hypothesis is summarized in Fig. 3. On only 159 CHF patients and 189 matched controls, they reported odds ratios for the a2C deletion polymorphism alone, which increased to an odds ratioof 5.65 (95% CI: 2.67-11.95) and 10.11 (95% CI: 2.11-48.53) when combined with the Pj-adrenergic receptor polymorphism. There was no correlation with the P1 receptor alone with CHF and insufficient data to make any conclusions in Caucasians. These data exhibit the highest odd ratios for any polymorphism to cardiac disease published to date.

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