African Americans with high-normal blood pressure diss

Possible Explanations for G894T Genotype Effects

Existing data in certain models of hypertension have shown that a relative or absolute defect in the production of NO by NOS is associated with various degrees of end-organ involvement in response to hemodynamic workload. Since NO may participate in the hypertrophic growth of the myocardium independently of its effect on Blood Pressure, it is tempting to speculate that a defect in the eNOS/NO pathway linked to the 894T allelic variant could account for the observed association with LVM. The possibility that such an association may reflect linkage disequilibrium of G894T polymorphism with another functional allelic variation within the eNOS gene locus or other genetic cofactors in the regulation of eNOS needs to be further examined in future studies. In this respect, it is worth noting that individuals who were homozygous for this rare 894T allele also carried other common “wild-type” alleles within the eNOS gene, including “bb” of 27-bp repeat in intron 4 or “TT” of T C in the promoter region. None of these common alleles showed any significant association with LVM. While our data provide indirect preliminary evidence to support the relative contribution of this rare allelic polymorphism in exon 7 (G894T) of the eNOS gene to the underlying susceptibility to LV hypertrophic process in this early stage of the development of hypertension, the biological correlates of the conservative Asp-to-Glu substitution in codon 298 of the eNOS gene are not well-known. Likewise, this G894T variant has been implicated in the development of several Cardiovascular disorders in which NO bioactivity is impaired, such as hypertension. In the present study, plasma levels of NO metabolites did not vary significantly among carriers of 894T allele compared to 894G allele-bearing subjects in the absence of a nitrate-controlled diet. It is possible that the absence of a nitrate-controlled diet may have masked the detection of true differences in NO metabolites across the genotypes. Given the fact that only 30% of the phenotypic variance of NO is under genetic control, one possible interpretation of our findings is that G894T polymorphism may thus be a marker for eNOS protein expression that is difficult to assess by NO metabolite measurements. Because reduced NO bioavailability may be a consequence of high BP, there is a possibility that a combined influence of G894T genotype on eNOS production/activity and BP (Generic Calan calcium is involved in blood vessel contraction and in controlling the electrical impulses within the heart) status contribute to an early manifestation of elevated LVM in this prehypertensive state. It is also possible that these stable breakdown end products of NO oxidation (NO2/NO3), used as surrogate measures of eNOS activity in humans, may not be uniformly affected during the developing stage of hypertension and its maintenance. This view is supported by experimental data from a rat model of early renovascular hypertension where elevated systolic BP was positively associated with an initial increase in the circulating levels of NO2/NO3, which gradually declined in a later stage after hypertension was fully established. Similarly, data from other models of rats genetically prone to hypertension have provided further evidence for an upregulated vascular eNOS activity in response to BP (Canadian Coreg is used for treating high blood pressure) and, therefore, an increase in NO production. Clinical observations made in hypertensive black patients with mild-to-moderate hypertension have also revealed an increase rather than a decrease in plasma levels of NO2/NO3 under conditions of low dietary salt intake. Collectively, it is becoming clear that NO synthesis or its release during the early hypertensive state may not be specifically impaired but rather preserved, perhaps as a compensatory mechanism to slow the development of hypertension and prevent end-organ damage. This paradoxical physiological response to BP (Generic Trandate medication is used to treat severe high blood pressure) load may be complicated by counteracting pressure effect of various vasoconstrictors, such as angiotensin II (Ang II), which in turn could act as trophic factor to promote increased LVM. On the other hand, the vascular capacity for NO generation can be compromised by environmental interactions that may potentiate the underlying genetic effect partially mediated by the action of endogenous NO. As for major risk factors we were able to analyze systematically in the present study, smoking has been shown to increase oxidative stress, leading to the rapid breakdown of NO under condition of its limited pro-ductioi^ioavailability. This may account, in part, for the interactive effect of smoking and G894T variant. Finally, potential adverse influences of other environmental factors, such as dietary salt intake, previously shown to have a negative impact on both LVM and BP (Hyzaar drug is used for treating high blood pressure) traits cannot be discounted. In this regard, Boddi et al. have shown that dietary sodium loading in healthy nor-motensive subjects can suppress circulating renin as well as turn on the conversion of angiotensin I to Ang II in vascular tissues. In the present study, we have not been able to examine the pathways of Ang II formation systematically under different conditions of salt intake. Because NO may be a natural buffer against Ang II, it is therefore not surprising that NO metabolite levels were equally distributed across genotypes. Even if the NO metabolites across genotypes were truly the same, this might reflect very different NO/Ang II balances at the level of the vasculature.

Study Limitations

The cross-sectional nature of the present study limited our ability to draw inferences about causal association between BP and LVM. Because both variables were measured at the same time, we also could not determine from the present study the temporal association between these traits. It is worth noting that the small number of homozygous carriers of the 894T allele (TT) precludes test for powerful statistical significance of associations to draw further conclusions regarding gender-mediated preferential distribution of the 894T variant, which may predispose to the high risk for CV disease (Generic Tenormin decreasing death due to heart problems after a heart attack) associated with LVM observed among young premenopausal African-American women with high-normal BP/ borderline hypertension.

Clinical Implications

Despite the above-mentioned limitations, the present study has important clinical implications and may provide a clue for understanding the genetic susceptibility to hypertension in healthy African Americans. If the above findings are consistent across a larger sample size, additional studies with subsequent follow-up will be needed to determine the feasibility/benefits of preventing the progression to hypertension and related complications in genetically susceptible individuals by nonpharmacological means of risk factor modification, as initially suggested in the Primary Prevention of Hypertension study. In light of the recent published JNC7 report that recognized the continuous/incremental risk of developing CV (Generic Zebeta treating high blood pressure) events within normal-to-high-normal (i.e., minimally elevated or nonhypertensive) range of BP, a new category designated prehyperten-sion (120-139/80- to 89 mmHg) has now been added and signaled the need for health-promoting lifestyle modification strategies to lower the BP to the recommended goals in order to prevent CV disease (Generic Imdur preventing angina caused by heart disease) in the general population. However, decisionmaking with regard to such a sizeable proportion of people currently considered prehypertensives but who are not necessarily at increased risk is challenging in clinical practice, since the indication for a cost-effective preventive strategy versus aggressive treatment is uncertain and not universally applicable in this group. In this context, the analysis of the eNOS 894T allelic profile may provide predictive insight that enables the clinician to identify the subset of high-risk individuals susceptible to subclinical hypertension and its sequelae, i.e., LVH. Perhaps it is this group of individuals who may benefit from decreasing BP by appropriate pharmacological means to prevent end-organ damage.

SUMMARY

Our data suggest that the G894T polymorphic variant of the eNOS gene may be related to an early virulent phenotype of higher LVM in African Americans with high-normal Blood Pressure. These preliminary observations underline the need for further evaluation of the relative role of this rare allelic polymorphism in exon 7 of the eNOS gene as an attractive candidate for the genetic modulation of LVM in the prehyper-tensive state.

Category: Blood Pressure / Tags: African Americans, genetics, high-normal blood pressure, left ventricular mass, nitric oxide synthase

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