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Figure 11: Correlations between CIMT and SBP.
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CHAPTER 5
DISCUSSION
The association between hyperuricemia and hypertension and the pathogenesis of atherosclerosis is still unclear. The present study was conducted in order to determine whether there was any relationship between SUA levels and a marker of subclinical target organ damage such as CIMT in non-diabetic essential hypertensive patients. A positive association would therefore mean that SUA may indeed serve as a surrogate marker for generalized atherosclerosis, and its early diagnosis and treatment would serve as an important step in the prevention of cardiovascular disease.
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relationship between SUA, CIMT and other cardiovascular risk factors like obesity, and dyslipidemia.
Most of the patients (59.7%) were middle-aged (40-59 years). There were more females than males in this study, a finding similar to a previous epidemiological study carried out in Port Harcourt to determine the prevalence of hypertension.95This might not be unconnected to the fact that women tend to use preventive and diagnostic services more frequently, whereas men make greater use of emergency services. 262
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which is responsible for the reabsorption of urate in the proximal convoluted tubule.267, 268
Previously, it was thought that this uricosuric effect was limited to Losartan conferring on it a molecule-specific effect269; it has however, being shown that irbesartan inhibits the uptake of UA at the URAT 1 and the glucose transporter 2 (GLUT 2) receptors leading to SUA reduction.270
Alikor et al, reported a prevalence of hyperuricemia of 17.2% in a population-based study in a rural community in the Niger Delta.211 Their lower prevalence may be due to the rural-urban dichotomy in the level of SUA which may not be unconnected to the exposure to environmental pollutants, 143, 157-159 and the higher prevalence of the components of the metabolic syndrome among the urban population 271, 272 which frequently conform with these cardiovascular risk factors.
In this study, the mean SUA values were significantly higher among the hypertensive patients than the control group (p=0.03). This is similar to the result reported by Ofori and Odia in Port Harcourt67 and Shi-Dou et al.163
The association between arterial hypertension and hyperuricemia is very common. It has been reported that 25-40% of patients with untreated hypertension and more than 80% with malignant hypertension have hyperuricemia.83 Hyperuricemia is more common in primary hypertension, especially in patients with hypertension of recent onset and in pre-hypertension associated with microalbuminuria.273 According to existing studies,15, 130, 133, 134 an increase in SUA concentration is thought to partially contribute to the pathogenesis of hypertension via the activation of the renin-angiotensin-aldosterone system by inducing renal vascular inflammation, preglomerular arteriolopathy, tubulointerstitial inflammation and fibrosis. The
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reabsorption of urate in the proximal convoluted tubule is thus increased as a consequence of the reduced renal blood flow due to renal vasoconstriction.
SUA concentration also interferes with blood vessel expansion by decreasing the response of blood vessels to acetylcholine and to increase blood pressure by endothelial dysfunction through the interference with vasodilation activity of nitric oxide.
A number of studies have shown that SUA plays a role in the development of cardiovascular morbidity in the general population2,3 as well as in patients with hypertension,4,5 type II diabetes,6 and cardiac or vascular diseases.7-9 A meta-analysis of data taken from eight trials that were performed on hypertensive patients revealed that for each standard deviation increment in SUA there was concurrent augmentation of cardiovascular risk that equals what is observed for similar changes in blood pressure or total cholesterol.10
Several studies over time have also attempted to establish whether SUA is related to coronary heart disease (CHD) events independent of known traditional risk factors.11-13 The above studies imply that SUA may help in cardiovascular risk stratification over and beyond traditional cardiovascular risk factors. Although the majority of the studies suggest that SUA is an independent risk factor for cardiovascular complications, it should be noted that not all studies are in agreement.
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the drug-induced hyperuricemia. Further analysis using the one-way ANOVA test revealed that the mean SUA of the three groups were not statistically different (p=0.076). Also a post-hoc subgroup analysis of the mean SUA levels among the three groups of subjects also failed to show any significant difference suggesting that antihypertensive drugs therapy alone may not adversely affect the SUA outcome levels in the subject populations. Put together, however, the reason(s) behind the discordance between the SUA levels across the group are still unclear as the use of anti-hypertensive drugs or otherwise may not fully explain this disparity. Furthermore, since this is a cross-sectional study, causality cannot be readily inferred.
When further analysed, it was observed that the prevalence of asymptomatic hyperuricemia varied with age between gender. In the male sex, a higher frequency of asymptomatic hyperuricemia was noted in the 20-39 years’ age, while it was higher from the sixth-decade onwards for the female. This is similar to the findings by Alikor et al211 and Shi-Dou et al.163 This result was not unexpected as it is known that estrogen promotes the excretion of UA.273
Interestingly in this study, CIMT was significantly higher in hypertensive-hyperuricemic patients (0.83±0.21mm) than among the hypertensive non hyperuricemic patients (0.73±0.15mm, p=0.006). This means hyperuricemia per se could be a risk factor for atherosclerosis in hypertensive patients and by necessary implication an indicator of increased cardiovascular disease. This is consistent with the findings by Elsayed et al.191 This study also showed that CIMT was higher in normotensive hyperuricemic controls (0.64± 0.09mm) than among the normotensive non hyperuricemic controls (0.61± 0.07mm), and that the difference was statistically significant (p<0.001). This was consistent with the results by Elsayed et al.191 and Tavil et al.274 This means that
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hyperuricemia could be a risk factor for atherogenesis independent from hypertension. So much so since, increased UA level has been noted to upregulate proinflammatory mediators in vascular smooth muscle cells 173 leading to vascular endothelial dysfunction (VED). VED plays a critical role in pathogenesis of various cardiovascular disorders such as atherosclerosis, hypertension, CAD, and heart failure.174
This is not unexpected as hypertension is a major risk factor for carotid intima-media thickening.
It is noteworthy to point out that since the mid-90s, a number of trials have sought to compare the effects of different antihypertensive drugs on carotid intima-media thickness.
The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) in which amlodipine was compared to placebo in its ability to slow down the progession of early coronary atherosclerosis showed that amlodipine significantly slowed-down carotid atherosclerosis progression.275 This is quite instructive since calcium channel blockers made up 42.7% of the antihypertensive agents prescribed in this study and this may explain the lower CIMT values in the drug-experienced hypertensive patients. Likewise, in the Swedish Irbesartan Left Ventricular Hypertrophy Investigations versus Atenolol (SILVHA) study it was shown that an ARB reduced the progression of CIMT.296 The possible mechanisms for the anti-atherosclerotic effect of antihypertensive agents lie in their ability to inhibit the production of ROS,
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reduce the expression of adhesion molecules in endothelial cells, and restore endothelial function.113-117
In this study the patients with elevated SUA also had higher levels of TG than those with normal SUA levels and this was statistically significant (p=0.036).
These findings were similar to that reported by Ofori and Odia 67 in Port Harcourt and Shi-Dou et al.163 In a study by Shi-Dou et al, abnormal TG had a stronger association with increasing UA level than all the other components of the lipid profile.163 The mechanism for the strong association between UA and TG has remained unclear. Although, genetic factors have been associated with the concurrence of gout and hypertriglyceridemia,164 most investigators tend to conclude that hyperuricemia simply reflect the lifestyle of the patient, as part of the metabolic syndrome.
In this study, SUA was found to be weakly associated to SBP (r=0.186, p=0.007) and DBP (r=0.205, p=0.003). This is similar to the findings by Emokpae and Abdu in Kano, North-Western Nigeria276 but in contrast to Ofori and Odia.67 This close association of SUA and essential hypertension has been demonstrated by several clinical, experimental, epidemiological and observational studies.15, 84
In this study, SUA levels were also independently associated with CIMT in regression analysis after adjusting for confounders including TG, and SBP (p<0.001). SBP made the largest unique contribution, although SUA also made a statistically significant contribution (p=0.013). This is consistent with the findings by other investigators.190-192
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Several potential mechanisms as previously elucidated may account for the link between SUA level and CIMT. For example, the reduction in the ability of the vascular endothelium to reduce the vaso-protective nitric oxide113, 117, 121 or the increase in the level of mitochondrial O2-, which is associated with mitochondrial calcium overload. Put together these pathways lead ultimately to endothelial dysfunction. In addition, UA acts as proinflammatory chemokine and plays an important role in the proliferation of vascular smooth muscle cells, which in turn leads to an increased thickness of the carotid arteries.113-117 It is established that only after atherosclerosis progresses to ischemic disease or when thrombi are generated from existing plaque as a result of rupture or erosion, do symptomatic cardiovascular events occur. It therefore becomes imperative to identify asymptomatic patients at high risk who may be candidates for more intensive, evidence-based interventions.
An important part of this study that should be highlighted is the positive association between mean total white cell count, which is a marker of inflammation and SUA level (p=0.004). The positive correlation persisted after controlling for confounders such as gender, smoking, SBP, DBP, and TG. This was consistent with the result by Nakanishi et al who also reported a statistically significant positive correlation between WCC and SUA.179 This inflammatory cascade is driven by cytokines such as IL-6 which is found elevated in individuals with atherosclerosis. IL-6 is involved in the recruitment of inflammatory mediators and stimulation of adhesion to the endothelium of white blood cells, all of which are important steps to atherosclerosis. UA may therefore exert its deleterious effect on the endothelium through leukocyte activation.120
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The contribution between SUA to atherosclerotic vascular disease remains the subject of much debate. Some studies have argued that the observed association between UA and atherosclerotic vascular disease is attributable to an indirect association of hyperuricemia with cardiovascular risk factors or clustering of these metabolic and hemodynamic factors, designated “metabolic syndrome”. Two of the major determinants of CVD, hypertension and dyslipidemia, commonly co-exist. In fact, a large proportion of the cardiovascular risk in patients with hypertension can be attributed to dyslipidemia.
Furthermore, it was observed in this study that there was an inverse but significant association between HDL-C and CIMT (r=-0.240, p=0.04). It is important to note that the concentration of HDL-C is inversely proportional to the risk of developing cardiovascular disease.277
The reason for this might lie in the lipid modifying effects of antihypertensive
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In conclusion, CIMT is increased in patients with hypertension as well as in patients with hyperuricemia without hypertension compared to the control group but it is more evident in hypertensive hyperuricemic patients. These results suggest that high SUA is associated with atherogenesis.
This study was also able to highlight the crucial role antihypertensive therapy plays in attenuating the effects of the traditional cardiovascular risk factors on cardiovascular morbidity, although a more robust study may be needed to further explore this finding.
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CHAPTER SIX
CONCLUSION, LIMITATIONS OF THE STUDY AND RECOMMENDATIONS: