|Year : 2015 | Volume
| Issue : 2 | Page : 129-135
Relationship between uric acid and left ventricular mass and geometry in Nigerian patients with untreated essential hypertension
Sandra N Ofori, Maclean Akpa
Department of Internal Medicine, University of Port Harcourt, Teaching Hospital, Rivers, Nigeria
|Date of Web Publication||30-Jul-2015|
Sandra N Ofori
Department of Internal Medicine, University of Port Harcourt Teaching Hospital, East-West Road, Choba, Rivers
Source of Support: None, Conflict of Interest: None
Background: Hypertension is associated with left ventricular hypertrophy (LVH). Serum uric acid is often elevated in hypertension.
Objective: To assess the relationship between serum uric acid and left ventricular mass and geometry in untreated patients with essential hypertension.
Materials and Methods: A cross-sectional study was carried out in 130 newly diagnosed untreated patients with essential hypertension. Sixty-five healthy age- and sex-matched non-hypertensive individuals served as controls for comparison. Left ventricular mass and geometry were evaluated by transthoracic echocardiography. Blood samples were collected for assessing uric acid levels.
Results: Hyperuricemia was present in 46.9% and 16.9% of cases and controls, respectively (P < 0.001). Mean serum uric acid was significantly higher among the patients with hypertension (384.79 ± 96.4 μmol/l) compared to controls (296.92 ± 89.8 μmol/l; P < 0.001). LVH was present in 55.4% of the cases and 10.8% of the controls (P < 0.001) and the commonest geometric pattern among the cases was concentric hypertrophy while the majority of the controls had normal left ventricular geometry. Among the hypertensive patients, LVH was commoner in the hypertensive patients with hyperuricemia compared to those with normal serum uric acid levels (70.5% versus 42.0%, P = 0.001) and the commonest geometry was concentric LVH. There was a significant linear relationship between mean uric acid levels and the left ventricular mass index (r = 0.346, P < 0.001). In regression analysis, uric acid was a significant independent predictor of LVH in women (β =0.406, P = 0.015) but not in men (β =0.161, P = 0.432).
Conclusion: These results indicate that serum uric acid is associated with LVH in patients with hypertension especially women even at the time of diagnosis, thus may be a reliable marker of greater cardiovascular risk.
Keywords: Essential hypertension, left ventricular hypertrophy, left ventricular geometry, serum uric acid
|How to cite this article:|
Ofori SN, Akpa M. Relationship between uric acid and left ventricular mass and geometry in Nigerian patients with untreated essential hypertension. Nig J Cardiol 2015;12:129-35
|How to cite this URL:|
Ofori SN, Akpa M. Relationship between uric acid and left ventricular mass and geometry in Nigerian patients with untreated essential hypertension. Nig J Cardiol [serial online] 2015 [cited 2021 Apr 21];12:129-35. Available from: https://www.nigjcardiol.org/text.asp?2015/12/2/129/152024
| Introduction|| |
Hypertension is an important global public health challenge . In the year 2000, it was estimated that 26.4% of the global adult population (972 million people) had systemic hypertension. Of these, 333 million were in economically developed countries and 639 million were in economically developing countries and the rate was projected to increase by about 60% by the year 2025.  The prevalence of hypertension is particularly high in urban sub-Saharan Africa; with between 8% and 25% of adults affected, depending on how hypertension is defined.  It is currently the commonest cardiovascular disease (CVD) in colored Africans. 
Serum uric acid (SUA) level is frequently elevated in hypertension, and its levels tend to vary with age and sex.  Uric acid is higher in men and postmenopausal women because estrogen is uricosuric.  Elevated uric acid is a risk factor for CVD and the Systolic Hypertension in the Elderly Program (SHEP) trial showed that subjects who developed hyperuricemia as a side effect of diuretic therapy sustained cardiovascular events at a rate similar to those treated with placebo despite a lowering of the blood pressure.  This suggested a causal role for uric acid in the development of CVD. Similarly, the Losartan Intervention for Endpoint reduction (LIFE) in hypertension study demonstrated that losartan, an angiotensin receptor blocker that also lowers uric acid, reduced the time-related increase in uric acid and that this contributed at least 29% to its total treatment effect on CVD endpoint.  They also showed that baseline SUA level was associated with increased risk for CVD in women (but not men) after adjustment for concomitant risk factors using the Framingham risk score. 
Left ventricular hypertrophy (LVH) is a marker of target organ (cardiac) damage in hypertension.  Previous studies have demonstrated positive associations between SUA and left ventricular (LV) mass and shown that the combination of high uric acid and LVH significantly predicts future CVD. ,
Moreover, there is some evidence to show that in patients with essential hypertension who have LVH; lower SUA levels are associated with better prognosis and increased SUA levels are related with increased cardiovascular risk, probably via interactions with other established risk factors.  Other investigators on the other hand do not support this and have shown that uric acid is neither an independent risk factor nor a causal risk factor for cardiovascular events because uric acid is not independent of hypertension. ,
In this study, we aim to test the null hypothesis that there is no significant relationship between SUA and LV hypertrophy and abnormal geometry independent of blood pressure, in untreated Nigerian patients with essential hypertension.
| Materials and methods|| |
This was a descriptive cross-sectional comparative study carried out at the medical outpatient clinics of the University of Port Harcourt Teaching Hospital, Port Harcourt, Rivers State, Nigeria. The study population consisted of an ethnically diverse group of colored Nigerians from Rivers State, and the neighboring south-south states of the Niger Delta, involved in the various economic activities in the area, mainly in the oil and gas sector.
A convenience sampling method was used whereby all consecutive patients who met the study inclusion criteria and had none of the exclusion criteria were recruited into this study. Inclusion criteria for cases were: (1) Newly diagnosed hypertensive patients aged between 30 and 70 years who had never been on antihypertensive therapy; (2) Patients who had no clinical or laboratory evidence of heart failure, coronary artery disease, significant valvular defects, secondary causes of hypertension, renal failure, overt proteinuria (on dipstick testing) or other concomitant systemic disease like diabetes mellitus. Cases were excluded if they had (1) previously diagnosed hypertension on antihypertensive medication or clinical evidence of secondary hypertension; (2) clinical evidence of gout; (3) history of use of uric acid lowering medication like allopurinol. Inclusion criteria for controls included: (1) Apparently healthy non-hypertensive subjects aged between 30 and 70 years who did not have any of the criteria for exclusion, and had given a verbal and written consent for the study.
A total of 130 consecutive patients with a new diagnosis of essential hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg;  the average of two blood pressure (BP) measurements taken 5 minutes apart was used) for which they had never received treatment were recruited over a 9-month period. Sixty-five healthy non-hypertensive individuals were included as controls for comparison.
They underwent a standardized medical history and examination, laboratory tests (for fasting lipid profile and SUA) and trans-thoracic echocardiographic assessment. Blood samples were obtained after an overnight fast. Venipuncture was carried out using a peripheral vein and 7 ml of blood was collected from each subject, 5 ml of which was put into lithium heparin bottles for assessment of fasting lipid profile, SUA, and serum creatinine. Two milliliters was put into fluoride oxalate bottles for fasting blood glucose. Fasting blood glucose and serum creatinine were analyzed to exclude patients with diabetes mellitus or chronic kidney disease, respectively. Serum creatinine was used to calculate the estimated glomerular filtration rate (GFR) using the Cockcroft-Gault formula.  Patients with estimated GFR levels of 60 ml/min or below  and those with fasting blood glucose levels of 7.0 mmol/l and above were excluded.
SUA was analyzed with the enzymatic colorimetric method using an auto analyzer. Normal values used in the hospital chemical pathology laboratory are less than 360 μmol/L and 420 μmol/L for women and men, respectively; therefore, individuals who had values above these levels were classified as having hyperuricemia. Fasting cholesterol and triglyceride levels were measured using the enzymatic method with a reagent from Atlas More Details Medical Laboratories. Fasting high-density lipoprotein (HDL) was measured with the precipitation method. Low-density lipoprotein (LDL) cholesterol values were calculated using the Friedewald equation when the triglyceride level was less than 4.0 mmol/l: LDL = TC - (HDL + TG/2.2). 
Definition of abnormal lipid profile: 
- Elevated triglyceride = TG > 1.7 mmol/l
- Hypercholesterolemia = TC > 5.2 mmol/l
- Low HDL cholesterol = HDL-c < 1.03 mmol/l
- Elevated LDL cholesterol = LDL-c > 3.0 mmol/l.
Left ventricular mass index (LVMI) and relative wall thickness were assessed by trans-thoracic echocardiography. Two-dimensional guided M-mode imaging was used for wall-thickness measurements. LVMI was calculated using the internal software of the machine (Aloka Prosound SSD 4000 echocardiography machine, Fair Medical Company Ltd, Matsudo, Japan equipped with a 2.5 Hz transducer). LVH was defined using cut-off values for LVMI 134 g/m 2 and 110 g/m 2 for men and women, respectively.  Relative wall thickness (RWT) was calculated as 2 Χ posterior wall thickness in end diastole/LV end diastolic diameter. A partition value of 0.45 for RWT was used for both men and women. 
The Ethics Committee of the University of Port Harcourt Teaching Hospital approved the study protocol.
All data were analyzed using the commercially available Statistical Package for the Social Sciences (SPSS) version 21.0 analytic software (IBM Corporation, Armonk, NY, USA). Data were expressed as mean ± standard deviations, and frequencies as a percentage. Continuous variables were compared with the Students t-test, or one-way analysis of variance, as considered appropriate. Proportions or categorical parameters were compared with the Chi-square test. Relations among continuous variables were assessed using Pearson's correlation coefficient and multiple linear regression analysis. All tests were considered to be statistically significant at the P value < 0.05.
| Results|| |
The baseline characteristics of the population are presented in [Table 1]. Cases and controls were matched for age and sex. Females constituted 65.4% of hypertensive cases. With regards to uric acid and LVMI among the hypertensive cases, these were 384.79 ± 96.4 μmol/l and 134.08 ± 52.3 g/m 2 , respectively. Both values were significantly higher than among the controls. Among the hypertensive cases, 22.3% had normal left ventricle geometry, 22.3% demonstrated concentric remodeling; 50.0% and 5.4% had concentric and eccentric LVH, respectively [Figure 1].
|Figure 1: Left ventricular geometry among the hypertensive and non-hypertensive individuals|
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In the hypertensive group, mean uric acid levels were significantly higher in patients with LVH compared with patients with normal ventricular mass (402.9 ± 104.3 μmol/l versus 362.3 ± 80.9μmol/l, respectively, P = 0.016). Regarding LV geometry, SUA levels differed significantly among concentric and eccentric LVH patterns (410.98 ± 101.5 3 μmol/l versus 328.0 ± 108.5 3 μmol/l, respectively, P = 0.013) [Figure 2]. Similarly, LVH was present in 70.5% of hypertensive individuals with hyperuricemia compared to 42.0% of those with normal uric acid levels (P = 0.001) [Table 2]. There was a significant positive linear relationship between mean uric acid levels and the LVMI among the individuals with hypertension (r = 0.346, P = 0.015) [Figure 3]. In standard multiple linear regression analysis, SUA was independently associated with LVMI after adjusting for possible confounders only among females with hypertension (standardized regression coefficient 0.367, P = 0.004) and not males (β =0.161, P = 0.432) [Table 3] and [Table 4].
|Figure 2: Comparison of the serum uric acid levels in the hypertensive patients with normal geometry, concentric remodeling, concentric hypertrophy and eccentric hypertrophy. Column height represents the mean; bars indicate 95% confidence intervals|
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|Figure 3: Correlation between serum uric acid and left ventricular mass index among the hypertensive individuals|
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|Table 2: Comparison of the hypertensive individuals with and without hyperuricaemia|
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|Table 3: Multiple linear regression analysis for left ventricular mass index in all individuals with hypertension|
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|Table 4: Multiple linear regression analysis for left ventricular mass index in men and women with hypertension|
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| Discussion|| |
Pertinent findings from this study were that at the time of clinical diagnosis of hypertension, 46.9% had hyperuricemia, 55.4% already had LVH with the most common geometric pattern being concentric LVH. Mean uric acid was higher among those who had LVH (especially concentric LVH) compared to those who did not, and similarly LVH was commoner among the hypertensive individuals who had hyperuricemia. Furthermore, there was a significant positive correlation between uric acid and LVMI and uric acid was an independent predictor of increased LVMI, but only in women. Concentric LVH among these patients at the time of diagnosis may be indicative of the fact that these patients likely have had hypertension for some time but were unaware of the condition. This emphasizes the need for regular screening to detect hypertension, which is largely a "clinically silent" condition until complications set in.
Several clinical and experimental studies have suggested that uric acid plays a primary role in the occurrence of hypertension ,, and the reported prevalence rates of hyperuricemia among newly diagnosed hypertensive patients range between 40 and 60%. , Several mechanisms have been elucidated including the direct effect of uric acid on the nephrons, impaired nitric oxide generation, induced endothelial dysfunction, and smooth muscle cell proliferation.  The implication of uric acid on onset of hypertension is further buttressed by the findings that hyperuricemia is usually present in young newly diagnosed patients with essential hypertension and not among those with secondary hypertension.  Age and duration of hypertension attenuates this relationship. The mean age of newly diagnosed patients in this present study was 46.8 years.
LVH is a predictor of adverse outcomes in hypertensive individuals, as it increases the susceptibility to arrhythmias and myocardial dysfunction.  Considering that the individuals in this study were newly diagnosed and presumed to be in the early stages of the disease process most of them had concentric LVH and this finding is in keeping with the documented evidence that concentric hypertrophy usually predominates early in the disease process due to pressure overload and is a compensatory mechanism to reduce wall stress in order to maintain systolic performance.  This may partly explain why the hypertensive patients in this study had higher mean ejection fraction and fractional shortening as compared with the controls although this form of abnormal LV geometry has been found to carry the highest risk for cardiovascular events.  Studies in Nigeria report varying prevalence rates of LVH among hypertensive patients. They range 30-72% and this is largely dependent on the cut-off values used to determine LVH and the patient selection criteria. , Salako et al., studied a similar group of patients as in this study and found prevalence of LVH of 36.7% half of whom were in the early stage (JNC VII stage 1) of hypertension.  Adebiyi et al. reported varying prevalence rates of LVH in a population of treated and untreated hypertensive patients using different partition values.  A prevalence rate of 56% was obtained when the cut-off for LVMI in men was 125 gm/m 2 and less (30.9%) when the LVMI cut-off for men was 131 gm/m 2 . These lower prevalence rates may not be unrelated to the fact that some of their patients were on anti-hypertensive medication, which may contribute to regression of LVH especially the angiotensin converting enzyme inhibitors and calcium channel blockers. Aje et al. reported a higher prevalence rate of 72% in newly diagnosed hypertensive patients; however, the LV mass in their study population was indexed to height to the allometric power of 2.7, which is reported to result in higher prevalence rates even though it may be more specific as it excludes potential confounders like gender. ,
The link between uric acid and LVMI might relate to an association of uric acid with other risk factors, especially including renal dysfunction, oxidative stress, severity of hypertension, and obesity.  In experimental and in vitro systems, uric acid appears to have the ability to induce inflammatory mediators, such as tumor necrosis factor α, and mitogen-activated proteinkinases, which are known to induce cardiac hypertrophy.  Uric acid by activating the renin-angiotensin-aldosterone system both at the local and systemic levels promotes cardiomyocyte growth and interstitial fibrosis, which are the pathologic hallmarks of LVH.  These suggest that cardiac hypertrophy may be, at least in part, attributable to an increase in uric acid itself, via stimulation of endothelial dysfunction, smooth muscle cell proliferation, and inflammation. The finding in this study that uric acid was a predictor of LVMI independent of the effects of obesity and blood pressure lends support to this theory.
The LIFE study demonstrated a 29% reduction in composite cardiovascular outcome (stroke, myocardial infarction, and cardiovascular deaths) in the losartan (an angiotensin receptor blocker) arm of the study, which was attributed to the additional benefit of losartan in reducing SUA levels (by reducing uric acid reabsorption in the renal proximal convoluted tubules).  However, other investigators have challenged the role of SUA by showing that it is the inhibition of xanthine oxidase that leads to better endothelial responses, and not just SUA-lowering strategies by means of uricosuric drugs.  The authors of a recent review article on uric acid, cardiovascular and renal complications also noted that there is not sufficient evidence to show that SUA-lowering is the mechanism underlying the benefit of allopurinol andother urate-lowering agents, as beyond lowering SUA, the inhibition of xanthine oxidase leads to better endothelial responses and modulation of oxidative stress.  Furthermore, there is also insufficient evidence to show the benefit of treating asymptomatic hyperuricemia and as pointed out by Fieg et al., the adverse effects of a drug like allopurinol can prove fatal.  This therefore raises questions about the direct pathophysiologic role of SUA on LVH.
Iwashima et al. studied the relationships between SUA, LVMI, and risk of CVD in patients with essential hypertension.  They found that overall uric acid levels were significantly higher in both males and females with LVH as compared with those without LVH. There was also a significant association between SUA and LVMI that persisted even after adjustment for taking diuretics and urate-lowering medication as 78.5% of their studied patients were on antihypertensive medication including diuretics and 9% were on uricosuric drugs at the onset of the study. Furthermore, during the follow-up period of 33.5 ± 0.8 months, 4.5% of their study population developed CVD (myocardial infarction, angina, congestive heart failure, transient ischemic attacks, and stroke). SUA level and LVMI were significantly higher in the patients who developed CVD during the follow-up period than in event-free subjects and it was concluded that the combination of SUA level and LVMI was an independent predictor for CVD. Post hoc analysis of data from the Framingham Offspring Study was aimed at assessing the association between hyperuricemia and subclinical myocardial dysfunction that increased the risk for subsequent heart failure.  Approximately 24 years after the onset of the study echocardiographic measurements of LV mass and thickness, end-diastolic LV thickness, and LV fractional shortening were carried out to assess subclinical myocardial dysfunction. Participants were separated into four groups based on baseline (at study onset) uric acid quartiles. Those in the highest SUA quartile (>368.8 μmol/l) had a significantly greater frequency of all the echocardiographic abnormalities compared with those in the lowest quartile (<255.8 μmol/l). They thus concluded that relatively young adults with elevated SUA were at a higher risk for subsequent heart failure. Even in children where essential hypertension is quite rare, it has been shown that LVH can develop and in one study, where 72 newly diagnosed patients with untreated essential hypertension were included, with a mean age of 14.5 years (range: 5-18 years), the LVH prevalence was 41.6%. Those with LVH had higher mean SUA levels than those without LVH and in addition, a higher uric acid level was found to be an independent predictor for LVMI. 
There exists age and sex differences in SUA levels and the association of uric acid and LVH in hypertension has been attributed to gender differences; however, different studies differ in their findings. , Adult men and postmenopausal women have higher uric acid levels than premenopausal women.  The LIFE study indicated that the association between SUA and cardiovascular events was stronger in women than in men with or without adjustment of Framingham risk score.  The finding that uric acid independently predicts LV mass only in women in the present study supports this. In contrast, studies in Japan have found positive significant correlation between LV geometry (LV mass, indexed LV mass, and relative wall thickness) and SUA level in male hypertensive patients but not in female hypertensive patients. , In a more recent study by Yoshimura et al. of 1,943 hypertensive and normotensive subjects, the relationship between SUA and LVH was significant only among males and not females. 
| Conclusion|| |
LVH is a marker of target organ damage in hypertension and heralds cardiovascular events. Uric acid has been shown to be positively associated with LV mass and abnormal geometry in this group of newly diagnosed untreated hypertensive individuals. Future studies are needed to determine whether lowering uric acid especially among women with hypertension will be beneficial in regressing LVH and thus attenuate cardiovascular risk in this group of individuals.
This cross-sectional study design did not allow for causal inferences and the effect of uric acid lowering was not assessed. In addition, the fact that it is a hospital based study limits its generalizability to the general population.
What this study adds
- Uric acid is elevated in Nigerian adult patients with newly diagnosed essential hypertension
- Cardiac hypertrophy is present even at time of diagnosis
- Mean uric acid was higher in those with concentric LVH
- Uric acid correlates with, and predicts LVH in patients with newly diagnosed hypertension especially women.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]