|Year : 2020 | Volume
| Issue : 1 | Page : 109-114
Possibility of association of hypertension and ischemic heart disease with primary hyperuricemia
Noor El-Deen Abd El-Azeem M. Elhefny1, Mona H Elzohri2, Sara Mostafa Taher3
1 Professor of Internal Medicine, Faculty of Medicine, Assiut University, Assuit, Egypt
2 Associate Professor of Internal Medicine Department, Rheumatology and Clinical Immunology Unit Faculty of Medicine, Assiut UniversityInternal Medicine Department, Assuit, Egypt
3 Resident Doctor of Internal Medicine Department, Assuit, Egypt
|Date of Submission||25-Jan-2019|
|Date of Decision||28-Jan-2019|
|Date of Acceptance||04-Feb-2019|
|Date of Web Publication||05-Feb-2020|
Sara Mostafa Taher
Department of Internal Medicine, Assuit University, Assuit
Source of Support: None, Conflict of Interest: None
The relations between serum uric acid and cardiovascular disease are complex, so in the past five decades, more than 40 epidemiologic and clinical studies involving up to 150 000 individuals have been carried out to assess this association.
This study aimed to investigate the association between high uric acid levels and cardiovascular disease and hypertension.
Patients and methods
A total of 40 patients with primary hyperuricemia selected from Internal Medicine Department, Rheumatology Unit, Assiut University Hospital, were included in this study. Age of the studied patients ranged between 23 and 87 years. None of the patients were diabetic, hypertensive, had ischemic heart disease, or were smoker. Moreover, none of them had gout, kidney diseases, or liver cirrhosis. All of the studied patients had normal abdominal ultrasonographic findings with normal urine analysis and normal BMI. Incident hypertension was defined as newly detected blood pressure of at least 140/90 mmHg, which was examined along with ischemic changes by echocardiography.
Overall, 37.5% patients were discovered to be hypertensive and 32.5% patients had ischemic changes on echocardiography.
There is a strong and significant association between high uric acid levels and ischemic heart disease and hypertension, and this relationship is independent of traditional risk factors.
Keywords: ischemic heart disease, hypertension, uric acid, hyperuricemia
|How to cite this article:|
Elhefny NE, Elzohri MH, Taher SM. Possibility of association of hypertension and ischemic heart disease with primary hyperuricemia. J Curr Med Res Pract 2020;5:109-14
|How to cite this URL:|
Elhefny NE, Elzohri MH, Taher SM. Possibility of association of hypertension and ischemic heart disease with primary hyperuricemia. J Curr Med Res Pract [serial online] 2020 [cited 2021 Apr 18];5:109-14. Available from: http://www.jcmrp.eg.net/text.asp?2020/5/1/109/277504
| Introduction|| |
Cardiovascular diseases (CVDs) are a set of multiple disorders of the heart and blood vessels, including coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis, and pulmonary embolism.
It is clear that reducing the burden of cardiac diseases depends on early identification of its risk factors. There are various risk factors involved for CVDs, including family history, sex, race, age, hypertension, hypercholesterolemia, diabetes mellitus, obesity, smoking, and stress. Several recent experimental and epidemiological studies have reported an association between elevated levels of serum uric acid (SUA) and the risk of CVDs.
The most important study of a representative sample of the entire US population was theFirst National Health and Nutrition Examination Survey (NHANES 1), which found that increased SUA levels were independently and significantly associated with risk of cardiovascular mortality among men and women, over an average 16.4 years of follow-up. However, it has not been definitively established whether SUA is merely a marker for risk or a causative agent in CVD, or whether treatment targeting SUA levels affects outcomes.
| Patients and Methods|| |
This is a cross-sectional study conducted in Assiut University Hospitals, Faculty of Medicine, Assiut University, Egypt, in the period from January 2017 to December 2017. The study was conducted after approval from the Ethical Committee of Faculty of Medicine. A total of 40 patients were included in the study after an informed consent.
Patients admitted to our hospital with primary hyperuricemia with SUA level greater than 7.0 mg/dl in men and greater than 6.0 mg/dl in women in the absence of the secondary causes of elevation of SUA, aged 18 years or older, were included.
Diabetics; patients with chronic kidney disease; patients on diuretics for any cause; patients with any hematological abnormalities like hemolytic anemia, leukemia, or other myeloproliferative disorder; and patients on medications causing secondary hyperuricemia such as cyclosporine and aspirin were excluded.
A detailed history and thorough clinical examination was carried out in each patient, with special concern paid to the following:
- Blood pressure (BP) measurement was performed according to WHO guidelines.
- BMI was calculated by dividing weight in kilograms by the square of height in meters. Normal weight was defined as 18.5 kg/m2–24.9 kg/m2.
- Laboratory investigations: a blood sample was collected for the laboratory assessments, which included SUA, random glucose level, complete blood count, liver function tests (aspartate transaminase, alanine transaminase, and albumin), and creatinine levels. The glomerular filtration rate was also calculated through the Cockroft–Gault formula (140 − age × weight/creatinine × 72 for men and for women, multiplied by the correction factor of 0.85). Total cholesterol, high-density lipoprotein cholesterol, triglycerides, and low-density lipoprotein cholesterol were also assessed. Hyperuricemia was defined as SUA greater than 7.0 mg/dl for men and SUA greater than 6.0 mg/dl for women.
A 12-lead standard resting ECG was performed in all patients during the hospital stay to detect ischemic changes (depressed or raised ST-segment and/or T-wave changes) and the diagnosis of left ventricular hypertrophy.
All patients received transthoracic full echocardiographic examinations. Complete M-mode, 2-dimensional, and Doppler echocardiography was performed. Grading of regional myocardial function depended on the quality of contraction: normal, hyperkinetic, hypokinetic, kinetic, or dyskinesia.
The data were tested for normality using the Shapiro–Wilk test and for homogeneity variances before further statistical analysis. Categorical variables were described by number and percentage, whereas continuous variables were described by mean, SD, and median. χ2-test and Fisher's exact test were used to compare between categorical variables, where comparison between continuous variables was done by t-test for normally distributed data and Mann–Whitney U-test for abnormally distributed data. A two-tailed P value less than 0.05 was considered statistically significant.
| Results|| |
All of the studied patients had normal abdominal ultrasonographic findings with normal urine analysis.
None of the patients were known to be diabetic, hypertensive, or smoker. Moreover, none of them had gout, kidney diseases, or liver cirrhosis [Table 1].
|Table 1: Demographic data of the studied patients. It was noticed that all of the included patients had normal BMI|
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Laboratory data of the studied patients
Full laboratory data are summarized in [Table 2]. It was noticed that all studied patients had normal laboratory range of the tests.
Level of serum uric acid in the studied patients
All studied patients had SUA above 7 mg/dl. Mean ± SD of serum acid was 9.95 ± 2.67 mg/dl, with range between 7 and 18 mg/dl [Table 3].
Frequency of hypertension and ischemic changes on echocardiography in the studied patients
It was shown that of 40 studied patients in the study, 15 (37.5%) patients were discovered to be hypertensive and 13 (32.5%) patients had ischemic changes on echocardiography [Table 4].
|Table 4: Frequency of hypertension and ischemic changes on echocardiography in the studied patients|
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Serum uric acid in patients with high blood pressure and patients with normal blood pressure
It was noticed that SUA was significantly higher in patients with high BP in comparison with patients with normal BP (10.26 ± 2.91 mg/dl in patients with high BP vs. 8.84 ± 1.59 mg/dl in patients with normal BP; P = 0.04) [Table 5].
|Table 5: Serum uric acid in patients with high blood pressure and patients without normal blood pressure|
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Serum uric acid in patients with ischemic heart disease and patients without ischemic heart disease
It was noticed that SUA was significantly higher in patients with ischemic heart disease (IHD) in comparison with patients without IHD (11.20 ± 3.61 mg/dl in patients with IHD vs. 9.34 ± 1.78 mg/dl in patients without IHD; P = 0.03) [Table 6].
|Table 6: Serum uric acid in patients with ischemic heart disease and patients without ischemic heart disease|
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Presence of hypertension and ischemic heart disease in relation to serum uric acid level
It was noticed that presence of high BP and ischemic changes in echocardiography was higher with higher levels of SUA in the studied patients [Figure 1].
|Figure 1: Increasing occurrence of hypertension and IHD with increasing levels of SUA. BP, blood pressure; IHD, ischemic heart disease; SUA, serum uric acid.|
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Correlation of serum uric acid with other parameters in the current study
SUA had a strong positive significant correlation with systolic BP and diastolic BP [r (P)=0.91 (0.00) and 0.78 (0.00), respectively], whereas correlations of uric acid with other variables were insignificant (P < 0.05) [Table 7], [Figure 2] and [Figure 3].
|Table 7: Correlation of serum uric acid with diastolic blood pressure and systolic blood pressure|
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|Figure 2: Correlation between serum uric acid (SUA) and diastolic blood pressure (DBP).|
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|Figure 3: Correlation between serum uric acid (SUA) and systolic blood pressure (SBP).|
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| Discussion|| |
The uric acid has several biological properties that can be either beneficial or detrimental. SUA is a powerful antioxidant, and it protects against free radical damage. Along with ascorbate, SUA accounts for up to 60% of the serum free radical scavenging capacity.
SUA levels can be measured at low cost in almost all hospitals in the world, especially in developing countries, where many hospitals have no facilities to measure other expensive prognostic markers such as high sensitive C-reactive protein, brain natriuretic peptide, interleukin-6, and many others as indicators of CVD.
Previous studies have demonstrated that SUA is associated with CVD in high-risk populations, including patients with metabolic syndrome, hypertension, diabetes, hyperlipidemia, congestive heart failure, and stroke [8–11].
Our study is the firstt in Egypt to handle this association after controlling for a wide range of traditional risk factors such as smoking, diabetes mellitus, HTN, dyslipidemia, kidney affection, anemia, diuretic use, and obesity.
In our study, we found that increased uric acid level was an independent risk factor for the presence of ischemic events by echocardiography. Our main observation is supported by the National Health and Nutrition Examination Survey (NHANES), which found an independent association of SUA with CVD, but contradicts other studies such as an analysis of the Framingham Heart Study which reported an absence of an independent association after adjusting for a number of traditional CVD risk factors, with a substantial contribution of diuretic use to the nonsignificance of SUA for the prediction of cardiovascular morbidity and mortality. In the present study, although we excluded diuretic use as well as a wealth of traditional CVD risk factors, the association of SUA with CVD was still maintained.
Moreover, in the study carried out in 2013 by Kivity et al., in 9139 healthy adults, with a mean 4.8-year follow-up, the hazard ratio for CVD, adjusted for age, serum creatinine level, BMI, systolic BP, low-density lipoprotein cholesterol level, triglyceride level, plasma fasting glucose, physical activity, cardiovascular family history, use of diuretics, and current smoking, was 1.24 (95% confidence interval: 1.08–1.41) and supported SUA as a marker of CVD risk in healthy populations.
In addition, more and more studies have revealed independent associations in various populations, as shown in the Multiple Risk Factor Intervention Trial (MRFIT) study, the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) Study, the Vorarlberg Health Monitoring and Promotion Program, and in studies of Chinese and Japanese cohorts.
In addition, several clinical studies link SUA to coronary artery disease, such as a report from Saito and colleagues showing a correlation of SUA with lipid-rich coronary plaques, a composition known to be a precursor of future cardiac events. Similar findings have been reported for carotid plaques. Moreover, SUA has been linked to the extent of coronary atherosclerosis, reduced coronary flow reserve, and impaired coronary microvascular function. A recent study published by Pagidipati et al., including the PLATO and TRACER study populations, could demonstrate a significant association of SUA with short-term adverse outcome independent of the presence of gout.
Recently, another study carried out by Chang et al. in Taiwan, investigated the association between SUA concentration and cardiovascular risk. This study prompted earlier surveillance of the SUA level in asymptomatic individuals and resulted in the identification of populations at high risk of CVD.
Our study did not determine the underlying mechanisms regarding the role of SUA in the development of CVDs; however, other research groups have proposed possible mechanisms. Intracellularly and in mitochondria, uric acid has been shown to release free radicals and induce oxidative stress, resulting in enhanced atherosclerosis. SUA might also induce vascular inflammation by stimulating the expression of chemokines, such as monocyte chemoattractant protein-1. SUA also has been significantly and independently associated with the levels of C-reactive protein, interleukin-6, interleukin-18, and tumor necrosis factor-α. Furthermore, SUA has been shown to be associated with a reduction in nitric oxide availability causing endothelial dysfunction.
Moreover, according to our results, SUA is not only significantly associated with IHD (P < 0.05) but is also positively and significantly associated with HTN.
Hypertension is probably the most important risk factors for CVD and affects a large percentage of the population worldwide. Thus, among the priorities for CVD prevention, the detection and correction of all the reversible causes of uncontrolled BP can play a major role.
From this study, it can be observed that there were higher means of BP at the highest levels of SUA, which corresponds to the results found in 2006 by Perlstein et al., in 2062 individuals, over a 21-year period, where arterial hypertension was also associated with higher quintiles of SUA.
In 2016, a study of 26 442 Japanese males aged 18–60 years free from hypertension or diagnosed CVD at baseline concluded that high SUA level was associated with future hypertension in young and middle-aged Japanese males. This association was stronger among patients 40 years or older.
A recent study published in 2018 evaluated a total of 2335 Japanese male workers without hypertension who ranged in age from 18 to 64 years at a worksite. These men were followed for 6 years. SUA levels were associated with the future incidence of hypertension, and the association was observed in the younger individuals, those without diabetes, and those with preserved high-density lipoprotein cholesterol levels.
The biological explanation for this fact is supported by studies carried out with animal models such as rats, which showed the development of arterial hypertension after the induction of hyperuricemia, caused by a probable decrease in nitric oxide in the renal macula densa and by direct stimulation of the renin–angiotensin system, with both mechanisms causing vasoconstriction and therefore, BP increase.
Our results are of interest as SUA is easily assessed and represents a treatable target. Early trials already have suggested a benefit of lowering SUA with allopurinol on endothelial dysfunction, carotid intimal thickness, angina in patients with stable coronary artery disease, ventricular hypertrophy, arterial stiffness, and progression of chronic kidney disease. Although it has been argued that this might be owing to a sole inhibition of xanthine oxidase, a recent study also showed a benefit using probenecid in lowering BP, such as a uricosuric. This points toward an independent pathophysiological role of SUA. Currently, the ALLHEART study, investigating the benefit of allopurinol as addition to secondary prevention therapy, is recruiting, but results are not expected to be available before 2020.
The association of uric acid with CVD is indisputable, given that uric acid is associated with CVD risk factors, such as diabetes and hypertension. Whether uric acid is independently associated with CVD remains unresolved. Moreover, the evidence of an independent role for uric acid, at least in some populations, does not indicate causality. Less obvious is the possibility of causality, even without an independent relation. The Framingham Heart Study, and more recently Panero et al., concluded that uric acid was not a causal risk factor for cardiovascular events, because it was not independent of hypertension. However, if uric acid causes hypertension, and hypertension causes CVD, then uric acid has a causal role in CVD, even if it does not show independence from hypertension when evaluated as a risk factor for CVD.
We recommend the following:
- Clinical practice still needs further clinical trials finalized to assess urate-lowering efficacy in the much more global context of cardiovascular prevention.
- Elevations of uric acid more than 6 mg/dl should be considered a 'red flag' in those patients at risk for CVD and should alert the clinician to strive to utilize a global risk reduction program in a team effort to reduce the complications of the atherogenic process resulting in the morbid–mortal outcomes of CVD.
| Conclusion|| |
There is a strong and significant association between high uric acid levels and IHD. Moreover, uric acid is strongly and positively associated with hypertension, and this relationship is independent of clinical risk factors. As SUA is an easily accessible and inexpensive biomarker, identification of hyperuricemia as a cause rather than a consequence of subclinical atherosclerosis might be a potentially useful monitoring tool and therapeutic target for future CVD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Maulik N. Potent beneficial effects of vegetables and fruits on cardiovascular diseases. CRC Press Taylor and Francis Group, Boca Raton; 2013. p. 421–437.
Kawai T, Ohishi M, Takeya Y, Onishi M, Ito N, Yamamoto K, et al
. Serum uric acid is an independent risk factor for cardiovascular disease and mortality in hypertensive patients. Hypertens Res 2012; 35:1087–1092.
Fang J, Alderman MH. Serum uric acid and cardiovascular mortality: the NHANES I epidemiologic follow-up study, 1971–1992. JAMA 2000; 283:2404–2410.
Jin M, Yang F, Yang I, Yin Y, Luo JJ, Wang H, et al
. Uric acid, hyperuricemia and vascular diseases. Front Biosci (Landmark Ed) 2012; 17:656–669.
Whelton PK, Carey RM, Aronow WS, Collins KJ, Himmelfarb CD, DePalma SM, et al
. 2017 ACC/AHA/AAPA/ABC/ ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation and management of high blood pressure in adults. J Am Coll Cardiol 2018; 71:1269–1324.
Cockcroft DW, Gault H. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31–41.
Iliesiu A, Campeanu A, Dusceac D. Serum uric acid and cardiovascular disease. Maedica (Buchar) 2010; 5:186–192.
Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension: the PIUMA study. Hypertension 2000; 36:1072–1078.
Strasak AM, Kelleher CC, Brant LJ, Rapp K, Ruttmann E, Concin H, et al
. Serum uric acid is an independent predictor for all major forms of cardiovascular death in 28 613 elderly women: a prospective 21-year follow-up study. Int J Cardiol 2008; 125:232–239.
Krishnan E, Baker JF, Furst DE, Schumacher HR. Gout and the risk of acute myocardial infarction. Arthritis Rheum 2006; 54:2688–2696.
Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al
. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003; 107:1991–1997.
Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999; 131:7–13.
Kivity S, Kopel E, Maor E, Abu-Bachar F, Segev S, Sidi Y, et al
. Association of serum uric acid and cardiovascular disease in healthy adults. Am J Cardiol 2013; 111:1146–1151.
Strasak A, Ruttmann E, Brant L, Kelleher C, Klenk J, Concin H, et al
. Serum uric acid and risk of cardiovascular mortality: a prospective long-term study of 83 683 Austrian men. Clin Chem 2008; 54:273–284.
Chen JH, Chuang SY, Chen HJ, Yeh WT, Pan WH. Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a Chinese cohort study. Arthritis Rheum 2009; 61:225–232.
Jensen MK, Chiuve SE, Rimm EB, Dethlefsen C, Tjønneland A, Joensen AM, et al
. Obesity, behavioral lifestyle factors, and risk of acute coronary events. Circulation 2008;117:3062–3069.
Saito Y, Nakayama T, Sugimoto K, Fujimoto Y and Kobayashi Y. Relation of Lipid Content of Coronary Plaque to Level of Serum Uric Acid. The American Journal of Cardiology, 2015; 116; 9: 1346-1350.
Xing L Higuma T, Wang Z, Aguirre AD. Clinical significance of lipid-rich plaque detected by optical coherence tomography: a 4-year follow-up study. J Am Coll Cardiol 2017; 69:2502–2513.
Pagidipati NJ, Hess CN, Clare RM, Akerblom A, Tricoci P, Wojdyla D, et al
. An examination of the relationship between serum uric acid level, a clinical history of gout, and cardiovascular outcomes among patients with acute coronary syndrome. Am Heart J 2017; 187:53–61.
Chang CC, Wu CH, Liu LK, Chou RH, Kuo CS, Huang PH, et al
. Association between serum uric acid and cardiovascular risk in nonhypertensive and nondiabetic individuals: The Taiwan I-Lan Longitudinal Aging Study. Sci Rep 2018; 8:5234.
Förstermann U, Xia N, Li H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res 2017; 120:713–735.
Spiga R, Marini MA, Mancuso E, Faata CD, Fuoco A, Perticone F, et al
. Uric acid is associated with inflammatory biomarkers and induces inflammation via activating the NF-κB signaling pathway in HepG2 cells. Arterioscler Thromb Vasc Biol 2017;37:1241–1249.
Gullu H, Erdogan D, Caliskan M, Tok D, Kulaksizoglu S, Yildirir A, et al
. Elevated serum uric acid levels impair coronary microvascular function in patients with idiopathic dilated cardiomyopathy. Eur J Heart Fail 2007; 9:466–468.
Perlstein TS, Gumieniak O, Williams GH, Sparrow D, Vokonas PS, Gaziano M, et al
. Uric acid and the development of hypertension: the normative aging study. Hypertension 2006; 48:1031–1036.
Yokoi Y, Kondo T, Okumura N, Shimokata K, Osugi S, Maeda K, et al
. Serum uric acid as a predictor of future hypertension: stratified analysis based on body mass index and age. Prev Med 2016; 90:201–206.
Kansui Y, Matsumura K, Morinaga Y, Inoue M, Kiyohara K, Ohta Y, et al
. Impact of serum uric acid on incident hypertension in a worksite population of Japanese men. J Hypertens 2018; 36:1499–1505.
Conen D, Wietlisbach V, Bovet P, Shamlaye C, Riesen W, Paccaud F, et al
. Prevalence of hyperuricemia and relation of serum uric acid with cardiovascular risk factors in a developing country. BMC Public Health 2004; 4:9.
Goicoechea M, Garcia de Vinuesa S, Verdalles U, Verde E, Macias N, Santos A, et al
. Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial. Am J Kidney Dis 2015; 65:543–549.
Mackenzie IS, Ford I, Walker A, Hawkey C, Begg A, Avery A, et al
. Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study. BMJ Open 2016;6:e013774.
Panero F, G G, Perotto M, Fornengo P, Barutta F, Greco E, et al
. Uric acid is not an independent predictor of cardiovascular mortality in type 2 diabetes: a population-based study. Atherosclerosis 2012; 221:183–188.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]