ASSOCIATION OF HYPERURICEMIA WITH THE PRESENCE AND SEVERITY OF CORONARY ARTERY DISEASE IN PATIENTS UNDERGOING CORONARY ANGIOGRAPHY

Objectives: To determine the association of hyperuricemia with the presence and severity of coronary artery disease in patients undergoing coronary angiography. Methodology: This case control study was carried out in the Department of Cardiology, Chaudhary Pervaiz Elahi Institute of Cardiology, Multan for six months. Total number of 292 patients (146 cases with coronary artery disease and 146 controls with normal coronary arteries) having age 40-60 years of both genders were included in this study. Coronary angiography was performed using standard angiographic techniques. After undergoing coronary angiography, patients with 50% luminal stenosis or more in any one of the coronary arteries were labeled case group. Patients with normal coronaries or less than 50% luminal stenosis in any one of the coronary vessels were taken as control group. Serum uric acid was advised and value was noted along with the basic demographic data and established risk factors of coronary artery disease . Results: Mean age was 50.79±6.08 years. Mean serum uric acid was 7.54±3.60 mg/dl. Hyperuricemia was diagnosed in 94 (64.40%) patients with significant CAD (case group) and in only 59 (40.40%) in control group. The odds ratio was 2.66 (95% CI 1.66 to 7.28) with p value of <0.001. Triple vessel disease was diagnosed in 66.7% patients with hyperuricemia and in only 33.3% patients without hyperuricemia [OR 4.0 (2.09-7.64), p-value <0.001]. Conclusion: There is a significant association between the presence and severity of coronary artery disease with hyperuricemia.


INTRODUCTION
The end oxidation product of purine metabolism is uric acid. 1 Increased levels of serum uric acid, hyperuricemia, are linked with multiple diseases like gout, hyperlipidemia, hypertension, resistance to insulin, diabetes and coronary artery disease. 2 Coronary artery disease (CAD) is the leading cause of death in developed as well as in developing world. 3 The literature has reported that there is one coronary event in every 34 seconds and one death in every one minute and 24 seconds. 4 Since a long time a there is quest to find out the risk factors so that managing them could help to lessen the burden of CAD. Gertler and colleagues postulated hyperuricemia as a risk factor for coronary artery disease in 1950's 5 and since then it has been a topic of debate. Kuwabara concluded that hyperuricemia in patients with cardiovascular risk factors like hypertension is considered as a risk factor for cardiovascular disease and appropriate intervention must be done at an early stage. 6 Gagliardi et al reported that hyperuricemia is independently associated with coronary artery calcification presence and severity. 7 At the same time there are many studies which showed the contradictory results. 8,9 Similarly there are studies which concluded further workup is needed for developing hyperuricemia as an independent risk factor and whether to modify it or not. [10][11][12] Our institute is the largest referral cardiology hospital of South Punjab region of Pakistan with a large catchment area. The rationale to design this study is that the available evidences shows contradictory results of different studies in different populations, As our population differs from others in terms of lifestyle, daily routine activity, fast food and meat consumption, we designed this study to see the association of hyperuricemia not only with the presence of CAD but to find out if there is association between hyperuricemia and the severity of CAD in the population of South Punjab. This study will help clinicians and cardiologists to look whether hyperuricemia is a potential risk factor for coronary artery or not and encourage more research in future to see if managing hyperuricemia could reduce the risk of CAD or not.

METHODOLOGY
The case-control study was decided to carry out at the Department of Cardiology, Chaudhary Pervaiz Elahi Institute of Cardiology, Multan from 10 th of July 2020 to 9 th of January 2021. Patients with luminal stenosis of greater than 50% in at least one of the coronary arteries assessed at coronary angiography were labeled as coronary artery disease (Case group). Patients with normal coronary arteries or luminal stenosis of less than 50% in any of the coronary arteries were labeled as control group. Sample size was calculated via Open Epi software. By keeping 95% of confidence level, 80% of power of study, ratio of control to cases 1:1, proportion of hyperuricemia in controls at 47% and proportion of hyperuricemia in cases at 64%, 13 total sample size of 292 was calculated consisting of 146 cases and 146 controls. After approval from Ethical Review board and taking informed consent 292 consecutive patients both male and females of any age were included in the study. Patients having on and off history of chest pain on exertion, acute or chronic ST-T changes on electrocardiography, pathological Q waves on ECG or evidence for stress induced ischemia on exercise tolerance testing of less than 3 months duration were subjected to coronary angiography. Patients with heart failure determined by history and examination like shortness of breath, paroxysmal nocturnal dysnea or pulmonary congestion, hematological or oncological disorders (leukemia) and chronic infections like TB determined through medical records, patients taking diuretics, uric acid lowering drugs (allopurinol), recent major surgical procedure or trauma, patients with nephropathy either acute or chronic determined by serum creatinine > 2 mg/dl and medical record and patients with previous percutaneous or surgical revascularization on history and medical record were excluded from the study. The femoral or radial approach was used to perform coronary angiogram following institutional protocols. The presence of CAD was labeled if any one of the epicardial arteries has more than 50% luminal stenosis. The severity of CAD was determined by clinical vessel score. The patients who had either no coronary lesions or less than 50% luminal stenosis were in control group. The angiograms having one, two or three major epicardial coronary arteries involvement with more than 50% luminal obstructions were labeled as mild, moderate or severe disease respectively. Left main stem (LMS) disease was labeled as 1 vessel. All the coronary angiographies were reported by two consultant cardiologist with at least 5 years post fellowship experience. After undergoing coronary angiography, patients were categorized into two groups: cases & controls as defined earlier. One hundred forty six (146) patients for cases and 146 patients for control group were enrolled in the study. Now under aseptic conditions, blood sample for uric acid level was drawn and was determined by using standard chemical analyzer in pathology laboratory. Serum uric acid >7.0 mg/dl in men and >6.0 mg/dl in women determined by chemical analyzer was deemed positive to label hyperuricemia. Basic demographic data like age, gender, body mass index along with established risk factors of coronary artery disease like hypertension, family history of coronary artery disease, diabetes, dyslipidemia and smoking was collected. Patient was labeled smoker if he or she has history of smoking 100 cigarettes in his or her lifetime and who currently smokes cigarettes. Hyperlipidemia was labeled if plasma total cholesterol level was ≥200 mg/dL, LDL-cholesterol level ≥130 mg/dL, triglyceride level ≥200 mg/dL, and HDLcholesterol level ≤40 mg/dL, or history of use of lipid lowering drugs for more than 3 months at the time of the study. Patients were considered to have hypertension if they had documented arterial pressure of more than 140/90 mmHg or were being treated with antihypertensive medications for two or more years. Patients were considered diabetics if they were having history of use of insulin or oral hypoglycemic agents for two or more years. Patients who had no idea of their diabetic status was considered diabetics if they have fasting blood glucose >126 mg/dL. Positive family history was labeled if there was history of coronary artery disease in a parent or sibling under the age of 55 for men and 65 for women. Patients having body mass index of 30kg/m 2 or more was considered obese. All the data was collected on a preformed proforma. Statistical package for social sciences (SPSS) version 23 was used to enter and analyze the collected data. Quantitative variables like age and serum uric acid were represented by mean and standard deviation. Categorical variables were represented by frequencies and percentages like gender, hyperuricemia (yes, no), presence of diabetes mellitus (yes, no), hypertension (yes, no), dyslipidemia (yes, no), family history of CAD (yes, no), obesity (yes, no) and smoking (yes, no), CAD (yes, no) and severity (mild, moderate or severe). Odds ratio with 95% confidence interval was calculated to determine the association between hyperuricemia, presence of coronary artery disease and its severity as per objective. Data was stratified on age, gender, presence of diabetes mellitus, hypertension, family history of CAD, dyslipidemia and smoking to control confounding and effect modification. Post stratification odds ratio with 95% confidence interval was also reported. A p value ≤ 0.05 was taken as significant which is calculated via Chi-Square test.   Table 2 shows the cross tabulation between the hyperuricemia and the case and control group.  Table 3 shows the stratification of results for different risk factors of CAD.

DISCUSSION
The literature has shown the association between raised levels of serum uric acid and CAD for last 60 years. 14 A number of epidemiologic studies have reported that a relation exists between serum uric acid levels and a wide variety of cardiovascular conditions. 15 But to date this is a topic of discussion whether hyperuricemia is an independent risk factor of CAD or not. Fang et al in the NHANES I epidemiologic study showed that hyperuricemia is directly related to increased death rate due to cardiovascular diseases. 16 Madsen et al showed that in patients with coronary artery stenosis of ≥70% proven in coronary angiography, hyperuricemia is a strong risk factor. 17 Goodarzynejad et al, also showed that hyperuricemia is independently linked with CAD (OR 1.75 95% CI 1.15-2.68). 13  Goodarzynejad et al showed that hyperuricemia is not only associated with the presence of CAD but also with the severity. 13 They also labeled severity as mild, moderate and severe on the basis of vessel involvement score as ours and showed that mild, moderate and severe disease had 64.4%, 60.0% and 66.1% prevalence of hyperuricemia and the p-value was 0.001. Qureshi et al; also reported that patients with hyperuricemia has tend to have more severe coronary artery disease on coronary angiogram. 19 A Turkish study by Gur et al., also reported that hyperuricemia has shown association with the severity of CAD although they evaluated severity with the Gensini score. 21 Similar findings were reported by Durran et al. 22 Our study also showed similar results that hyperuricemia is also linked with the severity of disease.
Our study also has limitations. First this is a single centre observational study with a small sample size and single measurement of uric acid levels. We know that serum uric acid has complex relationship with many other well established risk factors of CAD and dietary habits and it tends to change with the changes in lifestyle. To establish hyperuricemia as an independent factor of CAD and its association with the severity, multicenter Cohort study with larger sample size is needed.

CONCLUSION
Our study has showed that the raised levels of serum uric acid is more in patients having coronary artery disease as compare to control group. There is also a strong association of hyperuricemia with the severity of coronary artery disease. Hyperuricemia tend to be more prevalent with severe (3 vessel disease) coronary artery disease.

AUTHORS' CONTRIBUTION
AA: Concept and design, data acquisition, interpretation, drafting, final approval, and agree to be accountable for all aspects of the work. MZZ, RM, HYS, GZKN: Data acquisition, interpretation, drafting, final approval and agree to be accountable for all aspects of the work.