Abstract
Objective
Long-term uric acid exposure as an independent risk factor for cardiovascular disease remains unclear. This study investigated whether or not the running average serum uric acid (Ra-SUA) value measured after percutaneous coronary intervention (PCI) could be associated with the occurrence of subsequent cardiovascular events.
Methods
The clinical records of 1,761 patients who underwent successful PCI were retrospectively examined. The Ra-SUA values were calculated by adding consecutive SUA values and dividing them by the number of measurements. Based on the Ra-SUA value during an observation period of up to 10 years after PCI, the patients were divided into 3 groups based on the Ra-SUA: ＞7.0, 5.5-7.0, and ≤5.5 mg/dL. Among these groups, the incidence of major adverse cardiac events (MACEs) was investigated. Furthermore, patients with Ra-SUA ≤5.5 mg/dL were further classified into 3 groups according to Ra-SUA values to investigate the association with the incidence of MACEs. MACEs were defined as coronary-related death, nonfatal myocardial infarction, and new coronary stenosis of non-culprit lesions.
Results
A Kaplan-Meier analysis demonstrated that the incidence of MACEs was significantly higher in patients with Ra-SUA ＞7.0 mg/dL than in the other groups. A multivariate analysis indicated that the Ra-SUA value was significantly correlated with the incidence of MACEs. However, patients with Ra-SUA ＜4.0 mg/dL had an increased incidence of MACEs compared with patients with Ra-SUA 4.0-5.0 mg/dL.
Conclusion
High Ra-SUA values may be a predictor of increased recurrence of cardiovascular disease after PCI. There may also be a J-curve association between the incidence of MACEs and Ra-SUA values.
Keywords: running average serum uric acid value, coronary artery disease, secondary prevention, J-curve association
Introduction
Uric acid is an end-product of dietary and endogenous purine metabolism. Uric acid exists in body fluids as urate, approximately two-thirds of which is excreted by the kidneys and the remaining one-third by the intestines (1). Under physiological conditions, the synthesis and excretion of uric acid are balanced; however, if this balance is disturbed, hyperuricemia can lead to gout attacks and kidney stones. Epidemiological studies have demonstrated a positive relationship between serum uric acid (SUA) levels and the incidence of cardiovascular events (2-8). The 2018 European Society of Cardiology/European Society of Hypertension Guidelines of Arterial Hypertension officially introduced SUA levels as a cardiovascular risk factor that should be assessed to stratify patient risk (9).
However, the role of uric acid as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) remains controversial because elevated SUA levels are often associated with various other cardiovascular risk factors such as obesity, hypertension, lipid disorder, glucose intolerance, and kidney disease (10-13). The Framingham Heart Study also reported that SUA levels were not a causal risk factor for cardiovascular events (14). Furthermore, the cut-off value of SUA levels to prevent cardiovascular disease has not been established, and the possibility of a J-curve correlation between SUA levels and the incidence of cardiovascular events has also been noted (8).
ASCVD is a progressive disease that begins early in life and develops slowly over several decades before clinically manifesting. Gout attacks and kidney stones are also thought to be caused by uric acid accumulation owing to long-term exposure to high SUA levels. One possible reason why the association between SUA levels and ASCVD development is unclear may be that most clinical studies have only analyzed a single measurement of SUA levels and have not considered the potential effects of long-term cumulative exposure to high SUA levels.
In the present study, we hypothesized that the running average of SUA (Ra-SUA) may be associated with long-term exposure to high SUA levels and investigated whether or not the Ra-SUA value measured after percutaneous coronary intervention (PCI) could be associated with the occurrence of subsequent cardiovascular events. In addition, Ra-SUA values were used to examine whether sustained low SUA levels are associated with an increased incidence of cardiovascular events.
Materials and Methods
Study population
We retrospectively reviewed the clinical records of 1,761 patients who had undergone successful complete revascularization of major coronary artery branches by PCI for acute coronary syndrome (ACS) or stable angina (SA) between January 2009 and December 2019, and who had undergone regular outpatient checkups for at least 12 months after PCI. This study included 761 patients who underwent emergent PCI for ACS and 1,000 cases who underwent elective PCI for SA. However, patients with the following health conditions or histories, which may independently affect their outcomes, were excluded from this study in advance: residual stenosis in major coronary artery branches (9 patients), residual heart failure of New York Heart Association (NYHA) class 2-4 (2 patients), past history of coronary bypass surgery (8 patients), malignant tumors (4 patients), renal failure requiring dialysis treatment (21 patients), or hepatic damage with a Child-Pugh score of more than 5 (1 patient). One patient who experienced a cardiovascular event within three months of PCI was also excluded to avoid any potential effect of the PCI procedure or subacute thrombosis.
This study was approved by the ethics committee of KKR Takamatsu Hospital (reference number: E290) and performed in accordance with the Declaration of Helsinki.
Post-PCI management
The patient started exercise-based cardiac rehabilitation and received general lifestyle guidance and drug-taking instructions immediately after PCI. In addition, they were carefully monitored with interviews and clinical examinations every 2-6 months. Routine blood tests were performed at 3 months after PCI and at least once a year thereafter. Blood samples and body weights were typically obtained in a non-fasting state. Each biomarker, such as blood pressure, was checked in the visitor consultation room at our hospital. In addition, routine coronary angiography (CAG) was performed 6-8 months after PCI, and exercise electrocardiograms were performed every 6-12 months in patients with a preserved motor function. During follow-up, if relapses of some symptoms or a positive result on an exercise stress test were detected, CAG was performed. Anti-platelet agents were prescribed and continued according to the discretion of the attending physicians.
Measurement of the Ra-SUA value
The running average is the mean of a series of values up to a certain point. The running average is calculated by adding all measurements together as new measurements are added sequentially from the first measurement and then dividing that number by the number of measurements. For example, the running average for the nth blood test [Ra(n)] was calculated as follows:
Ra(n)＝(X1+X2+…+Xn)/n
where X1, X2, and Xn are the first, second, and nth blood test results respectively, and n is the number of samples.
In the present study, considering the differences in plaque characteristics and SUA levels at the start of ACS and SA treatment, the first SUA value (X1) was obtained 3 months after PCI. SUA values obtained thereafter (X2, X3,…, Xn) were used to calculate the Ra-SUA values for up to 10 years after PCI. If a cardiovascular event occurred within 10 years after PCI, the Ra-SUA values calculated prior to the event were used in the analyses. Patients who did not visit the outpatient clinic for 12 months or who had difficulty visiting the outpatient clinic regularly because of a disease other than a major adverse cardiovascular event (MACE) were treated as censored cases, and Ra-SUA at the time of their last visit was used in the analyses. Laboratory data obtained during random hospital visits for reasons other than cardiovascular events were also excluded. The running average of other laboratory parameters such as low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were also evaluated.
Ra-SUA cut-off value and patient classification
In accordance with the Japanese guideline for the management of hyperuricemia and gout (15), we classified patients with Ra-SUA ＞7.0 mg/dL into a high Ra-SUA group, and the remaining patients with Ra-SUA ≤7.0 mg/dL were divided into 2 groups based on the median value of 5.5 mg/dL, into an intermediate Ra-SUA group with Ra-SUA 5.5-7.0 mg/dL and a low Ra-SUA group with Ra-SUA ≤5.5 mg/dL. In addition, a very low Ra-SUA value was defined as an Ra-SUA value of ＜4 mg/dL.
Study protocol
We retrospectively investigated the following demographic and laboratory data in each group from the database: age at last PCI, sex, body mass index (BMI) three months after PCI, history of ACS, prevalence rate of hypertension, never smoking rates, LDL-C, HDL-C, triglyceride (TG), hemoglobin A1c (HbA1c), SUA, estimated glomerular filtration rate (eGFR) calculated using the Schwartz formula, and use of xanthine oxidase inhibitors (XOIs), uricosuric drugs, diuretics, sodium-glucose cotransporter 2 (SGLT2) inhibitors and statins. In addition, the running average of all laboratory data was measured and used for comparisons and analyses among the three groups. All laboratory data were obtained during a non-fasting state. Hypertension was defined as taking oral antihypertensive medication or have a blood pressure of ＞140/90 mmHg at an outpatient visit. Medication use was defined as continuous oral administration for 6 months during the observation period.
The cumulative incidence of MACEs for up to 10 years after PCI were investigated. MACEs were defined as coronary-related deaths, nonfatal myocardial infarction, and new coronary stenosis of non-culprit lesions. Restenosis in the culprit lesion was not included among MACEs. Coronary-related death was defined as fatal myocardial infarction or death due to suspected coronary artery disease (CAD). Myocardial infarction was diagnosed based on symptoms of myocardial ischemia, new ischemic changes on electrocardiograms, imaging evidence (e.g., new abnormality of myocardial wall motion), and an increase in markers related to myocardial necrosis. Coronary artery stenosis was defined as stenosis deemed necessary for intervention in quantitative coronary angiography.
In addition, the correlation between the incidence of MACEs and various risk factors was evaluated. To investigate the clinical course, laboratory data and drug use at 3 months after PCI and at the time of running average calculations were also performed. Furthermore, in order to evaluate the incidence of MACEs in patients with very low Ra-SUA values, the low Ra-SUA group was divided into 3 groups based on Ra-SUA values: ＜4.0, 4.0-5.0, and 5.0-5.5 mg/dL and investigated clinical characteristics including the use of SUA-lowering drugs and the incidence of MACEs among these three groups.
Statistical analyses
Continuous variables were expressed as the mean standard deviation, and a p value of less than 0.05 was considered statistically significant. A one-way analysis of variance (ANOVA), post hoc tests and chi-square tests were used to compare the baseline characteristics of the patients classified by the Ra-SUA value. The cumulative incidence of MACEs was analyzed using the Kaplan-Meier method and the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were performed to investigate the correlation between the incidence of MACE and coronary risk. Comparisons of laboratory data and medication at 3 months after PCI and at the time of the running average calculation were performed using paired t-tests and chi-square tests. In addition, comparisons of the incidence of MACEs and clinical characteristics in patients with Ra-SUA ＜4.0, 4.0-5.0, and 5.0-5.5 were performed using an ANOVA and unpaired t-tests. The data were analyzed using software programs StatMate V (Nihon 3B Scientific, Niigata, Japan) and R version 4.0.2 (The R Foundation, Vienna, Austria).
Results
The mean frequency of the blood tests was once every 5.4 months. The mean Ra-SUA value of all patients was 5.72 mg/dL. The number of patients with Ra-SUA values ＞7.0 mg/dL was 231, the number of patients with Ra-SUA 5.5-7.0 mg/dL was 781, and the number of patients with Ra-SUA ≤5.5 mg/dL was 749. The baseline clinical characteristics of the subjects are shown in Table 1. There was no marked difference in the history of ACS; however, differences in the age, sex, BMI, prevalence of hypertension and never-smoking rate were observed among the 3 groups. Regarding laboratory data, there were significant differences in the Ra-LCL-C, Ra-HDL-C, Ra-TG, Ra-HbA1c, and Ra-eGFR levels among the 3 groups. XOIs were more commonly prescribed in the high and moderate Ra-SUA groups than in the low group (Table 1).
Table 1.
Baseline Clinical Characteristics of the Enrolled Patients.
| Ra-SUA≤5.5 (n=749) | 5.5<Ra-SUA≤7.0 (n=781) | Ra-SUA>7.0 (n=231) | p value | |
|---|---|---|---|---|
| Age (years) at last PCI | 68.7±10.4 | 66.6±11.3† | 66.6±11.5† | <0.001 |
| Male | 513 (68.5%) | 655 (84.2%)† | 199 (86.1%)† | <0.001 |
| BMI (kg/mm2) at 3months after PCI | 23.2±3.6 | 24.7±3.6† | 24.7±3.3 | 0.018 |
| History of ACS | 307 (41.0%) | 352 (45.2%) | 101 (43.7%) | 0.241 |
| Hypertension | 428 (57.1%) | 511 (65.8%)† | 156 (67.5%)† | <0.001 |
| Never smoking | 399 (53.3%) | 371 (47.7%)† | 104 (45.0%)†‡ | 0.027 |
| Ra-LDL-C (mg/dL) | 90.4±21.1 | 91.2±19.9 | 96.7±22.9†‡ | <0.001 |
| Ra-HDL-C (mg/dL) | 55.9±14.3 | 54.0±13.3† | 51.2±11.7†‡ | <0.001 |
| Ra-TG (mg/dL) | 140.0±72.0 | 150.6±69.9† | 165.2±80.6†‡ | <0.001 |
| Ra-HbA1c (%) | 6.5±1.0 | 6.3±0.9† | 6.3±0.8† | <0.001 |
| Ra-SUA (mg/dL) | 4.6±0.7 | 6.2±0.4† | 7.7±0.7†‡ | <0.001 |
| Ra-eGFR (mL/min/1.73 m2) | 66.7±16.7 | 59.5±16.4† | 55.3±15.4†‡ | <0.001 |
| XOI | 68 (9.1%) | 134 (17.2%)† | 51 (22.1%)† | <0.001 |
| Uricosuric drug | 11 (1.5%) | 11 (1.4%) | 7 (3.0%) | 0.282 |
| Diuretics | 54 (7.2%) | 71 (9.1%) | 35 (15.2%)†‡ | <0.001 |
| SGLT2 inhibitor | 95 (12.7%) | 65 (8.3%)† | 13 (5.6%)† | <0.001 |
| Statin | 609 (81.3%) | 646 (82.7%) | 184 (79.7%) | 0.532 |
Data are expressed as mean±standard deviation or number (%), †p<0.05 vs. Ra-SUA ≤5.6; ‡p<0.05 vs. 5.6<Ra-SUA≤7.0. Ra: running average, BMI: body mass index, ACS: acute coronary syndrome, eGFR: estimated glomerular filtration rate, XOI: xanthine oxidase inhibitor, Diuretics: thiazide/loop diuretics
The median follow-up duration was 79 months. During the follow-up period, 346 patients were observed for several reasons, including discontinuation of outpatient treatment for unknown reasons (n=124), transfer due to relocation (n=135), death and transfer to another hospital due to diseases other than CAD (n=87). In addition, 485 patients (27.5%) experienced MACE, including coronary-related deaths (n=46), nonfatal myocardial infarction (n=41), and new coronary stenosis of non-culprit lesions (n=398).
Based on these data, a Kaplan-Meier analysis of the cumulative incidence of MACEs among three groups revealed that the incidence of MACEs was significantly higher in patients with Ra-SUA ＞7.0 mg/dL than in patients with Ra-SUA 5.5-7.0 mg/dL [hazard ratio (HR) 2.10; 95% confidence interval (CI) 1.47-3.00] and in patients with Ra-SUA ≤5.5 mg/dL (HR 3.16; 95%CI 2.18-4.59). Furthermore, the incidence of MACEs in patients with Ra-SUA 5.5-7.0 mg/dL was also higher than in patients with Ra-SUA ≤5.5 mg/dL (HR 1.51 95% CI 1.08-2.10) (Fig. 1). The details of MACEs in patients with Ra-SUA ＞7.0 mg/dL were coronary-related deaths in 15 patients, myocardial infarction in 10 patients, and the appearance of new coronary stenosis of non-culprit lesions in 88 patients. According to the univariate analysis using the Cox proportional hazard regression model, male sex, never smoking, Ra-LDL-C, Ra-HDL-C, Ra-TG, Ra-HbA1c, and Ra-SUA were significantly associated with the incidence of MACEs after PCI. Furthermore, the multivariate Cox proportional hazard regression analysis using these parameters demonstrated that the Ra-SUA value was independently associated with the occurrence of MACEs (Table 2).
Figure 1.
Incidence of major adverse cardiovascular event (MACE).
Table 2.
Univariate and Multivariate Analysis - Cox Proportional Hazard Model.
| Univariate Analysis | Multivariate Analysis | ||||||
|---|---|---|---|---|---|---|---|
| Hazard ratio | 95%CI | p value | Hazard ratio | 95%CI | p value | ||
| Age at last PCI | 0.995 | 0.987-1.003 | 0.211 | ||||
| Male patients | 1.455 | 1.144-1.849 | 0.002 | 1.438 | 1.104-1.872 | 0.007 | |
| BMI at 3months after PCI | 1.018 | 0.993-1.044 | 0.151 | ||||
| Hypertension | 1.180 | 0.979-1.423 | 0.083 | ||||
| Never smoking | 0.799 | 0.667-0.957 | 0.015 | 0.919 | 0.757-1.114 | 0.388 | |
| Ra-LDL-C | 1.038 | 1.034-1.042 | <0.001 | 1.039 | 1.035-1.043 | <0.001 | |
| Ra-HDL-C | 0.966 | 0.958-0.973 | <0.001 | ||||
| Ra-TG | 1.005 | 1.004-1.006 | <0.001 | 1.003 | 1.002-1.004 | <0.001 | |
| Ra-HbA1c | 1.202 | 1.098-1.318 | <0.001 | 1.132 | 1.033-1.241 | 0.009 | |
| Ra-eGFR | 1.002 | 0.997-1.008 | 0.430 | ||||
| Ra-SUA | 1.276 | 1.182-1.388 | <0.001 | 1.197 | 1.117-1.289 | <0.001 | |
| statin | 0.691 | 0.575-0.931 | <0.001 | 0.877 | 0.732-1.065 | 0.231 | |
| XOI | 0.786 | 0.601-1.029 | 0.078 | ||||
| Uricosuric drug | 0.535 | 0.222-1.292 | 0.164 | ||||
| SGLT2 inhibitor | 0.608 | 0.427-0.866 | 0.006 | 0.718 | 0.466-1.004 | 0.052 | |
| diuretics | 1.287 | 0.967-1.712 | 0.083 | ||||
CI: confidence interval, BMI: body mass index, Ra: running average, TG: triglyceride, eGFR: estimated glomerular filtration rate, SUA: serum uric acid
In addition, compared to laboratory data and medications at 3 months after PCI and at the time of the final running average calculation, there was an increase in the use of statins, XOIs, SGLT2 inhibitors, and diuretics, but no change in Ra-SUA values was observed (Table 3).
Table 3.
Laboratory Data and Medication at 3 Months after PCI and at the Time of Ra Value Calculation.
| Data/Medication | At 3 months after PCI | At the time of Ra value calculation | p value |
|---|---|---|---|
| LDL-C (mg/dL) | 96.0±26.5 | 91.6±20.9 | <0.001 |
| HDL-C (mg/dL) | 53.4±14.5 | 54.5±13.6 | <0.001 |
| TG (mg/dL) | 152.8±148.1 | 148.1±76.9 | 0.002 |
| HbA1c (%) | 6.4±1.0 | 6.4±0.9 | 0.004 |
| eGFR | 65.4±17.3 | 62.0±17.0 | <0.001 |
| SUA (mg/dL) | 5.7±1.4 | 5.7±1.2 | 0.190 |
| Statin | 1,345 (76.4%) | 1,439 (81.7%) | <0.001 |
| XO inhibitor | 128 (7.3%) | 253 (14.4%) | <0.001 |
| Uricosuric drug | 25 (1.5%) | 26 (1.5%) | 0.888 |
| SGLT2 inhibitor | 57 (3.2%) | 173 (9.8%) | <0.001 |
| diuretics | 122 (6.9%) | 160 (9.1%) | 0.018 |
Data are expressed as mean±standard deviation or number (%). eGFR: estimated glomerular filtration rate, SUA: serum uric acid, EPA: eicosapentaenoic acid
Moreover, the 749 patients with Ra-SUA ≤5.5 were further divided into 3 groups (Ra-SUA ＜4.0, 4.0-5.0, and 5.0-5.5), and the incidence of MACEs and use of SUA-lowering drugs were investigated among these groups. There was no marked difference in the age at last PCI, prevalence of hypertension and never-smoking rate; however, differences in the sex and BMI were observed. Regarding laboratory data, there were significant differences in the Ra-LDL-C, Ra-HDL-C, Ra-TG and Ra-eGFR values among these groups (Table 4). XOIs and SGLT2 inhibitors were not commonly prescribed in the very low Ra-SUA group (Table 4).
Table 4.
Baseline Clinical Characteristics in Patients with a Ra-SUA Value ≤5.5mg/dL.
| Ra-SUA<4.0 (n=139) | 4≤Ra-SUA<5.0 (n=305) | 5.0≤Ra-SUA≤5.5 (n=305) | p value | |
|---|---|---|---|---|
| Age (years) at last PCI | 70.1±9.2 | 69.1±10.3 | 67.7±10.9† | 0.057 |
| Male | 78 (56.1%) | 197 (64.6%) | 238 (78.0%)†‡ | <0.001 |
| BMI at 3months after PCI | 23.2±3.6 | 24.7±3.6† | 24.7±3.9†‡ | <0.001 |
| Hypertension | 72 (51.8%) | 169 (55.4%)† | 187 (61.3%)† | 0.125 |
| Never smoking | 82 (59.0%) | 169 (55.4%) | 148 (48.5%)†‡ | 0.076 |
| Ra-LDL-C (mg/dL) | 95.1±23.5 | 89.3±21.1† | 89.3±18.4†‡ | 0.014 |
| Ra-HDL-C (mg/dL) | 59.1±15.8 | 57.0±14.5 | 53.4±13.0†‡ | <0.001 |
| Ra-TG (mg/dL) | 137.0±72.0 | 131.0±56.6 | 149.5±77.4‡ | 0.006 |
| Ra-HbA1c (%) | 6.6±1.0 | 6.5±1.0 | 6.5±1.0 | 0.232 |
| Ra-eGFR (mL/min/1.73 m2) | 69.5±17.8 | 67.8±16.4 | 64.4±16.4†‡ | 0.004 |
| Alb (g/dL) at 3months after PCI | 4.4±0.4 | 4.3±0.3 | 4.3±0.3 | 0.767 |
| XOI | 6 (4.4%) | 21 (6.9%) | 24 (13.4%)†‡ | 0.002 |
| Uricosuric drug | 3 (2.2%) | 4 (1.3%) | 4 (1.3%) | 0.789 |
| Diuretics | 11 (7.9%) | 25 (8.2%) | 21 (6.9%) | 0.821 |
| SGLT2 inhibitor | 8 (5.7%) | 44 (14.4%)† | 40 (13.1%)† | 0.018 |
Data are expressed as mean±standard deviation or number (%), †p<0.05 vs. Ra-SUA ≤5.6; ‡p<0.05 vs. 5.6<Ra-SUA≤7.0, BMI: body mass index, eGFR: estimated glomerular filtration rate, Alb: albumin, XOI: xanthine oxidase inhibitor, Diuretics: thiazide/loop diuretics
Ultimately, this additional study showed that patients with Ra-SUA ＜4.0 mg/dL had a significantly higher rate of MACEs than patients with Ra-SUA 4.0-5.0 mg/dL (Fig. 2). In particular, male patients with Ra-SUA 4.0-5.0 mg/dL had a significantly lower incidence of MACEs than those with Ra-SUA ＜4.0 mg/dL and ≥5.0 mg/dL, indicating a clear J-curve association between Ra-SUA levels and MACEs incidence (Fig. 3).
Figure 2.
Incidence of MACE among patients with Ra-SUA value ≤5.5.
Figure 3.
Gender difference in incidence of MACE.
Discussion
The present study demonstrated that CAD patients with Ra-SUA ＞7.0 mg/dL had a significantly higher incidence of cardiovascular events after PCI than patients with Ra-SUA ≤7.0 mg/dL. In addition, a multivariate analysis of the clinical data from the present study showed that a high Ra-SUA value was independently associated with an increased incidence of cardiovascular events. These results indicate that long-term high SUA exposure may independently affect the occurrence of cardiovascular events and maintaining low SUA levels for a long period after PCI using Ra-SUA values may be useful for preventing the recurrence of CAD.
Although many previous reports have shown an association between SUA levels and cardiovascular disease, the role of SUA as a risk factor of cardiovascular disease remains controversial. These conflicting results may be because previous studies have relied on a single time point measurement of SUA and were unable to examine the longitudinal association between long-term SUA and cardiovascular events. In the present study, we considered that it would be desirable to have an index indicating long-term exposures to high UA levels that can be easily calculated, and we focused on the Ra-SUA value as a method for quantifying UA exposure. We believe that the Ra-SUA value, related to both the intensity and duration of high SUA levels, may be associated with UA accumulation. In addition, a study suggested that early high cumulative SUA levels contributed to a higher risk of subsequent myocardial infarction and all-cause mortality than the same cumulative SUA levels accumulated later in life (15). This suggests that it may be important to reduce SUA levels as early as possible and that the control of SUA levels using Ra-SUA values may be useful in preventing the progression of ASCVD.
Uric acid is a key intermediate in purine metabolism without which there is no deoxyribonucleic acid and no life. In humans, UA is an end product of purine metabolism because of the absence of uricase, which further degrades UA to allantoin and allantoic acid. Mammals who use urea to excrete nitrogen have low SUA levels; however, higher primates, including humans, lack uricase to degrade UA, and thus have much higher SUA levels than other mammals. Furthermore, in humans, a renal excretion ability and low solubility of UA in serum can also lead to crystallopathies such as gout or UA nephropathy (16). According to the Japanese Society of Gout and Nucleic Acid Metabolism 3rd edition, hyperuricemia is defined as an SUA level of ＞7.0 mg/dL regardless of sex (17); however, this SUA level does not represent a cut-off value for preventing cardiovascular diseases, but for preventing gout. The present study indicated that patients with Ra-SUA levels of ＞7.0 mg/dL had a significantly higher incidence of MACEs than patients with Ra-SUA levels of ≤7.0 mg/dL. Therefore, we believe that the treatment target for SUA levels in the secondary prevention of CAD should be ≤7 mg/dL, similar to the treatment target for gout prevention.
Another reason the relationship between SUA levels and the onset of cardiovascular events has been controversial is that SUA levels are strongly associated with various risk factors such as obesity, high blood pressure, and insulin resistance. Some studies have suggested that the elevation of SUA levels in patients with cardiovascular diseases could simply be a result of common factors such as reduced glomerular filtration rate, hyperinsulinemia, diuretics use, alcohol consumption, tissue ischemia or oxidative stress (10-14,18). In addition, male hormones promote uric acid production, whereas female hormones promote uric acid excretion. Therefore, average serum uric acid level may be influenced by sex and age. However, the multivariate analysis in the present study demonstrated that the Ra-SUA value was an independent predictor of MACEs after PCI. We believe that the Ra-SUA value is easy to calculate and understand and that it can be a useful indicator of uric acid levels and patient education in daily clinical practice.
Several possible mechanisms have been suggested to explain how elevated SUA levels can lead to cardiovascular diseases have been suggested. Some studies have indicated that uric acid directly infiltrates vascular endothelial cells through urate transporters (GLUT9/URATv1) leading to inflammation, endothelial dysfunction, and proliferation of vascular smooth muscle cells (19,20). Other studies have shown that oxygen radicals produced by xanthine oxidase (XO) damage endothelial, vascular smooth muscle, atrial muscle, and proximal renal tubular cells (21,22). Increased XO activity and decreased activation of nitric oxide (NO) have been observed in patients with CAD (23). Thus, there may be various mechanisms by which uric acid can affect the incidence of MACEs. However, the results of this study suggest that persistently high SUA levels may be associated with an increased incidence of MACEs, regardless of these mechanisms.
In addition, the J-shaped relationship between SUA levels and the occurrence of cardiovascular events observed in previous studies was particularly clearly demonstrated in the present study (8,24,25). As it now stands, the mechanism underlying this J-shaped relationship has not been fully elucidated. A study pointed out that hypouricemia caused by impaired UA reabsorption due to a genetic deficiency of URAT-1 may increase free radicals, which may lead to exercise-induced renal artery spasm and endothelial dysfunction (26). UA has also been shown to play a protective role as an antioxidant, leading to the inhibition of arteriosclerosis (27). The results of the present study did not show any evidence that SUA-lowering drugs caused abnormally low SUA levels or increased the incidence of cardiovascular events. In addition, decreased SUA levels may be associated with malnutrition and malignancies; however, no evidence of a J-curve relationship has been found. Considering this J-shaped phenomenon, men with extremely low Ra-SUA values without drug administration should be carefully monitored to detect atherosclerosis progression.
Furthermore, the present study showed that cardiovascular events were observed even in patients with Ra-SUA levels of 4.0-5.5 mg/dL. This result suggests that residual risks other than Ra-SUA levels must be considered in the secondary prevention of coronary artery disease. The cut-off value of Ra-SUA to prevent ASCVD has not been established; however, the results of multivariate analyses indicated that further lowering the target Ra-SUA value may also be beneficial. In addition, Ra-TG and Ra-LDL-C values may also be independent predictors of cardiovascular events after PCI. Therefore, we believe that appropriate management of Ra-LDL-C, Ta-TG values, and Ra-SUA values is necessary to prevent the progression of ASCVD.
Limitations
The greatest limitation of this study was the insufficient number of patients, which resulted in unevenness in patient characteristics, due to a single-center study. In addition, this study was a retrospective analysis that included many censored cases. As it was difficult to evaluate the period of exposure to high SUA levels prior to final PCI or a history of gout attacks, the degree of arteriosclerosis progression at the time of enrollment may not be equivalent among patients. Furthermore, although we used the running average of various clinical data during the observation period, we were unable to fully evaluate medication changes or fluctuations in the various data. Naturally, SUA concentrations are also affected by meal content, alcohol intake, fluid intake, medications such as diuretics, and the time of measurement. The results of this study, which was not an interventional trial, cannot demonstrate the usefulness of SUA-lowering therapy; however, Ra-SUA, which can stabilize these fluctuations in SUA levels, may have a greater impact on the clinical course than SUA values at a single time point. Further research is necessary to confirm these findings.
Conclusion
Long-term management of SUA levels using the Ra-SUA value is useful for preventing the recurrence of cardiovascular disease, and a high Ra-SUA value may be a predictor of increased cardiovascular events after PCI.
The authors state that they have no Conflict of Interest (COI).
References
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