Vázquez-Mellado, Janitzia MD, PhD*; García, Conrado García MD*; Vázquez, Silvia Guzmán MD*; Medrano, Gabriel MD*; Ornelas, Mario MD†; Alcocer, Luis MD†; Marquez, Alfredo MD‡; Burgos-Vargas, Rubén MD§
The association between gout and ischemic heart disease (IHD) has long been recognized, as well as the association between asymptomatic hyperuricemia with hypertension and IHD. Whether gout or hyperuricemia are independent or dependent risk factors for IHD has been a matter of controversy.1–4
Gout is related to metabolic abnormalities such as diabetes mellitus, hypertriglyceridemia, and obesity as well as hypertension.5,6 Hyperuricemia, on the other hand, is considered a marker of the X syndrome or metabolic syndrome, which is characterized by hyperglycemia or diabetes mellitus, hypertriglyceridemia, hyperuricemia, obesity, and hypertension. Besides the fact that some of these elements are known to increase the risk for cardiovascular disease, patients with metabolic syndrome have a high prevalence of atherosclerosis and consequently a high risk of IHD.7–9 Insulin resistance appears to play a major role in the pathogenesis of metabolic syndrome. Because insulin promotes uric acid and sodium reabsorption in the proximal tubule, hyperuricemia in patients with metabolic syndrome is likely to result from insulin resistance.7–9
Although some reports on metabolic syndrome had included patients with hyperuricemia or gout, there are actually no studies looking at the prevalence and characteristics of such syndrome in gout and their association with IHD. Therefore, in this article, we have investigated the prevalence of metabolic syndrome and IHD in patients with gout.
PATIENTS AND METHODS
This is a cross-sectional study of consecutive patients with primary gout who attended our outpatient clinic for the first time and had neither symptoms nor a previous diagnosis of IHD (angina or myocardial infarction). Gout was diagnosed according to previously published criteria.10 All patients underwent a complete clinical history and physical examination with emphasis in gout-related, cardiovascular, and metabolic history. Also, they answered the HAQ-Di (Health Assessment Questionnaire–Disability Index), which was previously validated and translated in our country.11 Information on past and current medications, including antihypertensives, diuretics, and therapy with glucocorticoids, was obtained in all cases. At their first visit, most of the patients were without treatment of the metabolic abnormalities because they were not previously diagnosed, although when the patients had regular treatment of hypertension or dyslipidemia or diabetes, they continued receiving it. Those in whom the diagnosis of hypertension was made during their first visit received the prescription of captopril as first choice. If dyslipidemia was detected, treatment was initiated after the laboratory tests. In our population, the patients frequently had a history of glucocorticoid therapy by auto-prescription. When this is noted, we prescribe equivalent doses of prednisone and taper it slowly until it is stopped.
Laboratory tests included complete cell count, blood chemistry, urinalysis, lipid profile, fasting insulin levels by enzyme linked immunosorbent assay, and creatinine clearance in 24-hour urine adjusted to 1.73 m2 body surface. Resting electrocardiogram (EKG) was performed on all the patients.
Myocardial single photon emission computed tomography (SPECT) imaging, before and after dipyridamole stress test, was performed according to standard methods.12,13 Rest imaging was started 45 to 90 minutes after 1 single intravenous injection of 10 to 15 mCi of Tc-99m sestamibi. Pharmacologic stress test started 3 hours later by infusing dipyridamole (0.56 mg/kg) for 4 minutes. A second dose of 25 to 30 mCi of Tc-99m sestamibi was injected 3 minutes after dipyridamole and myocardial perfusion imaging started 45 to 90 minutes later.12,14 EKG and blood pressure were recorded at short intervals during the whole study. The SPECT studies were performed with an Elscint scintillation camera, which included a high-resolution collimator and a semicircular orbit. Projection data were acquired over 180 grades anterior arc, from 45 grades left posterior oblique view to 45 grades right anterior oblique view, for 64 projections at 20 seconds per projection.12–14 SPECT images were displayed as polar maps and qualitatively and quantitative analyzed according to the Cedars Sinai method14 by an experienced nuclear cardiologist and nuclear medical doctor. SPECT studies were considered positive for myocardial ischemia when mild, moderate, or severe defect was present in at least 2 or 3 axes or in 3 consecutive tomographic sections on the same axis of the images obtained during the stress test and normal uptake at rest.14
IHD diagnosis was considered in patients having EKG signs of previous myocardial infarction and/or myocardial ischemia by SPECT.
The diagnosis of diabetes mellitus was considered in patients with fasting glucose serum levels above 126 mg/dL in 2 different instances15 and the diagnosis of metabolic syndrome in patients having 3 or more Adult Treatment Panel III (ATP III) criteria16: 1) fasting glucose ≥110 mg/dL, 2) blood pressure ≥130/85 mm Hg, 3) high-density lipoprotein (HDL) <40 mg/dL (men) or <50 mg/dL (women), 4) triglycerides ≥150 mg/dL, and 5) obesity. The diagnosis of obesity in this study was made in patients with a body mass index ≥27.5, because “abdominal obesity” as defined in the ATP III diagnostic criteria requires a waist circumference values (>102 cm in men and >88 cm in women) that could not be applicable in our country.17
Statistical analysis included chi-squared Student t test.
Sixty-four males with primary gout whose mean ages and duration of disease were 50.6 ± 12.8 years and 14.3 ± 10.4 years, respectively, were included in the study. Forty-one (64%) patients were previous or current cigarette smokers and 33 (52%) alcohol drinkers. Thirty (47%) patients had previously received chronic glucocorticoids by auto-prescription.
All 64 patients with gout fulfilled at least 1 criterion for the diagnosis of metabolic syndrome. Overall, 55 (86%) patients fulfilled ≥3 criteria and were therefore diagnosed with metabolic syndrome (Fig. 1). Thirty-five of them (63%) had hypertension and obesity on their first visit and metabolic syndrome was suspected clinically.
Ischemic Heart Disease
There was previous silent myocardial necrosis in 2 (4.6%) patients by EKG in the anterior wall in 1 patient and the posteroinferior wall in the other. These patients were sent for further cardiovascular evaluation. In all the other patients, SPECT was used. By SPECT, 8 (12.9%) of 62 patients had IHD involving the inferior wall in all of them, the septal wall in 3, and the anterior and lateral walls in 1 each. Overall, IHD was found in 10 (15.6%) patients with no previous symptoms of cardiovascular disease. There were additional EKG abnormalities in 31 (48%) patients, which consisted of left bundle branch block in 19%, left ventricle hypertrophy in 18%, and bradycardia in 6%.
There were no differences among the demographic variables, prevalence of alcoholism, and smokers between the patients with and without IHD.
All the patients with IHD (100%) and 83% without IHD had metabolic syndrome.
The overall prevalence of hyperglycemia or diabetes mellitus was 19%. In this study, 5 patients (without a history of it) had hyperglycemia (>110 mg/dL) and 7 others were already known to be patients with diabetes. Forty percent of patients with IHD and 15% of those without IHD had either hyperglycemia or diabetes mellitus (P = 0.08). The means of fasting glucose and insulin were higher in the group of patients with IHD (P = 0.000 and P = 0.03, respectively) (Table 1). Overall, there were 7 patients with fasting insulin levels >25 IU/mL.
Hypertriglyceridemia (>150 mg/dL) and low HDL (<40 mg/dL) were found in 87.5% and 84.4% of the patients, mostly in those with IHD. The means of low-density lipoprotein (LDL), cholesterol, and very-low-density lipoprotein (VLDL) values were higher in patients with IHD, but the difference between groups was only significant in LDL level (P = 0.014). Fifty-one (80%) patients were obese and 43 (67.2%) had hypertension. Although the frequency of obesity was slightly higher among patients with IHD, hypertension was more frequently found among patients without IHD (P = 0.053).
Characteristics of Gout and Renal Disease
Gout clinical manifestations were not different between the patients with and without IHD. With regard to the renal function, patients without IHD had higher urea, and creatinine levels, and lower 24 hours creatinine clearance and uric acid excretion (Table 2).
Most (86%) of our patients, including all 10 patients with IHD, fulfilled the ATP III diagnostic criteria for metabolic syndrome and therefore had an increased risk for cardiovascular disease. IHD was found in 16% of the patients.
These findings are particularly interesting because our patients were relatively young (mean age 50 years) and because IHD occurred in patients with no history of IHD.
The diagnosis of IHD in our group of patients with gout was mostly based on SPECT imaging of the myocardium. SPECT provides prognostic information on cardiac death or myocardial infarction risks, performs better than clinical and exercise test data, and plays a role in determining patients’ catheterization or revascularization.18,19 The prevalence of IHD by SPECT among individuals without a previous IHD, but classic cardiovascular risk factors, ranges from 7% to 25%.18,19 The prevalence of IHD in our patients, none of them having IHD previously diagnosed, was 12.6% by SPECT and 4.2% by EKG.
The prevalence of the metabolic syndrome in gout and the relative frequency of each of its components in our group seem higher than in the general population. Although the prevalence of metabolic syndrome among the U.S. adult population is 22%, in Mexican-American males between 40 and 60 years it is 25% to 34%.20
In our group, the prevalence reached 86% and all the patients included in this study had at least 1 ATP III diagnostic criterion for such diagnosis. Hypertension, low HDL, and hypertriglyceridemia20 were the most frequent components of metabolic syndrome in U.S. males, whereas hypertriglyceridemia, low HDL, and obesity were in our patients. It is important to note that nearly 70% of our patients had hypertension.
There are some data suggesting a role for genetic or ethnic factors in the prevalence of metabolic syndrome. Specifically, the prevalence of metabolic syndrome in Mexican Americans living in the United States is higher than in whites and even blacks.20 At this point, however, it is unknown whether such observations could be extrapolated to the Mexican population as a result of the fact that the role of environmental factors cannot be excluded. Unfortunately, the prevalence of metabolic syndrome in the general population in our country is still unknown.
Our patients with gout with IHD compared with those without had more frequent metabolic syndrome, hyperglycemia, or diabetes and obesity, higher insulin, triglycerides, cholesterol, LDL, VLDL levels, and lower HDL levels; in other words, more abnormalities associated with glucose metabolism and dyslipidemia.
On the other hand, we found significantly more evidence of renal damage in the subgroup of patients without IHD. Gout nephropathy is difficult to evaluate; most of the patients have associated diseases that can contribute to renal disease. These patients also had a higher frequency of hypertension that could explain subsequent renal disease.
Tarng et al. compared patients with gout with healthy control subjects of the same age and noted that patients with gout more frequently have decreased creatinine clearance, and this was more frequent when gout and hypertension were associated.22 One additional factor that, in some populations, that can contribute to gout, hypertension, and renal damage are environmental factors such as lead.22,23
Glucocorticoid therapy by self-prescription could be common in many countries where the patients can buy drugs without medical prescription or because they are used in “traditional medicine.”21 These therapies surely can have a role on metabolic parameters and atherosclerosis among these patients. Therefore, perhaps the prevalence of metabolic syndrome and IHD in patients with gout and without glucocorticoid treatment could be different, Unfortunately, there are no previous reports to compare.
Interestingly, none of our patients had a previous diagnosis of metabolic syndrome and none had been previously assessed for IHD because of the lack of any clinical sign of IHD. In contrast, nearly all of them had first sought medical care as a consequence of acute or chronic arthritis. Thus, it seems clear that for these patients, the first medical care provider could be the rheumatologist, who should be aware of the need for recognizing both metabolic syndrome and silent IHD. According to Emmerson,24 the rheumatologist should consider the potential and frequent metabolic-associated abnormalities and then be able to reduce the risk of IHD in patients with gout.
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