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Gout/hyperuricemia Increases Risk for Heart Disease
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"Gout and the risk of acute myocardial infarction"
Arthritis & Rheumatism
Volume 54, Issue 8 , Pages 2688 - 2696
Eswar Krishnan 1 *, Joshua F. Baker 2, Daniel E. Furst 3, H. Ralph Schumacher 2
1University of Pittsburgh, Pittsburgh, Pennsylvania
2University of Pennsylvania, Philadelphia
3University of California, Los Angeles
note from Jules Levin: HIV+ individuals sometimes have elevated uric scid for various reasons.
"....This study is the first to show that among men with no previous history of coronary artery disease, gouty arthritis is a significant independent correlate of subsequent acute MI. Confounders such as obesity, diuretic use, aspirin use, renal function, alcohol use, insulin resistance, metabolic syndrome, serum uric acid level, and other traditional risk factors did not account for this association. The absolute magnitude of the relative risk for the presence of gout was not high. Yet, the odds ratio associated with gout was the third largest among categorical variables, after smoking and family history of acute MI. Furthermore, the association was consistent across all analyses...... The available pathophysiologic evidence points toward inflammation, the characteristic difference between gout and hyperuricemia, as the likely pathway..... According to this model, persistent inflammation anywhere in the body can initiate and drive atherosclerosis .... Gout is the most common inflammatory arthritis in the US population, accounting for an estimated 3.9 million physician visits in 2002 ([36]). Even a small magnitude of risk elevation among these individuals can mean substantially higher absolute numbers of acute MI in the general population. We hope that our results will stimulate further research into this area...."
Abstract
Objective
To determine if hyperuricemia and gouty arthritis are independent risk factors for acute myocardial infarction (MI) and, if so, whether they are independent of renal function, diuretic use, metabolic syndrome, and other established risk factors.
Methods
We performed multivariable logistic and instrumental variable probit regressions on data from the Multiple Risk Factor Intervention Trial (MRFIT).
Results
Overall, there were 12,866 men in the MRFIT who were followed up for a mean of 6.5 years. There were 118 events of acute MI in the group with gout (10.5%) and 990 events in the group without gout (8.43%; P = 0.018). Hyperuricemia was an independent risk factor for acute MI in the multivariable regression models, with an odds ratio (OR) of 1.11 (95% confidence interval [95% CI] 1.08-1.15, P < 0.001). In multivariable regressions in which the above risk factors were used as covariates, gout was found to be associated with a higher risk of acute MI (OR 1.26 [95% CI 1.14-1.40], P < 0.001). Subgroup analyses showed that a relationship between gout and the risk of acute MI was present among nonusers of alcohol, diuretics, or aspirin and among those who did not have metabolic syndrome, diabetes mellitus, or obesity. In separate analyses, a relationship between gout and the risk of acute MI was evident among those with and without those hyperuricemia.
Conclusion
The independent risk relationship between hyperuricemia and acute MI is confirmed. Gouty arthritis is associated with an excess risk of acute MI, and this is not explained by its well-known links with renal function, metabolic syndrome, diuretic use, and traditional cardiovascular risk factors.
Background
The caricature of the typical patient with hyperuricemia is an obese middle-aged man with hypertension, diabetes mellitus, and hyperlipidemia who is given to excessive drinking. Among such individuals, it is not surprising to observe a surfeit of coronary artery disease as compared with the general population ([1-5]). While skeptics point toward residual confounding ([6]), evidence from prospective observational and interventional studies suggests that hyperuricemia is indeed a risk factor for cardiovascular disease independently of other risk factors, such as obesity, hyperlipidemia, diabetes mellitus, and hypertension ([7]).
When chronic and/or severe hyperuricemia leads to the precipitation of urate crystals within joints, it results in an inflammatory response that manifests as gouty arthritis (gout) ([8]). The inflammatory activity associated with gout can itself be proatherogenic and promote a prothrombotic environment that leads to acute coronary events ([9]). Thus, in theory, gout can be expected to increase the risk of acute myocardial infarction (MI). Yet, this important hypothesis has been examined in relatively few epidemiologic studies, and the results have been inconclusive ([10-12]). For a conclusive study, one would need to have a large cohort of high-risk individuals who had been followed up for long enough to accrue a sufficient number of outcome events. The Multiple Risk Factor Intervention Trial (MRFIT), a randomized primary cardiovascular prevention trial conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the MRFIT investigators, is one such study with the information on traditional and other confounding risk factors that has been unaccounted for in previous studies.
We used data from the MRFIT to test the following hypotheses: that hyperuricemia is an independent risk factor for acute MI, that gouty arthritis is an independent risk factor for acute MI, and that gouty arthritis increases the risk of acute MI independently of hyperuricemia.
DISCUSSION
This study is the first to show that among men with no previous history of coronary artery disease, gouty arthritis is a significant independent correlate of subsequent acute MI. Confounders such as obesity, diuretic use, aspirin use, renal function, alcohol use, insulin resistance, metabolic syndrome, serum uric acid level, and other traditional risk factors did not account for this association. The absolute magnitude of the relative risk for the presence of gout was not high. Yet, the odds ratio associated with gout was the third largest among categorical variables, after smoking and family history of acute MI. Furthermore, the association was consistent across all analyses.
For acute MI to occur, an environment that promotes atherogenesis and thrombogenesis is needed. Hyperuricemia is well known to be an independent risk factor for atherosclerotic diseases in general ([7]), and since chronic hyperuricemia is strongly associated with gout, it is not very surprising that an independent coronary risk for the presence of both hyperuricemia and gout was observed. The available pathophysiologic evidence points toward inflammation, the characteristic difference between gout and hyperuricemia, as the likely pathway. Even when there is no active arthritis, the synovial fluid of patients with gout shows low-grade inflammatory activity ([21]). Inflammation as a pathogenic process has been considered to be the key to coronary artery disease, in both atherogenesis and thrombogenesis ([9][22-24]). According to this model, persistent inflammation anywhere in the body can initiate and drive atherosclerosis and promote a prothrombotic environment that can lead to an acute coronary syndrome or stroke, depending on the site involved ([9][22][25]). Such a persistent inflammatory state is known to be present in rheumatic diseases such as lupus and rheumatoid arthritis, and the association of such diseases with premature atherovascular disease has been well established ([26-28]).
The link between gout and atherosclerosis has been observed for more than 100 years ([1-5][15][29]). While the link between acute MI and hyperuricemia has been well known, the link between acute MI and gout has been much less studied. One of the large-scale epidemiologic studies of this link was reported by Abbott et al ([10]), who used data from the Framingham Heart Study. They observed 37 events among 94 men (39%) with gout unrelated to diuretic use, compared with 509 events in 1,764 men without gout (29%). After risk adjustment, they found an excess risk of about 60% for coronary artery disease among subjects with gout as compared with those without gout ([10]). In their analyses, the investigators excluded cases of diuretic-induced gout and adjusted for potential confounding by age, systolic blood pressure, total cholesterol level, alcohol intake, BMI, and diabetes mellitus, but no adjustment for the effect of smoking was made. The association was observed only in men and was primarily due to excess cases of angina pectoris.
Another prospective observational study that addressed this question was based on the Meharry and Johns Hopkins Precursors cohorts of male physicians ([11]). The former group was composed entirely of African American subjects, and the latter group was composed entirely of white subjects. The confounders adjusted for in that analysis were cholesterol level, smoking, BMI, alcohol use, hypertension, and diabetes mellitus. However, the effect of other powerful confounders, such as family history and aspirin use, was not addressed. More importantly, information on uric acid levels, diuretic use, and renal function was not available. The results were contradictory to those of the Framingham Heart Study, with a pooled, risk-adjusted relative risk of 0.59 and a 95% CI ranging from 0.24 to 1.46. That study, however, was underpowered, with just 3 coronary artery disease events among the 31 subjects in the gout group of the Meharry cohort and 4 events in the corresponding group of 62 subjects of the Johns Hopkins Precursors cohort. Furthermore, the study subjects were relatively prosperous physicians, and serum uric acid measurements were not available.
Recently, analysis of 170 cases of gout in a general practice database in The Netherlands ([12]) showed that the cumulative incidence of cardiovascular disease (a pooled outcome combining angina pectoris, MI, heart failure, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease) was higher in individuals with gout (26%) than in controls matched for age, sex, and physician practice (20%). In a Cox proportional hazards regression model in which hypertension, diabetes mellitus, and hyperlipidemia were adjusted for, the risk associated with gout was 0.98 (95% CI 0.65-1.47). Other confounding factors, such as diuretic use, smoking, family history, aspirin use, etc., were not accounted for in that analysis. Information on serum uric acid levels was also unavailable. Interestingly, the risk estimate for hyperlipidemia (0.56 [95% CI 0.20-1.56]) was lower than that for gout.
There are important correlates of hyperuricemia that merit special consideration as potential confounders. The first, hypertension, is related to hyperuricemia through changes in renal vascular mechanisms ([30][31]). The second is the use of diuretics, since diuretics are known to be associated with clinically significant elevations in serum uric acid levels. The third is alcohol use; this can raise uric acid levels and can also independently influence the risk of coronary heart disease. As expected, in the MRFIT data, these factors had statistically significant intercorrelations; however, the magnitude of all of these correlations was very small (0.20).
The MRFIT examined a very highly selected group of men at high risk of developing coronary artery disease (3% of those screened). Men at lower risk and those at very high risk were excluded. Therefore, extrapolation of these results to routine clinical practice should be done cautiously. We did not perform time-to-event regression analyses (such as Cox proportional hazards regressions) because the data on gout and hyperuricemia were essentially left censored and because we could not date the occurrence of acute MIs that were detected from EKGs.
Our case definition for gout is less perfect than that used in the clinical practice setting. In the Meharry-Hopkins study, 75% of self-reported cases of gout were verifiable as meeting the American College of Rheumatology preliminary criteria for gout ([11][32]). Our definition that mandates the presence of persistent hyperuricemia has better face validity and is more conservative than the definition used in both the Framingham Heart Study and the Hopkins Study. Furthermore, our sensitivity analyses showed that the observed relationship between gout and acute MI is unlikely to be due to misclassification bias.
The traditional cardiac enzymes assayed for the detection of acute MI were the triad of lactate dehydrogenase, aspartate transaminase, and creatine kinase (CK) ([33]). The new diagnostic criteria include a characteristic rise and fall in blood concentrations of cardiac troponin and/or CK-MB in the context of spontaneous ischemic symptoms or coronary intervention ([34]). If it is accepted that any myocardial necrosis caused by ischemia constitutes acute MI, many patients who were formerly diagnosed as having unstable angina pectoris will now be diagnosed as having had a small acute MI. The limitations of the new definition of acute MI include the lack of a definition of cardiac arrest, as well as the lack of an acute MI classification in patients who present with characteristic symptoms of acute MI but die within 4-6 hours of symptom onset, a period during which cardiac markers, the EKG, and histologic findings (which take some hours to develop) may be nondiagnostic. The new definition will increase by 40% the number of patients with non-ST-segment elevation acute coronary syndromes who will be diagnosed as having had an acute MI ([35]).
Gout is the most common inflammatory arthritis in the US population, accounting for an estimated 3.9 million physician visits in 2002 ([36]). Even a small magnitude of risk elevation among these individuals can mean substantially higher absolute numbers of acute MI in the general population. We hope that our results will stimulate further research into this area.
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