The association between gout and cardiovascular diseases has been noted for centuries but was not subjected to rigorous epidemiologic studies until recently. The published literature is almost unanimous in the strength and consistency of this association. However, the impact of gout over and above that conferred by hyperuricemia and other risk factors of cardiovascular disease has not been well studied. Future studies are expected to shed light on the pathophysiologic basis of this association.
Key points
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Gout is associated with higher risk of cardiovascular events in almost all the published studies.
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Patients with gout undergoing medical therapy are statistically less likely to have cardiovascular disease (CVD) than those not undergoing therapy.
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The relative importance of anti-inflammatory therapies and urate-lowering therapies in potentially reducing the CVD risk is under intense investigation.
“The gout has treated me with more severity than any former time; it however never climbed higher than my ankles.”
Unfortunately, gout is known to climb much higher than ankles; the heart is the most important organ affected.
Introduction
Humans are distinguished from other mammals by the absence of serum uricase, a hepatic enzyme that converts uric acid to allantoin; the latter is soluble in water and readily excreted. The absence of uricase along with extensive reabsorption of uric acid in the proximal tubules of kidney results in tenfold higher levels of serum uric acid in humans than in other mammals. Serum uric acid may act as antioxidant, thus providing some protection against aging and cancer. In some individuals, however, serum uric acid levels are higher than normal; this condition is defined as hyperuricemia. For epidemiologic studies, Krishnan and colleagues defined hyperuricemia as a serum uric acid concentration greater than 7.0 mg/dL. Serum uric acid levels in premenopausal women are lower by about 1 mg/dL than in men, owing to higher renal clearance of urate in women, possibly due to their higher plasma estrogen levels. Therefore, it can be argued that definitions of hyperuricemia should differ based on gender. Therefore, hyperuricemia is also defined as a uric acid level greater than 7.0 mg/dL in men and greater than 5.7 mg/dL in women. Hyperuricemia may lead to gout and nephrolithiasis, although whether to treat subjects with asymptomatic hyperuricemia is debatable. Large population-based studies have shown that the incidence of gout increases with increasing serum uric acid levels. Gout is a common and excruciatingly painful inflammatory arthritis, characterized by recurrent attacks of acute arthritis due to the crystallization of monosodium urate within joints. In some patients, gout leads to development of chronic arthritis and urate tophi.
Galen, a Roman physician of the second century, astutely stated that gout is due to a “hereditary trait” and to “debauchery and intemperance.” The association between gout and cardiovascular disease (CVD) was also observed in Roman times. In the 19th century, physicians in England and elsewhere noted that people with gout tend to die from other causes earlier in life. In the 1950s, one of the founding objectives of the Framingham heart study was to test the hypothesis that gout is associated with coronary artery disease. The first modern article linking gout and unstable angina was published in 1988 and was based on data from the Framingham study. More recently, the focus has been on the association between hyperuricemia and CVD. Convincing cross-sectional associations have been reported linking progressive increase in serum uric acid with greater coronary artery calcifications ( Figs. 1 and 2 ). Prospective studies have demonstrated strong independent associations between serum urate concentrations and incidence of hypertension and incidence of heart failure ( Figs. 3 and 4 ). Over the past decade, there has been a resurgence of interest in the association between gout and heart disease driven by emerging epidemiologic data linking the two, the realization that gouty arthritis and hyperuricemia are not synonymous but distinct pathophysiologic entities, and that the inflammatory activity in gout may provide additional risk for CVD. This article focuses on the epidemiologic associations of gout with MI and CAD (collectively referred as CVD here) and with heart failure.
Introduction
Humans are distinguished from other mammals by the absence of serum uricase, a hepatic enzyme that converts uric acid to allantoin; the latter is soluble in water and readily excreted. The absence of uricase along with extensive reabsorption of uric acid in the proximal tubules of kidney results in tenfold higher levels of serum uric acid in humans than in other mammals. Serum uric acid may act as antioxidant, thus providing some protection against aging and cancer. In some individuals, however, serum uric acid levels are higher than normal; this condition is defined as hyperuricemia. For epidemiologic studies, Krishnan and colleagues defined hyperuricemia as a serum uric acid concentration greater than 7.0 mg/dL. Serum uric acid levels in premenopausal women are lower by about 1 mg/dL than in men, owing to higher renal clearance of urate in women, possibly due to their higher plasma estrogen levels. Therefore, it can be argued that definitions of hyperuricemia should differ based on gender. Therefore, hyperuricemia is also defined as a uric acid level greater than 7.0 mg/dL in men and greater than 5.7 mg/dL in women. Hyperuricemia may lead to gout and nephrolithiasis, although whether to treat subjects with asymptomatic hyperuricemia is debatable. Large population-based studies have shown that the incidence of gout increases with increasing serum uric acid levels. Gout is a common and excruciatingly painful inflammatory arthritis, characterized by recurrent attacks of acute arthritis due to the crystallization of monosodium urate within joints. In some patients, gout leads to development of chronic arthritis and urate tophi.
Galen, a Roman physician of the second century, astutely stated that gout is due to a “hereditary trait” and to “debauchery and intemperance.” The association between gout and cardiovascular disease (CVD) was also observed in Roman times. In the 19th century, physicians in England and elsewhere noted that people with gout tend to die from other causes earlier in life. In the 1950s, one of the founding objectives of the Framingham heart study was to test the hypothesis that gout is associated with coronary artery disease. The first modern article linking gout and unstable angina was published in 1988 and was based on data from the Framingham study. More recently, the focus has been on the association between hyperuricemia and CVD. Convincing cross-sectional associations have been reported linking progressive increase in serum uric acid with greater coronary artery calcifications ( Figs. 1 and 2 ). Prospective studies have demonstrated strong independent associations between serum urate concentrations and incidence of hypertension and incidence of heart failure ( Figs. 3 and 4 ). Over the past decade, there has been a resurgence of interest in the association between gout and heart disease driven by emerging epidemiologic data linking the two, the realization that gouty arthritis and hyperuricemia are not synonymous but distinct pathophysiologic entities, and that the inflammatory activity in gout may provide additional risk for CVD. This article focuses on the epidemiologic associations of gout with MI and CAD (collectively referred as CVD here) and with heart failure.
Association between gout and CVD
Case Series and Cross-sectional Studies
In general, case-series and cross-sectional studies are considered less valuable than cohort studies in establishing causality. Nevertheless, these studies are easier to perform, less expensive, provide important insights and corroborating data with respect to the association between gout and coronary artery disease, and have paved the path for future research. Table 1 summarizes the key studies of this type that have assessed associations between gout and CVD.
| Study (Ref.) | Subject Source | Number of Subjects Gout (Total) | Follow-up Years a | CVD Outcomes | Number of subjects with CVD outcomes, Gout (Total) | Adjusted Effect Size (95% CI) |
|---|---|---|---|---|---|---|
| Yü et al, 1980 (USA) | Research clinic case series | 2000 | 30 | Mortality | 382 | N/A (descriptive data) |
| Nishioka & Mikanagi, 1981 (Japan) | Clinics case series | 104 | 8 | CVD | 28 | N/A (descriptive data) |
| Darlington et al, 1983 (UK) | Clinics | 180 | 6 | CVD mortality | 5 | N/A (O/E, gout not significant) |
| Chen et al, 2007 (Taiwan) | Administrative data | 22,572 | N/A | Q waves in ECG | 393 | 1.18 (1.01–1.38); gout significant |
| Stamp et al, 2013 (New Zealand) | Population | 57 (751) | N/A | CVD by history | 10 (24) | Significant difference |
| Winnard et al, 2011 (New Zealand) | Administrative data | 119,234 (3,036,093) | N/A | CVD | 27,131 (165,042) | Age-standardized rate ratio 2.7 ( P <.001) |
a Follow-up years are the maximum number of years if given as a single number. If given in mean (SD) format then mean follow-up and standard deviation for that study is shown.
The earliest case series to report associations between gout and CVD mortality were published in the 1980s, but they were without comparative populations. In a large-scale cross-sectional study, Chen and colleagues evaluated whether the severity of gouty arthritis is associated with Q-wave myocardial infarction (QWMI). In multivariate analyses controlling for serum urate level, age, gender, smoking, drinking, diuretics use, total cholesterol, triglyceride, hypertension, diabetes, and body mass index (BMI), they found that increased affected joint count was associated with QWMI. A recent study from New Zealand showed that participants with gout were more likely to have cardiac disease history (defined as history of angina, myocardial infarction [MI], heart failure, stroke, cardiac intervention, pacemaker, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, or other cardiac intervention). About 17.5% of individuals with gout had cardiac history compared with only 3.5% without gout. The difference was significant after adjusting for age and gender. Another study conducted in New Zealand adults using administrative data showed that CVD is more prevalent in subjects with gout, compared with those without gout.
Case-control and Cohort Studies
In observational epidemiologic research, case-control studies, case-control studies nested in a cohort, and cohort studies are used to establish causality. Prospectively collected data, with minimal attrition, provides a wealth of information. Knowledge of the association between gout and CVD comes from data collected prospectively over the last several decades. The major cohort studies that have evaluated the association between fatal and nonfatal coronary artery disease and gout are summarized in Table 2 ; see later discussion.
| Study (Ref.) | Population | Number of Subjects Gout (Total) | Follow-up Years a | Outcomes | Number of Subjects with CHD Outcome (Total Number of Cases of Gout) | Adjusted Effect Size (95% CI) b |
|---|---|---|---|---|---|---|
| Abbott et al, 1988 (USA) | Framingham cohort c | 94 (1858) | 32 | CHD | 37 (509) | 1.60 (1.10–2.50); significant |
| Gelber et al, 1997 (USA) | Meharry-Hopkins cohort | 93 (1624) | 30 | CHD | 7 (182) | 0.59 (0.24–1.46); not significant |
| Janssens et al, 2003 (Netherlands) | Continuous Morbidity Registration cohort | 170 (510) | 11 | CVD | 44 (114) | 0.98 (0.65–1.47); not significant |
| Krishnan et al, 2006 (USA) | Multiple Risk Factor Intervention Trial cohort | 1123 (12,866) | 6.5 | Fatal MI | 22 (246) | 0.96 (0.66–1.44); not significant |
| All MI | 118 (1108) | 1.26 (1.14–1.40); significant | ||||
| Choi & Curhan, 2007 (USA) | Health Professionals Follow-up cohort | 2773 (51,297) | 12 | CVD mortality | 304 (2132) | 1.38 (1.15–1.66); significant |
| CHD mortality | 238 (1576) | 1.55 (1.24–1.93); significant | ||||
| Nonfatal MI | 23 (1152) | 1.59 (1.04–2.41); significant | ||||
| Krishnan et al, 2008 (USA) | MRFIT cohort | 655 (9105) | 17 | Fatal MI | 36 (360) | 1.35 (0.94–1.93); not significant |
| CHD mortality | 78 (833) | 1.35 (1.06–1.72); significant | ||||
| CVD mortality | 110 (1241) | 1.21 (0.99–1.49); not significant | ||||
| Cohen et al, 2008 (USA) | US Renal Data System dialysis subjects | 24,415 (234,794) | 5 | CVD mortality | Not reported | 1.47 (1.26–1.59); significant |
| Kuo et al, 2010 (Taiwan) | Participants of a health-screening program conducted by the Chang Gung Memorial Hospital in Taiwan (2000–2006) | 1311 (61,527) | 4.7 (2) | CVD mortality | 12 (198) | 1.97 (1.08–3.59); significant |
| De Vera et al, 2010 (Canada) | Case and control cohorts selected from British Columbia (Canada) Musculoskeletal Cohort: 3.5 million subjects with any musculoskeletal diagnosis between 1991 and 2004 | Men and women together: 9642 (57,852) Only women: 3890 (23,340) | 10 | Women | Women | |
| All MI | 244 (996) | 1.39 (1.20–1.61); significant | ||||
| Fatal MI | 61 (261) | 1.33 (0.99–1.78); not significant | ||||
| Nonfatal MI | 183 (735) | 1.41 (1.19–1.67); significant | ||||
| Men | Men | |||||
| All MI | 435 (2272) | 1.11 (0.99–1.23); not significant | ||||
| Fatal MI | 100 (517) | 1.10 (0.88–1.38); not significant | ||||
| Nonfatal MI | 335 (1755) | 1.11 (0.98–1.25); not significant | ||||
| Teng et al, 2012 (Singapore) | The Singapore Chinese Health Study, a population-based, prospective study of Chinese individuals in Singapore, 45–74 y at recruitment (1993–1998) | 2117 (52,322) | 8.1 (mean) | CHD deaths | 85 (1213) | 1.38 (1.10–1.73); significant |
| Kok et al, 2012 (Taiwan) | Taiwan National Health Insurance Research Database, nondiabetic ≥50 y | 164,463 (3,694,377) | 4 | CVD mortality | 5650 (74,367) | 1.10 (1.07–1.13); significant |
| Kuo et al, 2013 (Taiwan) | Taiwan National Health Insurance database | 26,556 (704,503) | 9 | All MI | 463 (3718) | 1.23 (1.11–1.36); significant |
| Fatal MI | 35 (299) | 0.97 (0.68–1.39); not significant | ||||
| Nonfatal MI | 428 (3419) | 1.26 (1.14–1.40); significant | ||||
| Individuals without cardiovascular risk factors all MIs | 112 (1739) | 1.84 (1.51–2.24); significant | ||||
| Individuals without cardiovascular risk factors nonfatal MIs | Not available | 1.80 (1.49–3.95); significant | ||||
| Stack et al, 2013 (USA) | NHANES III cohort | — (15,773) | 10 | Cardiovascular mortality | — (1276) | 1.46 (1.07–2.00); significant |
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