Gout and the Heart Vidula Bhole,
MD
a
, Eswar Krishnan,
MD, M.Phil
b,
*
KEYWORDS Gout Uric acid Risk cardiovascular Coronary Mortality KEY POINTS Gout is associated with higher risk of cardiovascular events in almost all the published studies. Patients with gout undergoing medical therapy are statistically less likely to have cardiovascular disease (CVD) than those not undergoing therapy. 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.” —British author and poet Samuel Johnson (1709–1784) 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.1 Serum uric acid may act as antioxidant, thus providing some protection against aging and cancer.2 In some individuals, however, serum uric acid levels are higher than normal; this condition is defined as hyperuricemia. For epidemiologic studies, Krishnan and colleagues3 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
Disclosures: Dr E. Krishnan has received honoraria, consultation fees, and research grants from the following entities in the past 3 years: Takeda, Metabolex, Savient, ARDEA (Currently owned by Astra Zeneca). Dr V. Bhole has no disclosures to declare. a 515 Olmsted Road, Palo Alto, CA 94305, USA; b ARAMIS Program, Department of Medicine, Stanford University, 1000 Welch Road, Suite 203, Palo Alto, CA 94304, USA * Corresponding author. E-mail address: [email protected] Rheum Dis Clin N Am 40 (2014) 125–143 http://dx.doi.org/10.1016/j.rdc.2013.10.004 rheumatic.theclinics.com 0889-857X/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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clearance of urate in women, possibly due to their higher plasma estrogen levels.4 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.5 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.6 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.7,8 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.9 The first modern article linking gout and unstable angina was published in 1988 and was based on data from the Framingham study.10 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.
Fig. 1. Prevalence of any coronary artery calcification (Agatston score >0) by serum uric acid concentration among participants (1211 men and 1287 women) in the Coronary Artery Risk Development in Young Adults (CARDIA) study cohort at year 15. P values are for trend test. CAC, coronary artery calcification; SUA, serum urate. (From Krishnan E, Pandya BJ, Chung L, et al. Hyperuricemia and the risk for subclinical coronary atherosclerosis–data from a prospective observational cohort study. Arthritis Res Ther 2011;13(2):R66.)
Gout and the Heart
Fig. 2. Relationship between burden of coronary artery calcification (unmodified Agatston score) and serum uric acid (SUA) concentrations among 238 subjects in the CARDIA study cohort who had an Agatston score of greater than zero. P values are for trend test. (From Krishnan E, Pandya BJ, Chung L, et al. Hyperuricemia and the risk for subclinical coronary atherosclerosis—data from a prospective observational cohort study. Arthritis Res Ther 2011;13(2):R66.)
Fig. 3. Time to develop hypertension among 803 men in the Multiple Risk Factor Intervention Trial (MRFIT) without metabolic syndrome but with baseline hyperuricemia (serum uric acid [SUA] >7.0 mg/dL) compared with 2270 men without hyperuricemia, adjusted for baseline values of age, systolic and diastolic blood pressure, serum creatinine, proteinuria, serum triglycerides, total cholesterol, alcohol use, smoking, and BMI. (From Krishnan E, Kwoh CK, Schumacher HR, et al. Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension 2007;49(2):298–303.)
127
128
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Fig. 4. Kaplan-Meier estimates for heart failure–free follow-up among the 4912 participants of the Framingham Offspring Study by quartiles of serum uric acid. For this survival model, the observation started at the first study visit and ended at the time of incident heart failure (n 5 196). The y-axis scale is adjusted for the sake of clarity. (From Krishnan E. Hyperuricemia and incident heart failure. Circ Heart Fail 2009;2(6):559; with permission.)
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. The earliest case series to report associations between gout and CVD mortality were published in the 1980s, but they were without comparative populations.11,12 In a large-scale cross-sectional study, Chen and colleagues13 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.14 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.15 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
Table 1 Major case-series and cross-sectional studies of gout and CVD Number of Subjects Gout (Total)
Follow-up Yearsa
CVD Outcomes
Number of subjects with CVD outcomes, Gout (Total)
Adjusted Effect Size (95% CI)
Study (Ref.)
Subject Source
Yu¨ et al,11 1980 (USA)
Research clinic case series
2000
30
Mortality
382
N/A (descriptive data)
Nishioka & Mikanagi,12 1981 (Japan)
Clinics case series
104
8
CVD
28
N/A (descriptive data)
Darlington et al,51 1983 (UK)
Clinics
180
6
CVD mortality
5
N/A (O/E, gout not significant)
Chen et al,13 2007 (Taiwan)
Administrative data
22,572
N/A
Q waves in ECG
393
1.18 (1.01–1.38); gout significant
Stamp et al,14 2013 (New Zealand)
Population
57 (751)
N/A
CVD by history
10 (24)
Significant difference
Winnard et al,15 2011 (New Zealand)
Administrative data
119,234 (3,036,093)
N/A
CVD
27,131 (165,042)
Age-standardized rate ratio 2.7 (P65 y (Canada) with symptomatic heart failure, in Quebec, Canada
Nested case-control in a retrospective cohort
7684 (157,582) 7
Heart failure readmission or death
1053 (14,327)
1.63 (1.48–1.80); significant
Krishnan,28 2012 (USA)
Framingham Heart Study Offspring Cohort
Cohort
228 (4519)
37
Incident heart failure Mortality of gout vs no gout among those with heart failure
22 (178)
1.74 (1.03–2.93); significant 1.50 (1.30–1.73); significant
Stack et al,24 2013 (USA)
NHANES III cohort (1988–94)
Cross-sectional
—
N/A
Congestive heart failure
9.7 (1.8)
N/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. b Significant or not significant indicates whether or not gout is an independent predictor of outcome. Data from Refs.24,28,30
Gout and the Heart
Fig. 5. Nelson-Aalen cumulative risk estimates for heart failure among subjects with and without gout (n 5 228 and 4761, respectively) in the Framingham Offspring Study. The number of participants at risk for heart failure in each group is provided in two rows. The number of incident cases of heart failure in each time interval is provided within parenthesis. (From Krishnan E. Gout and the risk for incident heart failure and systolic dysfunction. BMJ Open 2012;2(1):e000282.)
Table 4 Echocardiographic characteristics at the Framingham Offspring Study visit 6 (n 5 2337)
Adjusted for Age and BMI
Adjusted for Age Hypertension, BMI, Renal Dysfunction, Diabetes, Alcohol Use, Smoking, and Total Cholesterol to HDL Cholesterol Ratio
Echocardiographic Measure
Gout
No Gout
P Value
Gout
No Gout
P Value
Mean LV thickness (cm)
2.02
1.89
MD
a
, Eswar Krishnan,
MD, M.Phil
b,
*
KEYWORDS Gout Uric acid Risk cardiovascular Coronary Mortality KEY POINTS Gout is associated with higher risk of cardiovascular events in almost all the published studies. Patients with gout undergoing medical therapy are statistically less likely to have cardiovascular disease (CVD) than those not undergoing therapy. 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.” —British author and poet Samuel Johnson (1709–1784) 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.1 Serum uric acid may act as antioxidant, thus providing some protection against aging and cancer.2 In some individuals, however, serum uric acid levels are higher than normal; this condition is defined as hyperuricemia. For epidemiologic studies, Krishnan and colleagues3 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
Disclosures: Dr E. Krishnan has received honoraria, consultation fees, and research grants from the following entities in the past 3 years: Takeda, Metabolex, Savient, ARDEA (Currently owned by Astra Zeneca). Dr V. Bhole has no disclosures to declare. a 515 Olmsted Road, Palo Alto, CA 94305, USA; b ARAMIS Program, Department of Medicine, Stanford University, 1000 Welch Road, Suite 203, Palo Alto, CA 94304, USA * Corresponding author. E-mail address: [email protected] Rheum Dis Clin N Am 40 (2014) 125–143 http://dx.doi.org/10.1016/j.rdc.2013.10.004 rheumatic.theclinics.com 0889-857X/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
126
Bhole & Krishnan
clearance of urate in women, possibly due to their higher plasma estrogen levels.4 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.5 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.6 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.7,8 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.9 The first modern article linking gout and unstable angina was published in 1988 and was based on data from the Framingham study.10 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.
Fig. 1. Prevalence of any coronary artery calcification (Agatston score >0) by serum uric acid concentration among participants (1211 men and 1287 women) in the Coronary Artery Risk Development in Young Adults (CARDIA) study cohort at year 15. P values are for trend test. CAC, coronary artery calcification; SUA, serum urate. (From Krishnan E, Pandya BJ, Chung L, et al. Hyperuricemia and the risk for subclinical coronary atherosclerosis–data from a prospective observational cohort study. Arthritis Res Ther 2011;13(2):R66.)
Gout and the Heart
Fig. 2. Relationship between burden of coronary artery calcification (unmodified Agatston score) and serum uric acid (SUA) concentrations among 238 subjects in the CARDIA study cohort who had an Agatston score of greater than zero. P values are for trend test. (From Krishnan E, Pandya BJ, Chung L, et al. Hyperuricemia and the risk for subclinical coronary atherosclerosis—data from a prospective observational cohort study. Arthritis Res Ther 2011;13(2):R66.)
Fig. 3. Time to develop hypertension among 803 men in the Multiple Risk Factor Intervention Trial (MRFIT) without metabolic syndrome but with baseline hyperuricemia (serum uric acid [SUA] >7.0 mg/dL) compared with 2270 men without hyperuricemia, adjusted for baseline values of age, systolic and diastolic blood pressure, serum creatinine, proteinuria, serum triglycerides, total cholesterol, alcohol use, smoking, and BMI. (From Krishnan E, Kwoh CK, Schumacher HR, et al. Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension 2007;49(2):298–303.)
127
128
Bhole & Krishnan
Fig. 4. Kaplan-Meier estimates for heart failure–free follow-up among the 4912 participants of the Framingham Offspring Study by quartiles of serum uric acid. For this survival model, the observation started at the first study visit and ended at the time of incident heart failure (n 5 196). The y-axis scale is adjusted for the sake of clarity. (From Krishnan E. Hyperuricemia and incident heart failure. Circ Heart Fail 2009;2(6):559; with permission.)
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. The earliest case series to report associations between gout and CVD mortality were published in the 1980s, but they were without comparative populations.11,12 In a large-scale cross-sectional study, Chen and colleagues13 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.14 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.15 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
Table 1 Major case-series and cross-sectional studies of gout and CVD Number of Subjects Gout (Total)
Follow-up Yearsa
CVD Outcomes
Number of subjects with CVD outcomes, Gout (Total)
Adjusted Effect Size (95% CI)
Study (Ref.)
Subject Source
Yu¨ et al,11 1980 (USA)
Research clinic case series
2000
30
Mortality
382
N/A (descriptive data)
Nishioka & Mikanagi,12 1981 (Japan)
Clinics case series
104
8
CVD
28
N/A (descriptive data)
Darlington et al,51 1983 (UK)
Clinics
180
6
CVD mortality
5
N/A (O/E, gout not significant)
Chen et al,13 2007 (Taiwan)
Administrative data
22,572
N/A
Q waves in ECG
393
1.18 (1.01–1.38); gout significant
Stamp et al,14 2013 (New Zealand)
Population
57 (751)
N/A
CVD by history
10 (24)
Significant difference
Winnard et al,15 2011 (New Zealand)
Administrative data
119,234 (3,036,093)
N/A
CVD
27,131 (165,042)
Age-standardized rate ratio 2.7 (P65 y (Canada) with symptomatic heart failure, in Quebec, Canada
Nested case-control in a retrospective cohort
7684 (157,582) 7
Heart failure readmission or death
1053 (14,327)
1.63 (1.48–1.80); significant
Krishnan,28 2012 (USA)
Framingham Heart Study Offspring Cohort
Cohort
228 (4519)
37
Incident heart failure Mortality of gout vs no gout among those with heart failure
22 (178)
1.74 (1.03–2.93); significant 1.50 (1.30–1.73); significant
Stack et al,24 2013 (USA)
NHANES III cohort (1988–94)
Cross-sectional
—
N/A
Congestive heart failure
9.7 (1.8)
N/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. b Significant or not significant indicates whether or not gout is an independent predictor of outcome. Data from Refs.24,28,30
Gout and the Heart
Fig. 5. Nelson-Aalen cumulative risk estimates for heart failure among subjects with and without gout (n 5 228 and 4761, respectively) in the Framingham Offspring Study. The number of participants at risk for heart failure in each group is provided in two rows. The number of incident cases of heart failure in each time interval is provided within parenthesis. (From Krishnan E. Gout and the risk for incident heart failure and systolic dysfunction. BMJ Open 2012;2(1):e000282.)
Table 4 Echocardiographic characteristics at the Framingham Offspring Study visit 6 (n 5 2337)
Adjusted for Age and BMI
Adjusted for Age Hypertension, BMI, Renal Dysfunction, Diabetes, Alcohol Use, Smoking, and Total Cholesterol to HDL Cholesterol Ratio
Echocardiographic Measure
Gout
No Gout
P Value
Gout
No Gout
P Value
Mean LV thickness (cm)
2.02
1.89
