Association Between Gout and Aortic Stenosis

Accepted Manuscript Association Between Gout and Aortic Stenosis Kevin Chang, MS, Chio Yokose, MD, Craig Tenner, MD, Cheongeun Oh, PhD, Robert Donnino, MD, Alana Choy-Shan, MD, Virginia C. Pike, BA, Binita D. Shah, MD, MS, Jeffrey D. Lorin, MD, Svetlana Krasnokutsky, MD, MS, Steven P. Sedlis, MD, Michael H. Pillinger, MD PII:

S0002-9343(16)31010-5

DOI:

10.1016/j.amjmed.2016.09.005

Reference:

AJM 13721

To appear in:

The American Journal of Medicine

Received Date: 9 May 2016 Revised Date:

14 August 2016

Accepted Date: 15 September 2016

Please cite this article as: Chang K, Yokose C, Tenner C, Oh C, Donnino R, Choy-Shan A, Pike VC, Shah BD, Lorin JD, Krasnokutsky S, Sedlis SP, Pillinger MH, Association Between Gout and Aortic Stenosis, The American Journal of Medicine (2016), doi: 10.1016/j.amjmed.2016.09.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Association Between Gout and Aortic Stenosis

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Kevin Chang, MS1,2,9*; Chio Yokose, MD1,2,9*; Craig Tenner, MD3,4,9; Cheongeun Oh, PhD5,9; Robert Donnino, MD6,7,8,9; Alana Choy-Shan, MD6,7,9; Virginia C. Pike, BA1,2,9, Binita D. Shah, MD, MS6,7,9; Jeffrey D. Lorin, MD6,7,9; Svetlana Krasnokutsky, MD, MS1,2,9,‡, Steven P. Sedlis, MD6,7,9,‡, and Michael H. Pillinger, MD1,2,9,‡ 1

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Section of Rheumatology, Department of Medicine, Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA; 2Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA; 3Section of Primary Care, Department of Medicine, Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA; 4Division of Primary Care, Department of Medicine, New York University School of Medicine, 10016, USA; 5 Department of Biostatistics, New York University, New York, NY 10016; 6Section of Cardiology, Department of Medicine, Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA; 7Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA; 8Deparment of Radiology, New York University School of Medicine, New York, NY 10016, USA; and 9TRIAD (Translational Research in Inflammation and Atherosclerotic Disease), New York University School of Medicine, New York, NY 10016, USA *These authors contributed equally to this manuscript. These authors contributed equally to this manuscript.

‡

Manuscript #: 16-776

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Corresponding Author: Michael H. Pillinger, MD Professor of Medicine Section of Rheumatology, Department of Medicine VA New York Harbor Healthcare System, New York Campus United States Department of Veterans Affairs 423 E 23rd Street, New York, NY 10010 212-598-6119 (phone), 212-951-3329 (fax) E-mail: [email protected]

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Type of manuscript: clinical research study Word count: 2,994 Key words: aortic stenosis, gout, valvular heart disease All authors had access to the data and a role in writing this manuscript Conflict of Interest M.H.P. and B.D.S. receive support from NYU CTSA grant 1UL1TR001445 from the National Center for the Advancement of Translational Science (NCATS), NIH. B.D.S. was supported in part by the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (I01BX007080). S.K. was supported in part by an Investigator Award from the Rheumatology Research Foundation. B.D.S. and S.K. were supported in part by a New York State Empire Clinical Research Investigator Program (ECRIP) award. M.H.P. serves and/or has served as a consultant for AstraZeneca, Crealta/Horizon, and Sobi, and has been an investigative site for a sponsored trial by Takeda. S.K. has served as a consultant for Crealta/Horizon. B.D.S. receives research grant support from Siemens. M.H.P., B.D.S. and S.P.S. have previously received research grant support from Takeda. K.C., C.Y., C.T., A.C-S and R.D. report no disclosures.

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Abstract Background: An independent association between gout and coronary artery disease is well

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established. The relationship between gout and valvular heart disease, however, is unclear. The aim of this study was to assess the association between gout and aortic stenosis.

Methods: We performed a retrospective case-control study. Aortic stenosis cases were identified

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through a review of outpatient transthoracic echocardiography (TTE) reports. Age-matched

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controls were randomly selected from patients who had undergone TTE and did not have aortic stenosis. Charts were reviewed to identify diagnoses of gout and the earliest dates of gout and aortic stenosis diagnosis.

Results: Among 1085 patients who underwent TTE, 112 aortic stenosis cases were identified.

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Cases and non-aortic stenosis controls (n=224) were similar in age and cardiovascular comorbidities. A history of gout was present in 21.4% (n=24) of aortic stenosis subjects compared with 12.5% (n=28) of controls (unadjusted OR 1.90, 95% CI 1.05-3.48, p=0.038).

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Multivariate analysis retained significance only for gout (adjusted OR 2.08, 95% CI 1.00-4.32,

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p=0.049). Among subjects with aortic stenosis and gout, gout diagnosis preceded aortic stenosis diagnosis by 5.8 ± 1.6 years. The age at onset of aortic stenosis was similar among patients with and without gout (78.7 ± 1.8 vs. 75.8 ± 1.0 years old, p=0.16).

Conclusions: Aortic stenosis patients had a markedly higher prevalence of precedent gout than age-matched controls. Whether gout is a marker of, or a risk factor for the development of aortic stenosis remains uncertain. Studies investigating the potential role of gout in the pathophysiology of aortic stenosis are warranted and could have therapeutic implications.

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Introduction The prevalence of gout in the United States has been rising, with an estimated 3.9% of the population (approximately 8.3 million individuals), and 12.6% of individuals over the age of 80

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currently affected1-4. Gout is characterized by hyperuricemia and the precipitation of

monosodium urate crystals. The inflammatory response to monosodium urate crystals manifests as recurrent episodes of acute mono-, pauci-, or polyarticular arthritis that, over time, can lead to

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persistent inflammation, urate deposition (tophi), and soft tissue and joint damage. The systemic effects of elevated serum urate, as well as the recurrent and/or persistent production of

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inflammatory cytokines and acute phase reactants5, are an area of active investigation. Associations between gout and cardiovascular6-10, renal11, metabolic12-14 and other comorbidities have been identified and appear to increase with the prevalence of gout. Indeed, accumulating evidence suggests that gout and/or hyperuricemia may not only be associated with, but also

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contribute to these comorbidities. Increased mortality seen in gout patients15-18 has generated considerable research interest in the relationship between gout and cardiovascular disease in particular. While cardiovascular conditions such as coronary artery disease7, 8, 10, 17, 19, atrial

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fibrillation20, 21, congestive heart failure9, and peripheral vascular disease22 have been shown to

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be associated with gout, a possible relationship between gout and valvular heart disease, including aortic stenosis, has received scant attention.

Aortic stenosis is the most common valve disease in the Western world, with prevalence as high as 9.8% in adults 80 years or older23-25. Of particular concern is the lack of available medical therapy to halt or delay disease progression. Once even mildly symptomatic, the mortality rate has been reported to be as high as 50% over two years26 unless the valve is replaced or repaired through invasive measures. Efforts to better understand the pathophysiology and risk factors for

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aortic stenosis are ongoing, with the goal of non-surgical modification of the disease course. The pathological process leading to the development and progression of aortic stenosis shares certain similarities with the atherosclerotic process27-29. Importantly, many factors identified to be

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associated with the progression of aortic stenosis – age, sex, obesity, hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, and elevated inflammatory markers (C-reactive protein)30 – are also common comorbidities seen in gout patients, suggesting a potential link

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between gout and aortic stenosis.

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To date, studies of the valvular manifestations of gout have largely focused on case reports of valvular tophi31-34, with more frequent involvement of the mitral rather than the aortic valve. Studies looking more broadly at the relationship between gout and/or hyperuricemia and aortic stenosis are rare. Thus, the aim of the present study was to assess the epidemiologic relationship

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between gout and aortic stenosis.

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Methods Study Population

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The New York Campus of the Veterans Affairs (VA) New York Harbor Healthcare System is a regional center for cardiac surgery and a referral center for valvular heart disease. The

Computerized Patient Record System (CPRS) was used to identify all patients who underwent transthoracic echocardiograms (TTE) between October 20, 2014 and October 20, 2015. Subjects

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with a diagnosis of aortic stenosis documented on the TTE report were evaluated as cases.

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Exclusion criteria included any prior history of systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, calcium pyrophosphate deposition disease or rheumatic fever, as well as echocardiographic or other imaging evidence or diagnosis of bicuspid aortic valve and/or rheumatic valve disease. Two age-matched controls per case (2:1 control: case ratio) were selected from the group of subjects without aortic stenosis documented on TTE

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report. Perfect age matching (same year of birth) was prioritized; if more than two perfectly agematched patients were available, the selection was made randomly using a computer algorithm (MATLAB R2013a, The MathWorks, Inc.). If perfect age matching was not possible for a given

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case, the control subjects were randomly assigned from among the pool of control patients with

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the closest possible age(s) to the case. If any age-matched control met exclusion criteria upon subsequent chart review, the age-matching process was performed again to identify the next-best control. The study protocol was approved by the VA New York Harbor Institutional Review Board and a waiver of consent was obtained for chart review and data extraction.

Data Collection Review of the electronic medical records in CPRS and TTE reports were performed in an identical manner for cases and controls. The most recent TTE reports were accessed first to

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identify the presence/absence of aortic stenosis. When aortic stenosis was present, severity parameters were recorded including aortic valve area, mean pressure gradient, and peak jet velocity. Subjects whose TTE reports were lacking specific required data were aggregated into a

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group, and their TTEs were reread for the missing data by one of our echocardiography

cardiologists (R.D.), in a manner blinded to patient diagnosis or other clinical parameters. In addition, the date of initial aortic stenosis diagnosis (defined as the date of the earliest current or

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prior TTE in which aortic stenosis was reported) was documented. Further chart review was conducted for cases and age-matched controls. The physician-generated problem list, as well as

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the most recent primary care, cardiology and rheumatology notes (as available) were reviewed for any pre-existing diagnosis of gout, relevant rheumatologic and cardiac characteristics and exclusion criteria, and/or comorbidities. To ensure that no patient with gout was overlooked, if gout was not identified by the above process, all notes within the CPRS system were searched

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using natural language processing for the presence of the word “gout,” which was then manually reviewed for confirmation and earliest date of diagnosis. The medication list and relevant laboratory values that were closest in date to the date of the TTE were also manually extracted

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from the chart.

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Statistical Analyses

Descriptive statistics were used to characterize the baseline features of the cohort. Proportions were used to summarize categorical variables and mean [± SEM] for continuous variables. The Mann-Whitney-Wilcoxon test was used to compare continuous variables and the Fisher’s exact test to compare categorical variables between groups. Multivariable logistic regression models to identify variables that were independent predictors of aortic stenosis status were also fit, using a stepwise variable selection approach in order to control for confounders. Variables with p<0.1

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for the bivariate association with the outcome (i.e., non-specific arthropathy, hyperlipidemia, peripheral artery disease, loop diuretics) were considered for inclusion in the multivariate model, and only those which remained significant at the p<0.05 level were retained in the final model.

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Results are reported as odds ratios (OR) with 95% confidence intervals (CI). Two sided p-values <0.05 were considered to be statistically significant. All statistical analyses were conducted in R-

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statistical package (www.r-project.org).

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Results Study Population

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Among 48,144 patients with an active medical record during the study period, 1085 unique patients had undergone outpatient TTE’s. Review of TTE reports revealed 128 patients with aortic stenosis. Of these, 16 patients were excluded for historical or current TTE diagnoses of bicuspid aortic valve (n=8), rheumatoid arthritis (n=2), calcium pyrophosphate deposition

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disease (n=3), or rheumatic fever (n=3). Therefore, 112 cases were available for the study. From

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the remaining pool of 957 patients without aortic stenosis, 224 were selected as age-matched controls. Of these, 5 were subsequently excluded for diagnoses of calcium pyrophosphate deposition disease (n=1), rheumatoid arthritis (n=2), systemic lupus erythematosus (n=1), or ankylosing spondylitis (n=1). Following exclusion, 5 additional age-matched controls were randomly selected to complete a total of 224 controls. The age-matching process resulted in 191

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perfect matches out of 224 matches (85.3%). Among the non-perfect age-matches, the average difference in ages between matched aortic stenosis cases and non-aortic stenosis controls was 2.3

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years. A flow chart of the study population is shown in Figure 1.

The baseline characteristics and clinical comorbidities of cases and controls are shown in Table

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1. There were no significant differences between the groups for age, sex, body mass index, body surface area, smoking status, and medication intake within the past year. Of the clinical comorbidities, the only significant difference observed between the cases and controls was the presence of peripheral artery disease (21.4% in aortic stenosis cases vs. 8.5% in non-aortic stenosis controls, p=0.0015).

Increased Prevalence of Gout in Patients With Aortic Stenosis

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Overall, the prevalence of gout in our study population was 15.5% (52/336), roughly consistent with the previously reported prevalence of gout (12.6%) among patients 80 years of age or over1. The prevalence of gout was significantly higher in the aortic stenosis cases compared to age-

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matched non-aortic stenosis controls (24/112 vs. 28/224, 21.4% vs. 12.5%, p=0.038) (Figure 2). While gout, non-specific arthropathy, hyperlipidemia, peripheral artery disease, and loop diuretic use were selected as potential significant variables in the initial multivariate logistic regression

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model, only gout retained significance in the final model (Table 2). The presence of gout was associated with approximately twice the risk of incident aortic stenosis compared to subjects

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without gout (adjusted OR 2.08, 95% CI 1.00-4.32, p=0.0496). Among subjects with both gout and aortic stenosis, the gout diagnosis preceded aortic stenosis diagnosis by 5.8 ± 1.6 years.

Comparison of Aortic Stenosis Patients With and Without Gout

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Baseline characteristics, clinical comorbidities, and echocardiographic parameters of aortic stenosis cases with and without gout are shown in Table 3. Aortic stenosis subjects with and without gout were similar in most comorbidities. Consistent with prior reports, the gout group

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had more osteoarthritis35 and renal insufficiency11. Not surprisingly, medications used for gout (colchicine, allopurinol) were seen exclusively in the gout group. We observed no significant

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association between gout presence/absence and indicators of aortic stenosis severity including aortic valve peak velocity and aortic valve gradient. Aortic valve area and percent of patients with reduced aortic valve area were also not significantly different between the groups. The age when aortic stenosis was first diagnosed was similar in patients with and without gout (78.7 ± 1.8 vs. 75.8 ± 1.0 years, p=0.16).

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Discussion Although the association between gout and cardiovascular disease has been an area of active

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investigation, there has been very little inquiry into the relationship between gout and valvular heart disease, particularly aortic stenosis. We showed in our study that aortic stenosis is

independently associated with a historical diagnosis of gout, with a two-fold higher adjusted

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prevalence of aortic stenosis in those members of our patient population with gout.

Our review of the literature revealed only one relevant clinical study by Demir et al, which

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described a relationship between serum urate concentrations and the severity of aortic stenosis36. The authors identified a positive correlation between serum urate level and aortic stenosis mean aortic gradient, and an inverse correlation between serum urate and aortic valve area. While that study was limited by a small sample size (n=64) and lack of clear causality, the results are

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consistent with the pathophysiology of aortic stenosis and how it might be affected by hyperuricemia/gout. Since gout patients are both hyperuricemic and prone to inflammatory states, we believe our findings to be consistent with the study by Demir et al. However, among

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aortic stenosis patients, we observed no association between the presence or duration of gout and

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aortic valve peak velocity and gradient, suggesting that gout per se, in contrast to hyperuricemia, may be a marker for aortic stenosis incidence rather than severity. Taken together, these results may shed light on the pathophysiology of aortic stenosis and the possibility that this disease process may be influenced by both serum urate and pro-inflammatory states such as gout.

Aortic stenosis has been long considered a degenerative condition associated with progressive calcium deposition. Recent investigation, however, has revealed aortic stenosis to involve a series of complex processes that can be characterized by two phases – an initiation phase and

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propagation phase37. The hallmark of the initiation phase is similar to that of atherosclerosis, encompassing valvular and endothelial injury, lipid deposition38, 39, and subsequent inflammation. Immunohistological examinations of early aortic valve lesions have revealed a

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milieu consisting predominantly of inflammatory cells such as macrophages and T-cells40-42. These processes provide the substrate for the propagation phase of aortic stenosis, which is

largely driven by pro-calcific and pro-osteogenic factors27, 37, 43. Over time, heart valve cells

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develop an osteogenic phenotype and deposit calcium on the valve, eventually progressing to

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valvular stenosis.

The similarities between the pathophysiology of aortic stenosis and atherosclerosis27-29, 41 suggest how gout could mechanistically influence the development and progression of aortic stenosis. Multiple mechanisms through which gout (as well as hyperuricemia, even in the absence of gout)

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may promote atherosclerosis have already been identified in in vitro and animal models. Chronic inflammation, accumulation of reactive oxygen species, and loss of vasoactive mediators, particularly nitric oxide, have been implicated in gout to cause endothelial dysfunction and

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vascular remodeling19, 44, 45. These effects may ultimately lead to accelerated atherosclerosis and vascular calcification46-50. Indeed, in a recently reported rat model, hyperuricemia induced by a

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high-adenine diet resulted in accelerated aortic calcification51. Conceivably, these same processes in gout could promote aortic valvular calcification and stenosis.

There were several limitations to our study. First, it is not possible to assign causality between gout and aortic stenosis given the retrospective and observational nature of the data. However, we did observe that in most cases, documented gout diagnosis preceded documented aortic stenosis diagnosis, suggesting a possible causal or at least chronological relationship. Indeed, our

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use of first recorded gout diagnosis within our institution, as a surrogate for actual gout onset probably led us to underestimate the lead-time between gout and aortic stenosis, since a gout diagnosis may have previously been made at an outlying institution, and in any event gout may

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not be diagnosed for several years after an initial attack. On the other hand, since the initial

pathogenesis of aortic stenosis also inevitably precedes its echocardiographic diagnosis, the temporal gap between the gout and aortic stenosis pathogenic processes could not be definitively

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assessed. As in the case of gout, the diagnosis of aortic stenosis may first have been made at a referring facility and in that case would not be recorded in our own TTE database. Thus,

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although unlikely, our observations do not formally preclude the possibility that changes in cardiovascular status observed in the setting of aortic stenosis, for example relating to production of urate by cardiomyocytes in the setting of heart failure, could have influenced the presentation of gout rather than the other way around. The uncertainties inherent in the assigning an accurate

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date of diagnosis for either gout or aortic stenosis also preclude our ability to draw any accurate conclusions about the degree, rate of development or severity of aortic stenosis as a function of

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duration of gouty disease.

Second, although an attempt was made to record serum urate levels and inflammatory markers

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(erythrocyte sedimentation rate and C-reactive protein), much of this data was either lacking, collected during unreliable time periods (e.g., during acute gouty flares), or not applicable to the relevant timeframe. This problem is not uncommon in retrospective studies of gout, since in the United States measurements of serum urate and C-reactive protein are not routinely included in basic metabolic panels and instead depend upon physician choice. To the extent that a possible causal relationship between gout and aortic stenosis can be postulated, our data therefore do not permit us to address whether such a relationship might be mediated through hyperuricemia,

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inflammation, or both. It is also possible that a relationship between gout and aortic stenosis is mediated through comorbidities that are common in patients with gout and/or hyperuricemia; consistent with this possibility, our patients with aortic stenosis and gout had greater rates of

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several of these co-morbidities than those without gout. However, in our initial analyses, we saw no difference in rates of these co-morbidities in patients with, versus without aortic stenosis. Finally, our population consisted of veterans and was almost exclusively male, so that the

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generalizability of our data remains to be confirmed in wider populations. Nonetheless, this is, to our knowledge, the first study to evaluate the association between gout and aortic stenosis. Since

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widespread clinical significance.

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nearly a quarter of our aortic stenosis patients had gout, these findings may potentially be of

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Conclusion Our results support an independent association between gout and aortic stenosis. While definitive

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conclusions cannot be drawn from a single retrospective case-control study, these results suggest that gout could be a marker, or possibly a risk factor, for aortic stenosis. Future studies are warranted to confirm and examine this relationship in more detail, including potential

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implications for the medical prevention of aortic stenosis.

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Acknowledgments

No outside support was received for the conduct of this research or the preparation of this

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manuscript.

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References

1.

Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general

RI PT

population: The National Health and Nutrition Examination Survey 2007–2008. Arthritis & Rheumatism. 2011;63:3136-3141. 2.

So A. Developments in the scientific and clinical understanding of gout. Arthritis

3.

SC

research & therapy. 2008;10:221.

Smith E, Hoy D, Cross M, et al. The global burden of gout: estimates from the Global

4.

M AN U

Burden of Disease 2010 study. Annals of the Rheumatic Diseases. 2014;73:1470-1476. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II. Arthritis & Rheumatism. 2008;58:26-35.

Scott P, Ma H, Viriyakosol S, Terkeltaub R, Liu-Bryan R. Engagement of CD14

TE D

5.

mediates the inflammatory potential of monosodium urate crystals. Journal of immunology. 2006;177:6370-6378.

Abbott RD, Brand FN, Kannel WB, Castelli WP. Gout and coronary heart disease: The

EP

6.

framingham study. Journal of Clinical Epidemiology. 1988;41:237-242. Kuo C-F, Yu K-H, See L-C, et al. Risk of myocardial infarction among patients with

AC C

7.

gout: a nationwide population-based study. Rheumatology. 2013;52:111-117.

8.

Krishnan E, Baker JF, Furst DE, Schumacher HR. Gout and the risk of acute myocardial infarction. Arthritis & Rheumatism. 2006;54:2688-2696.

9.

Krishnan E. Gout and the risk for incident heart failure and systolic dysfunction. BMJ Open. 2012;2.

10.

Seminog OO, Goldacre MJ. Gout as a risk factor for myocardial infarction and stroke in England: evidence from record linkage studies. Rheumatology. 2013;52:2251-2259.

ACCEPTED MANUSCRIPT Page 17 of 22 Gout and Aortic Stenosis Pillinger

11.

Yu K-H, Kuo C-F, Luo S-F, et al. Risk of end-stage renal disease associated with gout: a nationwide population study2012.

12.

Puig JG, Martínez MA. Hyperuricemia, gout and the metabolic syndrome. Current

13.

RI PT

Opinion in Rheumatology. 2008;20:187-191.

Kuo C-F, Grainge MJ, Mallen C, Zhang W, Doherty M. Comorbidities in patients with gout prior to and following diagnosis: case-control study. Annals of the Rheumatic

14.

SC

Diseases. 2016;75:210-217.

Kim SC, Liu J, Solomon DH. Risk of incident diabetes in patients with gout: a cohort

15.

M AN U

study. Arthritis & rheumatology (Hoboken, N.J.). 2015;67:273-280.

Kuo C-F, Yu K-H, See L-C, et al. Elevated risk of mortality among gout patients: A comparison with the National Population in Taiwan. Joint Bone Spine. 2011;78:577-580.

16.

Kuo C-F, See L-C, Luo S-F, et al. Gout: an independent risk factor for all-cause and

17.

TE D

cardiovascular mortality. Rheumatology. 2010;49:141-146.

Choi HK, Curhan G. Independent Impact of Gout on Mortality and Risk for Coronary Heart Disease. Circulation. 2007;116:894-900. Krishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH, Group MR. LOng-term

EP

18.

cardiovascular mortality among middle-aged men with gout. Archives of Internal

19.

AC C

Medicine. 2008;168:1104-1110. Shah A, Keenan RT. Gout, hyperuricemia, and the risk of cardiovascular disease: cause and effect? Current rheumatology reports. 2010;12:118-124.

20.

Kuo C-F, Grainge MJ, Mallen C, Zhang W, Doherty M. Impact of gout on the risk of atrial fibrillation. Rheumatology. 2015.

21.

Kim SC, Liu J, Solomon DH. Risk of incident atrial fibrillation in gout: a cohort study. Annals of the Rheumatic Diseases. 2015.

ACCEPTED MANUSCRIPT Page 18 of 22 Gout and Aortic Stenosis Pillinger

22.

Clarson LE, Hider SL, Belcher J, Heneghan C, Roddy E, Mallen CD. Increased risk of vascular disease associated with gout: a retrospective, matched cohort study in the UK Clinical Practice Research Datalink. Annals of the Rheumatic Diseases. 2015;74:642-647. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M.

RI PT

23.

Burden of valvular heart diseases: a population-based study. Lancet. 2006;368:10051011.

Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: disease

SC

24.

prevalence and number of candidates for transcatheter aortic valve replacement: a meta-

2013;62:1002-1012. 25.

M AN U

analysis and modeling study. Journal of the American College of Cardiology.

Rashedi N, Otto CM. Aortic Stenosis: Changing Disease Concepts. Journal of cardiovascular ultrasound. 2015;23:59-69.

Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or

TE D

26.

surgical aortic-valve replacement. The New England journal of medicine. 2012;366:16861695.

Freeman RV, Otto CM. Spectrum of Calcific Aortic Valve Disease: Pathogenesis,

EP

27.

Disease Progression, and Treatment Strategies. Circulation. 2005;111:3316-3326. Agmon Y, Khandheria BK, Meissner I, et al. Aortic valve sclerosis and aortic

AC C

28.

atherosclerosis: different manifestations of the same disease?Insights from a population-

based study. Journal of the American College of Cardiology. 2001;38:827-834.

29.

Liebe V, Brueckmann M, Borggrefe M, Kaden JJ. Statin therapy of calcific aortic

stenosis: hype or hope? European Heart Journal. 2006;27:773-778.

ACCEPTED MANUSCRIPT Page 19 of 22 Gout and Aortic Stenosis Pillinger

30.

Kamath AR, Pai RG. Risk factors for progression of calcific aortic stenosis and potential therapeutic targets. The International Journal of Angiology : Official Publication of the International College of Angiology, Inc. 2008;17:63-70. Jaworski RC, Gibson M. Tophaceous aortic valve: a case report. Pathology.

RI PT

31.

1983;15:197-199. 32.

Gawoski JM, Balogh K, Landis WJ. Aortic valvular tophus: identification by X-ray

SC

diffraction of urate and calcium phosphates. Journal of clinical pathology. 1985;38:873876.

Moore GE, Anderson AL. Runner with gout and an aortic valve nodule. Medicine and

M AN U

33.

science in sports and exercise. 1995;27:626-628. 34.

Scalapino JN, Edwards WD, Steckelberg JM, Wooten RS, Callahan JA, Ginsburg WW. Mitral stenosis associated with valvular tophi. Mayo Clinic proceedings. 1984;59:509-

35.

TE D

512.

Howard RG, Samuels J, Gyftopoulos S, et al. Presence of Gout is Associated With Increased Prevalence and Severity of Knee Osteoarthritis: Among Older Men: Results of

EP

a Pilot Study. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2015;21:63-71. Demir B, Caglar IM, Ugurlucan M, et al. The relationship between severity of calcific

AC C

36.

aortic stenosis and serum uric acid levels. Angiology. 2012;63:603-608.

37.

Pawade TA, Newby DE, Dweck MR. Calcification in Aortic Stenosis: The Skeleton Key.

Journal of the American College of Cardiology. 2015;66:561-577.

38.

O’Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E Accumulate in the Morphologically Early Lesion of

ACCEPTED MANUSCRIPT Page 20 of 22 Gout and Aortic Stenosis Pillinger

‘Degenerative’ Valvular Aortic Stenosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:523-532. 39.

Olsson M, Thyberg J, Nilsson J. Presence of Oxidized Low Density Lipoprotein in

RI PT

Nonrheumatic Stenotic Aortic Valves. Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1218-1222. 40.

Wallby L, Janerot-Sjöberg B, Steffensen T, Broqvist M. T lymphocyte infiltration in non-

aortic valves. Heart. 2002;88:348-351.

Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O'Brien KD. Characterization of the

M AN U

41.

SC

rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid

early lesion of 'degenerative' valvular aortic stenosis. Histological and immunohistochemical studies. Circulation. 1994;90:844-853. 42.

Olsson M, Dalsgaard C-J, Haegerstrand A, Rosenqvist M, Rydén L, Nilsson J.

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Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheumatic stenotic aortic valves. Journal of the American College of Cardiology. 1994;23:1162-1170.

Rajamannan NM, Subramaniam M, Rickard D, et al. Human Aortic Valve Calcification

EP

43.

Is Associated With an Osteoblast Phenotype. Circulation. 2003;107:2181-2184. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. The New England

AC C

44.

journal of medicine. 2008;359:1811-1821.

45.

Kanno Y, Into T, Lowenstein CJ, Matsushita K. Nitric oxide regulates vascular calcification by interfering with TGF- signalling. Cardiovascular research. 2008;77:221230.

ACCEPTED MANUSCRIPT Page 21 of 22 Gout and Aortic Stenosis Pillinger

46.

Berezin AE, Kremzer AA. Serum uric Acid as a marker of coronary calcification in patients with asymptomatic coronary artery disease with preserved left ventricular pump function. Cardiology research and practice. 2013;2013:129369. Rodrigues TC, Maahs DM, Johnson RJ, et al. Serum uric acid predicts progression of

RI PT

47.

subclinical coronary atherosclerosis in individuals without renal disease. Diabetes care. 2010;33:2471-2473.

Mitsutake R, Miura S, Saku K. Association between coronary artery calcification score as

SC

48.

assessed by multi-detector row computed tomography and upstroke time of pulse wave.

49.

M AN U

Internal medicine. 2007;46:1833-1836.

Atar AI, Yilmaz OC, Akin K, Selcoki Y, Er O, Eryonucu B. Serum uric acid level is an independent risk factor for presence of calcium in coronary arteries: an observational case-controlled study. Anadolu kardiyoloji dergisi : AKD = the Anatolian journal of

50.

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cardiology. 2013;13:139-145.

Grossman C, Shemesh J, Koren-Morag N, Bornstein G, Ben-Zvi I, Grossman E. Serum uric acid is associated with coronary artery calcification. Journal of clinical hypertension.

Liu Z, Chen T, Niu H, et al. The Establishment and Characteristics of Rat Model of Atherosclerosis Induced by Hyperuricemia2016.

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51.

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2014;16:424-428.

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Figure Legends

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Figure 1. Enrollment Diagram

Figure 2. Prevalence of gout history in aortic stenosis cases and non-aortic stenosis controls

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(24/112 vs. 28/224, 21.4% vs. 12.5%). Fisher’s exact test was used to compare groups.

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Table 1. Characteristics of Aortic Stenosis Cases and non-Aortic Stenosis Controls Aortic Stenosis Non-Aortic p-value (n=112) Stenosis (n=224) Baseline Parameters Age (year) 80.1 ± 0.81 80.0 ± 0.55 0.87 Male sex 111 (99.1%) 221 (98.7%) 1.00 Body mass index (kg/m2) 26.9 ± 0.45 26.6 ± 0.35 0.29 Body surface area (m2) 1.95 ± 0.022 1.95 ± 0.016 0.96 Medical History Osteoarthritis 41 (36.6%) 67 (29.9%) 0.22 Non-specific arthropathy 33 (29.5%) 48 (21.4%) 0.11 Hypertension 100 (89.2%) 189 (84.4%) 0.25 Hyperlipidemia 91 (81.3%) 163 (72.8%) 0.11 Diabetes mellitus 40 (35.7%) 66 (29.5%) 0.26 Coronary artery disease 53 (47.3%) 105 (46.9%) 1.00 Congestive heart failure 26 (23.2%) 57 (25.5%) 0.69 Stroke or transient ischemic attack 18 (16.1%) 40 (17.9%) 0.76 Peripheral artery disease 24 (21.4%) 19 (8.5%) 0.0015 Serum creatinine (mg/dl) 1.3 ± 0.1 1.3 ± 0.06 0.75 eGFR (ml/min) 73.7 ± 2.9 75.1 ± 2.1 0.80 Current smoker (within last year) 7 (6.3%) 13 (5.8%) 1.00 Left ventricular ejection fraction (%) 59.2±1.7 57.1±0.8 0.17 Left ventricular ejection fraction <50% 22 (19.6%) 49 (21.9%) 0.67 Medications (within last year) Colchicine 3 (2.7%) 5 (2.2%) 1.00 Allopurinol 6 (5.4%) 15 (6.7%) 0.81 Loop diuretic 42 (37.5%) 63 (28.1%) 0.10 Thiazide diuretic 13 (11.6%) 20 (8.9%) 0.44 NSAID (standing) 3 (2.7%) 14 (6.3%) 0.19 Continuous variables are presented as mean ± SEM and compared using MannWhitney-Wilcoxon test Categorical variables are presented as n (%) and compared using Fisher’s exact test Abbreviations: eGFR, estimated glomerular filtration rate, NSAID, non-steroidal antiinflammatory drug

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p-value 0.0496 0.44 0.55 0.47 0.62

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Table 2. Association between Gout and Aortic Stenosis Unadjusted OR Adjusted OR Variables p-value [95% CI] [95% CI] Gout 1.91 [1.05, 3.48] 0.038 2.08 [1.001, 4.32] Non-specific arthropathy 1.53 [0.91, 2.57] 0.11 1.34 [0.64, 2.80] Hyperlipidemia 1.62 [0.93, 2.83] 0.09 1.30 [0.55, 3.07] Peripheral artery disease 2.94 [1.53, 5.65] 0.0015 1.43 [0.54, 3.80] Loop diuretic 1.53 [0.95, 2.48] 0.08 0.83 [0.39, 1.76]

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Table 3. Characteristics of Aortic Stenosis Cases with and without Gout Gout (n=24) Non-Gout (n=88) p-value Baseline Parameters Age (year) 83.6 ± 1.6 79.2 ± 0.9 0.021 Male sex 24 100%) 87 (98.9%) 1.00 Body mass index (kg/m2) 25.9 ± 0.6 27.3 ± 0.6 0.23 Body surface area (m2) 1.93 ± 0.04 1.95 ± 0.03 0.85 Medical history Osteoarthritis 14 (58.3%) 27 (30.7%) 0.017 Non-specific arthropathy 9 (37.5%) 24 (27.3%) 0.33 Hypertension 24 (100%) 76 (86.4%) 0.067 Hyperlipidemia 19 (79.2%) 72 (81.8%) 0.77 Diabetes mellitus 9 (37.5%) 31 (35.2%) 0.82 Coronary artery disease 10 (41.7%) 43 (48.9%) 0.65 Congestive heart failure 6 (25.0%) 20 (22.7%) 0.79 Stroke or transient ischemic attack 7 (29.2%) 11 (12.5%) 0.062 Peripheral artery disease 6 (25.0%) 18 (20.5%) 0.59 Serum creatinine (mg/dl) 1.7 ± 0.4 1.2 ± 0.09 0.033 eGFR (ml/min/1.73m2) 61.1 ± 6.0 77.1 ± 3.2 0.028 Current smoker (within last year) 3 (12.5%) 4 (4.6%) 0.17 Age of AS diagnosis (year) 78.7 ± 1.8 75.8 ± 1.0 0.16 Echocardiographic Parameters Left ventricular ejection fraction (%) 58.1 ± 3.0 59.5 ± 1.5 0.68 Left ventricular ejection fraction <50% 4 (16.7%) 13 (14.7%) 0.76 Aortic valve peak velocity (m/s) 3.05 ± 0.18 3.17 ± 0.10 0.59 Aortic valve mean gradient (mmHg) 23.5 ± 2.8 25.9 ± 1.7 0.70 1.21 ± 0.09 1.00 ± 0.07 Aortic valve area (cm2) 0.14 (n=12) (n=44) Medications (within last year) Colchicine 3 (12.5%) 0 (0%) 0.009 Allopurinol 6 (25.0%) 0 (0%) 0.0001 Loop diuretic 9 (37.5%) 33 (37.5%) 1.00 Thiazide diuretic 3 (12.5%) 10 (11.4%) 1.00 NSAID (standing) 2 (8.3%) 1 (1.1%) 0.12 Continuous variables are presented as mean ± SEM and compared using MannWhitney-Wilcoxon test Categorical variables are presented as n (%) and compared using Fisher’s exact test Abbreviations: eGFR, estimated glomerular filtration rate, NSAID, non-steroidal antiinflammatory drug

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Eligible TTEs (n=1085)

Excluded (n=16):

No Aortic Stenosis (n=957)

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Aortic Stenosis (n=128)

Age-Matched Controls selected with 2:1 Control:AS Ratio

Bicuspid AV (8) Rheumatoid Arthritis (2) Rheumatic Fever (3) CPPD* (3)

Non-AS Controls Analyzed (n=224)

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Aortic Stenosis Analyzed (n=112)

Figure 1. Enrollment diagram.

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Excluded (n=5): Rheumatoid Arthritis (2) CPPD* (1) SLE** (1) Ankylosing spondylitis (1)

Replaced (n=5)

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Figure 2. Prevalence of gout history in aortic stenosis cases and non-aortic stenosis controls (24/112 vs. 28/224, 21.4% vs. 12.5%). Fisher’s exact test was used to compare groups.

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Clinical Significance Patients with aortic stenosis had an adjusted OR of 2.08 for having gout. Gout diagnoses preceded aortic stenosis diagnoses by a mean of 5.8 ± 1.6 years. Gout may be a biomarker or risk factor for the development of aortic stenosis.

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