Having more than three treated gout flares a year could identify patients with substantially higher long-term cardiovascular risk, new research suggests.
Patients with frequent gout flares may need more intensive cardiovascular risk assessment, with new research suggesting that experiencing more than three treated flares a year marks a sustained increase in the risk of heart failure, stroke, and myocardial infarction for at least seven years.
The multinational observational study, published in Rheumatology, found a clear dose-response relationship between gout flare frequency and major adverse cardiovascular events (MACE), with heart failure emerging earliest and most consistently, while stroke and myocardial infarction were largely confined to patients with the highest flare burden.
The findings add to growing evidence that gout is more than a painful crystal arthritis and should increasingly be viewed as a chronic inflammatory disease with important cardiovascular implications.
Researchers analysed electronic health records from 44,705 adults in the TriNetX Global Collaborative Network who experienced their first recorded treated gout flare during 2017. Patients were followed using a landmark study design that classified them according to flare frequency over the following 12 months before tracking cardiovascular outcomes for up to seven years.
Patients were divided into three groups: low flare frequency (three or fewer treated flares annually), moderate frequency (four to six flares), and high frequency (seven or more flares). Individuals with previous myocardial infarction, stroke, or heart failure were excluded to allow assessment of new cardiovascular events.
After propensity score matching to minimise differences between groups, patients experiencing seven or more flares annually had a 45% greater risk of major adverse cardiovascular events over seven years than those with three or fewer flares.
Even patients with four to six flares annually demonstrated a 24% increase in cardiovascular risk compared to individuals in the low flare frequency group.
Absolute risks also separated steadily over time. By seven years, 18.6% of patients in the high-flare group had experienced a major cardiovascular event compared with 12.9% of patients in the low-flare group. Among those with a moderate flare burden, the seven-year risk was also significantly higher than the low-flare cohort.
When the researchers examined individual cardiovascular outcomes, heart failure proved to be the most sensitive marker of inflammatory burden. Patients experiencing four to six flares annually had a 17% higher risk of heart failure over seven years, while those with seven or more flares had a 27% increased risk.
Stroke and myocardial infarction followed a different pattern. Both outcomes became significantly more common only among patients experiencing at least seven flares annually. Stroke risk became apparent after three years, while myocardial infarction emerged later, reaching statistical significance after five years and remaining elevated through seven years.
The researchers said these findings suggested different cardiovascular complications may require different levels or durations of inflammatory exposure before becoming clinically evident.
Previous studies have shown that cardiovascular events are more likely to occur immediately after an acute gout flare, with the greatest risk occurring during the first two weeks. However, those studies treated flares as isolated inflammatory events.
The current analysis instead examined whether flare frequency itself could identify patients with an ongoing high-risk inflammatory phenotype.
“These findings suggest that flare frequency above three episodes per year is a practical threshold for long-term cardiovascular risk stratification in gout,” the researchers wrote.
“This supports flare frequency as a practical marker of sustained cardiovascular vulnerability and may help prioritise patients for closer review of gout management and cardiovascular prevention.”
They stressed that the proposed threshold was intended for cardiovascular risk assessment rather than guiding gout treatment.
Current American College of Rheumatology guidelines recommend initiating urate-lowering therapy in patients experiencing two or more flares each year.
The new threshold instead identifies a subgroup with particularly high healthcare-recorded flare burden who may warrant closer cardiovascular monitoring and more aggressive management of modifiable cardiovascular risk factors.
The biological explanation may lie in persistent systemic inflammation, the researchers said. They proposed that repeated activation of the NLRP3 inflammasome by monosodium urate crystals sustains production of inflammatory cytokines such as interleukin-1β, interleukin-6, and tumour necrosis factor-α.
These inflammatory pathways have been implicated in endothelial dysfunction, vascular injury, cardiac remodelling, and progressive atherosclerosis.
The particularly strong association with heart failure may reflect inflammatory effects on myocardial fibrosis and diastolic dysfunction, while atherosclerotic complications such as myocardial infarction and stroke may require longer cumulative inflammatory exposure before clinical events occur, the researchers said.
“These effects may be amplified by coexisting chronic kidney disease, a common comorbidity in this population,” they wrote.
“Furthermore, NLRP3 may directly modulate collagen synthesis and myofibroblast activity, providing a biological bridge between systemic inflammation and cardiac fibrotic remodelling.”
Related
The study also raises the possibility that flare frequency could become an easily recognised clinical marker for identifying gout patients who would benefit from multidisciplinary management, particularly given the high prevalence of hypertension, diabetes, chronic kidney disease and dyslipidaemia already seen in this population.
However, the researchers were careful not to overstate the findings.
As an observational study based on electronic health records, it cannot establish that recurrent gout flares directly cause cardiovascular disease.
The flare definition relied on healthcare-recorded treated episodes and almost certainly underestimated the total number of flares experienced, particularly milder attacks managed at home.
Treatment changes after the first year, including initiation or escalation of urate-lowering therapy and colchicine prophylaxis, were also not included in the analysis and could have influenced cardiovascular outcomes.
Nevertheless, sensitivity analyses using a stricter definition of gout flares produced similar findings, strengthening confidence that the observed association was not simply an artefact of coding or treatment definitions.
The researchers said that annual gout flare frequency could provide clinicians with a pragmatic and readily available marker of long-term cardiovascular vulnerability.
A threshold of >3 flares/year may aid risk stratification and may prompt earlier review of gout management and cardiovascular prevention,” they concluded.
“Future interventional studies are needed to determine whether reducing flare burden can directly lower MACE incidence.”
