Non-steroidal anti-inflammatory drug (NSAID) related inhibition of aldosterone glucuronidation and arterial dysfunction in patients with rheumatoid arthritis: a cross-sectional clinical study.
Non-steroidal anti-inflammatory drug (NSAID) related inhibition of aldosterone glucuronidation and arterial dysfunction in patients with rheumatoid arthritis: a cross-sectional clinical study.
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DOI：
10.1136/bmjopen-2011-000076
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发表时间：
2011-05-20
期刊：
影响因子：
2.9
通讯作者：
Mangoni AA
中科院分区：
文献类型：
--
作者：
Crilly MA;Mangoni AA
Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular (CV) disease and are also commonly prescribed non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs). New in vitro evidence suggests that this increased CV risk may be mediated through aldosterone glucuronidation inhibition (AGI), which differs between NSAIDs (diclofenac>naproxen>indomethacin>ibuprofen). Our aim was to explore the association between ns-NSAID-related AGI and arterial dysfunction. The extent (augmentation index, AIX%) and timing (reflected wave transit time, RWT, ms) of aortic wave reflection (measured using radial applanation pulse wave analysis, PWA, SphygmoCor device) were assessed on a single occasion in 114 consecutive RA patients without overt CV disease aged 40–65 years. A higher AIX% and lower RWT indicate arterial dysfunction. Assessment included a fasting blood sample, patient questionnaire and medical record review. Multivariate analysis was used to adjust for age, sex, mean blood pressure, smoking, cumulative erythrocyte sedimentation rate (ESR-years) and Stanford disability score. We identified 60 patients taking ns-NSAIDs and 25 non-users. Using a ns-NSAID with the highest AGI was associated with a higher AIX% (and lower RWT) versus treatment with a ns-NSAID with the lowest AGI (diclofenac AIX% 32.3, RWT 132.7 ms vs ibuprofen AIX% 23.8, RWT 150.9 ms): adjusted mean differences AIX% 6.5 (95% CI 1.0 to 11.9; p=0.02); RWT −14.2 ms (95% CI −22.2 to −6.3; p=0.001). Indomethacin demonstrated an intermediate level of arterial dysfunction. In relation to arterial dysfunction, both indomethacin and naproxen were more similar to diclofenac than to ibuprofen. ns-NSAID-related AGI is associated with arterial dysfunction in patients with RA. These findings provide a potentially novel insight into the CV toxicity of commonly used ns-NSAIDs. However, the findings are limited by the small number of patients involved and require further replication in a much larger study. Aldosterone glucuronidation inhibition (AGI) potentiates the adverse cardiovascular effects of aldosterone. Recently published in vivo research suggests that such inhibition differs between non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs), with a ranked order of diclofenac>naproxen>indomethacin>ibuprofen, but no previous studies have assessed the relationship between ns-NSAID-related AGI and arterial dysfunction in chronic users. This study assessed arterial dysfunction using pulse wave analysis. In patients with rheumatoid arthritis we found that chronic use (>3 months) of diclofenac (high AGI) was associated with greater arterial dysfunction compared to ibuprofen (lower AGI); this association was independent of other cardiovascular and rheumatological factors. Indomethacin (intermediate AGI) was associated with an intermediate level of arterial dysfunction, although naproxen (intermediate AGI) did not fit the anticipated pattern. Our findings support the concept that AGI may play a role in the cardiovascular toxicity of some ns-NSAIDs commonly used in routine clinical practice. A single research nurse assessed rheumatoid arthritis patients who were recruited from a consecutive series attending a hospital rheumatology clinic. We adjusted for several important cardiovascular and rheumatological factors known to be independently associated with arterial function and our multivariate analysis explained a high proportion of the variability in arterial dysfunction among chronic ns-NSAID users. The observational cross-sectional design of our study means that we cannot assess causation, nor exclude residual confounding as an explanation for our findings. The small number of patients taking each NSAID meant that the confidence intervals are wide.
Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular (CV) disease and are also commonly prescribed non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs). New in vitro evidence suggests that this increased CV risk may be mediated through aldosterone glucuronidation inhibition (AGI), which differs between NSAIDs (diclofenac>naproxen>indomethacin>ibuprofen). Our aim was to explore the association between ns-NSAID-related AGI and arterial dysfunction. The extent (augmentation index, AIX%) and timing (reflected wave transit time, RWT, ms) of aortic wave reflection (measured using radial applanation pulse wave analysis, PWA, SphygmoCor device) were assessed on a single occasion in 114 consecutive RA patients without overt CV disease aged 40–65 years. A higher AIX% and lower RWT indicate arterial dysfunction. Assessment included a fasting blood sample, patient questionnaire and medical record review. Multivariate analysis was used to adjust for age, sex, mean blood pressure, smoking, cumulative erythrocyte sedimentation rate (ESR-years) and Stanford disability score. We identified 60 patients taking ns-NSAIDs and 25 non-users. Using a ns-NSAID with the highest AGI was associated with a higher AIX% (and lower RWT) versus treatment with a ns-NSAID with the lowest AGI (diclofenac AIX% 32.3, RWT 132.7 ms vs ibuprofen AIX% 23.8, RWT 150.9 ms): adjusted mean differences AIX% 6.5 (95% CI 1.0 to 11.9; p=0.02); RWT −14.2 ms (95% CI −22.2 to −6.3; p=0.001). Indomethacin demonstrated an intermediate level of arterial dysfunction. In relation to arterial dysfunction, both indomethacin and naproxen were more similar to diclofenac than to ibuprofen. ns-NSAID-related AGI is associated with arterial dysfunction in patients with RA. These findings provide a potentially novel insight into the CV toxicity of commonly used ns-NSAIDs. However, the findings are limited by the small number of patients involved and require further replication in a much larger study. Aldosterone glucuronidation inhibition (AGI) potentiates the adverse cardiovascular effects of aldosterone. Recently published in vivo research suggests that such inhibition differs between non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs), with a ranked order of diclofenac>naproxen>indomethacin>ibuprofen, but no previous studies have assessed the relationship between ns-NSAID-related AGI and arterial dysfunction in chronic users. This study assessed arterial dysfunction using pulse wave analysis. In patients with rheumatoid arthritis we found that chronic use (>3 months) of diclofenac (high AGI) was associated with greater arterial dysfunction compared to ibuprofen (lower AGI); this association was independent of other cardiovascular and rheumatological factors. Indomethacin (intermediate AGI) was associated with an intermediate level of arterial dysfunction, although naproxen (intermediate AGI) did not fit the anticipated pattern. Our findings support the concept that AGI may play a role in the cardiovascular toxicity of some ns-NSAIDs commonly used in routine clinical practice. A single research nurse assessed rheumatoid arthritis patients who were recruited from a consecutive series attending a hospital rheumatology clinic. We adjusted for several important cardiovascular and rheumatological factors known to be independently associated with arterial function and our multivariate analysis explained a high proportion of the variability in arterial dysfunction among chronic ns-NSAID users. The observational cross-sectional design of our study means that we cannot assess causation, nor exclude residual confounding as an explanation for our findings. The small number of patients taking each NSAID meant that the confidence intervals are wide.
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