Abstract
Endothelial dysfunction plays a key role in development of atherosclerosis and lower extremity arterial disease (LEAD). Homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are sensitive markers for endothelial dysfunction and independent risk factors for cardiovascular death. However, homoarginine may influence the proatherogenic effects of ADMA and SDMA suggesting homoarginine/ADMA ratio or homoarginine/SDMA ratio as further predictors for cardiovascular mortality. Therefore, we investigated the predictive value of homoarginine/ADMA ratio and homoarginine/SDMA ratio related to cardiovascular mortality and cardiovascular events in claudicant patients with LEAD. 151 patients with intermittent claudication were included in a prospective observational study (observation time 7.7 ± 2.5 years) with cardiovascular mortality as main outcome parameter and the occurrence of cardiovascular events as secondary outcome parameter. Homoarginine, ADMA and SDMA were measured by high-performance liquid chromatography at baseline. Low homoarginine/ADMA ratio and homoarginine/SDMA ratio were independently associated with higher cardiovascular mortality (HR 2.803 [95% CI 1.178–6.674], p = 0.020; HR 2.782 [95% CI 1.061–7.290], p = 0.037, respectively) and higher incidence of cardiovascular events (HR 1.938 [95% CI 1.015–3.700], p = 0.045; HR 2.397 [95% CI 1.243–4.623], p = 0.009, respectively). We observed that homoarginine/ADMA ratio and homoarginine/SDMA ratio are independent predictors for long-term cardiovascular mortality and events in claudicant patients with LEAD.
Highlights
Lower extremity arterial disease (LEAD) refers to atherosclerotic stenosis or occlusions of the arteries of the lower limbs
The lowest quartiles of both homoarginine/asymmetric dimethylarginine (ADMA) ratio and homoarginine/symmetric dimethylarginine (SDMA) ratio were associated with a significantly increased risk of cardiovascular death when compared to the highest quartiles, respectively (HR 3.012 [95% CI 1.316–6.892], p = 0.009; HR 4.118 [95% CI 1.633–10.383], p = 0.003) (Fig. 1A,B)
In this prospective observational study, we demonstrated that homoarginine/ADMA ratio and homoarginine/ SDMA ratio were inversely associated with cardiovascular death and independent predictors for cardiovascular mortality in claudicant patients with lower extremity arterial disease (LEAD)
Summary
Lower extremity arterial disease (LEAD) refers to atherosclerotic stenosis or occlusions of the arteries of the lower limbs. Endothelial dysfunction plays a key role in development and clinical manifestation of atherosclerosis and consecutive cardiovascular diseases like LEAD, and represents an independent risk factor of cardiovascular morbidity and mortality[2]. Accumulating evidence indicates that higher levels of ADMA and SDMA as well as lower levels of homoarginine seem to be independent risk factors for cardiovascular death with a direct association of the occurrence of cardiovascular events[6,7,8,9]. The bioavailability of NO is modulated by both homoarginine and ADMA due to an intracellular competition for NO-synthase[14] Due to this modulating effect of homoarginine on ADMA, homoarginine/ADMA ratio may be an interesting indicator for endothelial dysfunction and atherosclerosis. There are studies indicating an association between l-arginine/ADMA ratio or homoarginine/ADMA ratio and atherosclerotic diseases or mortality[15,16,17,18] while data for l-arginine/SDMA ratio or homoarginine/SDMA are still missing, probably because no obvious influence between homoarginine or l-arginine and SDMA is yet known
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