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Il rischio cardiovascolare degli antiinfiammatori non steroidei è mediato dall'assetto genetico

L'uso prolungato di inibitori selettivi della ciclo ossigenasi (COX-2) è associato ad un aumento di eventi cardiovascolari con un meccanismo ancora poco chiaro. L'ipotesi più favorita è quella di uno squilibrio nella sintesi delle prostaglandine ad azione pro-trombotica (tromboxano A2, regolato dalla COX-1) e ad azione antitrombotica (prostaciclina, regolata dalla COX-2). Il rischio comunque è basso (1,5/100 pazienti-anno, secondo lo studio APPROVe) e solo pochi utilizzatori degli inibitori COX-2 vanno incontro ad eventi cardiovascolari, forse per suscettibilità genetica. E' stato infatti osservato che varianti genetiche di PTGS1 (prostaglandin-endoperoxide synthase -1) e CRP (C-reactive protein) sono associate ad un aumento del rischio cardiovascolare connesso all'uso di anti infiammatori non steroidei. Rimane da spiegare perché queste varianti genetiche che si accompagnano ad un ridotto livello di marcatori infiammatori, che suggerirebbe perciò un più basso profilo di rischio cardiovascolare, debbano invece aumentare il rischio in presenza di anti infiammatori non steroidei.

Genetic polymorphisms and the cardiovascular risk of non-steroidal anti-inflammatory drugs

St Germaine CG, Bogaty P, Boyer L, Hanley J, Engert JC, Brophy JM.

Am J Cardiol 2010;105:1740-45

The cardiovascular safety of cyclooxygenase-2-selective (coxibs) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is of concern, although most users remain free of adverse outcomes. A gene-drug interaction could modulate this cardiovascular risk through prostaglandin synthesis or inflammatory pathways. From an existing acute coronary syndrome cohort (Recurrence and Inflammation in the Acute Coronary Syndromes Study) (n = 1,210), a case-only study was performed by identifying 115 patients exposed to NSAIDs (rofecoxib [n = 43], celecoxib [n = 49], or nonselective NSAIDs [n = 23]) and 345 unexposed patients matched for age, gender, and hospital center. These patients were genotyped for 115 candidate single-nucleotide polymorphisms (SNPs). Statistically significant associations between NSAID exposure and 9 SNPs in 6 genes were observed. Analyzing patients exposed only to coxibs and their matched unexposed cases, significant associations remained for 5 SNPs at 4 loci (prostaglandin-endoperoxide synthase-1 [PTGS1], chromosome 9p21.3, C-reactive protein [CRP], and klotho [KL]). Two independent SNPs from the PTGS1 gene gave similar results under a recessive model, with odds ratios for the association with NSAID exposure of 6.94 (95% confidence interval 1.35 to 35.65, p = 0.016) and 7.11 (95% confidence interval 1.38 to 36.74, p = 0.033). A significant association was also observed for a SNP in the CRP gene (rs1205) (additive odds ratio 1.64, 95% confidence interval 1.18 to 2.27, p = 0.003). In conclusion, these findings suggest that genetic variability may contribute to the susceptibility for acute coronary syndromes observed in some NSAID users. In particular, genetic polymorphisms in the PTGS1 and CRP genes appear to be candidates for a possible gene-drug interaction influencing the acute coronary risk associated with NSAID use, but these findings will require confirmation in larger cohorts.

Am J Cardiol 2010;105:1740-45