Aspirin-resistance in cardiovascular diseases

Author: daniele viarisio
Date: 18/09/2007


Therapy with antiplatelet drugs has become one of the most exploited treatment to avoid thrombotic occlusions in atherosclerotic patients. Clinical trials have proven that aspirin could be an effective antiplatelet in the prevention of myocardial infarction (MI) in patients at high risk for cardiovascular events. The efficacy of the treatment has been demonstrated also in people who have already undergone MI and stroke. Actually recent studies show that patients treated with acetylsalicylic acid present a reocclusion rate relatively high and that ischemic events are reduced only by 25%. Till today nobody has given a satisfying explanation about this possible drug resistance, but, starting from the evidence that the target enzyme of aspirin is COX-1/2, there are a lot of studies looking for a correlation between weak answer to the drug and COX mutations.

Cipollone et al. found a promising polymorphism in COX-2 promoter, -765G>C, with an allelic frequency of G/G 50.7%, G/C 43.3%, C/C 6% in control population (n=864) and of G/G 81% , G/C 17.9%, C/C 1.1% in cases (n=864). The polymorphism is located in a putative binding sequence for Sp1.G/C and C/C genotypes are correlated with a reduced expression of COX-2, a lower probability to develop cardiovascular diseases, a lower expression of MMP-9, MMP-2 and C-reactive protein (CRP) if compared to G/G genotype. The author suggests that lower COX-2 expression lead to a reduced inflammatory response and that lower metalloprotease activity involve a smaller atherosclerotic plaque degradation with a lower risk of thrombotic occlusion. In this paper there are not linkage between the polymorphism studied and aspirin-resistance.

Colaizzo et al. reported data similar to the previous article.

Ulrich et al. correlate -765G>C polymorphism and aspirin response, also if in a different contest. The authors have seen that the G/G genotype has an higher frequency in patients with colorectal adenoma if compared with healthy population. Also in this kind of pathology the polymorphism is correlated with a lower expression/activity of COX-2 and a lower concentration of CRP. The treatment with aspirin or other NSAIDs shows positive effects only on G/G and, partially, on G/C genotype, while is completely ineffective on C/C genotype. Actually people with the double mutation are insensitive to the drug because are yet characterized by a low COX-2 activity: the G/G cases treated with aspirin show result very similar to C/C cases not treated.

Halushka et al. have found a new COX-1 haplotype, -842A>G/50C>T; they found it in heterozygosis in 8 cases in a total population of 37 cases. The mutation leads to a significative reduction of prostaglandin PGF2, but seems to have no effect on thromboxane synthesis. The more important effect of the polymorphism is the lowering of the platelet aggregation after arachidonic acid stimulus. The treatment with aspirin, after arachidonic acid administration, leads to a blockage of prostaglandin synthesis that is higher in heterozygotic genotypes. The authors assume that the haplotype, and particularly the mutation in -842, leads to a COX-1 synthesis reduction and, thereafter, to an abated platelet aggregation and to an higher inhibition by aspirin. In this case the polymorphism strengthen the aspirin effect.

Ulrich et al. in a study about the COX-1 involvement in colorectal adenoma demonstrate how the haplotype previously indicated is associated with a lower inhibition when treated with aspirin, if compared to the wild-type. But actually, also in this case, the haplotype is related with a reduced thromboxane synthesis and platelet aggregation. The authors cannot see inhibition after aspirin administration because the haplotype is already characterized by a low basal COX-1 activity.

So, currently COX-1/2 polymorphism directly related to aspirin-resistance are not known and actually this phenomenon still miss a real explanation (Mason e Patrono ).

Nevertheless some data are now quite supported and some considerations can be made:
COX-1/2 polymorphism directly related to aspirin resistance are, by now, not known;
aspirin-resistance can be developed after a long chronic administration of the drug, leading to think to a systemic adaptation instead of a genetic origin;
COX-2 is no inhibited at acetylsalicylic acid concentration used in prevention treatments, and an higher expression of this enzyme can be the reason of acquired resistance.;
people not responding to aspirin administration present higher risk to develop cardiovascular diseases, if compared to sensible cases;
people that genetically don not profit from aspirin administration, can be treated from the beginning with different drugs, to avoid the side effect of aspirin and NSAIDs.

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