Aurora de la Peña-Díaz

Lipoprotein Lp(a) and Atherothrombotic Disease

High plasma concentrations of lipoprotein (a) [Lp(a)] are now considered a major risk factor for atherosclerosis and cardiovascular disease. This effect of Lp(a) may be related to its composite structure, a plasminogen-like inactive serine-proteinase, apoprotein (a) [apo(a)], which is disulfide-linked to the apoprotein B100 of an atherogenic low-density lipoprotein (LDL) particle. Apo(a) contains, in addition to the protease region and a copy of kringle 5 of plasminogen, a variable number of copies of plasminogen-like kringle 4, giving rise to a series of isoforms. This structural homology endows Lp(a) with the capacity to bind to fibrin and to membrane proteins of endothelial cells and monocytes, and thereby inhibits binding of plasminogen and plasmin formation. This mechanism favors fibrin and cholesterol deposition at sites of vascular injury and impairs activation of transforming growth factor-beta (TGF-beta) that may result in migration and proliferation of smooth muscle cells into the vascular intima. It is currently accepted that this effect of Lp(a) is linked to its concentration in plasma, and an inverse relationship between apo(a) isoform size and Lp(a) concentrations that is under genetic control has been documented. Recently, it has been shown that inhibition of plasminogen binding to fibrin by apo(a) from homozygous subjects is also inversely associated with isoform size. These findings suggest that the structural polymorphism of apo(a) is not only inversely related to the plasma concentration of Lp(a), but also to a functional heterogeneity of apo(a) isoforms. Based on these pathophysiological findings, it can be proposed that the predictive value of Lp(a) as a risk factor for vascular occlusive disease in heterozygous subjects would depend on the relative concentration of the isoform with the highest affinity for fibrin.

C3435T polymorphism of the ABCB1 gene is associated with poor clopidogrel responsiveness in a Mexican population undergoing percutaneous coronary intervention

BACKGROUND Clopidogrel is a pro-drug and its intestinal absorption is limited by the P-glycoprotein encoded by the ABCB1 gene. It is metabolized hepatically by cytochrome P450 enzymes encoded by CYP genes to produce an active metabolite that antagonizes the P2Y12 platelet receptor. Some patients exhibit poor clopidogrel responsiveness due to polymorphisms, resulting in thrombotic events. The aim of this study was to determine the relationship between poor clopidogrel responsiveness and the ABCB1, CYP and P2RY12 gene polymorphisms among patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS Two hundred seventy-six patients who underwent PCI were included in this study. Clopidogrel responsiveness was determined via optical aggregometry in platelet-rich plasma using 10 μM ADP. Patients exhibiting a platelet aggregation response higher than 70% were classified as poor responders. The genetic polymorphisms were analyzed via real-time PCR. Poor responsiveness to clopidogrel was noted in 22.1% of the patients. The TT genotype of the C3435T polymorphism of the ABCB1 gene and omeprazole usage were each associated with poor clopidogrel responsiveness (Exp (β) 2.73, p=0.009 and Exp (β) 3.86, p=0.04, respectively). CONCLUSION Poor clopidogrel responsiveness is associated with the TT genotype of the C3435T polymorphism of the ABCB1 gene.

Relationship between angiotensin II receptor expression and cardiovascular risk factors in Mexican patients with coronary occlusive disease

The density of Angiotensin II (Ang) receptors on tissue surfaces is regulated by multiple hormones, cytokines and metabolic factors and is profoundly affected by various pathological conditions, such as age, diet and environmental conditions. The participation of several cardiovascular risk factors in the regulation of Angiotensin II receptor expression has been incompletely studied. We performed an ex-vivo study with human aortic postsurgical specimens to test the hypothesis that Ang AT1 and AT2 receptor expression in human aortic arteries is associated with the presence of cardiovascular risk factors. We included 31 Mexican patients with coronary artery disease. We evaluated Angiotensin II receptor expression by immunostaining and angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphisms by polymerase chain reaction. AT1 and AT2 receptor expression was increased in the aortic segments from the cardiovascular patients compared with control arteries and in patients with the DD genotype. There was a correlation between increased AT1 receptor expression and the number of cardiovascular risk factors present in the patient. Furthermore, reduction of AT1 expression correlated with the number of drug combinations used in the patients. These correlations were not present with respect to AT2 receptor expression. We suggest that increased AT1 receptor expression is associated with the DD genotype. Thus the presence of several cardiovascular risk factors as well as DD genotype, induce AT1 expression increasing the probability to develop coronary occlusive disease.

Effects of steroids on embryonic subjects I. Action of fluorinated glucocorticoids on the carbohydrate, water and electrolyte metabolism in the developing chick embryo

Abstract Doses of triamcinolone or fluoromethylprednisolone as low as 0.3 micrograms injected into developing chick embryos produced: 1) marked inhibition of growth; 2) water retention; 3) increase in liver glycogen, embryonic fluids glucose and phosphates similar to the known gluconeogenic effects of glucocorticoids in mammals, and 4) alterations in the distribution of sodium and potassium different to the changes observed in mammals treated with fluorinated steroids. The developing chick embryo constitutes an extraordinarily sensitive experimental subject for metabolic studies of synthetic steroidal hormones, inasmuch as the corresponding doses of the natural hormones cortisone and cortisol that produce similar effects are one thousand or more times bigger than those of the former.

Association between Stable Coronary Artery Disease and In Vivo Thrombin Generation

Background. Thrombin has been implicated as a key molecule in atherosclerotic progression. Clinical evidence shows that thrombin generation is enhanced in atherosclerosis, but its role as a risk factor for coronary atherosclerotic burden has not been proven in coronary artery disease (CAD) stable patients. Objectives. To evaluate the association between TAT levels and homocysteine levels and the presence of coronary artery disease diagnosed by coronary angiography in patients with stable CAD. Methods and Results. We included 95 stable patients admitted to the Haemodynamics Department, including 63 patients with significant CAD and 32 patients without. We measured the thrombin-antithrombin complex (TAT) and homocysteine concentrations in all the patients. The CAD patients exhibited higher concentrations of TAT (40.76 μg/L versus 20.81 μg/L, p = 0.002) and homocysteine (11.36 μmol/L versus 8.81 μmol/L, p < 0.01) compared to the patients without significant CAD. Specifically, in patients with CAD+ the level of TAT level was associated with the severity of CAD being 36.17 ± 24.48 μg/L in the patients with bivascular obstruction and 42.77 ± 31.81 μg/L in trivascular coronary obstruction, p = 0.002. Conclusions. The level of in vivo thrombin generation, quantified as TAT complexes, is associated with the presence and severity of CAD assessed by coronary angiography in stable CAD patients.