ATR1 A1166C (rs5186), FII G20210A (rs1799963), FV G1691A (rs6025), FXIII 97G > T (rs11466016) and MTHFR A1298C (rs1801131) polymorphisms and the risk of ST-elevation myocardial infarction in young Mexican individuals.

BACKGROUND: Previous studies had identified genetic variants associated with Myocardial Infarction, but results are inconclusive. We examined the association between FII G20210A (rs1799963), FV G1691A (rs6025), FXIII 97G > T (rs11466016), ATR1 A1166C (rs5186) and MTHFR A1298C (rs1801131) polymorphisms and ST elevation Myocardial Infarction in young Mexican individuals. METHODS: We included a total of 350 patients with Myocardial Infarction <45 years old and 350 controls matched by age and gender. The polymorphisms were analyzed by PCR-RFLP using specific restriction enzymes. DNA fragments were separated by electrophoresis in 2% gel of agarose and visualized using SYBR green. RESULTS: The A1166C (p = 0.004) but not FXIII 97G > T (p = 0.19), G20210A (p = 0.32), G1691A (p = No significant) and A1298C (p = 0.21) polymorphisms were associated with increased risk for ST elevation Myocardial Infarction. Moreover, dyslipidemia, hypertension, smoking and family history of atherothrombotic disease were associated. CONCLUSIONS: We found that A1166C represented increased risk for ST elevation Myocardial Infarction. However, G20210A, G1691A, 97G > T, and A1298C were not associated. In addition, we had determined that Glu298Asp, PLA1/A2, TAFI Thr325Ile, ACE I/D, AGT M235T and PAI-1 4G/5G polymorphisms represented increased risk in the same group of patients. However, MTHFR C677T, AGT T174M, FV G1691A, TSP-1 N700S, MTHFR C677T and TAFI 174 M polymorphisms were no associated. Our results suggest that in young patients with ST Myocardial Infarction, those polymorphisms could contribute to premature endothelial dysfunction, atherothrombosis, vasoconstriction, increased platelet aggregation, muscle cell migration and proliferation. Further studies are required to try to better assess gene-gene and gene-modifiable factors interaction.

Soluble Endoglin and Uterine Artery Flow Doppler Ultrasonography as Markers of Progression to Preeclampsia in Women with Gestational Hypertension.

INTRODUCTION: Gestational hypertension (GH) pregnancies are at a high risk of developing adverse outcomes, including progression to preeclampsia. Prediction of GH-related adverse outcomes is challenging because there are no available clinical tests that may predict their occurrence. OBJECTIVE: The aim of the study was to determine the clinical usefulness of the soluble endoglin (sEng) and parameters of uterine artery flow (UtAF) measured by Doppler ultrasonography as markers of progression to preeclampsia in women with GH. SETTING: Mexico City, Mexico. MATERIAL AND METHODS: We included 77 singleton pregnant women with GH in a nested case-control study. Cases were women who progressed to preeclampsia (n = 36), and controls were those who did not (n = 41). Serum sEng and UtAF measurements were performed at enrollment. The main outcomes measured were progression to preeclampsia and occurrence of preterm delivery (PD) <37 and <34 weeks of gestation, small for gestational age infant (SGA), and fetal growth restriction (FGR). RESULTS: Women with sEng values in the highest tertile had higher risk of progression to preeclampsia, preterm delivery <34 weeks of gestation, and fetal growth restriction, odds ratios (ORs) ≥3.7. Patients with abnormal UtAF Dopp-ler-pulsatility index had higher risk of progression to preeclampsia, preterm delivery <34 weeks of gestation, small for gestational age infant, and fetal growth restriction (ORs ≥3.3). The presence of notch was associated with higher risk of progression to preeclampsia, preterm delivery <37 and <34 weeks of gestation, SGA infant, and fetal growth restriction (ORs ≥2.9). However, logistic regression analysis revealed that only serum sEng was a significant and independent risk factor for progression of GH to preeclampsia, preterm delivery <34 weeks of gestation, and fetal growth restriction (ORs ≥3.1). CONCLUSIONS: In GH pregnancies, UtAF Doppler ultrasonography is associated with increased risk of adverse outcomes and progression to preeclampsia. However, serum sEng concentration appears to be a better predictor to assess the risk of adverse maternal and perinatal outcomes and progression to preeclampsia.

Interleukin-6 in Amniotic Fluid: A Reliable Marker for Adverse Outcomes in Women in Preterm Labor and Intact Membranes.

INTRODUCTION: Amniotic fluid (AF) interleukin-6 (IL-6) concentration has been associated to preterm delivery and perinatal morbidity and mortality in women with preterm labor and intact membranes. Nevertheless, the clinical significance of this biomarker of intra-amniotic inflammation (IAI) is still unclear due in part to the paucity of large studies. METHODS: AF IL-6 concentrations were determined in 452 consecutive women with preterm labor and intact membranes, categorized into 3 groups: 302 without IAI (IL-6 of <2.6 ng/mL), 64 with mild IAI (IL-6 of 2.6-11.2 ng/mL), and 86 with severe IAI (IL-6 of ≥11.3 ng/mL). RESULTS: The severe IAI group had a short pregnancy duration from amniocentesis to delivery (median 3 days) than in without IAI group (median 45 days); meanwhile, the mild IAI group had a latency that was intermediate to the severe and without IAI groups (median 9.5 days). As compared to women without IAI, women with mild and severe IAI had higher rates of preterm delivery at both <34 and <37 weeks of gestation and perinatal morbidity and mortality. Furthermore, the risk of various individual adverse outcomes (short latency from amniocentesis to delivery [at ≤3 days, ≤7 days, and ≤14 days], preterm delivery at both <34 and <37 weeks of gestation, histologic chorioamnionitis, respiratory distress syndrome, and congenital sepsis) was higher in women with severe IAI (OR ≥ 2.8), compared with women without IAI. CONCLUSIONS: AF IL-6 concentrations appear to be suitable marker to assess the degree of IAI and are associated with increased risk of adverse outcomes.

Analysis of the quality of anticoagulation with vitamin K antagonists in three clinical scenarios in Mexico.

INTRODUCTION: Vitamin K antagonists (VKA) are a therapeutic alternative in patients with venous thromboembolic disease; however, numerous factors affect their pharmacology. OBJECTIVE: To evaluate the quality of VKA anticoagulation at three different time periods in Mexico. METHODS: Prospective study, nested in patient cohorts at three different clinical scenarios between 2013 and 2019. Outpatients with indication for treatment with VKAs for at least 12 months were included. Patients were managed according to the criteria of the treating physician. RESULTS: Patient general characteristics were similar between groups, except for the VKA indication. The results of 4,148 patients and 38,548 INR assessments were analyzed. The times in therapeutic range during the three phases of the study and pooled data were significantly higher for the anticoagulation clinic. Only the number of patient visits was significantly associated with the results, unlike age, gender, and type of VKA. CONCLUSIONS: VKAs are widely used, but it is difficult for therapeutic goals to be achieved, especially in non-specialized clinical services. Creation of anticoagulation clinics is an urgent need for the Mexican health system.

INTRODUCCIÓN: Los antagonista de la vitamina K (AVK) son una alternativa terapéutica en los pacientes con enfermedad tromboembólica venosa; sin embargo, numerosos factores afectan su farmacología. OBJETIVO: Evaluar la calidad de la anticoagulación AVK durante tres diferentes periodos en México. MÉTODOS: Estudio prospectivo, anidado en cohortes de pacientes en tres escenarios clínicos entre los años 2013-2019. Se incluyeron pacientes no hospitalizados con indicación para recibir AVK por al menos 12 meses, quienes fueron manejados de acuerdo con el criterio del médico tratante. RESULTADOS: Las características generales de los pacientes fueron similares entre los grupos, excepto por la indicación para usar los AVK. Se analizaron los resultados de 4148 pacientes y 38 548 evaluaciones de INR. Los tiempos en rango terapéutico durante las tres fases del estudio y los datos acumulados fueron significativamente mayores en la clínica de anticoagulación. Solo el número de visitas de control de los pacientes se asoció significativamente con los resultados, a diferencia de la edad, el sexo y el tipo de AVK. CONCLUSIONES: Los AVK se utilizan ampliamente, pero es difícil alcanzar la meta terapéutica, sobre todo en servicios clínicos no especializados. La creación de clínicas de anticoagulación es una necesidad urgente en el sistema mexicano de salud.

von Willebrand Disease and other hereditary haemostatic factor deficiencies in women with a history of postpartum haemorrhage.

INTRODUCTION: Postpartum haemorrhage (PPH) is the main cause of maternal morbidity and mortality globally, but it is far more important in non-developed countries. PPH represents 25% of all maternal deaths worldwide. Women with von Willebrand disease (VWD) and other inherited haemorrhagic disorders are at increased risk of PPH. Our aim was to establish a probable association of severe PPH in women with a history of haemostatic abnormalities. METHODS: An observational, controlled study of adult women with a one or more episodes of severe PPH requiring treatment in an intensive care unit or >10 units of blood products during the 24-hour period after diagnosis and their controls. The tests performed were blood cell count, blood group, renal, viral, liver function and haemostatic tests, fibrinogen, activity of the plasma factors and specific test to diagnose and classify VWD. RESULTS: We included 124 women with 133 PPH events and their controls. The median age at the first event was 25.5 years old. Results were significantly different between the groups in terms of fibrinogen concentration, VWF:Ag, VWF:RCo and FVIII. A specific diagnosis was established in 69 (55.6) and 4 (3.2%) patients in the PPH group and controls, respectively. Of 61 patients with VWD, 57 had type 1, two had type 2A, and another two had type 2B. CONCLUSION: Our results show a relationship between PPH and inherited haemostatic disorders. VWD was the most frequent diagnosis. Appropriate and opportune diagnosis before pregnancy of inherited haemostatic disorders may be important to effectively prevent and treat PPH.

Effects of Rivaroxaban on Platelet Aggregation.

Rivaroxaban is a direct oral anti-factor Xa anticoagulant. It has recently been suggested that rivaroxaban may affect platelet function in vitro; however, little is known about the clinical impact of this likely antiplatelet effect and whether this probable phenomenon is dose-dependent. Our aim was to determine whether rivaroxaban at 4 different doses inhibits direct platelet aggregation. We included adult patients of both sexes and who were allocated to one of the following groups depending on the prescribed daily dose of rivaroxaban: 5, 10, 15, and 20 mg. In 80 patients (20 patients/group), the percentage of platelet aggregation was determined by means of platelet aggregometry tests before and after rivaroxaban use. Basal samples were obtained before starting rivaroxaban and 1 month after treatment, both 2 and 24 hours after the last dose of the drug (12 hours after in the case of rivaroxaban 5 mg). We used 5 platelet agonists: adenosine diphosphate, epinephrine, arachidonic acid, collagen, and thrombin. There were no significant changes in the percentage of platelet aggregation before and after rivaroxaban use independently of the dose administered and the agonist used. Our results have clearly shown that rivaroxaban, even at a high dose, does not directly affect platelet aggregation.

[Polimorfismos asociados a disfunción endotelial y a un estado protrombótico en jóvenes mexicanos con infarto cerebral].

OBJECTIVE: To examine the contribution the polymorphisms G20210A, G1691A and G10976A in the coagulation factors FII, FV, FVII, respectively; Glu298Asp and C677T in eNOS and 5,10 MTHFR in young Mexican population with cerebral infarction (CI). METHODS: 224 patients ≤ 45 years of age with CI and 224 controls matched by age and gender were recruited from 2006 and 2014. The polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We identified a significant difference in the genotype distribution of Glu298Asp (p = 0.001) and C677T (p = 0.01) polymorphisms between CI patients and control groups. The genotype distribution in the FII G20210A, FV G1691A and FVII G10976A polymorphisms were similar. There were independent factors for ischemic stroke: Glu298Asp and C677T polymorphisms, smoking; hypertension, and familial history of thrombotic disease. CONCLUSIONS: The Glu298Asp and C677T, but not FII G20210A, FV G1691A and FVII G10976A polymorphisms were associated with CI. Our results suggest that endothelial dysfunction and the synergist interaction with other factors such as smoking and hypertension contribute to CI in young individuals.

OBJETIVO: Examinar la contribución de los polimorfismos G20210A, G1691A y G10976A en los factores de coagulación FII, FV y FVII respectivamente; Glu298Asp y C677T en la óxido nítrico sintasa endotelial y 5,10 metilentetrahidrofolato reductasa, en población joven mexicana con infarto cerebral (IC). MÉTODO: Se incluyeron 224 pacientes ≤ 45 años de edad con diagnóstico de IC y 224 controles pareados por edad y sexo, de 2006 a 2014. Los polimorfismos fueron determinados por la técnica de reacción en cadena de la polimerasa-polimorfismos de longitud de fragmentos de restricción. RESULTADOS: Identificamos una diferencia significativa en la distribución genotípica de los polimorfismos Glu298Asp (p = 0.001) y C677T (p = 0.01) entre el grupo de pacientes con IC y el control. La distribución genotípica de los polimorfismos FII G20210A, FV G1691A y FVII G10976A fue similar entre ambos grupos. Se identificaron como factores independientes de IC los polimorfismos Glu298Asp y C677T, el tabaquismo, la hipertensión y el antecedente de familiar de enfermedad trombótica. CONCLUSIONES: Los polimorfismos Glu298Asp y C677T, pero no FII G20210A, FV G1691A y FVII G10976A, se asociaron con IC. Nuestros resultados sugieren que la disfunción endotelial en interacción sinérgica con otros factores de riesgo, como tabaquismo e hipertensión, contribuye al IC en individuos jóvenes.

GLU298ASP and 4G/5G Polymorphisms and the Risk of Ischemic Stroke in Young Individuals.

BACKGROUND: Polymorphisms in the endothelial nitric oxide synthase (eNOS) and in the plasminogen activator inhibitor -1 (PAI-1) genes have been implicated in stroke pathogenesis but results are still controversial. The aim of this study was to examine the possible contribution of Glu298Asp in the eNOS and 4G/5G in the PAI-1polymorphisms with ischemic stroke in a young Mexican population. MATERIALS AND METHODS: In a case-control study, conducted between January 2006 and June 2010, 204 patients ≤45 years of age with ischemic stroke and 204 controls matched by age and gender, were recruited. The Glu298Asp and 4G/5G polymorphisms were determined in all participants by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: There was a significant difference in the Glu298Asp genotype distribution (P=0.001) and allele frequency between the two groups (P=0.001). The 4G/5G genotype distribution (P=0.40) and the allele frequency was similar between groups; (P=0.13). There were independent factors for ischemic stroke: Asp carriage (GluAsp+AspAsp) (P=0.02); smoking (P=0.01); hypertension (P=0.03), and familial history of atherothrombotic disease (P=0.04). CONCLUSIONS: The Asp allele from the Gu298Asp gene represents an independent risk factor for ischemic stroke in a young Mexican population. In contrast, the 4G/5G was not associated with an increased risk for this disease in the same group of patients, as previously has been demonstrated in other populations.

Metabolic effects of the contraceptive skin patch and subdermal contraceptive implant in Mexican women: a prospective study.

BACKGROUND: The contraceptive skin patch (CSP) accepted by the U.S. FDA in 2001 includes ethinylestradiol and norelgestromine, whereas the subdermal contraceptive implant (SCI) has etonogestrel and is also approved by the FDA. In Mexico, both are now widely used for contraception but their effects on Mexican population are unknown. The objective of the study was to evaluate if these treatments induce metabolic changes in a sample of indigenous and mestizo Mexican women. METHODS: An observational, prospective, longitudinal, non-randomized study of women between 18 and 35 years of age assigned to CSP or SCI. We performed several laboratory tests: clinical chemistry, lipid profile, and liver and thyroid function tests. Also, serum levels of insulin, C-peptide, IGF-1, leptin, adiponectin, and C reactive protein were assayed. RESULTS: Sixty-two women were enrolled, 25 used CSP (0 indigenous; 25 mestizos) and 37 used SCI (18 indigenous; 19 mestizos). Clinical symptoms were relatively more frequent in the SCI group. Thirty-four contraceptive users gained weight without other clinical significant changes. After 4 months of treatment, significant changes were found in some biochemical parameters in both treatment groups. Most were clinically irrelevant. Interestingly, the percentage of users with an abnormal atherogenic index diminished from 75% to 41.6% after follow-up. CONCLUSIONS: The CSP slightly modified the metabolic variables. Most changes were nonsignificant, whereas for SCI users changes were more evident and perhaps beneficial. Results of this attempt to evaluate the effects of contraceptives in mestizo and native-American populations show that clinical symptoms are frequent in Mexican users of CSP and SCI. Although these medications may affect some metabolic variables, these changes seem clinically irrelevant. Induction of abnormalities in other physiological pathways cannot be ruled out.

[Reference values for blood coagulation factor activity in the Mexican population].

INTRODUCTION: During the fluid phase of hemostasis, fibrinogen is converted into fibrin, but other hemostatic factors are required. Reference values of hemostatic factors are established by manufacturers producing reagents using individuals with a specific genetic background. OBJECTIVE: To establish reference values for hemostatic factors in the Mexican indigenous and Mestizo populations. MATERIAL AND METHODS: We carried out a cross-sectional, descriptive study of healthy adult Mexicans. Clotting activity was evaluated using coagulometric assays. Blood donors were informed about the nature of the study and informed consent was obtained prior to blood being drawn. The protocol was approved by the Ethics Committee of our institution. RESULTS: One hundred and twenty samples were assayed (60 females and 60 males). Fibrinogen was higher in mestizos and in females. Reference values for factor XII ranged from 40-170% in indigenous subjects and from 36-159% in mestizos. Factor VIII ranged from 57-160% in indigenous subjects and from 51-209% in mestizo subjects. Reference values for the other hemostatic factors were also clearly different from the commercial reference values. Reference values for hemostatic factors in the Mexican population are different from traditionally used commercial reference values. There were significant differences between indigenous and mestizo Mexicans in the concentration of hemostatic factors with a tendency among mestizos to have higher factor concentrations. Low levels of plasma factor XII are frequent and perhaps may represent a risk factor for thrombotic events. Using these reference values may individualize the reposition of factors in Mexican hemophiliac patients.

Platelet glycoprotein IIIA PIA1/A2 polymorphism in young patients with ST elevation myocardial infarction and idiopathic ischemic stroke.

It has been identified that platelet glycoprotein IIIa PIA1/A2 polymorphism plays an important role in atherothrombotic disease such as myocardial infarction and stroke, but results remain controversial. Here, we investigated whether the PIA2 allele is associated with ST myocardial infarction or idiopathic ischemic stroke in young individuals in two independent studies. In a case-control study 275 patients with ST elevation myocardial infarction ≤45 years of age and 278 controls were recruited. In a second study, 200 patients with idiopathic ischemic stroke ≤45 years of age and 200 controls were enrolled. In both studies cases and controls were matched by age and gender. The PIA1/A2 polymorphism was determined in all participants by a polymerase chain reaction-restriction fragment length polymorphism assay. There was a significant difference in the PIA1/A2 genotype distribution (P = 0.001) and allele frequency (P = 0.001), between ST elevation myocardial infarction and control groups, but not in the PIA1/A2 genotype distribution (P = 0.61) and allele frequency (P = 0.80), between idiopathic ischemic stroke. The allele PIA2 represented an independent risk for ST elevation myocardial infarction but not for idiopathic ischemic stroke. Hypertension, smoking, and family history of atherothrombotic disease were also associated with ST elevation myocardial infarction and idiopathic ischemic stroke. Our results suggest that PA2 allele represents a risk factor for ST elevation myocardial infarction in young Mexican individuals but not for idiopathic ischemic stroke.

Safety of the oral methionine load test: effects on the clinical performance and laboratory tests.

INTRODUCTION: Hyperhomocysteinemia is a prothrombotic risk factor. Homocysteine is evaluated during fasting and after an oral methionine load (OML). AIM: To determine the safety of the OML test according to the general performance status and clinical laboratory tests. We studied healthy nonsmoking volunteers and patients with several thrombotic conditions. Before and after receiving an OML, blood samples were obtained to perform several laboratory tests. We also evaluated acute and subacute adverse effects and 30-day associated morbidity and mortality. Of 353 individuals, three were eliminated because they did not tolerate the OML. We studied 175 healthy individuals and 175 patients without age differences. After OML, mild to moderate clinical abnormalities were recorded in 78 subjects (22.1%): nausea (n = 69; 88.5%), dizziness (n = 13; 16.7%) and decreased or increased blood pressure (n = 8; 10.2%). Nausea always disappeared after breakfast in affected individuals. Prevalence of complications was similar in patients and controls. No patient required hospitalization and there was no mortality during the 30-day study period. In conclusion, OML test had no significant undesirable effects on the clinical status or the general laboratory tests of patients and healthy controls. Some mild and moderate symptoms associated with OML tests were observed, and OML test did not negatively affect general laboratory tests. OML test is a safe diagnostic procedure in patients with previous thrombotic events (and with the consequent associated risk factors such as diabetes mellitus or dyslipidemia) and in healthy subjects.

Polymorphisms in the Renin-Angiotensin System and eNOS Glu298Asp Genes Are Associated with Increased Risk for Essential Hypertension in a Mexican Population.

Background: Essential hypertension is the result of modifiable and genetic factors, and it is associated with increased risk for atherothrombosis. Some polymorphisms are associated with hypertensive disease. The objective was to analyze the association between eNOS Glu298Asp, MTHR C677T, AGT M235T, AGT T174M, and A1166C and ACE I/D polymorphisms with essential hypertension in the Mexican population. Materials and Methods: In the present study, 224 patients with essential hypertension and 208 subjects without hypertension were included. The Glu298Asp, C677T, M235T, T174M, A1166C, and I/D polymorphisms were determined by the PCR-RFLP technique. Results: We found statistical differences in age, gender, BMI, systolic and diastolic blood pressure, and total cholesterol between control and cases. However, we found no significant differences in HbA1c and triglycerides between both groups. We observed statistical significant differences in the genotype distribution of Glu298Asp (P = 0.001), I/D (P = 0.02), and M235T (P = 0.004) polymorphisms between both groups. In contrast, there were no differences related to distribution of genotypes of MTHFR C677T (P = 0.12), M174T (P = 0.46), and A1166C (P = 0.85) between cases and control groups. Conclusions: We identified that Glu298Asp, I/D, and M234T polymorphisms represented an increased risk for essential hypertension and those genetic variants could contribute to the presence of endothelial dysfunction and vasopressor effect, hyperplasia, and hypertrophy of smooth muscle cells, which had an impact for hypertension. In contrast, we found no association between C677C, M174T, and A1166C polymorphisms and hypertensive disease. We suggested that those genetic variants could be identified in individuals with high risk to avoid hypertension and thrombotic disease.

Genetic Variants Associated with High Susceptibility of Premature Ischemic Stroke.

Background: Several polymorphisms had been associated with an increased risk of ischemic stroke, but results are inconclusive. The aim of this study was to examine the association between AGTR1 A1166C and TSP-1 N700S polymorphisms and ischemic stroke in a young Mexican population. Methods: In a case-control study, 250 patients ≤ 45 years of age with ischemic stroke and 250 controls matched by age and gender were included. The polymorphisms were determined in all participants by polymerase chain reaction. Results: There were statistical differences in genotype distribution (p = 0.01) and allele frequency (p = 0.001) of AGTR1 A1166C polymorphism. In contrast, there was a similar genotype distribution (p = 0.96) and allele frequency (p = 0.76) of the TSP1 N700S genetic variant between groups. Hypertension (p = 0.03), smoking (p = 0.02), and family history of atherothrombotic disease (p = 0.04) were associated with stroke, but not diabetes (p = 0.30) and dyslipidemia (p = 0.08). Conclusions: This is the first study in Mexican population to explore several genetic variants in young patients with ischemic stroke. Our results suggest that polymorphisms in the renin-angiotensin-aldosterone system could contribute to premature hypertension, endothelial dysfunction, atherothrombosis, vasoconstriction, smooth muscle cell migration, and proliferation. In contrast, polymorphisms in the coagulation factors are not associated with ischemic stroke. Environmental factors such as diabetes and dyslipidemia could be less important in the pathogenesis of ischemic stroke at a young age. We suggest that those polymorphisms should be determined in individuals with a family history of thrombosis to avoid the stroke development. Therefore, genotype-environmental combination could determine several possible phenotypes at different moments in life.

Platelet glycoprotein IIIA PIA2 polymorphism is associated with ST elevation acute myocardial infarction in young Mexican population.

Platelet membrane glycoprotein IIb/IIIa plays an important role in adhesion and platelet aggregation. Polymorphisms of genes in platelet activation and fibrinolysis have been associated with myocardial infarction (MI), however this has not been confirmed by others, and results are still controversial. The aim of this study was to determine the frequency distribution and association of polymorphism in the platelet glycoprotein GPIIIa PLA/A2 and the possible interaction with the 4G/5G in the plasminogen activator inhibitor genes with ST elevation acute myocardial infarction (STEAMI) in young Mexican subjects. A total of 254 unrelated patients with first STEAMI ≤45 years of age, who were admitted to a cardiovascular intense care unit and 254 healthy controls matched by age and gender were recruited from January 2006 and May 2011. The PIA1/A2 and 4G/5G polymorphism were determined in all participants by a PCR restriction based restriction endonuclease digestion. There was a difference in the PIA2 allele distribution between both groups (P = 0.001). Also, we found an increased percent of 4G allele in the group of patients compared to control group (P = 0.001). There was an increased risk for STEAMI in carries with the allele PIA2 and 4G (OR = 4.3, CI 95 % 1.7-6.5). The modifiable risk factors such: smoking, hypertension, family history of cardiovascular disease, and dyslipidemia were associated with myocardial infarction. This is the first study to evaluate the role of gene polymorphism in both the thrombotic and fibrinolytic pathways in young Mexican individuals with STEAMI and suggest a synergistic effect between PIA2 and 4G allele.

Self-regulation of TNF-α Induces Dysfunction of Endothelial Colony-forming Cells from Patients with Venous Thromboembolic Disease.

BACKGROUND: Endothelial colony-forming cells (ECFCs) contribute to postnatal vasculogenesis. In venous thromboembolic disease (VTD), they are functionally abnormal and produce high concentrations of TNF-α. OBJECTIVE: To analyze the TNF-α signaling pathway and its relationship with the expression of cell-cycle regulators. METHODS: Mononuclear cells (MNCs) were collected from the peripheral blood of 20 healthy human volunteers (controls) and 30 patients with VTD matched by age (20-50 years) and sex to obtain ECFCs. We analyzed the relative quantification of the gene transcripts of TNF, NFkB1, PLAU, HMOX1, GSS, eNOS, CDKN1A, and CDKN1B through quantitative RT-PCR (qRT-PCR assays). Identification of NF-κB and activated targets of each pathway: NF-κB (Ser536); IκBα (Ser32/Ser36); p38 (Thr180/Tyr182) JNK (Thr183/Tyr185), p53 and cell-cycle regulators: p16, p18, p21, p27, p57, Cyclin D, Cyclin E, Cyclin A, Cyclin B, CDK2, CDK4; cell-cycle status was determined by KI-67 and 7-AAD. Cells were analyzed with flow cytometry and the FlowJo vX software. RESULTS: In ECFCs from VTD patients, TNF-α receptor and NFkB were overexpressed and hyper-phosphorylated; eNOS and HMOX1 were down-regulated; cell-cycle regulators (p53, p18, p21) were elevated. In addition, the cell cycle was locked in the G2 phase. CONCLUSIONS: Our results strongly suggest that these molecular alterations in the pathway of TNF-α and cell cycle regulation induce endothelial dysfunction, reduced proliferation potential and vascular regeneration, and consequently, the occurrence of new thrombotic events.

Circulating angiogenic factors are associated with progression to preeclampsia and the occurrence of adverse outcomes in women with gestational hypertension.

OBJECTIVE: Gestational hypertension is characterized by an imbalance in angiogenic factors. The goal of the current study was to evaluate whether circulating concentrations of proangiogenic and antiangiogenic factors are associated with the risk of progression to preeclampsia and development of adverse outcomes in women with gestational hypertension. METHODS: We studied 496 women with gestational hypertension. Patients were divided into three groups based on their degree of angiogenic imbalance, evaluated by the soluble fms-like tyrosine kinase-1/placental growth factor ratio: no angiogenic imbalance (≤38), mild angiogenic imbalance (>38-<85), and severe angiogenic imbalance (≥85) or stratified into tertiles according to soluble endoglin (sEng) levels. RESULTS: The concentrations of all angiogenic factors were significantly different in patients with gestational hypertension than in healthy pregnancy. A significant trend towards higher serum sEng levels was observed as the degree of angiogenic imbalance increased. Patients with severe angiogenic imbalance had higher rates of adverse maternal and perinatal outcomes and progression to preeclampsia (P < 0.001) when compared with patients with no or mild angiogenic imbalance. The risk of combined adverse maternal outcomes and specific adverse outcomes (hemolysis, elevated liver enzymes, low platelet count syndrome, preterm delivery, small-for-gestational-age infant, perinatal death, and progression to preeclampsia within 7, 14, 28, and 56 days) was higher in patients with severe angiogenic imbalance or sEng values in the highest tertile (odds ratio ≥5.6 and ≥2.0, respectively), compared with no angiogenic imbalance or the lowest tertile. CONCLUSION: In women with gestational hypertension at the time of initial evaluation, circulating concentrations of the soluble fms-like tyrosine kinase-1/placental growth factor ratio and sEng appear to be suitable markers to assess the risk of adverse maternal and perinatal outcomes and progression to preeclampsia.

The C677T polymorphism of the methylenetetrahydrofolate reductase gene is associated with idiopathic ischemic stroke in the young Mexican-Mestizo population.

BACKGROUND AND PURPOSE: Previous studies have demonstrated that a common polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with an increased risk for stroke. However, this relation remains controversial. Our aim was to investigate the possible association between the C677T polymorphism in the MTHFR gene and idiopathic ischemic stroke in the young Mexican-Mestizo population. METHODS: One hundred seventy-eight patients <45 years with idiopathic ischemic stroke and 183 controls were tested for the C677T polymorphism in the MTHFR gene. Causes of primary thrombophilia as well as classical risk factors for atherothrombotic disease were also evaluated. RESULTS: There was a significant difference in the genotype distribution between patients and controls (p = 0.01), but the allele frequency was similar in both groups (p = 0.09). The univariate analysis identified the T allele as a risk factor for ischemic stroke (TT and CT carriers), as compared with homozygous for C allele (p = 0.01). Hypertension and smoking prevalences were significantly higher in the group of patients. Also the T allele was significantly associated with large-vessel ischemic stroke. The postoral methionine load homocysteine levels were higher in patients with ischemic stroke versus controls (p < 0.001). There was a low prevalence of primary thrombophilia markers. CONCLUSIONS: The T allele from the C677T polymorphism of the MTHFR gene represents an independent risk factor for idiopathic ischemic stroke at young age in the Mexican-Mestizo population. Also, hypertension and smoking were independent risk factors in our study population. Primary thrombophilic risk factors were not associated with ischemic stroke in our population.

Usefulness of the sFlt-1/PlGF (Soluble fms-Like Tyrosine Kinase-1/Placental Growth Factor) Ratio in Diagnosis or Misdiagnosis in Women With Clinical Diagnosis of Preeclampsia.

Preeclampsia is characterized by angiogenic imbalance (AI), sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) is useful for its diagnosis and prediction of adverse outcomes, but the relationship among the degrees of AI as assessed by this ratio with the correct diagnosis, clinical characteristics, and outcomes in women with clinical diagnosis of preeclampsia are unclear. We studied 810 women with clinical diagnosis of preeclampsia. Patients were divided into 3 groups based on their degree of AI, evaluated by the sFlt-1/PlGF ratio: no AI (≤38), mild AI (>38-<85), and severe AI (≥85). Patients with no AI were more likely to have comorbidities and false significant proteinuria compared with patients with mild and severe AI (P<0.001). The rates of preterm delivery, delivery within 14 days, and small-for-gestational-age infant were higher among patients with severe AI than in patients with no and mild AI (P<0.001) and in patients with mild AI that in those with no AI (P≤0.01). The occurrence of any adverse maternal outcome (HELLP syndrome, elevated liver enzymes, thrombocytopenia, placental abruption, acute kidney injury) was only present in patients with severe AI. Interestingly, the frequency of misdiagnosis of preeclampsia was progressively lower as the degrees of AI increased (no AI: 100%, mild AI: 88.2%, and severe AI: 15.6%). We concluded that in women with clinical diagnosis of preeclampsia, severe AI is characterized by high frequency of true preeclampsia and preeclampsia-related adverse outcomes, in contrast, no and mild AI, are characterized by unnecessary early deliveries, often due to misdiagnosis.

D-dimer as A Biomarker of Severity and Adverse Outcomes in Patients with Community Acquired Pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) stands as a main cause of hospitalization and mortality worldwide. Because of their limitation scoring systems such as CURB-65 and Pneumonia Severity Index (PSI) may underestimate the severity of the disease. Intravascular and intra-alveolar activation of coagulation factors may lead to fibrin deposition in alveoli and lung interstitium. The clinical utility of D-dimer measurement in patients with CAP is still unclear. The aim of this study was to evaluate the association of D-dimer levels with severity of CAP, need for invasive mechanical ventilation, vasopressor support, and 7 d in-hospital mortality. METHODS: Prospective observational study from August 2016-November 2017 in a secondary care level hospital at Mexico City. CURB-65 and PSI scores were calculated on admission. D-dimer levels were measured by a fluorescence immunoassay. RESULTS: A total of 61 adult patients with CAP were analyzed and categorized into low or high-risk groups using CURB 65 and PSI score. The average age was 71.6 ± 15 years, predominantly men (52%). Statistically significant higher D-dimer levels, vasopressor support, and mechanical ventilation were observed in high-risk groups. The AUC to predict 7 d in-hospital mortality was 0.93 (p <0.0001) for PSI, 0.853 (p = 0.01) for CURB 65, and 0.789 (p = 0.001) for D-dimer. A D-dimer cut-off point of 2400 mcg/L showed a sensitivity = 1 and a specificity = 0.614, as well as a positive predictive value = 0.154 and a negative predictive value = 1. CONCLUSION: D-dimer plasma levels are associated with the severity of CAP. Patients with D-dimer below 2400 mcg/L have low probability of mortality at 7 d after admission to the emergency department.