Dynamic regulation of MTHFR mRNA expression and C677T genotype modulate mortality in coronary artery disease patients after revascularization.

INTRODUCTION: A large body of evidence links plasma homocysteine (Hcy) concentrations and cardiovascular disease. A common MTHFR polymorphism (C677T) leads to a variant with reduced activity and associated with increased Hcy levels. Coronary surgery precipitates a significant and sustained increase in the blood concentrations of Hcy and elevated levels of plasma Hcy have been associated to saphenous vein (SV) graft disease after CABG. However, the effects of MTHFR genotypes in the incidence of cardiovascular events after CABG have not been investigated prospectively. Here, we investigate whether MTHFR gene variants are associated with an increased cardiovascular risk in individuals submitted to CABG. We also propose a molecular mechanism to explain our findings. METHODS: We performed MTHFR C677T genotypes in 558 patients with two or three vessel-disease and normal left ventricular function prospectively followed in the MASS II Trial, a randomized study to compare treatments for multivessel CAD and preserved left ventricle function. Follow-up time was 5 years. Survival curves were calculated with the Kaplan-Meier method, and evaluated with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, myocardial infarction and refractory angina using a Cox proportional hazards survival model. Finally, using an ex-vivo organ culture we have reproduced the arterialization of SV implants by culturing human SV either under venous hemodynamic condition (flow: 5 mL/min; no pressure) or arterial hemodynamic condition (flow: 50 mL/min; pressure: 80 mm Hg) for 1 day. MTHFR gene expression was quantified by real time RT-PCR in 15 SV from different individuals in both experimental conditions. RESULTS: There were no significant differences among individuals within each genotype group for baseline clinical characteristics. A statistically significant association between the TT genotype, associated with increased serum levels of Hcy, and cardiovascular mortality after 5 years was verified (p=0.007) in individuals submitted to CABG surgery. In addition, MTHFR TT genotype was still significantly associated with a 4.4 fold increased risk in cardiovascular outcomes (p=0.01) even after adjustment of a Cox multivariate model for age, sex, hypertension, diabetes, LDL, HDL, triglycerides, and number of diseased vessels in this population. Finally, a significant reduction in MTHFR gene expression was demonstrated in human SV when submitted to an arterial hemodynamic condition (p=0.02). CONCLUSIONS: There is a dynamic regulation of MTHFR gene expression during the arterialization process of human saphenous vein grafts resulting in lower levels of gene expression when in an arterial hemodynamic condition. In addition, the C677T MTHFR functional variant is associated with a worse outcome in individuals submitted to CABG. Taken together, these data suggest an important role of Hcy metabolism in individuals after CABG.

Substituição da valva mitral com tração dos músculos papilares em pacientes com miocardiopatia dilatada / Mitral valve replacement with chordae tendineae preservation, traction and fixation in end-stage dilated cardiomyopathy

OBJETIVO: Avaliar a geometria e a função do ventrículo esquerdo (VE) após a troca mitral com tração e fixação dos papilares, em portadores de insuficiência cardíaca terminal com insuficiência mitral secundária. MÉTODO: Dos 20 pacientes avaliados, 70 por cento eram homens, com idade média de 50,2 anos e 55 por cento recebiam inotrópicos. A fração de ejeção (FEVE) foi menor que 30 por cento em todos; 85 por cento estavam em classe funcional (CF) IV. Dezoito receberam próteses de pericárdio bovino e dois, mecânicas. Os períodos considerados foram: 3, 6, 12 e 18 meses. As variáveis consideradas: volume sistólico do VE (VS), a FEVE, os diâmetros sistólico e diastólico finais (DSF e DDF) e os volumes sistólico e diastólico finais (VSF e VDF). No estudo estatístico, empregou-se da análise de variância (AV) e o teste de Friedmann (F). A sobrevida foi aferida pelo método de Kaplan-Meyer. RESULTADOS: Dois (10 por cento) faleceram no período imediato. A sobrevida no primeiro ano foi de 85 por cento, no segundo, 44 por cento, no terceiro, 44 por cento, no quarto, 44 por cento e no quinto, 44 por cento. A comparação entre pré e 3 meses, empregando-se a AV, não revelou alteração significativa para o VS (p=0,086). Houve acréscimo da FEVE (p=0,008) e decréscimo do DDF (p=0,038); do DSF (p=0,008); do VDF (p=0,029) e do VSF (p=0,009). Os momentos pré, 3 e 6 meses, com o teste F, não revelaram alterações. Entre os momentos pré, 3 meses e final, empregando-se a AV, não houve significância. CONCLUSÃO: Há melhora da FEVE, dos VDF, VSF, DDF e DSF; até o terceiro mês. A partir de então, as variáveis permanecem estáveis.

OBJECTIVE: This study aimed at evaluating results of mitral valve replacement using a new technique of complete chordae tendineae adjustment for left ventricular remodeling. METHODS: Twenty end-stage idiopathic dilated cardiomyopathy patients with severe functional mitral valve regurgitation underwent mitral valve replacement. Seventeen (85 percent) were in functional class IV. Both anterior and posterior leaflets of the mitral valve were divided to obtain 4 pillars of chordae tendineae. These were displaced with traction toward the left atrium and anchored between the mitral annulus and a valvular prosthesis. To evaluate the left ventricular remodeling, Doppler echocardiography was performed. For statistical analysis, variance analysis and the Friedman's test were employed. RESULTS: Two (10 percent) early deaths occurred. Kaplan-Meyer showed survival at one year post-operative was 85 percent, 2 years it was 44 percent, at 3 years 44 percent, at 4 years 44 percent and at 5 years it was 44 percent. In the 48- and 54-month follow-ups, the McNemar test showed improvement in the functional class (p<0.001). In the third month of follow-up, variance analysis showed improvement in the ejection fraction (p=0.008) and reductions of the end diastolic diameter (p=0.038), end systolic diameter (p=0.008), end systolic volume (p=0.029) and end diastolic volume (p=0.009). No statistical differences were noted in the systolic volume. Comparing pre-operative and third- and six-month follow-ups, the Friedman test showed no statistical differences for all studied variables. Variance analyses between pre, three-month and final evaluations showed no significant differences. CONCLUSION: This technique of mitral valve replacement improved the left ventricle ejection fraction and decreased the end diastolic and systolic diameters and the end systolic diastolic volumes up to the third month of follow-up. From then on the variables stabilized.

Contrast echocardiography can save nondiagnostic exams in mechanically ventilated patients.

Patients in an intensive care unit (ICU) under mechanical ventilation (MV) are very difficult to image by transthoracic echocardiography, diminishing the beneficial information that could be obtained by this noninvasive approach. The objective of this study is to assess whether the addition of a contrast agent to fundamental imaging (FI) can improve or change the initial diagnosis in cardiac postoperative patients under mechanical ventilation by enhancing endocardial border delineation and Doppler flow signal. Thirty mechanically ventilated post-cardiac surgery patients (20 men, mean age 61 +/- 13 years) were evaluated with FI before and after intravenous injection of contrast. Left ventricular endocardial border delineation score index (EBDSI), estimated left ventricular ejection fraction (LVEF), and color and spectral Doppler were analyzed. The use of contrast resulted in a significant increase in the number of well-delineated segments, with a salvage rate of 77% of nondiagnostic studies. EBDSI was 1.62 +/- 0.61, before contrast, increasing to 2.05 +/- 0.53 after it (P < 0.001). There was a change in the LVEF estimation in 5 exams, and a new wall motion abnormality was detected in other 4 exams, after the use of contrast. Moreover, a significant change was observed in the quantification of mitral regurgitation in 5 patients, in the aortic transvalvular peak gradient in 1 patient, and measurement of tricuspid regurgitation peak flow velocity in 8 patients. It is concluded that in cardiac postoperative patients under mechanical ventilation, intravenous injection of a contrast agent using FI resulted in a high salvage rate of studies and changed the initial diagnosis in a significant number of patients.

Effect of glycoprotein IIIa PlA2 polymorphism on outcome of patients with stable coronary artery disease and effect of smoking.

A polymorphism of glycoprotein IIb/IIIa has been associated with myocardial infarction and restenosis after percutaneous coronary intervention. The influence on outcome and the interaction of the Pl(A1) genotype with classic risk factors for coronary artery disease (CAD) were characterized in patients with chronic CAD followed prospectively for 3 years. Pl(A1) genotypes were assessed in 592 patients enrolled in the Medical, Angioplasty, or Surgery Study II, a randomized trial comparing treatments for patients with CAD and preserved left ventricular function. The incidence of the composite end point of cardiac death, myocardial infarction, and refractory angina requiring revascularization were determined in each genotype group. Risk was assessed with the Cox proportional-hazards model. The clinical characteristics and treatment of each genotype were similar. Although the composite end point tended to be more common in patients with the Pl(A2) allele, only smokers with the Pl(A2) allele had a significantly increased incidence of the composite end point (p = 0.01). Moreover, a 2.2-fold increased risk was apparent in smokers with the Pl(A2) allele (p = 0.03). Thus, taken together, these data provide support for the interaction effect between smoking and the Pl(A1) gene variant. Smokers with the Pl(A2) polymorphism of platelet glycoprotein IIIa are at greater risk for subsequent cardiac events in stable coronary disease.