Cirilo Pereira da Fonseca Neto

Impact of Net Atrioventricular Compliance on Clinical Outcome in Mitral Stenosis

Background—Net atrioventricular compliance (Cn) has been reported to be an important determinant of pulmonary hypertension in mitral stenosis (MS). We hypothesized that it may be useful in assessing prognosis because Cn reflects hemodynamic consequences of MS. To date, limited data with an assumed Cn cutoff have indicated the need for larger prospective studies. This prospective study was designed to determine the impact of Cn on clinical outcome and its contribution to pulmonary pressure in MS. In addition, we aimed to identify a cutoff value of Cn for outcome prediction in this setting. Methods and Results—A total of 128 patients with rheumatic MS without other significant valve disease were prospectively enrolled. Comprehensive echocardiography was performed and Doppler-derived Cn estimated using a previously validated equation. The end point was either mitral valve intervention or death. Cn was an important predictor of pulmonary pressure, regardless of classic measures of MS severity. During a median follow-up of 22 months, the end point was reached in 45 patients (35%). Baseline Cn predicted outcome, adding prognostic information beyond that provided by mitral valve area and functional status. Cn ⩽4 mL/mm Hg best predicted unfavorable outcome in derivation and validation sets. A subgroup analysis including only initially asymptomatic patients with moderate to severe MS without initial indication for intervention (40.6% of total) demonstrated that baseline Cn predicted subsequent adverse outcome even after adjustment for classic measures of hemodynamic MS severity (hazard ratio, 0.33; 95% confidence interval, 0.14–0.79; P=0.013). Conclusions—Cn contributes to pulmonary hypertension beyond stenosis severity itself. In a wide spectrum of MS severity, Cn is a powerful predictor of adverse outcome, adding prognostic value to clinical data and mitral valve area. Importantly, baseline Cn predicts a progressive course with subsequent need for intervention in initially asymptomatic patients. Cn assessment therefore has potential value for clinical risk stratification and monitoring in MS patients.

Atheromatosis Extent in Coronary Artery Disease is not Correlated with Apolipoprotein-E Polymorphism and its Plasma Levels, but Associated with Cognitive Decline

BACKGROUND Apolipoprotein-E (apoE) ε4 allele is a known risk factor for Alzheimers disease (AD). Polymorphism of apoE is also one of the most important genetic markers for coronary artery disease (CAD). The allelic variation in the apoE gene has a significant effect on inter-individual variation of lipids and lipoprotein plasma levels as well. This study investigated whether apoE polymorphism affects the plasma levels of apoE and the possible association to CAD extent and cognitive functions. METHODS Plasma apoE levels and apoE genotypes were evaluated of subjects with normal coronary arteries, and individuals with angiographycally confirmed mild/moderate or severe atheromatosis. The cognitive performance of the volunteers was also measured by mini-mental state examination (MMSE). RESULTS Out of the 6 expected genotypes, only 5 were detected in participants: E3/3 (56.0%), E3/4 (23.6%), E4/4 (8.2%), E2/4 (3.3%), E2/3 (8.9%). The ε3 allele (72%) was the most frequent, followed by ε4 (22%) and ε2 (6%). No difference was found in plasma levels of either apoE or in apoE genotype frequencies among the groups, however MMSE scores of CAD patients irrespective of their atheromatosis extent were significantly lower than that seen in the normal population. CONCLUSIONS Although neither apoE plasma levels, nor apoE polymorphism in patients presenting with mild/moderate or severe atheromatosis showed to be associated with CAD severity, the presence of atheromatosis in the heart vessels positively correlated with cognitive dysfunction.

Proteína C-reativa ultra-sensível em pacientes com diagnóstico de doença arterial coronariana estabelecido por angiografia

C-reactive protein (CPR) is an acute phase protein, synthesized by the liver in response to cytokines, and reflects active inflammation. Inflammation has a potential role in atherosclerosis triggering and progression. Plasma markers of chronic inflammation have been consistently associated to the risk of coronary artery disease (CAD), being high-sensitivity C-reactive protein the marker most studied. The aim of the present study was to determine the high-sensitivity C-reactive protein plasma levels in a group of subjects undergoing coronary angiography, trying to establish a possible correlation between this parameter and the severity of the CAD. High-sensitivity C-reactive protein plasma levels had been determined in blood of 17 subjects with no atheromatosis (controls), 12 subjects presenting mild/moderate atheromatosis and 28 subjects presenting severe atheromatosis, using Biotechnical Reactive C-Protein Turbidimetric Kit with specific high-sensitivity methodology for Cardiology, with linearity to 0.1 up 15mg/l. Significant differences between the means of the three groups were not observed, however the mean values of mild/moderate atheromatosis and severe atheromatosis had remained above the reference values used in Cardiology (0.1-2.5mg/dl). The mean values of the three groups presented an increasing rise from the control group to the severe atherosclerosis, suggesting inflammatory progression due to atherosclerotic injury.

Homocysteine and methylenetetrahydrofolate reductase in subjects undergoing coronary angiography

OBJECTIVE To determine plasma homocysteine levels and the incidence of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in a group of subjects who underwent coronary angiography, in an attempt to establish a correlation between these parameters and the severity of coronary artery disease (CAD), as well as investigate the correlation between hyperhomocysteinemia and the presence of polymorphism. METHODS Twenty subjects with no coronary atheromatosis (controls), fourteen subjects with mild/moderate atheromatosis, and twenty-nine subjects with severe atheromatosis were evaluated. RESULTS Significant differences were observed in mean homocysteine levels between the control and the severe atheromatosis groups (p < 0.001). No significant differences were observed among the other groups. The severe atheromatosis group showed rates of 62.0% and 6.9% for the C677T MTHFR gene polymorphism, in heterozygous and homozygous subjects, respectively. However, there was no correlation between the presence of mutation and hyperhomocysteinemia. A positive correlation of 41.91% (p < 0.001) was found between hyperhomocysteinemia and CAD. CONCLUSION The most important finding of this study was the association between hyperhomocysteinemia and coronary stenosis > 70%; yet, whether elevated plasma homocysteine worsens atherosclerosis or is a consequence remains to be established.

PAI-1 4G/5G polymorphism and plasma levels association in patients with coronary artery disease

BACKGROUND Type-1 plasminogen activator inhibitor (PAI-1) 4G/5G polymorphism may influence the PAI-1 expression. High plasma levels of PAI-1 are associated with coronary artery disease (CAD). OBJECTIVE This study investigated the influence of PAI-1 4G/5G polymorphism on plasma PAI-1 levels and its association with CAD assessed by coronary angiography. METHODS Blood sample of 35 individuals with angiographically normal coronary arteries, 31 individuals presenting mild/moderate atheromatosis, 57 individuals presenting severe atheromatosis and 38 healthy individuals (controls) were evaluated. In patients and controls, the PAI-1 4G/5G polymorphism was determined by PCR amplification using allele-specific primers. Plasma PAI-1 levels were quantified by ELISA assay (American Diagnostica). RESULTS No difference was found between groups regarding age, gender and body mass index. Plasma PAI-1 levels and 4G/4G genotype frequency were significantly higher in the severe atheromatosis group compared to the other groups (p<0.001). Furthermore, patients with 4G/4G genotype (r=0.28, p<0.001) had significantly higher plasma PAI-1 levels than those with 5G/5G genotype (r=0.02, p=0.4511). In addition, in a multiple logistic regression model, adjusted for all the other variables, PAI-1 was observed to be independently associated with CAD > 70% (p<0.001). CONCLUSION The most important finding of this study was the association between 4G/4G genotype, high plasma PAI-1 levels and coronary stenosis higher than 70% in Brazilian individuals. Whether high plasma PAI-1 levels are a decisive factor for atherosclerosis worsening or it is a consequence remains to be established.

Níveis plasmáticos elevados de lipoproteína(a) correlacionados com a gravidade da doença arterial coronariana em pacientes submetidos à angiografia

OBJETIVO: Determinar os niveis plasmaticos de lipoproteina(a) e perfil lipidico de um grupo de individuos submetidos a angiografia coronariana, buscando estabelecer a possivel correlacao entre estes parâmetros e a gravidade da doenca coronariana. METODOS: Niveis plasmaticos de colesterol total, HDLC, LDLC, triglicerides, lipoproteina(a), apolipoproteinas A-I e B foram medidos em amostras de sangue de 17 individuos com ausencia de ateromatose nas coronarias (controles), 12 individuos apresentando ateromatose leve/moderada e 28 individuos apresentando ateromatose grave. RESULTADOS: Nao foram encontradas diferencas estatisticamente significativas entre as medias dos tres grupos para os parâmetros avaliados, exceto para os niveis plasmaticos de lipoproteina(a) que apresentaram diferencas significativas entre as medias dos grupos controle, ateromatose leve/moderada e ateromatose grave (p<0,001). CONCLUSAO: As medias obtidas nos tres grupos para Lp(a) sinalizam um aumento progressivo nos niveis plasmaticos deste parâmetro, de acordo com a gravidade da ateromatose coronariana. Estes achados sugerem a necessidade de estudos adicionais, visando obter suficiente evidencia para a introducao rotineira da avaliacao dos niveis de Lp(a) em laboratorios clinicos, no monitoramento de pacientes apresentando risco para doenca arterial coronariana (DAC).

Fragmento 1+2 da protrombina em indivíduos submetidos à angiografia coronariana

Thrombin plays a basic role in the conversion of fibrinogen to fibrin in the coagulation process. Activated factor X transforms the prothrombin into thrombin and breaks up prothrombin fragment 1+2 (F1+2). F1+2 plasma levels reflect the thrombin generation and can be used as in vivo markers of hypercoagulability since the thrombin is an unstable and easily degraded substance that cannot be directly measured in the plasma. The present study aims at determining the F1+2 plasma levels of a group of subjects undergoing coronary angiography, attempting to establish a possible correlation between this parameter and the severity of the coronary artery disease. F1+2 plasma levels were determined in blood samples of 17 subjects with absence of atheromatosis in coronary arteries (controls), 12 subjects presenting mild/moderate atheromatosis and 28 subjects presenting severe atheromatosis, using the Enzignost F1+2 (Behring® Diagnostics GmbH, Marburg, Germany) diagnostic Kit. Significant differences between the averages for the three groups in respect to the evaluated parameters were not found. Therefore, F1+2 plasma level averages for the three groups did not point to a state of hypercoagulability in the studied population. However, 73.7% of the individuals were taking acetylsalicylic acid, which may have influenced the F1+2 plasma levels, considering that this medicine promotes the inhibition of the enzyme cyclo-oxygenase, diminishing the release of thromboxane A2 and the platelet aggregation. Therefore, it is presumed that platelet activation reduction could be contributing to a lower formation of thrombin and, consequently, diminishing the hypercoagulability potential.

D-Dimer plasma levels in patients with coronary artery disease

We have previously reported that prothrombin fragment 1+2 levels were not associated to the presence or severity of coronary artery disease (CAD) and do not provide further information on subjects with CAD diagnosed by angiography. Thus, in the present study another marker of hypercoagulability was evaluated in the same subjects. This study aimed at determining D-Dimer plasma levels in a group of subjects undergoing coronary angiography to establish a likely relation between this parameter and the severity of CAD. D-Dimer plasma levels were determined in 17 subjects with no coronary atheromatosis (controls), 12 subjects with mild/moderate atheromatosis and 28 subjects with severe atheromatosis. No significant differences were observed among the three groups. Data analysis enables an inference on a tendency towards an increase in fibrinolytic activity in patients with atheromatosis, reflected by the increase in D-Dimer concentrations in the severe atheromatosis group in subjects with CAD diagnosed by coronary angiography.