Polymorphisms of endothelial nitric oxide synthase gene in systolic heart failure: an haplotype analysis.

BACKGROUND: Endothelial nitric oxide synthase (eNOS) gene polymorphisms have been associated with the pathogenesis of cardiovascular diseases, but few studies have evaluated the role of eNOS haplotypes on the risk and prognosis of heart failure (HF). This prospective study was designed to analyze the impact of three eNOS polymorphisms (T-786C, VNTR4a/b and Glu298Asp) and their haplotypes on the susceptibility and clinical outcomes in HF outpatients with systolic dysfunction. METHODS AND RESULTS: We conducted a case-control and a cohort study in which 316 HF patients and 360 healthy controls were recruited from a tertiary care university hospital. DNA was extracted from peripheral blood and eNOS polymorphisms were detected by PCR or PCR-RFLP. Patients were predominantly men, had a mean left ventricular ejection fraction of 31% and were followed-up for a median of 41months; there were 96 deaths, including 58 HF-related deaths. Genotype distribution of the eNOS T-786C, VNTR 4a/b and Glu298Asp was similar between HF patients and controls. Haplotype frequencies differed between HF patients and controls only in African-Brazilians (p=0.043). African-Brazilian patients that carried the haplotype -786C/4b/Asp298 had a better prognosis than patients that carried other haplotypes (log rank p value=0.016 for all-cause mortality). In a Cox proportional hazard model adjusted for clinical variables of risk, the -786C/4b/Asp298 haplotype remained as an independent genetic predictor of survival (adjusted HR=0.11; 95% CI=0.01-0.83; p=0.03). CONCLUSIONS: The -786C/4b/Asp298 eNOS haplotype had a significant impact on HF susceptibility and prognosis, particularly in African-Brazilian patients.

Polymorphisms of matrix metalloproteinases in systolic heart failure: role on disease susceptibility, phenotypic characteristics, and prognosis.

BACKGROUND: The role of matrix metalloproteinases (MMPs) polymorphisms on heart failure (HF) susceptibility, phenotypic characteristics, and prognosis has been poorly explored. METHODS AND RESULTS: We studied 313 HF patients with left ventricular systolic dysfunction and 367 healthy control subjects. Genotyping of MMP-1 (-1607 1G/2G), MMP-3 (-1171 5A/6A), and MMP-9 (-1562 C/T) polymorphisms was performed by polymerase chain reaction. Allelic and genotypic frequencies of MMP-1, -3, and -9 were similar in HF patients and controls. MMP1 2G allele carriers were positively associated to ischemic etiology and history of myocardial infarction (all P values <.05). Patients were followed-up for a median of 40 months and 58 HF-related deaths occurred during this period. HF-related survival was significantly better in MMP1 2G allele carriers (71% versus 42% for 1G/1G patients, P = .002) and in MMP-3 6A allele carriers (70% versus 61% for 5A/5A patients, P = .064), particularly in non-ischemic patients (P = .039). MMP1 2G allele was independently associated to HF survival after adjustment for several other predictors of risk (hazard ratio 0.47, 95% confidence interval 0.27 to 0.82; P = .008). CONCLUSIONS: MMP-1, -3, and -9 polymorphisms were not associated to HF susceptibility. However, MMP1 2G allele carriers were related to a higher prevalence of ischemic etiology among patients with systolic HF and better HF-related prognosis.

Cigarette smoking and antioxidant defences in packed red blood cells prior to storage.

BACKGROUND: Red blood cells from smoking donors can have more lesions from oxidative stress, decreasing the benefits of blood transfusion. We aimed to explore the effect of cigarette smoking on the oxidative status of packed red blood cells (PRBCs) prior to storage. MATERIALS AND METHODS: We compared serum vitamin C, plasmatic malondialdehyde (MDA), and non-protein thiol groups (GSH) levels in PRBCs, as well glutathione peroxidase (GPx) and glutathione s-transferase (GST) activity in PRBCs from smoking (n=36) and non-smoking (n=36) donors. We also correlated urinary cotinine levels with these parameters. RESULTS: Cigarette smoking was associated with decreased serum levels of vitamin C and GPx, and increased GST activity in PRBCs. We found negative correlations between cotinine, GPx activity and vitamin C levels, and a positive correlation between cotinine and GST activity. DISCUSSION: Cigarette smoking changed antioxidant defences of PRBCs prior to storage and these parameters are correlated with cotinine levels. Increased RBC antioxidants such as GST may reflect an exposure to oxidants during erythropoiesis. Because of the inability of mature RBCs to resynthesise antioxidants, PRBCs from smokers may have higher risk of storage lesions than those from non-smoker donors.

An analysis of the global expression of microRNAs in an experimental model of physiological left ventricular hypertrophy.

BACKGROUND: MicroRNAs (miRs) are a class of small non-coding RNAs that regulate gene expression. Studies of transgenic mouse models have indicated that deregulation of a single miR can induce pathological cardiac hypertrophy and cardiac failure. The roles of miRs in the genesis of physiological left ventricular hypertrophy (LVH), however, are not well understood. OBJECTIVE: To evaluate the global miR expression in an experimental model of exercise-induced LVH. METHODS: Male Balb/c mice were divided into sedentary (SED) and exercise (EXE) groups. Voluntary exercise was performed on an odometer-monitored metal wheels for 35 days. Various tests were performed after 7 and 35 days of training, including a transthoracic echocardiography, a maximal exercise test, a miR microarray (miRBase v.16) and qRT-PCR analysis. RESULTS: The ratio between the left ventricular weight and body weight was increased by 7% in the EXE group at day 7 (p<0.01) and by 11% at day 35 of training (p<0.001). After 7 days of training, the microarray identified 35 miRs that were differentially expressed between the two groups: 20 were up-regulated and 15 were down-regulated in the EXE group compared with the SED group (p = 0.01). At day 35 of training, 25 miRs were differentially expressed: 15 were up-regulated and 10 were decreased in the EXE animals compared with the SED animals (p<0.01). The qRT-PCR analysis demonstrated an increase in miR-150 levels after 35 days and a decrease in miR-26b, miR-27a and miR-143 after 7 days of voluntary exercise. CONCLUSIONS: We have identified new miRs that can modulate physiological cardiac hypertrophy, particularly miR-26b, -150, -27a and -143. Our data also indicate that previously established regulatory gene pathways involved in pathological LVH are not changed in physiological LVH.