Period3 VNTR polymorphism influences the time-of-day pain onset of acute myocardial infarction with ST elevation.

It is well established that the incidence and infarct size in acute myocardial infarction (AMI) is subject to circadian variations. At the molecular level, circadian clocks in distinct cells, including cardiomyocytes, generate 24-h cycles of biochemical processes. Possible imbalance or impairment in the cell clock mechanism may alter the cardiac metabolism and function and increase the susceptibility of cardiovascular diseases. One of the key components of the human clock system PERIOD3 (PER3) has been recently demonstrated to affect circadian expression of various genes in different tissues, including the heart. The variable number tandem repeat (VNTR) polymorphism (rs57875989) in gene Period3 (Per3) is related to multiple phenotypic parameters, including diurnal preference, sleep homeostasis, infection and cancer. The aim of our study was to investigate the effect of this polymorphism in AMI with ST elevation (STEMI). The study subjects (314 patients of Caucasian origin with STEMI, and 332 healthy controls) were genotyped for Per3 VNTR polymorphism using an allele-specific polymerase chain reaction. A gender difference in circadian rhythmicity of pain onset was observed with significant circadian pattern in men. Furthermore, the Per3(5/5) variant carriers were associated with higher levels of interleukin-6, B-type natriuretic peptide and lower vitamin A levels. By using cosinor analysis we observed different circadian distribution patterns of AMI onset at the level of genotype and allelic frequencies. Genotypes with at least one 4-repeat allele (Per3(4/5) and Per3(4/4)) (N = 264) showed remarkable circadian activity in comparison with Per3(5/5) (N = 50), especially in men. No significant differences in genotype and/or allele frequencies of Per3 VNTR polymorphism were observed when comparing STEMI cases and controls. Our results indicate that the Per3 VNTR may contribute to modulation of cardiac functions and interindividual differences in development and progression of myocardial infarction.

[Dynamics of interleukin 6 levels in the patients with cardiogenic and septic shock and in a control group of patients with uncomplicated AMI]. / Dynamika hladiny interleukinu 6 u pacientu v septickém a kardiogenním soku a u pacientu s akutním infarktem myokardu s elevacemi ST.

INTRODUCTION: Cardiogenic shock (CS) is the leading cause of mortality in patients with acute myocardial infarction (AMI). Inflammatory response seems to be common response in patients with AMI, especially those with CS. We have therefore conducted a study to determine diagnostic and prognostic utility of interleukin 6 (IL6) levels in the cohort of patients with cardiogenic and septic shock (SS) and in a control group of patients with uncomplicated AMI. METHODS: In this prospective study 71 patients fulfilled the inclusion criteria: 30 patients with cardiogenic shock, 21 patients with septic shock and 20 patients with ST elevation myocardial infarction (STEMI). Plasma levels of IL6 were measured at 8 time points. The main endpoint was 3 month mortality. RESULTS: We have shown that the highest IL6 levels during the first week were recorded in patients with septic shock with peak value at admission. The maximum level of IL6 was detected between 12 to 24 hours after the onset of MI among patients with cardiogenic shock. According to Receiver operating characteristic (ROC) statistics levels of IL6 > 357 pg/ml at admission (AUC 0.730, p = 0.031) were typical for patients with CS in comparison with control group of STEMI patients. Values of IL6 > 1 237 pg/ml at admission and > 1 071 pg/ml at 24 hours (after admission?) were typical for thouse in septic shock in comparison with CS patients. We found only a non-significant trend of IL6 for the prediction of mortality in the cohort of CS patients for levels 1 854 pg/ml (AUC 0.769, p = 0.066) sampled 12 hours after admission. There was no association of plasma levels of IL6 with mortality in septic shock patients. CONCLUSIONS: Patients with cardiogenic shock demonstrated more pronounced cytokine response as evidenced by increased levels of IL6 compared to patients with uncomplicated STEMI. Levels of IL6 peaked in SS patients at admission, in CS patients 12-24 hours after admission. In daily clinical practice routine measurement of IL6 levels for prediction of prognosis both in cardiogenic and septic shock are of little value mainly due to significant interindividual variability of IL6 values.

ACE2 gene polymorphisms and invasively measured central pulse pressure in cardiac patients indicated for coronarography.

BACKGROUND AND AIM: The objective of this research was to determine whether invasively measured central pulse pressure (PP) in patients indicated for coronarography is associated with two common polymorphisms in the ACE2 region (rs4646156 and rs4646174). METHODS: A total of 307 patients were enrolled in the study. The genotyping of both SNPs from peripheral blood samples was carried out using 5'exonuclease (Taqman®) chemistry on the ABI Prism® 7000 system (Applied Biosystems, Foster City, CA, USA). RESULTS: In both polymorphisms, the associations with central PP were found to be highly significant when all five possible genotypes in the population had been compared (p = 0.0001). In men, there was a higher incidence of previous myocardial infarction in G0 genotype carriers of rs54646174 (OR ratio = 7; p = 0.005). The AA genotype of rs4646156 had a 7.81× higher risk of severe angina pectoris in women (OR = 7.81, p = 0.05). A significant difference in allelic frequency of ACE2rs4646174 was found between women with and without significant stenoses of the circumflex branch of the left coronary artery. CONCLUSION: More research into the role of ACE2 genetic variability in PP regulations is necessary for more detailed physiological and pathophysiological comprehension of PP regulation.

The association between levels of tissue inhibitor of metalloproteinase-1 with acute heart failure and left ventricular dysfunction in patients with ST elevation myocardial infarction treated by primary percutaneous coronary intervention.

AIMS: Tissue inhibitors of metalloproteinase (TIMPs) bind to active matrix metalloproteinase (MMPs), and thereby inhibit their proteolytic activity. We investigated the role of polymorphisms in the gene for TIMP-1 and serum levels of TIMP-1 in association with postmyocardial infarction (MI), left ventricular (LV) dysfunction, and symptoms of acute heart failure (AHF) in patients treated with primary percutaneous coronary intervention. METHODS: In total, 556 patients with STEMI were evaluated. Levels of TIMP-1 were measured at admission and 24 h after MI onset. The TIMP-1 exon 5 SNP rs4898 (F124F with T>C) located at X chromosome was assayed. RESULTS: TIMP-1 levels were higher for men with AHF as well as for men with LV dysfunction (ejection fraction [EF]<40%). According to multivariate analysis, the TIMP-1 level was a factor with an independent negative relationship to EF and AHF in men. An independent relationship between exon 5 TIMP-1 gene polymorphism and EF, AHF or TIMP-1 level was not documented. CONCLUSION: These results provide evidence that a higher level of circulating TIMP-1 is independently associated with worse EF and AHF.

Matrix metalloproteinase 13 genotype in rs640198 polymorphism is associated with severe coronary artery disease.

Atherosclerosis as a main etiopathogenetic source for coronary artery disease (CAD) development is intimately related to dynamic changes in the extracellular matrix (ECM). Elevated levels of MMP-13 have been observed in human atherosclerotic plaques which could also involve variability in MMP-13 gene. The aim of the study was to associate rs640198 polymorphism with CAD and/or with its severity. The study comprised 1071 consecutive patients with suspected or known coronary artery disease (CAD), confirmed by coronary angiography. Genotyping for the rs640198 polymorphism in MMP-13 gene was performed using Taqman® assay. The TT and TG genotypes of rs640198 polymorphism in MMP-13 gene confer the significantly increased risk of triple vessel disease compared to patients without atherosclerotic lesions in coronary arteries (odds ratio=1.64, Pcorr=0.05). Furthermore, an increased risk of having 5 and more stenoses (odds ratio=1.90, Pcorr=0.004) was observed in TT and TG carriers (sensitivity of 0.613 and a specificity of 0.544; power of the test is 0.87). T allele of MMP-13 intron polymorphism rs640198 is associated with the severity of coronary artery disease, represented by the number of affected arteries as well as by the number of stenoses confirmed by coronarography.

Soluble ST2 levels in patients with cardiogenic and septic shock are not predictors of mortality.

BACKGROUND: Soluble ST2 (sST2) is an interleukin-33 receptor. sST2 was found to be an independent prognostic factor in patients with myocardial infarction, sepsis and heart failure. OBJECTIVES: To assess sST2 levels in patients with cardiogenic shock (CS) and septic shock (SS), and to evaluate the prognostic value of sST2 for short-term mortality. METHODS: The present prospective observational study evaluated 32 patients with CS, 17 patients with SS and 61 patients with ST segment elevation myocardial infarction (STEMI )(control group). Samples of serum were collected eight times and the follow-up time was three months. RESULTS: sST2 levels were elevated from admission in SS patients relative to patients with CS and STEMI, who exhibited peak sST2 levels 24 h after admission. On admission, CS patients had a median (5th percentile; 95th percentile) sST2 level of 62.5 pg/mL (8.3 pg/mL; 315.8 pg/mL) and SS patients had a median sST2 level of 216.4 pg/mL (46.8 pg/mL; 364.4 pg/mL). ROC analysis found sST2 to be a biomarker that could distinguish between CS and SS at admission (area under the curve [AUC] 0.813; P<0.01) with a cut-off value of 210.4 pg/mL. Patients with STEMI had significantly lower sST2 levels at admission (20.3 pg/mL (4.2 pg/mL; 339.8 pg/mL) compared with CS patients. The AUC of the ROC analysis was 0.671 (P=0.007) for the detection of CS in patients with STEMI. Only a weak correlation was observed between sST2 and B-type natriuretic peptide (r=0.376, P=0.05) and sST2 and N-terminal pro-B-type natriuretic peptide (r=0.496, P=0.019). No statistically significant differences were observed in sST2 levels in patients with CS and SS relative to three-month mortality. CONCLUSION: Levels of sST2 at admission are significantly higher in patients with SS compared with CS. sST2 could be a diagnostic marker to distinguish SS and CS as well as CS and STEMI at the time of admission. Levels of sST2 are related to levels of natriuretic peptides in CS but not in SS. sST2 levels are not a suitable prognostic marker for patients with CS and SS.

ACE gene insertion/deletion polymorphism has a mild influence on the acute development of left ventricular dysfunction in patients with ST elevation myocardial infarction treated with primary PCI.

BACKGROUND: We evaluated the associations among angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, ACE activity and post-myocardial infarction (MI) left ventricular dysfunction and acute heart failure (AHF) early after presentation with MI with ST-segment elevation (STEMI). METHODS: A total of 556 patients with STEMI treated by primary PCI (421 patients without AHF and 135 patients with AHF) were the study population. The activity of BNP, NT-ProBNP and ACE were measured at hospital admission and 24 h after MI onset. Left ventricular angiography was done before PCI; echocardiography was undertaken between the third and fifth day after MI. RESULTS: In comparison with the II genotypes group, the DD/ID group had a higher level of ACE activity upon hospital admission (p < 0.001). We found a significantly higher level of ACE activity in patients with moderate LV dysfunction (EF 40-54%) in comparison both with patients with preserved LV function (EF ≥ 55%) and with patients with severe LV dysfunction (p = 0.028). A non-significant trend towards a higher incidence of mild AHF (22.1% vs. 16.02%, p = 0,093), a significantly higher value of end-systolic volume (ESV/BSA) (30.0 ± 12.3 vs. 28.5 ± 13.0; p < 0.05) and lower EF (50.2 ± 11.1 vs. 52.7 ± 11.7; p < 0.05) in the DD/ID genotypes group was noted. Even after multiple adjustments according to multivariate models, the EF for the DD/ID group remained significantly lower (p = 0,033). The DD/ID genotypes were associated with a significantly higher risk of EF <45% (OR 2.04 [95% CI 1.28; 3.25]). CONCLUSIONS: These results suggest that the I/D polymorphism of ACE is associated with the development of LV dysfunction in the acute phase after STEMI. We demonstrated for the first time an association of the low ACE activity with the severe LV dysfunction, although patients with moderate LV dysfunction had higher level ACE activity than patients with preserved LV function.

Association of polymorphisms in interleukin-10 gene promoter with autoantibody production in patients with rheumatoid arthritis.

Interleukin-10 (IL-10) is a major anti-inflammatory cytokine that plays a crucial role in the regulation of the immune system. Allelic polymorphisms in the IL-10 gene promoter may contribute to the regulation of autoantibody production. To examine the association between both individuals IL-10 single nucleotide polymorphisms and the production of autoantibodies and the radiographic progression of rheumatoid arthritis (RA), a total of 144 RA patients were recruited into the study. We found significant differences in genotype distribution of the -1082G/A polymorphism between IgG, IgA, and IgM rheumatoid factor(RF)-positive/negative RA patients. We also found significant differences in allelic frequencies of the -3575T/A, -819C/T, and -592A/C polymorphisms between anticyclic citrullinated peptide (anti-CCP)-positive/negative RA patients. The haplotype TGAATA was found to be less frequent within anti-CCP-positive RA patients. Results obtained in this study provide evidence of an association between polymorphisms in IL-10 gene promoter and the production of autoantibodies in RA patients.