Identification of plasma miR-4505, miR-4743-5p and miR-4750-3p as novel diagnostic biomarkers for coronary artery disease in patients with type 2 diabetes mellitus: a case-control study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are commonly coexisting clinical entities with still growing incidence worldwide. Recently, circulating microRNAs (miRNAs) have emerged as novel molecular players in cardiometabolic diseases. This study aimed to identify a specific miRNA signature as a candidate biomarker for CAD in T2DM and to delineate potential miRNA-dependent mechanisms contributing to diabetic atherosclerosis. METHODS: A total of 38 plasma samples from T2DM patients with and without CAD, CAD patients and healthy controls were collected for expression profiling of 2,578 miRNAs using microarrays. To investigate the regulatory role of differentially expressed (DE)-miRNA target genes, functional annotation and pathway enrichment analyses were performed utilizing multiple bioinformatics tools. Then, protein-protein interaction networks were established leveraging the STRING database in Cytoscape software, followed by cluster analysis and hub gene identification. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was carried out for microarray data validation in the larger replication cohort of 94 participants. Receiver operating characteristic analysis was applied to evaluate the diagnostic values of miRNAs. Multivariate logistic regression analysis was used to develop miRNA-based diagnostic models. RESULTS: In the discovery stage, overexpression of hsa-miR-4505, hsa-miR-4743-5p, hsa-miR-6846-5p, and down-regulation of hsa-miR-3613-3p, hsa-miR-4668-5p, hsa-miR-4706, hsa-miR-6511b-5p, hsa-miR-6750-5p, hsa-miR-4750-3p, hsa-miR-320e, hsa-miR-4717-3p, hsa-miR-7850-5p were detected in T2DM-CAD patients. The DE-miRNA target genes were significantly enriched in calcium ion binding, regulation of actin cytoskeleton, and gene expression. hsa-miR-4505, hsa-miR-4743-5p, and hsa-miR-4750-3p were found to be involved in fatty acid metabolism, leukocyte transendothelial migration, and neurotrophin signaling pathway. Dysregulation of hsa-miR-4505, hsa-miR-4743-5p, and hsa-miR-4750-3p in T2DM-CAD patients compared with T2DM subjects and controls (all p < 0.001) was further confirmed by RT-qPCR. All validated miRNAs demonstrated good discriminatory values for T2DM-CAD (AUC = 0.833-0.876). The best performance in detecting CAD in T2DM was achieved for a combination of three miRNAs (AUC = 0.959, 100% sensitivity, 86.67% specificity). CONCLUSIONS: Our study revealed a unique profile of plasma-derived miRNAs in T2DM patients with CAD. Potential miRNA-regulated pathways were also identified, exploring the underlying pathogenesis of CAD in T2DM. We developed a specific three-miRNA panel of hsa-miR-4505, hsa-miR-4743-5p and hsa-miR-4750-3p, that could serve as a novel non-invasive biomarker for CAD in patients with T2DM.

The Influence of Balneotherapy Using Salty Sulfide-Hydrogen Sulfide Water on Selected Markers of the Cardiovascular System: A Prospective Study.

Background: The sulfide-hydrogen sulfide brine balneotherapy (HSBB), including a combination of dissolved hydrogen sulfide (H2S) gas, inorganic sulfur ions (S2-), and hydrosulfide ions (HS-), is one of the most important and most effective forms of spa treatment in patients with osteoarticular disorders (OADs). Some cardiovascular diseases (CVDs) are often considered to be contraindications to HSBB since the presence of thiol groups may lead to an increased quantity of reactive oxygen species (ROS), which damage the vascular endothelium, and endothelial dysfunction is considered to be the main cause of atherosclerosis. However, there are a number of literature reports suggesting this theory to be false. H2S is a member of the endogenous gaseous transmitter family and, since it is a relatively recent addition, it has the least well-known biological properties. H2S-NO interactions play an important role in oxidative stress in CVDs. The general objective of this study was to assess the cardiovascular safety of HSBB and analyze the effect of HSBB on selected cardiovascular risk markers. Methods: A total of 100 patients at the age of 76.3 (±7.5) years from the Wlókniarz Sanatorium in Busko-Zdrój were initially included in the study. The following parameters were assessed: age, sex, height, body weight, body surface area (BSA), body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), heart rate, the diagnosis of OAD that was the indication for balneotherapy, creatinine (CREAT), glomerular filtration rate (GFR), lipid panel, C-reactive protein (CRP), uric acid (UA), and fibrinogen (FIBR) and cardiovascular markers: (cardiac troponin T (cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP). Results: A significant decrease in DBP and a trend towards SBP reduction were observed over the course of the study. A significant decrease was observed in CRP levels decreasing from 2.7 (±3.6) mg/L to 2.06 (±1.91) mg/L, whereas FIBR rose significantly from 2.95 (±0.59) g/L to 3.23 (±1.23) g/L. LDL-C levels decreased slightly, statistically significant, from 129.36 (±40.67) mg/dL to 123.74 (±36.14) mg/dL. HSBB did not affect the levels of evaluated cardiovascular biomarkers, namely NT-proBNP (137.41 (±176.52) pg/mL vs. 142.89 (±182.82) pg/mL; p = 0.477) and cTnT (9.64 (±4.13) vs. 9.65 (±3.91) ng/L; p = 0.948). A multiple regression analysis of pre-balneotherapy and post-balneotherapy values showed cTnT levels to be independently correlated only with CREAT levels and GFR values. None of the assessed parameters independently correlated with the NT-proBNP level. Conclusions: HSBB resulted in a statistically significant improvement in a subclinical pro-inflammatory state. HSBB has a beneficial effect in modifying key cardiovascular risk factors by reducing LDL-C levels and DBP values. HSBB has a neutral effect on cardiovascular ischemia/injury. Despite slightly elevated baseline levels of the biochemical marker of HF (NT-proBNP), HSBB causes no further increase in this marker. The use of HSBB in patients with OAD has either a neutral effect or a potentially beneficial effect on the cardiovascular system, which may constitute grounds for further studies to verify the current cardiovascular contraindications for this form of therapy.

Genotypes and Variants of BKPyV in Organ Donors after Brain Death.

Kidney transplantation from a donor with latent BKPyV might be the cause of serious complications, such as BK virus-associated nephropathy. The aim of the study was to determine the prevalence of BKPyV infection in donors after brain death (DBDs), to analyse the molecular variation of BKPyV and to compare clinical and inflammation parameters of DBDs infected with various genotypes of BKPyV. BKPyV was investigated in blood and urine samples of 103 DBDs using PCR followed by sequencing and bioinformatic analysis, and the viral load was assessed by qPCR. Clinical parameters, including cellular markers of inflammation were assessed. The results confirm high prevalence of BKPyV (48%),and genotype IV (49%) over genotype I (43%) and the co-infection with genotypes I and IV in 8.2%. Viral load ranged from 102 to 107 copies/mL, with an average of 1.92 × 106 copies/mL. No specific markers for BKPyV infection were detected among the parameters tested. Infection with genotype I may be associated with the adverse impact on thekidney function, while infection with genotype IV was associated with the anemia Not only the viral load but also the genotype of BKPyV may have an impact on the course of infection.

Molecular Epidemiology and Variation of the BK Polyomavirus in the Population of Central and Eastern Europe Based on the Example of Poland.

The BK polyomavirus (BKPyV) is a widespread pathogen in humans. Polymorphism of the region encoding the VP1 protein of BKPyV provides the basis for classifying the virus into types and subtypes, whose frequency varies depending on geographic location. The aim of our study was to determine the frequency of BKPyV in the Polish population and to assess its variation by analysing polymorphism in the typing region. The study was conducted on 168 healthy, Polish volunteers, whose blood (plasma) and urine were sampled. The virus was detected using PCR, products, sequenced and subjected to bioinformatic analysis. In addition, viral load was assessed by qPCR. The presence of the genetic material of the BK virus was noted in 61/168 urine samples but in none of the plasma sample. Sequencing and phylogenetic analysis confirmed that the BKPyV isolates were of types I and IV, dominant in Europe (63.93% and 36.07%, respectively). All isolates from genotype I belonged to subtype Ib-2, showing polymorphism at position 1809 with a frequency of 61.54% (G1809A) and 38.46% (G1809C). To the best of our knowledge, this is the first study of this magnitude on the genetic variation of BKPyV among healthy volunteers in Poland.

BK Polyomavirus-Biology, Genomic Variation and Diagnosis.

The BK polyomavirus (BKPyV), a representative of the family Polyomaviridae, is widespread in the human population. While the virus does not cause significant clinical symptoms in immunocompetent individuals, it is activated in cases of immune deficiency, both pharmacological and pathological. Infection with the BKPyV is of particular importance in recipients of kidney transplants or HSC transplantation, in which it can lead to the loss of the transplanted kidney or to haemorrhagic cystitis, respectively. Four main genotypes of the virus are distinguished on the basis of molecular differentiation. The most common genotype worldwide is genotype I, with a frequency of about 80%, followed by genotype IV (about 15%), while genotypes II and III are isolated only sporadically. The distribution of the molecular variants of the virus is associated with the region of origin. BKPyV subtype Ia is most common in Africa, Ib-1 in Southeast Asia, and Ib-2 in Europe, while Ic is the most common variant in Northeast Asia. The development of molecular methods has enabled significant improvement not only in BKPyV diagnostics, but in monitoring the effectiveness of treatment as well. Amplification of viral DNA from urine by PCR (Polymerase Chain Reaction) and qPCR Quantitative Polymerase Chain Reaction) is a non-invasive method that can be used to confirm the presence of the genetic material of the virus and to determine the viral load. Sequencing techniques together with bioinformatics tools and databases can be used to determine variants of the virus, analyse their circulation in populations, identify relationships between them, and investigate the directions of evolution of the virus.

Heat Shock Protein 27 Is an Emerging Predictor of Contrast-Induced Acute Kidney Injury on Patients Subjected to Percutaneous Coronary Interventions.

Contrast-induced acute kidney injury (CI-AKI) is a serious complication associated with considerable morbidity and mortality. Heat-shock protein 27 (HSP27) plays a role in the defense of the kidney tissue against various forms of cellular stress, including hypoxia and oxydative stress, both features associated with CI-AKI. The aim of our study was to evaluate a potential predictive value of HSP27 for CI-AKI in patients subjected to percutaneous coronary interventions (PCI). Included were 343 selected patients subjected to PCI. Exclusion criteria were conditions that potentially might influence HSP27 levels. HSP27 serum levels were evaluated prior to PCI, together with serum creatinine, the concentration of which was also evaluated twice at 48 and 72 h post PCI. CI-AKI was diagnosed in 9.3% of patients. Patients in whom CI-AKI was diagnosed were older (p < 0.001), were more often females (p = 0.021), had higher prevalence of diabetes (p = 0.011), hypotension during PCI (p < 0.001), albuminuria (p = 0.004) as well as multivessel disease (p = 0.002), received higher contrast volume (p = 0.006), more often received contrast volume (CV) above the maximum allowed contrast dose (MACD) (p < 0.001), and had lower HSP27 level (p < 0.001). On multivariate analysis, CV > MACD (OR 1.23, p = 0.001), number of diseased vessels (OR 1.27, p = 0.006), and HSP27 (OR 0.81, p = 0.001) remained independent predictors of CI-AKI. Low concentration of HSP27 is an emerging, strong and independent predictor of CI-AKI in patients subjected to PCI.

An analysis of anxiety and selected aspects of personality in women with ischemic heart disease according to P.T. Costa and R. R. McCrae theory - The role of psychosocial factors in ischemic heart disease.

INTRODUCTION: Risk factors for ischemic heart disease (IHD) are very numerous and not fully defined. In addition to classic risk factors, different factors are also distinguished, among them psychological aspects chich have rarely been subject to detailed analyses. OBJECTIVE: The aim of study was an analysis of the anxiety structure, including the five factors of personality: neuroticism (NEU), extraversion (EXT), openness (OPE), agreeableness (AGR) and conscientiousness (CON), in women with IHD. MATERIAL AND METHODS: The study involved 140 women aged 37-74 years with IHD confirmed by coronary angiography. Psychological examination was conducted using R.B. Cattell's IPAT Anxiety Scale and P.T. Costa and R.R. McCrae's NEO-FFI Personality Inventory. RESULTS: The results obtained from the IPAT Anxiety Scale showed that the study group of 140 women with IHD had the correct level of internal integrity (Q3- ). The dominant factor in the anxiety structure in 88.7% of subjects was neurotic tension (Q4+). A lack of sense of safety was indicated by 72.6% of subjects (L+), 69.3% experienced a strong tendency to self-blame and experience a sense of guilt (O + ), and over 51.6% of women with IHD expressed decreased emotional stability (C - ). The level of general anxiety was high (GA=7.3). The analysis of the five factors of personality revealed that the dominant factors in the structure of personality of women with IHD were CON in 69.3%, AGR in 46.7% and EXT in 45.2%. NEU and OPE were moderately significant factors. CONCLUSIONS: Women with IHD are characterised by a high level of anxiety, increased neurotic tension, decreased emotional stability, auto-aggression and a sense of danger and distrust. Women with IHD demonstrate a high level of factors, such as extraversion, agreeableness and conscientiousness.

The inflammation link between periodontal disease and coronary atherosclerosis in patients with acute coronary syndromes: case-control study.

BACKGROUND: Coronary atherosclerosis and periodontal disease, due to their prevalence, are a serious epidemiological problem. Pathophysiological evidence points to their possible common inflammatory etiopathological background. The aim of the study was to analyze the relationship between the presence and severity of periodontitis, systemic inflammation and selected parameters of myocardial injury and heart function in patients with acute myocardial infarction. METHODS: The study group consisted of 71 patients 54.22 (7.05)-year-old hospitalized due to acute myocardial infarction. The patients underwent a coronary angiographic examination and echocardiography. The following laboratory parameters were determined: blood morphology, high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), fibrinogen, troponin I, creatine kinase myocardial band (CK-MB), brain natriuretic peptide (BNP), lipidogram, glucose, creatinine, glomerular filtration rate (GFR), thyroid stymulating hormone (TSH), glycated hemoglobin (HbA1c). Dental assessment of the patients was performed and the following indicators were included: the number of teeth preserved, approximal plaque index (API), bleeding on probing (BoP), pocket depth (PD), the number of bleeding periodontal pockets ≥ 4 mm in depth (NoPD ≥ 4 mm), the percentage of bleeding periodontal pockets ≥ 4 mm in depth (%PD ≥ 4 mm), clinical attachment loss (CAL). The control consisted of 40 patients 52 (± 8.43)-year-old without a history of coronary heart disease. These patients were subjected to a periodontal examination using the above parameters and classification methods. The following statistical tests were implemented: Shapiro-Wilk test, Levene's test, Mann Whitney's U analysis, Univariate Analysis of Variance (ANOVA); the post-hoc analysis was performed with the use of Tukey's honest significant difference test (HSD), Kruskal-Wallis's non-parametric test, Spearman's rank correlation, logistic regression analysis, linear regression analysis and ROC analysis. RESULTS: The BoP (bleeding on probing) significantly correlated with fibrynogen (R-0.36; p-0.006). All indices regarding the pocket depth correlated significantly with the number of leukocytes: PD (R-0.27; p-0.02), NoPD ≥ 4 mm (R-0.28, p-0.02), %PD ≥ 4 mm (R-0.27; p-0.02). PD (R-0.28; p-0.01) and NoPD ≥ 4 mm (R-0.24; p-0.04) were also associated significantly with the level of hsCRP. The BoP is correlated closely with the levels of BNP (R-0.29, p-0.02). The multifactorial analysis showed that significant predictors of myocardial infarction are API and BoP. The analysis showed that API and BoP are important predictors of troponin levels. Linear regression analysis showed that only CAL is a significant predictor of BNP. CONCLUSIONS: Patients with acute myocardial infarction have worse periodontal status compared to people without coronary heart disease. Greater severity of periodontitis, plaque accumulation and bleeding on probing are associated with acute myocardial infarction. Periodontitis is a risk factor for myocardial infarction and also affects the degree of post-infarction left ventricular damage, which means that there is an inflammatory link between these two diseases.

Atypical Cardiac Location of Melanoma of Unknown Origin.

The subject was a 66-year-old woman, suffering from the chest pain evoked by physical activity. Transthoracic echocardiography (TTE) revealed an abnormal structure, 41 × 29 mm. In MSCT, a hypodensic mobile tissue lesion that was infiltrating the whole thickness of left ventricle was confirmed. PET excluded the existence of other remote lesions. After surgical tumor removal, histopathological differential diagnosis revealed melanoma, myoepithelial cancer, and MPNST "high-grade" sarcoma. A control TTE detected a tumor that was 14 × 10 mm. After immunohistochemical results, immunotherapy with pembrolizumab was used, which resulted in complete tumor resolution. Presently, surgical resection and neoadjuvant targeted immunochemotherapy remain the treatment of choice for clinical stage III/IV melanoma.

Neutrophil-Lymphocyte Ratio (NLR) Reflects Myocardial Inhomogeneities in Hemodialyzed Patients.

INTRODUCTION: Cardiovascular diseases (CVDs) are a leading cause of death in chronically hemodialyzed (HD) patients. In this group, inflammation exerts significant impact on the prevalence of CVD morbidity and mortality. Spatial QRS-T angle is an independent and strong predictor of CV events, including sudden cardiac death (SCD), both in general population and HD patients. Pathogenesis of widened QRS-T angle is complicated and is not well established. OBJECTIVES: The study is aimed at evaluating whether inflammation process can contribute to the wide QRS-T angle. Patients and Methods. The retrospective study was performed on 183 HD patients. The control group consisted of 38 patients. Demographic, biochemical, vectorcardiographic, and echocardiographic data were evaluated in all patients. Inflammation process was expressed as neutrophil-lymphocyte ratio (NLR), as well as C-reactive protein (CRP). RESULTS: Both NLR (3.40 vs. 1.95 (p < 0.0001)) and spatial QRS-T angle (50.76 vs. 93.56 (p < 0.001)) were higher in the examined group, compared to the control group. Similarly, CRP was higher in the examined group than in the control group (8.35 vs. 4.06 (p < 0.001), respectively). The QRS-T angle correlated with NLR, CRP, some structural echocardiographic parameters, parathormone (PTH), and calcium (Ca) concentrations. Multiple regression analysis showed that NLR is an independent QRS-T angle predictor (r = 0.498, p = 0.0027). The ROC curve analysis indicated the cut-off point of NLR equaled 4.59, where the sensitivity and specificity were the highest for predicting myocardial inhomogeneities expressed as widened QRS-T angle. CONCLUSION: The NLR, as an inflammation marker, may indicate myocardial inhomogeneities in HD patients.

Aortic stiffness-Is kynurenic acid a novel marker? Cross-sectional study in patients with persistent atrial fibrillation.

OBJECTIVE: Although a number of modifiable and non-modifiable causes were implicated in arterial stiffness, its pathogenesis remains elusive, and very little is known about aortic elasticity in supraventricular arrhythmias. The potential role of disturbed kynurenine metabolism in the pathogenesis of cardiovascular disease has been recently suggested. Thus, we studied the correlations of aortic stiffness and echocardiographic parameters with biochemical markers and serum level of kynurenic acid (KYNA), an endothelial derivative of tryptophan, formed along the kynurenine pathway, among patients with atrial fibrillation (AF). METHODS: Study cohort comprised 100 patients with persistent AF (43 females/57 males). Arterial stiffness index (ASI), structural and functional indices of left atrium (LA) and left ventricle (LV) were evaluated electrocardiographically. Biochemical analyses included the measurements of serum KYNA (HPLC) and of the selected markers of lipids and glucose metabolism, thyroid status, kidney function, inflammation and coagulation. RESULTS: KYNA (ß = 0.389, P = 0.029), homocysteine (ß = 0.256, P = 0.40), total cholesterol (ß = 0.814; P = 0.044), LDL (ß = 0.663; P = 0.44), TSH (ß = 0.262, P = 0.02), fT3 (ß = -0.333, P = 0.009), fT4 (ß = -0.275, P = 0.043) and creatinine (ß = 0.374, P = 0.043) were independently correlated with ASI. ASI was also independently associated with LV end-systolic diameter (LVEDd; ß = 1.751, P = 0.045), midwall fractional shortening (mFS; ß = -1.266, P = 0.007), ratio mFS/end-systolic stress (mFS/ESS; ß = -0.235, P = 0.026), LV shortening fraction (FS; ß = -0.254, P = 0.017), and LA volume index (LAVI; ß = 0.944, P = 0.022). CONCLUSIONS: In patients with AF, aortic stiffness correlated positively with KYNA, biochemical risk factors of atherosclerosis and with the indices of diastolic dysfunction of LV and LA. Revealed relationship between ASI and KYNA is an original observation, suggesting a potential role of disturbed kynurenine metabolism in the pathogenesis of arterial stiffening. KYNA, synthesis of which is influenced by homocysteine, emerges as a novel, non-classical factor associated with ASI in patients with AF.

The improvement of QRS-T angle as a manifestation of reverse electrical remodeling following renal transplantation in end-stage kidney disease patients on haemodialysis.

BACKGROUND: Successful renal transplantation (RT) reverses some of the cardiac changes and reduces cardiac mortality in hemodialysis (HD) patients. Widened QRS-T angle reflects both ventricular repolarization and depolarization. It is considered a sensitive and strong predictor of heart ventricular remodeling as well as a powerful and independent risk stratifier suitable in predicting cardiac events in various clinical settings. The study aimed to assess the influence of the RT on QRS-T angle and to evaluate factors influencing QRS-T changes in renal transplanted recipients (RTRs). METHODS: Fifty-four selected HD patients who have undergone RT were included. Blood chemistry, echocardiography, and QRS-T angle were evaluated 5 times: about 1 week, 3 months, 6 months, 1 year and 3 years after RT. RESULTS: An improvement of echocardiographic parameters was observed. The dynamics of changes in individual parameters were, however, variable. QRS-T angle correlated with echocardiographic parameters. The biphasic pattern of the decreases of QRS-T angle was observed. The first decrease took place in the third month of follow-up. The second decrease of QRS-T angle was observed after 1 year of follow-up. The QRS-T angle was higher in RTRs compared with controls during each evaluation. Multivariable analysis demonstrated that the decrease of left ventricle enddiastolic volume was an independent predictor of early QRS-T angle improvement. The increase of left ventricle ejection fraction was found to be the independent predictor of the late QRS-T angle improvement. CONCLUSIONS: RT induces biphasic reverse electrical remodeling as assessed by the narrowing of QRS-T angle. Early decrease of QRS-T angle is mainly due to the normalization of volume status, whereas late decrease is associated predominantly with the improvement of cardiac contractile function.