A Review of MicroRNAs and lncRNAs in Atherosclerosis as Well as Some Major Inflammatory Conditions Affecting Atherosclerosis.

It is generally accepted that atherosclerosis is a chronic inflammatory disease. The link between atherosclerosis and other inflammatory diseases such as psoriasis, type 2 diabetes mellitus (T2DM), and rheumatoid arthritis (RA) via metabolic, inflammatory, and immunoregulatory pathways is well established. The aim of our review was to summarize the associations between selected microRNAs (miRs) and long non-coding RNAs (lncRNAs) and atherosclerosis, psoriasis, T2DM, and RA. We reviewed the role of miR-146a, miR-210, miR-143, miR-223, miR-126, miR-21, miR-155, miR-145, miR-200, miR-133, miR-135, miR-221, miR-424, let-7, lncRNA-H19, lncRNA-MEG3, lncRNA-UCA1, and lncRNA-XIST in atherosclerosis and psoriasis, T2DM, and RA. Extracellular vesicles (EVs) are a method of intracellular signal transduction. Their function depends on surface expression, cargo, and the cell from which they originate. The majority of the studies that investigated lncRNAs and some miRs had relatively small sample sizes, which limits the generalizability of their findings and indicates the need for more research. Based on the studies reviewed, miR-146a, miR-155, miR-145, miR-200, miR-133, and lncRNA-H19 are the most promising potential biomarkers and, possibly, therapeutic targets for atherosclerosis as well as T2DM, RA, and psoriasis.

SMAD3 rs17228212 Polymorphism Is Associated with Advanced Carotid Atherosclerosis in a Slovenian Population.

Smad proteins influence the TGFß signaling pathway, which plays an important role in the progression of atherosclerosis. The aim of our study was to investigate the association between the rs17228212 polymorphism of the SMAD3 gene and advanced carotid atherosclerosis in Slovenian subjects and to investigate the effect of the rs17228212 SMAD3 polymorphism on the expression of SMAD3 in endarterectomy sequesters. In this cross-sectional case-control study, 881 unrelated Caucasians were divided into two groups. The first group included 308 patients with advanced carotid atherosclerosis of the common or internal carotid artery with stenosis greater than 75% that underwent a revascularization procedure (cases). The control group consisted of 573 subjects without hemodynamically significant carotid atherosclerosis. We analyzed the rs17228212 polymorphism of the SMAD3 gene using the StepOne real-time polymerase chain reaction system and TaqMan SNP genotyping assay. The results in the two genetic models showed a statistically significant association, codominant (OR 4.05; CI 1.10-17.75; p = 0.037) and dominant (OR 3.60; CI 1.15-15.45; p = 0.045). An immunohistochemical analysis of SMAD3 expression was conducted for 26 endarterectomy specimens. The T allele of the rs17228212 SMAD3 gene was shown to be associated with an increased numerical area density of SMAD3-positive cells in carotid plaques.

SLC22A3 rs2048327 Polymorphism Is Associated with Diabetic Retinopathy in Caucasians with Type 2 Diabetes Mellitus.

The Solute Carrier Family 22 Member 3 (SLC22A3) is a high-capacity, low-affinity transporter for the neurotransmitters norepinephrine, epinephrine, dopamine, serotonin, and histamine. SLC22A3 plays important roles in interorgan and interorganism small-molecule communication, and also regulates local and overall homeostasis in the body. Our aim was to investigate the association between the rs2048327 gene polymorphism and diabetic retinopathy (DR) in Slovenian patients with type 2 diabetes mellitus (T2DM). We also investigated SLC22A3 expression in the fibrovascular membranes (FVMs) of patients with proliferative DR (PDR). Our study involved 1555 unrelated Caucasians with T2DM with a defined ophthalmologic status: 577 of them with DR as the study group, and 978 without DR as the control group. The investigated polymorphisms were genotyped using the KASPar genotyping assay. The expression of SLC22A3 (organic cation transporter 3-OCT3) was examined via immunohistochemistry in human FVM from 16 patients with PDR. The C allele and CC genotype frequencies of the rs2048327 polymorphism were significantly higher in the study group compared to the controls. The logistic regression analysis showed that the carriers of the CC genotype in the recessive genetic models of this polymorphism have a 1.531-fold increase (95% CI 1.083-2.161) in the risk of developing DR. Patients with the C allele of rs2048327 compared to the homozygotes for the wild type T allele exhibited a higher density of SLC22A3 (OCT3)-positive cells (10.5 ± 4.5/mm2 vs. 6.1 ± 2.7/mm2, respectively; p < 0.001). We showed the association of the rs2048327 SLC22A3 gene polymorphism with DR in a Slovenian cohort with type 2 diabetes mellitus, indicating its possible role as a genetic risk factor for the development of this diabetic complication.

The rs3825807 Polymorphism of ADAMTS7 as a Potential Genetic Marker for Myocardial Infarction in Slovenian Subjects with Type 2 Diabetes Mellitus.

BACKGROUND: A disintegrin and metalloprotease with thrombospondin motif 7 (ADAMTS-7) was reported to play a role in the migration of vascular smooth muscle cells and neointimal formation. The object of the study was to investigate the association between the rs3825807 polymorphism of ADAMTS7 and myocardial infarction among patients with type 2 diabetes mellitus in a Slovenian cohort. METHODS: 1590 Slovenian patients with type 2 diabetes mellitus were enrolled in this retrospective cross-sectional case-control study. In total, 463 had a history of recent myocardial infarction, and 1127 of the subjects in the control group had no clinical signs of coronary artery disease. Genetic analysis of an rs3825807 polymorphism of ADAMTS7 was performed with logistic regression. RESULTS: Patients with the AA genotype had a higher prevalence of myocardial infarction than those in the control group in recessive [odds ratio (OR) 1.647; confidence interval (CI) 1.120-2.407; p = 0.011] and co-dominant (OR 2.153; CI 1.215-3.968; p = 0.011) genetic models. CONCLUSION: We found a statistically significant association between rs3825807 and myocardial infarction in a cohort of Slovenian patients with type 2 diabetes mellitus. We report that the AA genotype might be a genetic risk factor for myocardial infarction.

The GG genotype of erythropoietin rs1617640 polymorphism affects the risk of proliferative diabetic retinopathy in Slovenian subjects with type 2 diabetes mellitus: enemy or ally?

PURPOSE: The aim of this study was to investigate the relationship between erythropoietin rs1617640 polymorphism and proliferative diabetic retinopathy (PDR) in Slovenian subjects with type 2 diabetes mellitus. The second aim was to find whether erythropoietin expression in fibrovascular membranes varies among individuals carrying different genotypes of the rs1617640. METHODS: This was a retrospective cross-sectional study based on 797 unrelated Slovenian (Caucasian) participants with type 2 diabetes mellitus. The study group consisted of 217 cases with PDR and 580 controls without clinical signs of diabetic retinopathy. Each subject was genotyped for rs1617640 polymorphism. Fibrovascular membranes from 27 subjects who underwent vitreoretinal surgery were analysed with immunohistochemistry. We searched for expression of erythropoietin, its cognate receptor and for a pan-endothelial marker CD-34. RESULTS: Our results show that subjects carrying a minor GG genotype had significantly higher risk for PDR in both unadjusted (p = 0.02) and adjusted (p = 0.04) recessive genetic models. Subjects with the GG genotype had a 1.6-fold increased risk of developing PDR compared to subjects carrying the major T allele. In fibrovascular membranes from subjects with PDR, the mean number of cells expressing EPO was significantly higher in G allele carriers compared to the homozygotes for the common T allele. CONCLUSION: In Slovenian subjects with type 2 diabetes mellitus, a significant increased risk of PDR was found in GG carriers of the erythropoietin gene rs1617640 polymorphism.

Sirtuin 1 rs7069102 polymorphism is associated with diabetic nephropathy in patients with type 2 diabetes mellitus.

The global prevalence for diabetes mellitus nearly doubled from 4.7% in 1980 to 8.5% in 2014. Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that is expressed in a variety of tissues. It modifies proteins that participate in DNA repair, stress, and inflammatory response. The aim of the study was to investigate the relationship between SIRT1 rs7069102 polymorphism and diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM). In our retrospective association study, we included 724 Slovene (Caucasian) patients who have had T2DM for at least 10 years. We classified the participants into two groups, the first group was comprised of 301 patients with DN, and the second (control) group was comprised of 423 patients without DN. We analyzed the rs7069102 polymorphism using StepOne real-time polymerase chain reaction (PCR) System and TaqMan SNP Genotyping Assay. We found a statistically significant difference in the distribution of rs7069102 genotypes and alleles between the two groups. We used logistic regression analysis and adjusted for systolic pressure, arterial hypertension (AH), duration of AH, triglycerides, the value of HbA1c, carotid disease, diabetic foot, and diabetic retinopathy. Furthermore, we discovered that patients with the CC genotype are significantly more likely to develop DN according to both the codominant (odds ratio [OR] = 1.94; 95% confidence interval [CI] = 1.09-3.45; p = 0.02) and recessive (OR = 2.39; 95% CI = 1.12-5.08; p = 0.02) models of inheritance. We found a significant association between the SIRT1 rs7069102 polymorphism and DN in T2DM. We speculate that SIRT1 rs7069102 might be an interesting marker of DN.

The Role of microRNAs in Heart Failure: A Systematic Review.

MicroRNAs are highly investigated for their role in the pathogenesis of cardiovascular diseases. Nevertheless, evidence for clinical implementation is still lacking. In our systematic review, we evaluated the potential of microRNAs as pathophysiological and diagnostic biomarkers of heart failure. We identified 72 differentially expressed microRNA molecules among groups of heart failure patients and control groups by searching the PubMed database. We did not identify a substantial overlap of differentially expressed microRNAs among different studies; only five microRNAs (miR-1228, miR-122, miR-423-5p, miR-142-3p, and exosomal miR-92b-5p) were differentially expressed in more than one included study. Gene set enrichment analysis, based on the gene targets of microRNAs presented in the included studies, showed that gene targets of differentially expressed microRNAs were enriched in the MAPK, TGFß, PI3K-Akt, and IL-2 signaling pathways, as well as apoptosis pathway, p53 activity regulation, and angiogenesis pathway. Results of our systematic review show that there is currently insufficient support for the use of any of the presented microRNAs as pathophysiological or prognostic biomarkers in the clinical setting.

Association of Peroxisome Proliferator-Activated Receptors (PPARs) with Diabetic Retinopathy in Human and Animal Models: Analysis of the Literature and Genome Browsers.

Diabetic retinopathy (DR) is a condition that develops after long-lasting and poorly handled diabetes and is presently the main reason for blindness among elderly and youth. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in carbohydrate and fatty-acid metabolism and have also been associated with DR. Three PPAR isoforms are known: PPARG, PPARA, and PPARD. In the present study, we retrieved articles reporting associations between PPARs and DR from PubMed database and compiled the data in two catalogues, for human and animal models. Extracted data was then complemented with additional relevant genomic information. Seven retrieved articles reported testing an association between PPARs with DR in human. Four of them concluded association of PPARG and PPARA with DR in European and Asian populations, having a protective role on DR development. One study reported pathogenic role of PPARG, while two articles reported no association between PPARG and DR among Indian and Chinese populations. Six retrieved articles reported testing of involvement of PPARG and PPARA in DR in animal models, including mouse and rat. The review includes case-control studies, meta-analysis, expression studies, animal models, and cell line studies. Despite a large number of documented sequence variants of the PPAR genes available in genome browsers, researchers usually focus on a small set of previously reported variants. Data extraction from Ensembl genome browser revealed several sequence variants with predicted deleterious effect on protein function which present candidates for further experimental validation. Results of the present analysis will enable more holistic approach for understanding of PPARs in DR development. Additionally, developed catalogues present a baseline for standardized reporting of PPAR-phenotype association in upcoming studies.

The ALOXA5AP gene (rs38022789) is associated with diabetic nephropathy in Slovenian patients with type 2 diabetes mellitus.

BACKGROUND: Although the pathogenesis of diabetic nephropathy (DN) is multifactorial, and the precise mechanisms are unclear, there is a growing body of evidence suggesting that inflammatory processes and immune cells might be involved in the development and progression of DN. Leukotrienes (LTs) are a family of lipid mediators, which act as pro-inflammatory mediators. The study was designed to investigate the association between the polymorphism of the ALOX5 gene (rs12762303) and the ALOX5AP gene (rs3802278), and DN in patients with T2DM. METHODOLOGY: 651 subjects with diabetes mellitus type 2 (T2DM) were classified into two groups according to the presence of DN, and tested for ALOX5 and ALOX5AP gene polymorphisms using the KASPar genotyping chemistry with validated assay. Biochemical analyses were performed using standard biochemical methods. RESULTS: Logistic regression analysis demonstrated that the carriers of the CC genotype had a 3.14 higher risk for DN compared to TT genotype. Serum cystatin C was found to be statistically significantly higher in cases with DN in comparison with subjects without DN (p < 0.001). CONCLUSION: An association between the rs3803278 of the ALOX5AP gene and DN was found in Slovenian patients with T2DM. The rs3803278 CC allele appears to confer increased risk of DN possibly by increasing the production of LTs-potent drivers of inflammation.

Impact of drugs on venous thromboembolism risk in surgical patients.

PURPOSE: This review focuses on the most common drugs administered to surgical patients during the perioperative period that affect the risk of venous thromboembolism (VTE). RESULTS: Among analgesics, the risk of VTE is increased in patients treated with diclofenac, ibuprofen, and rofecoxib, but not naproxen, while metamizole can confer a protective effect. The relationship between sedatives and VTE has not been sufficiently studied. Tricyclic antidepressants, low-potency serotonin reuptake inhibitors, and antipsychotics have been associated with increased risk of VTE. The use of diuretics in the perioperative period is poorly researched; however, hyponatremia is considered a risk factor. Other factors that may influence the risk of VTE include bridging anticoagulation, allogeneic transfusion, and hemostatic management before surgery. Pharmacotherapy for HIV or cancer may also increase VTE risk. CONCLUSION: Increased monitoring for VTE is therefore advisable in surgical patients and those receiving antipsychotics, antidepressants, diuretics, or analgesics.

The joint effect of the endothelin receptor B gene (EDNRB) polymorphism rs10507875 and nitric oxide synthase 3 gene (NOS3) polymorphism rs869109213 in Slovenian patients with type 2 diabetes mellitus and diabetic retinopathy.

Increasing evidence suggests that endothelin and nitric oxide synthase genes and their products exert biological effects on the vasculature via the nitric oxide or endothelin pathway. The aim of the study was to evaluate the association of rs10507875 and rs869109213 (alone or in interaction) with diabetic retinopathy (DR) in subjects with type 2 diabetes mellitus (T2DM). We genotyped the single nucleotide polymorphism rs10507875 of the endothelin receptor B gene (EDNRB) and variable number tandem repeats rs869109213 of the nitric oxide synthase 3 gene (NOS3) in 270 Slovenian patients with DR and T2DM and 256 controls with T2DM without clinical signs of DR. The genotyping was performed using either real-time polymerase chain reaction (PCR) or standard PCR. We found a significant association between the genotypes of NOS3 rs869109213 polymorphism and the risk of DR in the co-dominant model (4a4b genotype; 1.99-fold increased risk [1.09-3.65]; 95% confidence interval [CI]; p = 0.02), co-dominant model (4a4a genotype; 4.16-fold increased risk [1.03-16.74]; 95% CI; p = 0.04), and dominant model (4a4a and 4a4b genotypes; 2.22-fold increased risk [1.26-3.92]; 95% CI; p = 0.01) compared to the 4b4b genotype. Moreover, the joint effect of the two polymorphisms on DR risk was greater than the individual effect of each polymorphism in the analyzed genetic models. Additionally, adjusted odds ratio showed an increased risk in dominant × dominant (4.15-fold [1.40-12.26]; 95% CI; p = 0.01) and recessive × dominant (2.24-fold [1.25-4.01]; 95% CI; p = 0.02) genotype combinations of the two polymorphisms. In conclusion, our results indicate that NOS3 rs869109213 polymorphism alone or in a combination with EDNRB rs10507875 polymorphism may be associated with DR in Slovenian patients with T2DM.

Phosphoprotein 1 (osteopontin) gene (rs4754) affects markers of subclinical atherosclerosis in patients with type 2 diabetes mellitus.

BACKGROUND: Our study was designed to test a possible association between polymorphisms of the SPP1 gene (rs4754, rs28357094) and markers of carotid atherosclerosis (CIMT, number of affected segments of carotid arteries, sum of plaque thickness, presence of carotid plaques, and presence of unstable carotid plaques) in subjects with T2DM. The second aim was to test the possible association between polymorphisms of the SPP1 gene (rs4754, rs28357094) and the progression of carotid atherosclerosis (CIMT progression, change in total plaque thickness, change in the number of sites with plaques) in subjects with T2DM. METHODS: In the prospective study 595 T2DM subjects were enrolled. Markers of carotid atherosclerosis were assessed ultrasonographically. rs4754 and rs28357094 polymorphisms of the phosphoprotein 1 (SPP1) gene were determined with real-time PCR. RESULTS: In our study we found an association between SPP1 rs4754 and the presence of plaques at the time of recruitment, whereas we did not find any association between SPP1 rs28357094 and subclinical markers of carotid atherosclerosis at the time of recruitment. Moreover, we did not find any statistically significant effect of either rs4754 or rs28357094 on subclinical markers of carotid atherosclerosis progression (CIMT progression, change in total plaque thickness, change in the number of sites with plaques). As shown by the multiple linear regression analysis, genotypes of either rs4754 or rs28357094 did not have a statistically significant effect on the progression of subclinical markers of carotid atherosclerosis (CIMT progression, change in total plaque thickness, change in the number of sites with plaques) after the adjustment for confounding variables. CONCLUSIONS: We demonstrated an important effect of the SPP1 rs4754 on subclinical markers of carotid atherosclerosis in subjects with T2DM; however, as demonstrated by the multiple linear regression analysis, neither rs4754 nor rs28357094 had an important impact on the progression of subclinical markers of carotid atherosclerosis in subjects with T2DM.

C-reactive protein as a marker of progression of carotid atherosclerosis in subjects with type 2 diabetes mellitus.

BACKGROUND: This prospective study was designed to evaluate the effect of inflammatory markers on the presence and progression of subclinical markers of carotid atherosclerosis in a 3.8-year follow-up period in patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: A total of 595 subjects with T2DM were enrolled. Subclinical markers of carotid atherosclerosis (carotid intima media thickness (CIMT), plaque thickness, and plaques presence) were assessed with ultrasound at the time of recruitment and again after 3.8 years. Subjects with T2DM were divided into 2 groups according to the plasma high sensitive C-reactive protein (hs-CRP) levels (subjects with hs-CRP ≥ 2 mg/L and subjects with hs-CRP below 2 mg/L). RESULTS: Subjects with T2DM and hs-CRP levels ≥ 2 mg/L had higher CIMT in comparison with subjects with T2DM and hs-CRP levels below 2 mg/L, and higher incidence of plaques/unstable plaques in comparison with subjects with T2DM and hs-CRP levels below 2 mg/L. Multivariate logistic regression analysis found the association between the HDL cholesterol level and presence of plaques, whereas the inflammatory marker hs-CRP was not associated with subclinical markers of progression of carotid atherosclerosis. Multiple linear regression analysis found the association between the hs-CRP levels and either CIMT progression rate or a change in the number of sites with plaques in a 3.8-year follow-up. CONCLUSIONS: We demonstrated an association between the inflammatory marker hs-CRP and either CIMT or incidence of plaques/unstable plaques at the time of recruitment in Caucasians with T2DM. Moreover, we found the association between hs-CRP levels and either CIMT progression rate or a change in the number of sites with plaques in a 3.8-year follow-up in subjects with T2DM.

Polymorphism rs5498 of the ICAM-1 gene affects the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus.

BACKGROUND: Adhesion molecules are involved in the development of atherosclerosis. An increased level of the ICAM 1 molecule is associated with numerous inflammatory diseases including atherosclerosis of carotid arteries. The rs5498 (K469E) polymorphism of the ICAM-1 gene leads to an increase in the level of serum ICAM. We investigated the association between the rs5498 (K469E) polymorphism of the ICAM-1 gene and the progression of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). METHODS: The study included 595 patients with T2DM and 200 subjects in the control group without T2DM. The control examination was made 3.8 years after the initial examination. Indicators of atherosclerosis (carotid intima-media thickness (CIMT), total plaque sum and sum of the plaques thickness) were detected by ultrasound examination. Genetic analyses of the polymorphism rs5498 of the ICAM-1 gene were made by RT-PCR. RESULTS: The distribution of genotypes and frequencies of rs5498 polymorphism was not significantly different between the group with type 2 diabetes ( T2DM) and the control group. Genotype EE K469E polymorphism is associated with a statistically significant annual plaques growth. CONCLUSION: The EE genotype of the rs5498 of the ICAM-1 gene was associated with a more rapid progression of carotid atherosclerosis in patients with T2DM in comparison with other genotypes.

Polymorphisms of the PPAR-γ (rs1801282) and Its Coactivator (rs8192673) Have a Minor Effect on Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus.

Background. The present study was designed to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 (PGC-1α) gene (rs8192673) are associated with markers of carotid and coronary atherosclerosis in Caucasians with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled in the cross-sectional study. Markers of carotid atherosclerosis were assessed ultrasonographically. In 215 out of 595 subjects with T2DM, a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of either rs1801282 or rs8192673 was performed using KASPar assays. Results. In our study, we demonstrated an effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM in univariate and in multivariable linear regression analyses. Finally, we did not demonstrate any association between either rs1801282 or rs8192673 and markers of coronary atherosclerosis. Conclusions. In our study, we demonstrated a minor effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM. Moreover, we demonstrated a minor effect of the rs8192673 on CIMT progression in the 3.8-year follow-up in Caucasians with T2DM.

SOX6 gene polymorphism (rs16933090) and markers of subclinical atherosclerosis in patients with type 2 diabetes mellitus.

BACKGROUND: The present study was designed to investigate the association between the polymorphism of the SOX6 gene (rs16933090) and subclinical markers of carotid atherosclerosis, such as carotid intima media thickness (CIMT), the number of affected segments of carotid arteries and the sum of plaque thickness in patients with type 2 diabetes mellitus (T2DM). The second aim of the study was to demonstrate an association between the rs16933090 and subclinical markers of coronary artery disease in the same subset of patients with T2DM. METHODS: A total of 595 T2DM subjects were enrolled in the cross-sectional study. Markers of carotid atherosclerosis were assessed by ultrasonography. Additionally, in a subset of subjects with T2DM a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of SOX6 gene (rs16933090) was performed using KASPar assays. RESULTS: In our study we demonstrated the effect of the rs16933090 on coronary calcium score obtained at CCTA, whereas we did not demonstrate any association between the tested polymorphism (rs16933090) and the presence of more than 50% stenotic lesions in coronary arteries, the sum of plaque thickness, the number of involved carotid segments, high-sensitivity C-reactive protein, the presence of carotid plaques, and the presence of unstable carotid plaques. CONCLUSIONS: In our study, we demonstrated the effect of the rs16933090 on coronary calcium score obtained at CCTA, whereas we did not demonstrate an important effect of the rs16933090 on either subclinical markers of carotid atherosclerosis or the presence of more than 50% stenotic lesions in coronary arteries in Caucasians with T2DM. We presume that the rs16933090 plays a minor role in the development of subclinical atherosclerosis in subjects with T2DM.

Is diabetic cardiomyopathy a specific entity?

Diabetes mellitus (DM) is characterised by hyperglycemia, insulin resistance and metabolic dysregulation leading to diastolic and systolic dysfunction in diabetes. In this review, the pathogenetic and pathomorphological changes leading to diastolic and systolic dysfunction in diabetes are discussed. Changes in metabolic signalling pathways, mediators and effectors contribute to the pathogenesis of cardiac dysfunction in DM called diabetic cardiomyopathy (DC). Echocardiographic studies report on the association between DM and the presence of cardiac hypertrophy and myocardial stiffness that lead to diastolic dysfunction. More recently reported echocardiographic studies with more sensitive techniques, such as strain analysis, also observed systolic dysfunction as an early marker of DC. Depression of systolic and diastolic function is continuum and the line of separation is artificial. To conclude, according to current knowledge, DC is expected to be a common single phenotype that is caused by different pathogenetic and pathomorphological changes leading to diastolic and systolic dysfunction in diabetes.

Viability of human articular chondrocytes harvested postmortem: changes with time and temperature of in vitro culture conditions.

Different studies of long-term chondrocytes viability have shown a gradual reduction as a function of time and ambient temperature. The aim of our in vitro study was to establish chondrocyte postmortem viability curves for 4°C, 11°C, 23°C, 35°C during 63 days after the donors' death. Osteochondral cylinders were procured from the knees of 16 male donors (20-47 years), stored in preservation media that was not changed, and analyzed in 3-day intervals using a confocal laser scanning microscope. A significant influence of time on viability was found from Day 9 (p = 0.0029) and onwards (p < 0.0001). The lowest overall chondrocyte viability was at 35°C, followed by 4°C (p < 0.0001). The conditions used in this in vitro analysis suggest that similar viabilities may occur while in situ in the decedent. Further studies of chondrocyte viability from individuals with known postmortem intervals may show premise to help evaluate time since death in the late postmortem interval.

Carotid intima media-thickness and genes involved in lipid metabolism in diabetic patients using statins--a pathway toward personalized medicine.

The prognostic importance of large artery structure and function in relation to cardiovascular morbidity and mortality, together with the identification of new genetic risk factors have been two major areas of investigation in recent years. Carotid intima-media thickness (CIMT), as measured by B-mode ultrasound, is a surrogate marker for atherosclerosis and can be used to detect an accelerated disease process as well as subclinical disease. However, the genetic basis for CIMT variation is almost unknown. Cardiovascular genetics has led to numerous clinical studies generally focused on only one candidate gene and were frequently conducted in subjects with cardiovascular diseases and/or taking drugs that could affect CIMT. Pharmacogenetics is the study of the effect of a medication as it relates to single or defined sets of genes. An important goal of pharmacogenetics in cardiovascular disorders is to integrate the two (drugs plus genes) so that true personalized therapy can be delivered. In this paper, we will discuss the interaction between genes involved in lipid metabolism and statin therapy that affects intermediate phenotype (plasma lipid levels) and CIMT in patients with type 2 diabetes.

Association of the C242T polymorphism in the NADPH oxidase p22 phox gene with carotid atherosclerosis in Slovenian patients with type 2 diabetes.

Oxidative stress plays an important role in the pathogenesis of diabetes and its complications. Genetic variations of enzymes producing reactive oxygen species could change their activity, thus contributing to the susceptibility to oxidative stress. The aim of this study was to examine the role of the NADPH oxidase C242T polymorphism in the development of carotid atherosclerosis in patients with type 2 diabetes. 286 diabetic patients and 150 healthy controls were enrolled in the study. Carotid atherosclerosis was quantified ultrasonographically as carotid intima-media thickness, plaque score (0-6) and plaque type (1-5). Diabetic patients were divided into low and high risk groups based on ultrasound phenotypes of carotid atherosclerosis. Genotypes were determined by real-time PCR. Levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) were measured by enzyme-linked immunosorbent assay (ELISA). Diabetic patients demonstrated a statistically significant difference compared to healthy controls in the following parameters: age, BMI, waist circumference, smoking prevalence, glucose, triglyceride and 8-OHdG serum levels. Control subjects had significantly higher levels of HDL, LDL and total cholesterol than diabetics (p < 0.001). The NADPH C242T polymorphism was not related with clinical characteristics, lipid parameters and 8-OHdG serum levels. We found no significant difference in the NADPH genotype distribution between diabetics and controls (p = 0.19) nor between low and high risk subgroups of diabetics (mean CIMT: p = 0.67; plaque score: p = 0.49, plaque type: p = 0.56). In the present study the NADPH C242T polymorphism was not associated with the degree of oxidative stress and carotid atherosclerosis. Further studies will show if it can be used as a genetic marker for carotid atherosclerosis in diabetic patients.