In diabetic patients, cardiomyopathy is an important cause of heart failure, but its pathophysiology has not been completely understood thus far. Myocardial hypertrophy and diastolic dysfunction have ...been considered the hallmarks of diabetic cardiomyopathy (DCM), while systolic function is affected in the latter stages of the disease. In this article we propose the potential pathophysiological mechanisms responsible for myocardial hypertrophy and increased myocardial stiffness leading to diastolic dysfunction in this specific entity. According to our model, increased myocardial stiffness results from both cellular and extracellular matrix stiffness as well as cell⁻matrix interactions. Increased intrinsic cardiomyocyte stiffness is probably the most important contributor to myocardial stiffness. It results from the impairment in cardiomyocyte cytoskeleton. Several other mechanisms, specifically affected by diabetes, seem to also be significantly involved in myocardial stiffening, i.e., impairment in the myocardial nitric oxide (NO) pathway, coronary microvascular dysfunction, increased inflammation and oxidative stress, and myocardial sodium glucose cotransporter-2 (SGLT-2)-mediated effects. Better understanding of the complex pathophysiology of DCM suggests the possible value of drugs targeting the listed mechanisms. Antidiabetic drugs, NO-stimulating agents, anti-inflammatory agents, and SGLT-2 inhibitors are emerging as potential treatment options for DCM.
Calcium deposits in the vessel wall in the form of hydroxyapatite can accumulate in the intimal layer, as in atherosclerotic plaque, but also in the medial layer, as in medial arterial calcification ...(MAC) or medial Möenckeberg sclerosis. Once considered a passive, degenerative process, MAC has recently been shown to be an active process with a complex but tightly regulated pathophysiology. Atherosclerosis and MAC represent distinct clinical entities that correlate in different ways with conventional cardiovascular risk factors. As both entities coexist in the vast majority of patients, it is difficult to estimate the relative contribution of specific risk factors to their development. MAC is strongly associated with age, diabetes mellitus, and chronic kidney disease. Given the complexity of MAC pathophysiology, it is expected that a variety of different factors and signaling pathways may be involved in the development and progression of the disease. In this article, we focus on metabolic factors, primarily hyperphosphatemia and hyperglycemia, and a wide range of possible mechanisms by which they might contribute to the development and progression of MAC. In addition, we provide insight into possible mechanisms by which inflammatory and coagulation factors are involved in vascular calcification processes. A better understanding of the complexity of MAC and the mechanisms involved in its development is essential for the development of potential preventive and therapeutic strategies.
Classical risk factors play a major role in the initiation and development of atherosclerosis. However, the estimation of risk for cardiovascular events based only on risk factors is often ...insufficient. Efforts have been made to identify biomarkers that indicate ongoing atherosclerosis. Among important circulating biomarkers associated with peripheral arterial disease (PAD) are inflammatory markers which are determined by the expression of different genes and epigenetic processes. Among these proinflammatory molecules, interleukin-6, C-reactive protein, several adhesion molecules, CD40 ligand, osteoprotegerin and others are associated with the presence and progression of PAD. Additionally, several circulating prothrombotic markers have a predictive value in PAD. Genetic polymorphisms significantly, albeit moderately, affect risk factors for PAD via altered lipoprotein metabolism, diabetes, arterial hypertension, smoking, inflammation and thrombosis. However, most of the risk variants for PAD are located in noncoding regions of the genome and their influence on gene expression remains to be explored. MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that modulate gene expression at the post-transcriptional level. Patterns of miRNA expression, to some extent, vary in different atherosclerotic cardiovascular diseases. miRNAs appear to be useful in the detection of PAD and the prediction of progression and revascularization outcomes. In conclusion, taking into account one’s predisposition to PAD, i.e., DNA polymorphisms and miRNAs, together with circulating inflammatory and coagulation markers, holds promise for more accurate prediction models and personalized therapeutic options.
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).
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).
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.
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.
Obravnava žensk v obdobju predmenopavze, ob menopavzi in kasneje se je v novem tisočletju pomembno spremenila. Randomizirane klinične raziskave so bistveno omejile indikacije za uvedbo hormonskega ...zdravljenja (HZ) in s tem menopavzno medicino postavile pred velik izziv. Na srečo so najnovejša dognanja potrdila, da je ob pravilni uporabi in izbiri HZ korist še vedno bistveno večja od tveganja. Zato smo pripravili posodobljena stališča o menopavzni medicini, ki so v skladu z aktualnimi mednarodnimi priporočili in prilagojena posebnostim slovenskega prostora.
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.
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.
The study was designed to test the possible association between either polymorphisms of the matrix metalloproteinase-9 (MMP-9) gene (rs17576, rs3918242) or the MMP-3 5A/6A gene polymorphism ...(rs3025058) with markers of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The second aim of the study was to demonstrate an association between either the rs17576, rs3918242 or rs3025058 and subclinical markers of coronary artery disease in the same subset of patients with T2DM.
A total of 595 subjects with T2DM and 200 subjects without T2DM (control group) were enrolled in the prospective study. Subclinical markers of carotid atherosclerosis were assessed ultrasonographically. Additionally, in a subset of subjects with T2DM a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of all three polymorphisms (rs17576, rs3918242, rs3025058) was performed with real-time PCR systems.
The comparison of atherosclerosis parameters was performed with regard to different genotypes of MMP-9 rs17576, rs3918242, and MMP-3 rs3025058 polymorphisms upon enrolment and during follow-up. In our study, we found an association between the MMP-3 rs3025058 and CIMT at the time of recruitment. Multiple linear regression analysis revealed the association of either the A- allele or the A- genotypes of the rs3025058 (MMP-3) with carotid intima media thickness (CIMT) progression in a 3.8-year follow-up. We demonstrated the effect of the rs3025058 on subclinical markers of coronary atherosclerosis (coronary calcium score, number of coronary arteries with more than 50 % stenosis, and presence of at least one vessel with more than 50 % stenosis).
We found an association between the MMP-3 rs3025058 and subclinical markers of carotid (CIMT) and coronary atherosclerosis at the time of recruitment. Moreover, we demonstrated the effect of the MMP-3 rs3025058 on CIMT progression in the 3.8-year follow-up in patients with T2DM.
Abstract Aim In the present study we investigated the association between genetic polymorphisms with functional effects on redox regulation: Val16Ala of manganese superoxide dismutase (MnSOD), ...polymorphic deletions of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) and Ile105Val of glutathione S-transferase P1 (GSTP1) and myocardial infarction (MI) in a group of patients with type 2 diabetes mellitus. Methods The study population consisted of 463 Caucasian subjects with type 2 diabetes mellitus of more than 10 years’ duration: 206 patients with MI and 257 patients with no history of coronary artery disease (CAD). Genotypes were determined by polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP) and with multiplex PCR. Results The genotype distributions of tested single nucleotide polymorphisms did not show significant difference between cases and controls. After adjustment for age, gender, smoking, BMI, duration of diabetes and lipid parameters carriers of GSTM1/GSTT1-null haplotype showed an increased risk for MI (OR = 3.22, 95% CI 1.37–5.04, p = 0.03). Conclusions The GSTM1/GSTT1 haplotype might be a genetic risk factor for MI in patients with type 2 diabetes mellitus.
Background. The current study was designed to reveal possible associations between the polymorphisms of the vascular endothelial growth factor (VEGF) gene (rs2010963) and its receptor, kinase insert ...domain-containing receptor (KDR) gene polymorphism (rs2071559), and markers of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Genotyping of VEGF/KDR polymorphisms (rs2010963, rs2071559) was performed using KASPar assays. Results. Genotype distributions and allele frequencies of the VEGF/KDR polymorphisms (rs2010963, rs2071559) were not statistically significantly different between diabetic patients and controls. In our study, we demonstrated an association between the rs2071559 of KDR and either CIMT or the sum of plaque thickness in subjects with T2DM. We did not, however, demonstrate any association between the tested polymorphism of VEGF (rs2010963) and either CIMT, the sum of plaque thickness, the number of involved segments, hsCRP, the presence of carotid plaques, or the presence of unstable carotid plaques. Conclusions. In the present study, we demonstrated minor effect of the rs2071559 of KDR on markers of carotid atherosclerosis in subjects with T2DM.
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