Obesity in Hypertensive Patients Is Characterized by a Dawn Phenomenon in Systolic Blood Pressure Values and Variability.

One of the causes of hypertension is excess weight gain, which can also affect the course of this disease. Both the diagnosis and management of hypertension commonly use ambulatory blood pressure monitoring; the results of which correlate more strongly with cardiovascular diseases and cardiovascular death than office blood pressure monitoring. We evaluated blood pressure values and their variability from hour to hour to see if and when they differed between hypertensive patients with and without obesity. The study included 1345 patients who underwent 24 h ambulatory blood pressure monitoring and then were divided into groups according to body mass index and waist circumference. The obtained data were analyzed according to the subjects' wake-up time, and short-term blood pressure variability parameters were calculated as the mean of the absolute values of the differences between consecutive measurements. The systolic blood pressure in obese subjects was significantly higher between 1 and 5 h before waking than in normal-weighted individuals. In turn, the variability in systolic and diastolic blood pressure was higher with increasing body mass index. The difference in systolic blood pressure values and blood pressure variability was most prominent in the last 5 h of sleep in obese patients.

Predictive role of monocyte count for significant coronary artery disease identification in patients with stable coronary artery disease.

BACKGROUND: The coronary artery disease (CAD) remains the leading cause of morbidity that is characterized by broad spectrum of symptoms. Up to 30% of performed angiographies reveal normal coronary arteries. The aim of the study was to find simple predictor for significant epicardial artery stenosis among patients with chronic coronary syndrome. METHODS: There were 187 patients (131 (709%) men and 56 (30%) women) in the median (Q1-Q3) age of 67 [58-72] presenting with stable CAD symptoms enrolled into the present retrospective analysis. The demographical, clinical and laboratory characteristics between patients with normal and significant coronary artery stenosis were compared. RESULTS: The multivariable analysis revealed coexistence of hypercholesterolemia as significant differentiation factor (odds ratio [OR]: 4.38, 95% confidence interval [CI]: 1.78-10.80, p = 0.001) for significant CAD and inverse relation to serum high density lipoprotein (OR: 0.19, 95% CI: 0.05-0.72, p = 0.015) and relation to creatinine concentration (OR: 1.03, 95% CI: 1.00-1.05, p = 0.012). Among whole peripheral blood count analysis, the significant relation was noticed to be hemoglobin concentration (OR: 1.09, 95% CI: 1.10-1.18, p = 0.022) and monocyte count (OR: 32.3, 95% CI: 1.09-653.6, p = 0.017). Receiver operator curve revealed (AUC: 0.641, p = 0.001) with the optimal cut-off value above 0.45 K/uL for monocyte, yelding sensitivity of 81.82% and specificity of 58.06%. CONCLUSIONS: The peripheral monocyte count above 0.45 k/uL may be considered as a predictor of significant coronary artery disease in symptomatic patients with chronic coronary syndrome.

Serum starvation-based method of ovarian cancer cell dormancy induction and termination in vitro.

Awakening and growth reinitiation by dormant cells may contribute to epithelial ovarian cancer (EOC) relapse. The links between these phenomena are loose because of the limited stock of compelling models of EOC dormancy. Here, we show a simple and convenient dormancy research protocol based on serum starvation. This study was conducted on established EOC cell lines A2780, OVCAR-3, and SKOV-3, as well as on primary EOC cells. Cell growth arrest and proliferation were monitored by assessing the Ki67 antigen, PKH26 fluorescence, and cell cycle distribution. In addition, cells were tested for ERK1/2/p38 MAPK activity ratio, apoptosis, and senescence. The study showed that 72-h serum starvation induces G0/G1 growth arrest of a significant fraction of cells, accompanied by reduced Ki67 and ERK1/2/p38 MAPK activity ratio, without signs of apoptosis or cellular senescence. Moreover, providing cells with 72 h of a medium enriched in 5% serum allows the culture to regain its proliferative potential. At the same time, we attempted to induce and terminate dormancy with Mitomycin C addition and withdrawal, which were unsuccessful. In conclusion, serum starvation is a convenient way to reliably induce dormancy in EOC cells, allowing them to be efficiently awakened for further mechanistic research in vitro.

Target Blood Pressure Values in Ambulatory Blood Pressure Monitoring.

INTRODUCTION: 2018 ESC/ESH guidelines have recommended 24-h ambulatory blood pressure monitoring to assess hypotensive therapy in many circumstances. Recommended target blood pressure in office blood pressure measurements is between 120/70 and 130/80 mmHg. Such targets for 24-h ambulatory blood pressure monitoring lacks. AIM: We aimed to define target values of blood pressure in 24-h ambulatory blood pressure monitoring in hypertensive patients. METHODS: Office blood pressure measurements and 24-h ambulatory blood pressure monitoring data were collected from 1313 hypertensive patients and sorted following increasing systolic (SBP)/diastolic (DBP) blood pressure in office blood pressure measurements. The corresponding 24-h ambulatory blood pressure monitoring to office blood pressure measurements values were calculated. RESULTS: Values 130/80 mmHg in office blood pressure measurements correspond in 24-h ambulatory blood pressure monitoring: night-time SBP/DBP mean: 113.74/66.95 mmHg; daytime SBP/DBP mean: 135.02/81.78 mmHg and 24-h SBP/DBP mean: 130.24/78.73 mmHg. Values 120/70 mmHg in office blood pressure measurements correspond in 24-h ambulatory blood pressure monitoring: night-time SBP/DBP mean: 109.50/63.43 mmHg; daytime SBP/DBP mean: 131.01/78.47 mmHg and 24-h SBP/DBP mean: 126.36/75.31 mmHg. CONCLUSIONS: The proposed blood pressure target values in 24-h ambulatory blood pressure monitoring complement the therapeutic target indicated in the ESC/ESH recommendations and improves 24-h ambulatory blood pressure monitoring usefulness in clinical practice.

Pro-cancerogenic effects of spontaneous and drug-induced senescence of ovarian cancer cells in vitro and in vivo: a comparative analysis.

BACKGROUND: Clinical outcomes of cancer cell senescence are still elusive. Here, we reveal and compare pro-cancerous activity of spontaneously and drug-inducible senescent ovarian cancer cells. Experiments were performed on tumors and tumor-derived primary epithelial ovarian cancer cells (pEOCs) that were obtained from chemotherapy-naïve patients and from patients who received carboplatin (CPT) and paclitaxel (PCT) before cytoreduction. RESULTS: The analysis of tumors showed that senescent cancer cells are present in patients from both groups, albeit most frequently and covering a greater area in tissues from chemotherapy-positive women. This in vivo senescence of pEOCs translated to an expression of senescence markers in early-passage cells in vitro. A conditioned medium from senescent pEOCs fueled the cancer progression, including adhesion of non-senescent pEOCs to normal peritoneal cells, and their increased proliferation, migration, invasion, and EMT. Senescent pEOCs' secretome promoted angiogenic activity of vascular endothelium, induced senescence of normal peritoneal cells, reprogrammed their secretome towards hypersecretion of cancer-promoting proteins, and stimulated motility of cancer cells subjected to a mesothelium- and fibroblast-derived medium. The most striking finding was, however, that spontaneously senescent pEOCs supported all the above pro-cancerous effects more efficiently than drug-inducible senescent cells, which was plausibly related to augmented release of several cancer spread mediators by these cells. The prevalence of spontaneously senescent pEOCs was most evident in experiments on mice when they were able, unlike the drug-inducible cells, to promote the development of drug-sensitive i.p. xenografts. CONCLUSIONS: Our study shows that spontaneous senescence of pEOCs should be treated as an independent pathogenetic factor of cancer progression.

Circulating microRNAs in patients with aneurysmal dilatation of coronary arteries.

To understand the mechanism underlying coronary artery abnormal dilatation (CAAD), the present study identified and compared the expression of circulating microRNAs (miRNAs) in three groups of patients. Group 1 included 20 patients with CAAD, Group 2 included 20 patients with angiographically confirmed coronary artery disease (CAD), and Group 3 included 20 patients with normal coronary arteries (control). miRNAs were isolated from plasma samples and were profiled using PCR arrays and miRCURY LNA Serum/Plasma Focus PCR Panels. The present study demonstrated that the plasma miRNA levels were significantly different in Group 1 compared with in Group 2 and Group 3 (fold change >2 and P<0.05). The comparison of Group 1 with Group 3 identified 21 significantly upregulated and two downregulated miRNAs in patients with CAAD compared with in the control group. Moreover, six upregulated and two downregulated miRNAs were identified in patients with CAD compared with in the controls. The third comparison revealed four upregulated and three downregulated miRNAs in Group 1, when compared with patients with CAD. In conclusion, the present study identified a specific signature of plasma miRNAs, which were upregulated and downregulated in patients with CAAD compared with in patients with CAD and control individuals.

Involvement of Angiogenesis in the Pathogenesis of Coronary Aneurysms.

The present study aimed to evaluate the plasma concentration of pro and antiangiogenic factors and their role in the pathogenesis of coronary artery abnormal dilation (CAAD). We measured the plasma concentration of matrix metalloproteinase-8 (MMP-8), transforming growth factor beta 1 (TGF-ß1), Angiopoietin-2, vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) using a sandwich ELISA technique in the plasma of patients with coronary artery abnormal dilation (CAAD, Group 1), coronary artery disease (CAD, Group 2), and normal coronary arteries (NCA, Group 3). Patients suffering from CAAD showed significantly higher plasma concentrations of VEGF (p = 0.002) than those from the control group. Both pathological angiogenesis and inflammation appear to be crucial in the pathogenesis of aneurysmal dilatation of the coronary arteries.

Endocan expression correlated with total volume of coronary artery dilation in patients with coronary artery ectasia.

INTRODUCTION: Inflammation and angiogenesis disturbances are considered as factors contributing to the development of coronary artery ectasias (CAE). Endocan (endothelial cell-specific molecule-1 - ESM-1) regulates both inflammatory and angiogenetic processes. However, there are no data about the correlation between endocan level and the severity of CAE measured with total volume of coronary artery dilation. AIM: To assess whether the severity of the inflammatory process measured as endocan concentration correlates with the total volume of CAE. MATERIAL AND METHODS: We selected prospectively a total of 43 consecutive patients with coronary artery ectasia from 2240 patients who underwent coronary angiography in our center. Determination of endocan was performed by using the Human Endothelial cell-specific Molecule 1 (ECSM1/ENDOCAN) ELISA Kit. 3D QCA (three-dimensional quantitative coronary angiography) was used for coronary lesion and aneurysm quantification. The total volume of dilation was defined as the volume of all aneurysms and ectasias of coronary arteries in 1 patient. RESULTS: The mean volume of all aneurysms in 1 patient was 677 ±878.7 mm3. The total aneurysm volume was positively strongly correlated with endocan concentration (Pearson correlation coefficient: 0.811; 2-tailed p < 0.001). CONCLUSIONS: Endocan is a potential marker of vascular wall damage mainly as a result of inflammation in the course of atherosclerosis, but also vascular remodeling as a result of a disturbance of pro- and anti-angiogenic processes. Endocan level reflects the intensity of the above processes and therefore correlates with the severity of CAE, measured as the total volume of dilation.

Senescence-related deterioration of intercellular junctions in the peritoneal mesothelium promotes the transmesothelial invasion of ovarian cancer cells.

Mechanisms of transmesothelial invasion of ovarian cancer are still poorly understood. Here we examined whether this phenomenon may be determined by an expression of intercellular junctions in peritoneal mesothelial cells (PMCs). Analysis of ovarian tumors showed that cancer cells are localized below an intact layer of PMCs. The PMCs located near the invaded cancer cells displayed low expression of connexin 43, E-cadherin, occludin, and desmoglein, as well as expressed SA-ß-Gal, a marker of senescence. Experiments in vitro showed that senescent PMCs exhibited decreased levels of the four tested intercellular junctions, and that the invasion of ovarian cancer cells through the PMCs increased proportionally to the admixture of senescent cells. Intervention studies showed that the expression of connexin 43, E-cadherin, occludin, and desmoglein in senescent PMCs could be restored upon the blockade of p38 MAPK, NF-κB, AKT, JNK, HGF, and TGF-ß1. When these molecules were neutralized, the efficiency of the transmesothelial cancer cell invasion was diminished. Collectively, our findings show that the integrity of the peritoneal mesothelium, which is determined by the expression of junctional proteins, is critical for the invasion of ovarian cancer. They also indicate a mechanism by which senescent PMCs may promote the invasive potential of cancer cells.

Is hyperhomocysteinemia a causal factor for heart failure? The impact of the functional variants of MTHFR and PON1 on ischemic and non-ischemic etiology.

BACKGROUND: Hyperhomocysteinemia was found to be uniformly associated with the development of heart failure (HF) and HF mortality; however, it is uncertain whether this relation is causative or not. We used Mendelian randomization to examine the associations of the methylene tetrahydrofolate gene (MTHFR) and paraoxonase 1 gene (PON1) variants as a proxy for lifelong exposure to high Hcy and Hcy-thiolactone concentrations with the development of HF in men aged ≤60years and the occurrence of adverse effects at one-year follow-up. METHODS: The study enrolled 172 men with HF: 117 with ischemic etiology (iHF) related to coronary artery disease (CAD) and 55 with non-ischemic etiology (niHF) related to dilated cardiomyopathy (DCM). The reference group of 329 CAD patients without HF and the control group of 384 men were also analyzed. RESULTS: Hyperhomocysteinemia (OR=2.0, P<0.05) and the MTHFR 677TT/1298AA, 677CC/1298CC genotypes (OR=1.6, P=0.03) were associated with HF regardless of its etiology, especially among normotensives (OR=4.6, P=0.001 and OR=2.3, P=0.003, respectively). In niHF, the PON1 162AA (OR=2.3, P=0.03) and 575AG+GG (OR=0.46, P=0.01) genotypes also influenced the risk. The interaction between HDLC<1mmol/L and the PON1 575GG genotype was found to influence the risk of iHF (OR=7.2, P=0.009). Hyperhomocysteinemia improved the classification of niHF patients as 'high-risk' by 10.1%. Ejection fraction <30% and DCM increased the probability of HF death or re-hospitalization within one year. CONCLUSION: Our results provide evidence that hyperhomocysteinemia is a causal factor for niHF in DCM, while dysfunctional HDL could contribute to the pathogenesis of iHF.

[Smoking enhances the decrease of adiponectin level in patients with coronary artery disease, carriers of MTHFR 677T and PON1 55M alleles]. / Palenie tytoniu nasila obnizenie poziomu adiponektyny u osób z miazdzyca tetnic wiencowych, nosicieli alleli MTHFR 677T i PON1 55M.

Decreased adiponectin level, the adipose tissues hormone, is related to high body mass and insulin resistance, which are risk factors for atherosclerosis. It was shown, that cigarette smoking and high homocysteine (Hcy) level are associated with low level of adiponectin. In the presented study we search for the associations between 5 polymorphisms in genes involved in Hcy metabolism - methylenetetrahydrofolate reductase (MTHFR) and paraoxonase 1 (PON1), smoking, adiponectin levels and insulin resistance in subjects with coronary artery disease (CAD). The studied group consisted of 152 patients subjected to coronary arteriography. In 116 patients significant atherosclerotic changes in vascular vessels were confirmed (CAD group), remaining patients were considered as the control group. In studied group, the levels of glucose, insulin, adiponectin and blood lipids profile were measured. Adiponectin and insulin levels were determined by radioimmunological assays. The insulin resistance was calculated using mathematical HOMA model. MTHFR 677C>T, 1298A>C, PON1 -108C>T, L55M, Q192R polymorphisms were ascertained by PCR-RFLP methods. In the studied group (N = 152), significantly decreased adiponectin levels and higher degree of insulin resistance were present in subjects with angina pectoris (N = 129) and peripheral atherosclerosis (N = 32), whereas in the cases of CAD, confirmed in coronary arteriography (N = 116), only the higher degree of insulin resistance was noted. Arterial hypertension (p = 0.004), diabetes mellitus (p = 0.03) and smoking (p = 0.04) were the most significant vascular risk factors associated with the low adiponectin levels. In CAD group, negative correlations between the level of adiponectin and the dose of MTHFR 677T (r = - 0.238; p < 0.05) and PON1 55M (r = -0.251; p < 0.05 alleles were found. The MTHFR 677T allele was also correlated with degree of insulin resistance (r = 0.391; p < 0.05). In smokers, these genetic associations were stronger (r = -0.394; = -0.353; r = 0.440; respectively), which demonstrates, that the negative effects of MTHFR 677T and PON1 55M alleles are enhanced by smoking. Moreover, only in smokers the correlations between adiponectin levels and: the degree of insulin resistance (r = -0.465; p < 0.01) and the levels of HDLC (r = 0.479; p < 0.01) were seen. In summary, in CAD patients, particularly in smokers, occurrence of MTHFR and PON1 risk alleles is associated with the decreased adiponectin levels and/or increased degree of insulin resistance.