Monocytic microRNAs-Novel targets in atherosclerosis therapy.

Atherosclerosis is a chronic proinflammatory disease of the vascular wall resulting in narrowing of arteries due to plaque formation, thereby causing reduced blood supply that is the leading cause for diverse end-organ damage with high mortality rates. Monocytes/macrophages, activated by elevated circulating lipoproteins, are significantly involved in the formation and development of atherosclerotic plaques. The imbalance between proinflammatory and anti-inflammatory macrophages, arising from dysregulated macrophage polarization, appears to be a driving force in this process. Proatherosclerotic processes acting on monocytes/macrophages include accumulation of cholesterol in macrophages leading to foam cell formation, as well as dysfunctional efferocytosis, all of which contribute to the formation of unstable plaques. In recent years, microRNAs (miRs) were identified as factors that could modulate monocyte/macrophage function and may therefore interfere with the atherosclerotic process. In this review, we present effects of monocyte/macrophage-derived miRs on atherosclerotic processes in order to reveal new treatment options using miRmimics or antagomiRs.

Prognosis of pacing-dependent patients with cardiovascular implantable electronic devices.

BACKGROUND: Data on the prognostic significance of pacing dependency in patients with cardiovascular implantable electronic devices (CIEDs) are sparse. METHODS: The prognostic significance of pacing dependency defined as absence of an intrinsic rhythm ≥ 30 bpm was determined in 786 patients with CIEDs at the authors' institution using univariate and multivariate regression analysis to identify predictors of all-cause mortality. RESULTS: During 49 months median follow-up, death occurred in 63 of 130 patients with pacing dependency compared to 241 of 656 patients without pacing dependency (48% versus 37%, hazard ratio [HR] 1.34; 95% confidence interval [CI]: 1.02-1.78, P = 0.04). Using multivariate regression analysis, predictors of all-cause mortality included age (HR 1.07; 95% CI: 1.05-1.08, P < 0.01), history of atrial fibrillation (HR 1.32, 95% CI: 1.03-1.69, P < 0.01), chronic kidney disease (HR 1.28; 95% CI: 1.00-1.63, P = 0.048) and New York Heart Association (NYHA) class ≥ III (HR 2.00; 95% CI: 1.52-2.62, P < 0.01), but not pacing dependency (HR 1.15; 95% CI: 0.86-1.54, P = 0.35). CONCLUSIONS: In contrast to age, atrial fibrillation, chronic kidney disease and heart failure severity as indexed by NYHA functional class III or IV, pacing dependency does not appear to be an independent predictor of all-cause mortality in patients with CIEDs.

New-Onset Atrial Fibrillation in the Setting of COVID-19 Infection Is a Predictor of Mortality in Hospitalized Patients: CovAF-Study.

Recent studies show that hospitalized COVID-19 patients have an increased incidence of arrhythmia, especially atrial fibrillation (AF). This single-center study included 383 hospitalized patients with positive polymerase chain reaction tests for COVID-19 from March 2020 to April 2021. Patient characteristics were documented, and data were analyzed for episodes of AF on admission or during the hospital stay, intrahospital mortality, need for intensive care and/or invasive ventilation, inflammatory parameters (hs-CRP, IL-6, and procalcitonin), and differential blood count. We demonstrated that in the setting of hospitalized cases of COVID-19 infection, there is an incidence of 9.8% (n = 36) for the occurrence of new-onset AF. Furthermore, it was shown that a total of 21% (n = 77) had a history of episodes of paroxysmal/persistent AF. However, only about one-third of patients with pre-existing AF had relevant documented tachycardic episodes during the hospital stay. Patients with new-onset AF had a significantly increased intrahospital mortality compared to the control and the pre-existing AF without rapid ventricular rate (RVR) group. Patients with new-onset AF required intensive care and invasive ventilation more frequently. Further analysis examined patients with episodes of RVR and demonstrated that they had significantly elevated CRP (p < 0.05) and PCT (p < 0.05) levels on the day of hospital admission compared to patients without RVR.

Comparison of Mechanical Support with Impella or Extracorporeal Life Support in Post-Cardiac Arrest Cardiogenic Shock: A Propensity Scoring Matching Analysis.

Our aim was to compare the outcomes of Impella with extracorporeal life support (ECLS) in patients with post-cardiac arrest cardiogenic shock (CS) complicating acute myocardial infarction (AMI). This was a retrospective study of patients resuscitated from out of hospital cardiac arrest (OHCA) with post-cardiac arrest CS following AMI (May 2015 to May 2020). Patients were supported either with Impella 2.5/CP or ECLS. Outcomes were compared using propensity score-matched analysis to account for differences in baseline characteristics between groups. 159 patients were included (Impella, n = 105; ECLS, n = 54). Hospital and 12-month survival rates were comparable in the Impella and the ECLS groups (p = 0.16 and p = 0.3, respectively). After adjustment for baseline differences, both groups demonstrated comparable hospital and 12-month survival (p = 0.36 and p = 0.64, respectively). Impella patients had a significantly greater left ventricle ejection-fraction (LVEF) improvement at 96 h (p < 0.01 vs. p = 0.44 in ECLS) and significantly fewer device-associated complications than ECLS patients (15.2% versus 35.2%, p < 0.01 for relevant access site bleeding, 7.6% versus 20.4%, p = 0.04 for limb ischemia needing intervention). In subgroup analyses, Impella was associated with better survival in patients with lower-risk features (lactate < 8.6 mmol/L, time from collapse to return of spontaneous circulation < 28 min, vasoactive score < 46 and Horowitz index > 182). In conclusion, the use of Impella 2.5/CP or ECLS in post-cardiac arrest CS after AMI was associated with comparable adjusted hospital and 12-month survival. Impella patients had a greater LVEF improvement than ECLS patients. Device-related access-site complications occurred more frequently in patients with ECLS than Impella support.

JDP2, a Novel Molecular Key in Heart Failure and Atrial Fibrillation?

Heart failure (HF) and atrial fibrillation (AF) are two major life-threatening diseases worldwide. Causes and mechanisms are incompletely understood, yet current therapies are unable to stop disease progression. In this review, we focus on the contribution of the transcriptional modulator, Jun dimerization protein 2 (JDP2), and on HF and AF development. In recent years, JDP2 has been identified as a potential prognostic marker for HF development after myocardial infarction. This close correlation to the disease development suggests that JDP2 may be involved in initiation and progression of HF as well as in cardiac dysfunction. Although no studies have been done in humans yet, studies on genetically modified mice impressively show involvement of JDP2 in HF and AF, making it an interesting therapeutic target.

Biventricular Unloading with Impella and Venoarterial Extracorporeal Membrane Oxygenation in Severe Refractory Cardiogenic Shock: Implications from the Combined Use of the Devices and Prognostic Risk Factors of Survival.

Since mechanical circulatory support (MCS) devices have become integral component in the therapy of refractory cardiogenic shock (RCS), we identified 67 patients in biventricular support with Impella and venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) for RCS between February 2013 and December 2019 and evaluated the risk factors of mortality in this setting. Mean age was 61.07 ± 10.7 and 54 (80.6%) patients were male. Main cause of RCS was acute myocardial infarction (AMI) (74.6%), while 44 (65.7%) were resuscitated prior to admission. The mean Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment Score (SOFA) score on admission was 73.54 ± 16.03 and 12.25 ± 2.71, respectively, corresponding to an expected mortality of higher than 80%. Vasopressor doses and lactate levels were significantly decreased within 72 h on biventricular support (p < 0.05 for both). Overall, 17 (25.4%) patients were discharged to cardiac rehabilitation and 5 patients (7.5%) were bridged successfully to ventricular assist device implantation, leading to a total of 32.8% survival on hospital discharge. The 6-month survival was 31.3%. Lactate > 6 mmol/L, vasoactive score > 100 and pH < 7.26 on initiation of biventricular support, as well as Charlson comorbity index > 3 and prior resuscitation were independent predictors of survival. In conclusion, biventricular support with Impella and VA-ECMO in patients with RCS is feasible and efficient leading to a better survival than predicted through traditional risk scores, mainly via significant hemodynamic improvement and reduction in lactate levels.

Incidence of Atrial Fibrillation in Postmenopausal Women with Endometrial Cancer.

Endometrial cancer (EC) has been associated with an increased risk of cardiovascular disease, including atrial fibrillation (AF). We performed a prospective, case-controlled analysis among 310 Bulgarian women with new-onset, histologically confirmed EC, free of AF at the baseline survey, and women with normal (senile) endometrium/endometrial hyperplasia as a control group (n = 205). The risk of AF as well as relationship of adiponectin (APN) and high sensitivity C-reactive protein (hs-CRP) levels with AF in women with EC were calculated by Cox proportional hazards models. During the mean follow-up of 2.5 ± 0.5 years, new-onset AF had occurred in 11.7% of women with EC vs. 5.8% in the control group (p < 0.01). The risk of AF was highest in the first 6 months after new-onset EC, with an incidence rate ratio (IRR) of 1.19 (95% CI 1.10-1.29; p = 0.01). Women with EC, who were obese (body mass index (BMI) > 30 kg/m2) and younger (age < 60) were found to be more likely to develop AF (HR 1.95; 95% CI 1.18-3.32; p = 0.05). APN levels were not significantly associated with new-onset AF (95% CI 0.87-1.21; p = 0.063). However, the secondary analysis showed evidence of APN-AF association when adjusted for BMI (2.05; 95% CI 1.04-4.04; p = 0.037). We conclude that EC was significantly associated with the incidence of AF.

Predictors of pacing-dependency in patients with cardiovascular implantable electronic devices.

BACKGROUND: Data on the prevalence and predictors for the development of pacing-dependency in patients with cardiovascular implantable electronic devices (CIEDs) are sparse. METHODS: Pacing-dependency defined as an absence of intrinsic rhythm of ≥ 30 bpm was determined in 802 consecutive patients with CIEDs who visited the documented pacemaker or implantable cardioverter- defibrillator outpatient clinic for routine follow-up. RESULTS: A total of 131 (16%) patients were found to be pacing-dependent 67 ± 70 months after CIED implant. Multivariate analysis revealed a significant association between pacing-dependency and the following clinical variables: second or third-degree atrioventricular (AV) block at implant (OR = 19.9; 95% CI: 10.9-38.5, p < 0.01), atrial fibrillation at implant (OR = 2.15; 95% CI: 1.16-4.05, p = 0.02), left ventricular ejection fraction (LVEF) ≤ 30% (OR = 2.06; 95% CI: 1.03-4.15, p = 0.04), B-type natriuretic peptide (BNP) > 150 pg/mL (OR = 2.12; 95% CI: 1.16-3.97, p = 0.02), chronic kidney disease (OR = 1.86; 95% CI: 1.08-3.26, p = 0.03), and follow-up duration after implantation > 5 years (OR = 3.29; 95% CI: 1.96-5.64, p < 0.01). None of the remaining clinical variables including age, gender, diabetes mellitus, underlying heart disease, prior cardiac surgery or medication during follow-up including betablockers and amiodarone predicted pacing-dependency. CONCLUSIONS: Pacing-dependency is associated with second or third-degree AV-block at implant, atrial fibrillation before implant, low LVEF, elevated BNP, chronic kidney disease and follow-up duration after implant.

Structural, Pro-Inflammatory and Calcium Handling Remodeling Underlies Spontaneous Onset of Paroxysmal Atrial Fibrillation in JDP2-Overexpressing Mice.

BACKGROUND: Cardiac-specific JDP2 overexpression provokes ventricular dysfunction and atrial dilatation in mice. We performed in vivo studies on JDP2-overexpressing mice to investigate the impact of JDP2 on the predisposition to spontaneous atrial fibrillation (AF). METHODS: JDP2-overexpression was started by withdrawal of a doxycycline diet in 4-week-old mice. The spontaneous onset of AF was documented by ECG within 4 to 5 weeks of JDP2 overexpression. Gene expression was analyzed by real-time RT-PCR and Western blots. RESULTS: In atrial tissue of JDP2 mice, besides the 3.6-fold increase of JDP2 mRNA, no changes could be detected within one week of JDP2 overexpression. Atrial dilatation and hypertrophy, combined with elongated cardiomyocytes and fibrosis, became evident after 5 weeks of JDP2 overexpression. Electrocardiogram (ECG) recordings revealed prolonged PQ-intervals and broadened P-waves and QRS-complexes, as well as AV-blocks and paroxysmal AF. Furthermore, reductions were found in the atrial mRNA and protein level of the calcium-handling proteins NCX, Cav1.2 and RyR2, as well as of connexin40 mRNA. mRNA of the hypertrophic marker gene ANP, pro-inflammatory MCP1, as well as markers of immune cell infiltration (CD68, CD20) were increased in JDP2 mice. CONCLUSION: JDP2 is an important regulator of atrial calcium and immune homeostasis and is involved in the development of atrial conduction defects and arrhythmogenic substrates preceding paroxysmal AF.

Factor VII Activating Protease Expression in Human Platelets and Accumulation in Symptomatic Carotid Plaque.

Background Factor VII activating protease (FSAP) is of interest as a marker for vascular inflammation and plaque destabilization. The aim of this study was to analyze the expression profile of FSAP in endarterectomy specimens that were taken from patients with asymptomatic and symptomatic carotid atherosclerotic plaques and to compare them with circulating FSAP levels. Methods and Results Plasma FSAP concentration, activity, and mRNA expression were measured in endarterectomy specimens and in monocytes and platelets. Plaque and plasma FSAP levels were higher in symptomatic patients (n=10) than in asymptomatic patients (n=14). Stronger FSAP immunostaining was observed in advanced symptomatic lesions, in intraplaque hemorrhage-related structures, and in lipid-rich areas within the necrotic core. FSAP was also colocalized with monocytes and macrophages (CD11b/CD68-positive cells) and platelets (CD41-positive cells) of the plaques. Moreover, human platelets expressed FSAP in vitro, at both the mRNA and protein levels. Expression is stimulated by thrombin receptor-activating peptide and ADP and reduced by acetylsalicylic acid. Conclusions Plasma FSAP levels were significantly increased in patients with symptomatic carotid stenosis and thus may be involved in plaque development This plaque-associated FSAP may be produced by platelets or macrophages or may be taken up from the circulation. To establish FSAP's utility as a circulating or plaque biomarker in patients with symptomatic carotid atherosclerotic plaques, further studies are needed.

[Cardiac memory following pacemaker implantation]. / Cardiac Memory nach Schrittmacherimplantation.

BACKGROUND: Although T wave inversions due to cardiac memory were described already 50 years ago, little is known about the prevalence and about clinical predictors of this phenomenon. METHODS: After exclusion of 238 patients due to bundle branch block or pacemaker dependency, a total of 325 consecutive patients were enrolled in this study during routine outpatient control of their pacemaker. A 12-lead standard ECG was obtained in all patients during transient inhibition of pacing therapy. RESULTS: Cardiac memory could be documented in 115 of 325 patients (35%) and showed a strong association with the amount of ventricular stimulation. The prevalence of cardiac memory was 9% in patients with ≤25% ventricular stimulation and 86% in patients with ≥75% ventricular stimulation. DISCUSSION: Cardiac memory was observed in one third of patients following pacemaker implantation. The prevalence of cardiac memory in the ECG with intrinsic rhythm is above 80% in patients with frequent ventricular stimulation. Cardiac memory due to ventricular stimulation is benign and should not be confused with similar T wave inversions due to acute coronary syndrome, severe left ventricular hypertrophy, or myocarditis.

Expression of the Marburg I Single Nucleotide Polymorphism (MI-SNP) and the Marburg II Single Nucleotide Polymorphism (MII-SNP) of the Factor VII-Activating Protease (FSAP) Gene and Risk of Coronary Artery Disease (CAD): A Pilot Study in a Single Population.

BACKGROUND Factor VII-activating protease (FSAP) has a role in vascular inflammation and may have a role coronary artery disease (CAD). The aim of this study was to investigate the association between two naturally occurring single nucleotide polymorphisms (SNPs) in the FSAP gene and the risk of coronary artery disease (CAD). MATERIAL AND METHODS Of 733 patients, 173 patients had symptoms of angina, and 560 patients had CAD confirmed by coronary angiography. All patients were genotyped for SNPs of the FSAP gene, Marburg I (MI-SNP) and Marburg II (MII-SNP), using 5' exonuclease TaqMan assays. Logistic regression analysis was used to evaluate the association between two gene polymorphisms, metabolic and other cardiovascular risk factors in patients with CAD. RESULTS The presence of MI-SNP and MII-SNP FSAP gene polymorphisms were not associated with the presence of CAD. However, the MII-SNP polymorphism was significantly associated with a reduced risk of developing CAD (OR=0.422; 95% CI, 0.194-0.920; P=0.035); the MI-SNP polymorphism was associated with absence of hyperlipoproteinemia (OR=0.601; 95% CI, 0.344-1.051; P=0.074). There was no significant association between expression of the MI-SNP and MII-SNP FSAP gene polymorphisms and the incidence of myocardial infarction, or of a history of diabetes mellitus, arterial hypertension, obesity, or smoking. CONCLUSIONS The MI-SNP and MII-SNP FSAP gene polymorphisms were not predictive or prognostic biomarkers for CAD or its main risk factors. However, the presence of the MII-SNP polymorphism was associated with a reduced risk of developing CAD.

JDP2 overexpression provokes cardiac dysfunction in mice.

The transcriptional regulator JDP2 (Jun dimerization protein 2) has been identified as a prognostic marker for patients to develop heart failure after myocardial infarction. We now performed in vivo studies on JDP2-overexpressing mice, to clarify the impact of JDP2 on heart failure progression. Therefore, during birth up to the age of 4 weeks cardiac-specific JDP2 overexpression was prevented by doxycycline feeding in transgenic mice. Then, JDP2 overexpression was started. Already after 1 week, cardiac function, determined by echocardiography, decreased which was also resembled on the cardiomyocyte level. After 5 weeks blood pressure declined, ejection fraction and cardiac output was reduced and left ventricular dilatation developed. Heart weight/body weight, and mRNA expression of ANP, inflammatory marker genes, collagen and fibronectin increased. Collagen 1 protein expression increased, and fibrosis developed. As an additional sign of elevated extracellular matrix remodeling, matrix metalloproteinase 2 activity increased in JDP2 mice. Thus, JDP2 overexpression is deleterious to heart function in vivo. It can be concluded that JDP2 overexpression provokes cardiac dysfunction in adult mice that is accompanied by hypertrophy and fibrosis. Thus, induction of JDP2 is a maladaptive response contributing to heart failure development.

MicroRNA expression profile of human advanced coronary atherosclerotic plaques.

MicroRNA (miR) is reported to be involved in vascular inflammation and may represent a novel class of diagnostic biomarkers in cardiovascular disease. We aimed to identify the miR expression profile in human advanced coronary atherosclerotic plaques (CAP) and to connect this expression to the processes in atherosclerosis. Microarray techniques and TaqMan polymerase chain reaction were used to analyse the global expression of 352 miRs in CAP obtained during ACS MULTI-LINK study. 11 miRs were selected on the basis of their implication in atherosclerosis, endothelial activation, and inflammation. 6 miRs were found to be differently expressed in CAP when compared to non-atherosclerotic internal mammary arteries (IMA, p < 0.05). The expression of miR-21, -92a, and -99a was verified and found to be significantly up-regulated in CAP versus IMA (p < 0.001). We also performed bioinformatic analysis and found several potential target genes of miR-92a and -99a as well as several pathways with impact on atherosclerosis which could be differently expressed due to this miRNA profile. The most up-regulated miRs are involved in processes known to be connected to atherosclerosis. Interfering with the miR expression in the artery wall is a potential way to affect atherosclerotic plaque and cardiovascular disease development.

Publisher Correction: Identification of microRNAs as potential cellular monocytic biomarkers in the early phase of myocardial infarction: a pilot study.

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Identification of microRNAs as potential cellular monocytic biomarkers in the early phase of myocardial infarction: a pilot study.

MicroRNA has been increasingly suggested to be involved in vascular inflammation. The aim of this study was to assess the expression profile of miRs as possible novel cellular biomarkers in circulating monocytes in patients with ST-segment elevation myocardial infarction (STEMI). Microarray techniques and TaqMan polymerase chain reaction were used to analyse the global expression of 352 miRNAs in peripheral blood monocytes from healthy donors (n = 20) and patients (n = 24) with acute STEMI. The expression level of miR-143 in monocytes from STEMI patients compared to healthy controls was increased, whereas the expression of miR-1, -92a, -99a, and -223 was reduced significantly. During 3.5 ± 1.5 months of follow-up miR-1 and -223 were back to baseline, whereas miR-92a and -99a return to normal levels over 3 months, but remained lower than healthy controls. Furthermore, monocytic expression of miR-143 was positively correlated with hs-CRP (R2 = 0.338; P < 0.031), but not with cTnT. Importantly, treatment of monocytes isolated from healthy individuals with INFγ, but not LPS or TNFα caused an upregulation of miR-143 and downregulation of miR-1. Our findings identify circulating monocytes as putative biomarkers and as novel carriers for the cell-specific transfer of miRs in the early phase of myocardial infarction.

Home monitoring after ambulatory implanted primary cardiac implantable electronic devices: The home ambulance pilot study.

BACKGROUND: The Home Monitoring (HM) system of cardiac implantable electronic devices (CIEDs) permits early detection of arrhythmias or device system failures. The aim of this pilot study was to examine how the safety and efficacy of the HM system in patients after ambulatory implanted primary CIEDs compare to patients with a standard procedure and hospitalization. HYPOTHESIS: We hypothesized that HM and their modifications would be a useful extension of the present concepts for ambulatory implanted CIEDs. METHODS: This retrospective analysis evaluates telemetric data obtained from 364 patients in an ambulatory single center over 6 years. Patients were assigned to an active group (n = 217), consisting of those who were discharged early on the day of implantation of the primary CIED, or to a control group (n = 147), consisting of those discharged and followed up with the HM system according to usual medical practices. RESULTS: The mean duration of hospitalization was 73.2% shorter in the active group than in the control group, corresponding to 20.5 ± 13 fewer hours (95% confidence interval [CI]: 6.3-29.5; P < 0.01) spent in the hospital (7.5 ± 1.5 vs 28 ± 4.5 h). This shorter mean hospital stay was attributable to a 78.8% shorter postoperative period in the active group. The proportion of patients with treatment-related adverse events was 11% (n = 23) in the active group and 17% (n = 25) in the control group (95% CI: 5.5-8.3; P = 0.061). This 6% absolute risk reduction (95% CI: 3.3-9.1; P = 0.789) confirmed the noninferiority of the ambulatory implanted CIED when compared with standard management of these patients. CONCLUSIONS: Early discharge with the HM system after ambulatory CIED implantation was safe and not inferior to the classic medical procedure. Thus, together with lower costs, HM and its modifications would be a useful extension of the present concepts for ambulatory implanted CIEDs.

New Task Force Criteria Provide Evolution in Diagnosis of Arrhythmogenic Cardiomyopathy in Patients without Typical Progression of the Disease.

BACKGROUND The original Task Force Criteria from 1994 for the clinical diagnosis of ARVC were highly specific and based on structural, histological, EKG, and familial features of disease. However, recommendations for clinical diagnosis and management of ARVC are sparse and lacked sensitivity for early disease. CASE REPORT Ventricular electrical instability and sudden cardiac death are the hallmarks of ARVC, and are often present before structural abnormalities. In this case report, we describe a patient who had detectable electrical abnormalities and structural changes that remained unchanged for over 10 years. CONCLUSIONS The disease progression in this case was defined as the development of a new 2010 TFC, which was absent at enrolment in 1994 and in 2008.

Uridine Triphosphate Thio Analogues Inhibit Platelet P2Y12 Receptor and Aggregation.

Platelet P2Y12 is an important adenosine diphosphate (ADP) receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma, we demonstrate that UTP inhibits P2Y12 but not P2Y1 receptors and antagonises 10 µM ADP-induced platelet aggregation in a concentration-dependent manner with an IC50 value of ~250 °µM. An eight-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC50 of 30 µM. The 4-thio analogue (4S-UTP) with an IC50 of 7.5 µM was 33-fold more effective. A three-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4S- position. A complete loss of inhibition was observed with thio-modification of the γ phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y12 receptor was verified by P2Y12 receptor binding and cyclic AMP (cAMP) assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y12 receptor antagonists that may be useful for therapeutic intervention.

Differential Expression of MicroRNAs in Endarterectomy Specimens Taken from Patients with Asymptomatic and Symptomatic Carotid Plaques.

OBJECTIVE: Stroke and transient ischemic attacks are considered as clinical manifestations of atherosclerotic disease due to on-going vascular inflammation and finally atherothrombosis of the carotid arteries. MicroRNAs (miRNA/miR) are known to be involved in vascular inflammation and plaque destabilization. The aim of this study was to analyze the expression profile of selected miRNAs in endarterectomy specimen from carotid arteries that were taken from patients with asymptomatic and symptomatic atherosclerotic plaques. METHODS AND RESULTS: 11 miRNAs were selected and their expression was analyzed using real-time RT-PCR. Therefore, samples were divided into three different groups. On the one hand we investigated the expression patterns from patients in asymptomatic (n = 14) and symptomatic (n = 10) plaques; on the other hand we took samples from normal configurated internal mammary arteries (n = 15). Out of these 11 targets we identified some miRNAs, which were up- or down-regulated in either one of the two groups. Interestingly, the expression of two miRNAs was significantly different between asymptomatic and symptomatic samples, namely miR-21 (P<0.01) and miR-143 (P<0.05). CONCLUSION: In the present study, we identified miRNA subtypes which showed different expression in endarterectomy specimen from patients with asymptomatic and symptomatic plaques, suggesting that these miRNAs correlated with advanced vascular inflammation and plaque stability. They may represent new therapeutic targets for vascular proliferative diseases such as atherosclerosis.