Oral Anticoagulation in Patients With Atrial High-Rate Episodes: Focus on Clinical Implications.

Background Although previous studies showed that atrial high-rate episodes (AHREs) are associated with a higher risk of developing incident atrial fibrillation (AF) and thromboembolic events, their clinical significance is still unclear. The purpose of this study was to define whether there is any clinical impact on the occurrence of ischemic and hemorrhagic events in patients with AHREs and initiation of oral anticoagulation (OAC). Methodology Patients with AHREs who had received cardiac implantable electronic devices (CIEDs, i.e., dual-chamber pacemaker [PM] or implantable cardioverter defibrillator [ICD]) were included in the study. OAC initiation was decided by the assistant doctor. Patients who received OACs comprised the OAC group, while patients who were not referred for OAC initiation were included in the control group. The primary endpoint was the time to the event of the occurrence of thromboembolic events (thromboembolic event-free survival). Results A total of 154 individuals (77 in each group) were enrolled in the study, with a mean age of 72.5 years. The mean follow-up period for the OAC group was 19.1 months and for the control group, 18.9 months (P = 0.9). Thromboembolic events were noticed only in seven patients. Six of them were in the control group, and only one in the OAC group (P = 0.05). Major bleeding events were noticed in five patients, one of whom was in the control group and the rest in the OAC group (P = 0.17). Conclusions OAC therapy in patients with AHREs was not associated with a significant difference in the risk of thromboembolic and bleeding events. Baseline patient characteristics and AHRE duration may be useful to intensify the monitoring and management of patients with AHREs. Bleeding events may be indicators of cancer in patients with AHREs receiving OACs.

Vascular handlebar syndrome with blunt injury of common femoral artery.

Vascular handlebar syndrome with blunt injury of the common femoral artery is a rare vascular trauma mechanism, with high possibility of being missed or delayed. We present two cases of vascular handlebar syndrome treated in our hospital and a systematic review of the literature using MEDLINE and SCOPUS databases. Literature review identified 20 similar cases. The median age of patients was 18 years, and in vast majority males in gender. In most cases, the common femoral artery injury was an intimal flap and lumen occlusion with intramural thrombosis followed by transection and intimal injury without occlusion or thrombosis. The median time between injury and diagnosis/treatment was half an hour. Clinical presentation ranged from asymptomatic to acute limb ischemia. The grade of acute ischemia was mostly Rutherford class I (n=14), while acute IIa (n=4), chronic ischemia (n=3), and no ischemia (n=1) were also noticed. The correct diagnosis was revealed by clinical examination only (n=1), or by the combination of clinical and imaging techniques including computed tomography angiography (n=7) and duplex ultrasonography (n=4) or both (n=10). Management of the handlebar trauma syndrome injuries was surgical in most cases. Outcome was favorable in all patients. Vascular handlebar syndrome is extremely rare and high suspicion is required for early diagnosis and definitive treatment, as the early management is effective and crucial for averting the devastating consequences. An individualized approach to the vascular trauma patient is to be applied with considerations taken to the age of the patient, the mechanism of the injury, the anatomy of the lesion, and symptomatology of the case.

Expression of Tissue microRNAs in Ascending Aortic Aneurysms and Dissections.

Little is known about the role of serum and tissue mediators in the progression of ascending aortic aneurysms and dissections. We examined how the tissue expression of microRNAs and matrix metalloproteinases (MMPs), as well as the serum levels of osteoprotegerin, adiponectin, and high sensitivity C-reactive protein (hsCRP) are associated with these entities. We enrolled 21 patients with ascending aortic aneurysm, 11 with acute Stanford type A aortic dissection and 18 controls. The serum levels of osteoprotegerin, adiponectin, and hsCRP, as well as the tissue expression of MMPs 2 and 9 and tissue microRNAs 29 and 195 were compared among groups. There was no difference regarding serum osteoprotegerin, adiponectin, and tissue MMP2 and MMP9 levels. hsCRP was higher in the dissection group (P = .03). Tissue expression of microRNA 29 was 2.11-fold higher in the dissection (P = .001) and 2.99-fold higher in the aneurysm group (P < .001), compared with the control group. Tissue expression of microRNA 195 was 2.72-fold higher in the dissection (P < .001) and 2.00-fold lower in the aneurysm group (P = .08), compared with to the control group. These findings support the contribution of microRNAs in the progression of aneurysm formation and dissection, suggesting a role as potential biomarkers and future therapeutic targets.

A case report of left ventricular thrombus formation following aggressive decongestion treatment.

Background: Intracardiac thrombi are a complication associated with cardiomyopathies. In heart failure with reduced ejection fraction, there is a hypercoagulable state that can increase the incidence of left ventricular thrombus and result in higher risk of thromboembolism, either manifested as stroke or as peripheral thromboembolic event. Haemoconcentration following decongestion treatment may enhance blood viscosity. Case summary: A 63-year-old man with known long-standing heart failure (HF) of ischaemic aetiology and not any prothrombotic risk, admitted with congestive HF and treated with aggressive decongestion treatment with intravenous loop diuretics. During his hospital stay, and following decongestion and haemoconcentration, a left ventricular (LV) intracardiac thrombus formation was detected by echocardiography, which occurred in the absence of a recent myocardial infarction or adverse LV remodelling. The patient was treated with oral anticoagulation therapy. There was a complete resolution of the thrombus on repeat transthoracic echocardiography after 4 weeks of treatment. Discussion: Aggressive decongestive treatment, haemoconcentration and increased blood viscosity following HF decompensation may serve as a trigger for intracardiac thrombus formation under the appropriate prothrombotic background. Appropriate primary antithrombotic prophylaxis is an issue raised concerns and vulnerable patients need closed clinical and imaging follow-up.

The Association of Physical Activity with Arterial Stiffness and Inflammation: Insight from the "Corinthia" Study.

Diminished physical activity is a frequent phenomenon leading to a higher incidence of cardiovascular morbidity and mortality. Our study aimed to assess the impact of physical activity on arterial stiffness and inflammation. Classification of physical activity was performed in 1945 individuals of the cross-sectional "Corinthia" study using the International Physical Activity Questionnaire. Demographic and clinical characteristics were obtained via a standardized questionnaire. Arterial stiffness was estimated via carotid-femoral pulse wave velocity evaluation, and the inflammatory burden was assessed via high sensitivity C reactive protein (hsCRP) measurement. Participants with low physical activity had the most impaired carotid-femoral pulse wave velocity values while abnormally increased measurements-adjusted for age and blood pressure-were more frequently encountered in individuals with low physical activity. Participants characterized as having vigorous physical activity had the lowest inflammatory burden, as estimated by hsCRP levels. The results remained unaffected even after adjustment for confounders. In a subgroup analysis according to sex, increased arterial stiffness and inflammatory burden were noted similarly in female and male subjects within the lowest percentile of physical activity. In conclusion, a significant association between physical activity, arterial stiffness, and inflammation was observed, even after adjusting for known cardiovascular risk factors.

The association of diabetes mellitus with carotid atherosclerosis and arterial stiffness in the Corinthia study.

BACKGROUND AND AIMS: Evaluation of arterial stiffness and carotid atherosclerotic burden can provide important prognostic information regarding the risk of future cardiovascular events. The aim of this study was to assess these vascular properties in patients with diabetes mellitus (DM). METHODS AND RESULTS: In the context of the observational "Corinthia" study, we analyzed 1757 participants with determined DM status. Carotid ultrasonography was performed to evaluate intima-media thickness (cIMT) and carotid plaque burden. Arterial stiffness was estimated via assessment of carotid-to-femoral pulse wave velocity (cfPWV). Individuals with DM had increased mean cIMT, maximum cIMT, carotid plaque burden, and cfPWV compared to those without DM. After multivariable regression analysis, the presence of DM was still associated with significantly increased mean cIMT (by 0.074 mm, p = .004), maximum cIMT (by 0.134 mm, p = .007), cfPWV (by 0.929 m/s, p < .001), and a higher prevalence of carotid plaques (odds ratio 1.52, 95% confidence intervals 1.11, 2.10, p = .01). In a propensity score-matched cohort, mean cIMT, maximum cIMT, and carotid plaque burden were significantly higher in individuals with DM. Analysis according to territory of cIMT measurement displayed substantial differences in left (DM: 1.32 ± 0.78 mm vs. no DM: 1.20 ± 0.66 mm, p = .04) and right carotid bulbs (DM: 1.33 ± 0.82 mm vs. no DM: 1.18 ± 0.69 mm, p = .02) with respect to DM status while non-significant variations were observed in left (DM: 0.98 ± 0.49 mm vs. no DM: 0.91 ± 0.35 mm, p = .06) and right common carotid artery (DM: 0.95 ± 0.50 mm vs. no DM: 0.92 ± 0.40 mm, p = .36). CONCLUSIONS: Diabetes mellitus is associated with increased cfPWV and cIMT, with more pronounced lesions in the carotid bulb.

The Role of Endothelial Related Circulating Biomarkers in COVID-19. A Systematic Review and Meta-analysis.

BACKGROUND: Several studies have revealed the link between Coronavirus Disease 2019 (COVID-19) and endothelial dysfunction. To better understand the global pattern of this relationship, we conducted a meta-analysis on endothelial biomarkers related to COVID-19 severity. METHODS: We systematically searched the literature up to March 10, 2021, for studies investigating the association between COVID-19 severity and the following endothelial biomarkers: Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), E-selectin, P-selectin, Von Willebrand Factor Antigen (VWFAg), soluble Thrombomodulin (sTM), Mid-regional pro-adrenomedullin (MR-proADM), and Angiopoietin-2 (Ang-2). Pooled estimates and mean differences (PMD) for each biomarker were reported. RESULTS: A total of 27 studies (n=2213 patients) were included. Critically ill patients presented with higher levels of MR-proADM (PMD: 0.71 nmol/L, 95% CI: 0.22 to 1.20 nmol/L, p=0.02), E-selectin (PMD: 13,32 pg/ml, 95% CI: 4,89 to 21,75 pg/ml, p=0.008), VCAM-1 (PMD: 479 ng/ml, 95% CI: 64 to 896 ng/ml, p=0.03), VWF-Ag (PMD: 110.5 IU/dl, 95% CI: 44.8 to 176.1 IU/dl, p=0.04) and Ang-2 (PMD: 2388 pg/ml, 95% CI: 1121 to 3655 pg/ml, p=0.003), as compared to non-critically ill ones. ICAM-1, P-selectin and thrombomodulin did not differ between the two groups (p>0.05). CONCLUSION: Endothelial biomarkers display significant heterogeneity in COVID-19 patients, with higher MR-proADM, E-selectin, VCAM-1, VWF-Ag, and Ang-2 levels being associated with increased severity. These findings strengthen the evidence on the key role of endothelial dysfunction in disease progress.

The association of air pollutants exposure with subclinical inflammation and carotid atherosclerosis.

BACKGROUND: Air pollution is a well-described environmental factor with evidence suggesting a firm association with cardiovascular diseases. The purpose of this study was to determine the association of exposure to gaseous air pollutants on atherosclerosis burden. METHODS: 1955 inhabitants of the Corinthia region, aged 40 years or older, underwent clinical and biochemical assessment as well as carotid ultrasonography to evaluate carotid intima-media thickness (cIMT) and plaque burden. Analyzers recording time series concentration of CO, NO2, and SO2 were located at 4 different open sites (Regions 1, 2, 3 and 4) based on their proximity to industries, highways or shipyards. RESULTS: A higher concentration of CO, NO2, and SO2 was observed in Region 4 compared to the other regions. Mean cIMT (Region 1: 0.93 ± 0.24 mm; Region 2: 0.96 ± 0.40 mm; Region 3: 0.94 ± 0.39 mm; Region 4: 1.14 ± 0.55 mm, p < 0.001), maximum cIMT (p < 0.001) as well as carotid plaque burden (Region 1: 13.3%; Region 2: 18.8%; Region 3: 22.4%; Region 4: 38.6%, p < 0.001) were significantly higher in individuals of Region 4. Inhabitants of Region 4 had also higher levels of C reactive protein (Region 1: 4.56 ± 4.85 mg/l; Region 2: 3.49 ± 4.46 mg/l; Region 3: 4.03 ± 3.32 mg/l, Region 4: 5.16 ± 8.26 mg/l, p < 0.001). Propensity score analysis revealed higher inter-area differences in mean cIMT of individuals with coronary artery disease (CAD) (high vs low air pollution area: 1.56 ± 0.80 mm; vs. 1.18 ± 0.54 mm, p < 0.001) while there was no difference in cIMT of the matched population without CAD (p = 0.52). CONCLUSIONS: An increased carotid atherosclerotic and inflammatory burden is observed in inhabitants of areas with the highest concentration of air pollutants.

The impact of sleeping duration on atherosclerosis in the community: insights from the Corinthia study.

PURPOSE: Sleep is an essential physiologic process whose disturbances have been regarded as a risk factor in various pathophysiologic processes, including atherosclerosis and cardiovascular disease. Although the negative influence of short sleep duration has been well-established, recent data suggest a possible harmful effect of prolonged sleeping pattern. METHODS: In the setting of the Corinthia cross-sectional study, self-reported night sleep duration was recorded in 1752 apparently healthy individuals and was classified as normal sleep duration (NSD, 7-8 h), short sleep duration (SSD, 6-7 h), very short sleep duration (VSSD, < 6 h), and long sleep duration (LSD, > 8 h). Carotid duplex ultrasonography was performed in order to measure the mean and maximum carotid intima-media thickness (cIMT) as a non-invasive marker of atherosclerosis. RESULTS: Subjects with LSD and VSSD had significantly higher mean cIMT (VSSD: 1.02 ± 0.45 mm, SSD: 0.95 ± 0.35, NSD: 0.96 ± 0.38 mm, LSD: 1.07 ± 0.52 mm; p < 0.001) and maximum cIMT (VSSD: 1.39 ± 0.9 mm, SSD: 1.25 ± 0.71 mm, NSD: 1.23 ± 0.76 mm, LSD: 1.41 ± 0.93 mm). Following a regression analysis adjusting for known cardiovascular risk factors, individuals with LSD and VSSD had higher mean cIMT by 0.054 mm and 0.067 mm respectively compared to those with NSD. CONCLUSION: A balanced sleeping duration of 6-8 h is associated with decreased mean and maximum IMT while both very short sleep duration and long sleep duration are associated with increased carotid intima-media thickness, a marker of subclinical atherosclerosis.

Association of Soluble Suppression of Tumorigenesis-2 (ST2) with Endothelial Function in Patients with Ischemic Heart Failure.

Soluble suppression of tumorigenesis-2 (sST2) has been introduced as a marker associated with heart failure (HF) pathophysiology and status. Endothelial dysfunction is a component underlying HF pathophysiology. Therefore, we examined the association of arterial wall properties with sST2 levels in patients with HF of ischemic etiology. We enrolled 143 patients with stable HF of ischemic etiology and reduced left ventricular ejection fraction (LVEF) and 77 control subjects. Flow-mediated dilation (FMD) was used to evaluate endothelial function and pulse wave velocity (PWV) to assess arterial stiffness. Although there was no significant difference in baseline demographic characteristics, levels of sST2 were increased in HF compared to the control (15.8 (11.0, 21.8) ng/mL vs. 12.5 (10.4, 16.3) ng/mL; p < 0.001). In the HF group, there was a positive correlation of sST2 levels with age (rho = 0.22; p = 0.007) while there was no association of LVEF with sST2 (rho = -0.119; p = 0.17) nor with PWV (rho = 0.1; p = 0.23). Interestingly, sST2 was increased in NYHA III [20.0 (12.3, 25.7) ng/mL] compared to patients with NYHA II (15.0 (10.4, 18.2) ng/mL; p = 0.003) and inversely associated with FMD (rho = -0.44; p < 0.001) even after adjustment for possible confounders. In patients with chronic HF of ischemic etiology, sST2 levels are increased and are associated with functional capacity. There is an inverse association between FMD and sST2 levels, highlighting the interplay between the dysfunctional endothelium and HF pathophysiologic mechanisms.

A link between inflammation and thrombosis in atherosclerotic cardiovascular diseases: Clinical and therapeutic implications.

The association between thrombosis and acute coronary syndromes is well established. Inflammation and activation of innate and adaptive immunity are another important factor implicated in atherosclerosis. However, the exact interactions between thrombosis and inflammation in atherosclerosis are less well understood. Accumulating data suggest a firm interaction between these two key pathophysiologic processes. Pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin-6 and interleukin-1, have been implicated in the thrombotic cascade following plaque rupture and myocardial infarction. Furthermore, cell adhesion molecules accelerate not only atheromatosis but also thrombosis formation while activated platelets are able to trigger leukocyte adhesion and accumulation. Additionally, tissue factor, thrombin, and activated coagulation factors induce the release of pro-inflammatory cytokines such as prostaglandin and C reactive protein, which may further induce von Willebrand factor secretion. Treatments targeting immune activation (i.e. interleukin-1 inhibitors, colchicine, statins, etc.) may also beneficially modulate platelet activation while common anti-thrombotic therapies appear to attenuate the inflammatory process. Taken together in the context of cardiovascular diseases, thrombosis and inflammation should be studied and managed as a common entity under the concept of thrombo-inflammation.

Plasma signature of apoptotic microvesicles is associated with endothelial dysfunction and plaque rupture in acute coronary syndromes.

OBJECTIVE: Circulating microvesicles (MV) are surrogate biomarkers of atherosclerosis. However, their role in acute coronary syndromes (ACS) has not been fully elucidated yet. We sought to examine the association of circulating apoptotic MVs with ACS pathophysiology. APPROACH AND RESULTS: One hundred and fifty-three patients (n = 153) were included in the study; 49 patients with ST-elevation myocardial infarction (STEMI), 35 with non-STEMI (NSTEMI), 38 with unstable angina, 15 with stable coronary artery disease and 16 control individuals. Flow cytometry analysis was used to quantify circulating apoptotic/non-apoptotic (phospatidyloserine+/phospatidyloserine-) endothelial cell (EMV), red blood cell (RMV) and platelet (PMV) derived MV. Flow-mediated dilatation (FMD) of the brachial artery was assessed by ultrasound to estimate endothelial function. The inflammatory profile was assessed by serum C-reactive protein (hsCRP) levels. Apoptotic only (but not non-apoptotic) MV were increased in patients with ACS (EMV, P = 2.32 × 10-9; RMV, P = .0019; PMV, P = .01). Hierarchical clustering of the total population of ACS patients (n = 122) by circulating levels of phospatidyloserine+ EMV, RMV and PMV identified two discreet clusters of patients without any differences in traditional risk factors, but significant differences in brachial FMD (5.2% (2.5) vs. 4.1% (2.3), P < .05) that remained significant after adjustment for co-variates. The prevalence of STEMI, a surrogate for plaque rupture and vessel thrombotic occlusion, was significantly higher in the patient cluster with impaired endothelial function (60% vs 32%, P = .016, adjusted odds ratio for STEMI, 3.041, 95%CI, 1.160 to 7.968, p = .024). CONCLUSION: Our findings indicate that the circulating levels of apoptotic MV are increased in ACS patients and their plasma profiles associate with endothelial dysfunction and thrombotic complications in ACS patients.

The influence of resting heart rate on pulse wave velocity measurement is mediated by blood pressure and depends on aortic stiffness levels: insights from the Corinthia study.

OBJECTIVE: Increased resting heart rate as well as increased arterial stiffness are both independent predictors of cardiovascular events and mortality. Results of previous studies have failed to converge concerning the association between heart rate and arterial stiffness, regardless of other potential confounders, such as age, gender and particularly blood pressure (BP). We aimed to investigate: (a) the degree of association (if any) between resting heart rate and carotid-to-femoral pulse wave velocity (PWV), the gold standard index of arterial stiffness, (b) if the relationship between heart rate and PWV is mediated by BP levels and (c) whether their association is affected by the levels of aortic stiffening. APPROACH: Demographic, hemodynamic, laboratory and clinical data of 1566 subjects from the cross-sectional observational 'Corinthia' study were analyzed using univariate and multivariate regression models. Mediation analysis was performed to test whether mean arterial pressure (MAP) is a significant mediator in the heart rate-PWV relationship. The total population was divided in two groups of low and high arterial stiffness according to the median PWV value (8.6 m s-1). MAIN RESULTS: We found that (i) there is a significant association between heart rate and PWV, regardless of other confounding factors. An increase in heart rate by 20 b.p.m. can increase PWV by 0.5 m s-1. However, this association was significant only for subjects with increased aortic stiffness (PWV > 8.6 m s-1) and not for those with PWV ⩽ 8.6 m s-1. Further, (ii) heart rate-PWV association was partially mediated by MAP. SIGNIFICANCE: Increased resting heart rate is related to increased aortic stiffness, only in subjects with stiffer aortas, regardless of BP and other risk factors and subjects' characteristics. The synergistic prognostic effect of increased arterial stiffness and elevated heart rate on target organ damage, cardiovascular events and mortality should be explored in future studies.

Arterial stiffness and subclinical aortic damage of reclassified subjects as stage 1 hypertension according to the new 2017 ACC/AHA blood pressure guidelines.

Background: The 2017 ACC/AHA blood pressure (BP) guidelines generated controversies due to the new proposed BP cut-off values defining hypertension. We aimed to assess aortic stiffness of subjects who are reclassified as stage 1 hypertensive according to the new guidelines and compare them with the subjects of "elevated BP" category. Patients and methods. Data from the "Corinthia" study, an observational, cross-sectional survey of 2,043 participants were analyzed. Subjects were classified into 4 groups: group A: systolic pressure (SBP) 120-129 and diastolic pressure (DBP) < 80 mmHg, group B: SBP 130-139 or DBP 80-89 mmHg, group B1: SBP 130-139 and DBP < 80 mmHg and group B2: SBP 130-139 and DBP 80-89 mmHg. Aortic stiffness was assessed by carotid-to-femoral pulse wave velocity (PWV). A value of PWV > 10m/s was consider indicative of asymptomatic organ damage while values of PWV exceeded the 90 % percentile for each age group were consider as abnormal. Results: Groups B, B1 and B2 have significantly increased PWV compared to group A, independently from age and other risk factors (PWV: 9.2 ± 2.8 vs 9.4 ± 2.7 vs 8.6 ± 2.5 vs 8.1 ± 2.3 m/s, p < 0.01, respectively). The prevalence of PWV > 10 m/s and abnormal PWV values in group A was significantly lower than the corresponding prevalence in randomly selected, age-matched subjects from group B (13.5 % vs 24.4 %, p = 0.027 and 5.6 % vs 14.2 %, p = 0.022, respectively). Conclusions: The reclassified subjects as stage 1 hypertensive by the new guidelines have a significantly increased aortic stiffness and greater prevalence in asymptomatic aortic damage compared to subjects with elevated BP. This finding may indirectly explain the increased cardiovascular risk of this group.