CREB Coactivator CRTC2 Plays a Crucial Role in Endothelial Function.

The cAMP pathway is known to stabilize endothelial barrier function and maintain vascular physiology. The family of cAMP-response element binding (CREB)-regulated transcription coactivators (CRTC)1-3 activate transcription by targeting the basic leucine zipper domain of CREB. CRTC2 is a master regulator of glucose metabolism in liver and adipose tissue. However, the role of CRTC2 in endothelium remains unknown. The aim of this study was to evaluate the effect of CRTC2 on endothelial function. We focused the effect of CRTC2 in endothelial cells and its relationship with p190RhoGAP-A. We examined the effect of CRTC2 on endothelial function using a mouse aorta ring assay ex vivo and with photothrombotic stroke in endothelial cell-specific CRTC2-knock-out male mice in vivo CRTC2 was highly expressed in endothelial cells and related to angiogenesis. Among CRTC1-3, only CRTC2 was activated under ischemic conditions at endothelial cells, and CRTC2 maintained endothelial barrier function through p190RhoGAP-A expression. Ser171 was a pivotal regulatory site for CRTC2 intracellular localization, and Ser307 functioned as a crucial phosphorylation site. Endothelial cell-specific CRTC2-knock-out mice showed reduced angiogenesis ex vivo, exacerbated stroke via endothelial dysfunction, and impaired neurologic recovery via reduced vascular beds in vivo These findings suggest that CRTC2 plays a crucial protective role in vascular integrity of the endothelium via p190RhoGAP-A under ischemic conditions.SIGNIFICANCE STATEMENT Previously, the role of CRTC2 in endothelial cells was unknown. In this study, we firstly clarified that CRTC2 was expressed in endothelial cells and among CRTC1-3, only CRTC2 was related to endothelial function. Most importantly, only CRTC2 was activated under ischemic conditions at endothelial cells and maintained endothelial barrier function through p190RhoGAP-A expression. Ser307 in CRTC2 functioned as a crucial phosphorylation site. Endothelial cell-specific CRTC2-knock-out mice showed reduced angiogenesis ex vivo, exacerbated stroke via endothelial dysfunction, and impaired neurologic recovery via reduced vascular beds in vivo These results suggested that CRTC2 maybe a potential therapeutic target for reducing blood-brain barrier (BBB) damage and improving recovery.

Impact of Acute and Chronic Stress on Thrombosis in Healthy Individuals and Cardiovascular Disease Patients.

Psychological stress induces different alterations in the organism in order to maintain homeostasis, including changes in hematopoiesis and hemostasis. In particular, stress-induced hyper activation of the autonomic nervous system and hypothalamic-pituitary-adrenal axis can trigger cellular and molecular alterations in platelets, coagulation factors, endothelial function, redox balance, and sterile inflammatory response. For this reason, mental stress is reported to enhance the risk of cardiovascular disease (CVD). However, contrasting results are often found in the literature considering differences in the response to acute or chronic stress and the health condition of the population analyzed. Since thrombosis is the most common underlying pathology of CVDs, the comprehension of the mechanisms at the basis of the association between stress and this pathology is highly valuable. The aim of this work is to give a comprehensive review of the studies focused on the role of acute and chronic stress in both healthy individuals and CVD patients, focusing on the cellular and molecular mechanisms underlying the relationship between stress and thrombosis.

Factors influencing patient's perception of long-term treatment with low-molecular-weight heparins for cancer-associated thrombosis: an updated analysis of TROPIQUE, a prospective observational study.

PURPOSE: Our objective was to compare patient's expectations to their experience and to identify factors predictive of patient's perception of long-term LMWH for the treatment of cancer-associated thrombosis (CAT). METHODS: Results from the validated Perception Anticoagulant Treatment Questionnaires (PACTQ) completed before inclusion (PACTQ1 for expectations) and at the end (PACTQ2 for convenience and satisfaction) of the 6-month TROPIQUE study were studied with principal component analysis. Possible predictive factors of improved perception of LMWH treatment were analyzed with the Kruskall-Wallis test. RESULTS: Among 409 included patients treated with LMWH, 269 PACT-Q1 and 139 PACT-Q2 were evaluable for treatment perception. Patients had high expectations (A1-A7 score of 26.7 ± 3.5, max = 35). Treatment cost (A7 = 1.90 ± 1.31) and concern about a mistake in anticoagulation (A5 = 1.93 ± 1.12) had little importance while LMWH treatment was considered easy to use (A4 = 4.20 ± 0.93). Six-month treatment with LMWH was associated with a high rate of convenience (B1-B11, C1-C2 = 55.1 ± 8.38, max = 65) and a high satisfaction score (D1-D7 = 25.1 ± 4.32, max = 35). Patients' confidence in treatment and perception of possible LMWH side effects were moderate while perception of autonomy and independence significantly improved at the end of the study compared to inclusion. PACT-Q2 satisfaction score was low in patients who experienced bleeding (PACT-Q2 24.1 ± 3.3 vs. 25.1 ± 4.3). LMWH twice daily tended to be found less convenient compared than once daily (53.3 ± 7.2 vs. 55.0 ± 8.3). CONCLUSION: CAT patients had a good perception of the 6-month LMWH treatment when comparing expectations and experience. Using a quantitative scale validated in the general population for VTE and subcutaneous injection and including a large number of patients, bleeding complications and LMWH twice daily were associated with a nonsignificant trend towards a worsen perception.

[Thrombosis in patients with malignancy].

Thrombosis traditionally considered as a complication of cardiovascular disease, however, this problem until recently was rarely taken into account in the presence of cancer. Although the association between cancer and thrombosis has been known almost 150 years ago, awareness of the impact of thrombotic complications have increased only now. Cancer is an independent major risk factor for venous thromboembolism (VTE), which is the leading cause of death of cancer patient. The incidence of VTE is steadily increasing in these patients. Thrombotic events have a significant impact on the quality of life of patients, and are associated with worsening of their short-term and long-term survival. The objective of this review is to summarize modern views on pathophysiology, as well as to outline new approaches to risk assessment, prevention and treatment of thrombosis in cancer patients.

Association between cognition and gene polymorphisms involved in thrombosis and haemostasis.

An association between blood markers of thrombosis and haemostasis and cognitive decline has been described. These results may be confounded by lifestyle and environmental factors. We used a Mendelian randomisation approach to describe the association between thrombosis/haemostasis genotypes and cognition. We studied the genetic variants (single nucleotide polymorphisms) of circulating markers of thrombosis and haemostasis. Our chosen blood factors and associated polymorphisms were D-dimer [rs12029080], fibrinogen [rs1800789], plasminogen activator inhibitor [rs2227631], and von Willebrand factor [rs1063857]. We described association with multidomain cognitive test scores using data from the Scottish Family Health Study. Cognitive data were analysed for individual tests and combined to give a general cognitive factor. In 20,288 subjects, we found no evidence of association between cognitive function (individual tests and combined scores) and any of the above-mentioned single nucleotide polymorphisms. Lower scores on cognitive measures were associated with increasing age, socioeconomic deprivation, blood pressure, waist-hip ratio, smoking, and vascular comorbidity (all p < 0.001). In a post hoc sensitivity analysis restricted to those aged over 50 years, there was still no signal of association. Our data add to our understanding of determinants of cognition but are not definitive; the variation in blood levels explained by SNPs was modest and our sample size may have been insufficient to detect a modest association.

Targeting activation of specific NF-κB subunits prevents stress-dependent atherothrombotic gene expression.

Psychosocial stress has been shown to be a contributing factor in the development of atherosclerosis. Although the underlying mechanisms have not been elucidated entirely, it has been shown previously that the transcription factor nuclear factor-κB (NF-κB) is an important component of stress-activated signaling pathway. In this study, we aimed to decipher the mechanisms of stress-induced NF-κB-mediated gene expression, using an in vitro and in vivo model of psychosocial stress. Induction of stress led to NF-κB-dependent expression of proinflammatory (tissue factor, intracellular adhesive molecule 1 [ICAM-1]) and protective genes (manganese superoxide dismutase [MnSOD]) via p50, p65 or cRel. Selective inhibition of the different subunits and the respective kinases showed that inhibition of cRel leads to the reduction of atherosclerotic lesions in apolipoprotein(-/-) (ApoE(-/-)) mice via suppression of proinflammatory gene expression. This observation may therefore provide a possible explanation for ineffectiveness of antioxidant therapies and suggests that selective targeting of cRel activation may provide a novel approach for the treatment of stress-related inflammatory vascular disease.

Inflammatory and thrombotic changes in early bereavement: a prospective evaluation.

AIMS: Although there is an increased cardiovascular risk in the immediate weeks following bereavement, the mechanism is not well understood. The aim of this study was to determine whether inflammatory and thrombotic changes were present in acute bereavement. METHODS AND RESULTS: Eighty bereaved spouses or parents were prospectively studied within 2 weeks of bereavement (acute) and at 6 months, and compared to 80 non-bereaved participants. Haemostatic measures were obtained between 8 a.m. and 11 a.m. and processed within 1 h. Compared to non-bereaved participants, those acutely bereaved had a higher neutrophil count (4.34 ± 0.19 vs 3.79 ± 0.15, p = <0.001), von Willebrand factor antigen (132.33 ± 3.6 vs 119.95 ± 3.29, p = 0.02), Factor VIII (1.43 ± 0.06 vs 1.25 ± 0.04, p = 0.02) and platelet/granulocyte aggregates (median 383.0 vs 343.5, p = 0.02). Levels of neutrophils, monocytes, eosinophils, platelet count, platelet/monocyte granulocytes and von Willebrand factor were lower in bereaved at 6 months compared to acutely (all p < 0.05). CONCLUSION: Acute bereavement is associated with inflammatory and prothrombotic changes that may contribute to the increased cardiovascular risk with bereavement and provide clues for future preventative strategies.

Triggering mechanisms of stent thrombosis.

AIMS: The aim of this study was to determine the role of potential triggers of stent thrombosis. METHODS AND RESULTS: Patients (n = 437) with "definite" ST were recruited consecutively in the setting of a large multicentre observational cohort study. Patients were interviewed with validated questionnaires to identify one of the following triggers: i) timing of onset of ST, ii) performance of vigorous ( ≥ 6 MET) physical activity in the two hours preceding ST, iii) presence of emotional stress (experiencing a serious life event in the 14 days preceding the ST or feelings of anger in the 12 hours of ST) and iv) presence of a documented active infection at the time of ST. A total of 363 patients (83.1%) were able to supply adequate information. A significant trigger was identified in 83 patients (22.9%). Analysis of the different categories according to timing of ST revealed a higher prevalence of triggers with an increasing time-interval between index PCI and ST. Analysis of circadian variation showed a steep peak incidence from 7 am-12 pm. CONCLUSIONS: Triggering mechanisms such as time of the day, physical exertion, emotional stress and infection may play an important role in a considerable number of patients presenting with ST, in particular in patients with (very) late ST.

Clinician-patient discord: exploring differences in perspectives for discontinuing clopidogrel.

BACKGROUND: Premature stopping of anti-platelet therapy has potentially fatal consequences for myocardial infarction (MI) patients who have received a drug-eluting stent (DES). Exploring multiple perspectives to identify contributing factors to the problem is essential. AIM: We gained patient and clinician perspectives as to why MI patients prematurely stop anti-platelet therapy (clopidogrel) after DES implantation. METHODS: This qualitative, descriptive study of DES-treated MI patients (n=22) and of clinicians (physicians and nurse practitioners; n=17) from multiple U.S. cities used content analysis of interview data. Findings across patients and clinicians were then compared to examine congruent and contrasting reasons for premature clopidogrel discontinuance. FINDINGS: Patients frequently identified communication and education (e.g. unaware they should be taking clopidogrel, unaware of intended duration of therapy) as the primary reasons for having stopped. Patients rarely cited cost, while clinicians most commonly cited cost as a reason for premature stopping. CONCLUSIONS: The discrepancy in perceptions of patients and clinicians as to the primary reason for early discontinuance suggests an important opportunity for improving persistence. Rather than focusing on the high costs of medications, something outside of their control, physicians should consider communicating more effectively the importance and intended duration of clopidogrel to their patients.

Thrombosis and thrombophilia: principles for pediatric patients.

Thrombotic complications in pediatric patients are increasingly recognized due to increased use of invasive procedures, heightened awareness, improved imaging and prothrombotic lifestyle choices. Multiple risk factors are often present in pediatric patients with thrombosis. The most common risk factor is an indwelling catheter, followed by inflammatory conditions, malignancy, immobilization, thrombophilia and congenital heart disease. Rare severe thrombophilias, whether acquired or congenital, often present in children. Neonates have distinct patterns of thrombosis promoted by sepsis, inflammation, hypotension, hypoxia and the use of intravascular catheters in small caliber and umbilical vessels. Treatment of pediatric thromboembolic disease requires an understanding of developmental hemostasis, application of nonpediatric drug formulations and consolidation of expert guidelines and relevant adult literature. The acute and chronic consequences of thrombosis can be devastating in pediatrics and correlate with the length of time of vessel occlusion, underscoring the importance of rapid diagnosis and initiation of therapy. As trials begin to define recurrence risks, outcome predictors and optimal therapy for children with thrombosis and thrombophilia, consultation with an experienced pediatric hematologist provides the best available therapy today.

Research on psychoneuroimmunology: does stress influence immunity and cause coronary artery disease?

This review addresses the importance of psychoneuroimmunology (PNI) studies in understanding the role of acute and chronic psychological stressors on the immune system and development of coronary artery disease (CAD). Firstly, it illustrates how psychological stressors change endothelial function and lead to chemotaxis. Secondly, acute psychological stressors lead to leukocytosis, increased natural killer cell cytotoxicity and reduced proliferative response to mitogens while chronic psychological stressors may lead to adverse health effects. This will result in changes in cardiovascular function and development of CAD. Thirdly, acute and chronic psychological stressors will increase haemostatic factors and acute phase proteins, possibly leading to thrombus formation and myocardial infarction. The evidence for the effects of acute and chronic psychological stress on the onset and progression of CAD is consistent and convincing. This paper also highlights potential research areas and implications of early detection of immunological changes and cardiovascular risk in people under high psychological stress.

Cardioembolic outcomes in stress-related cardiomyopathy complicated by ventricular thrombus: a systematic review of 26 clinical studies.

BACKGROUND: The stress-related cardiomyopathy (SRC) is a relatively novel cardiac syndrome characterized by peculiar transient left ventricular dysfunction, which accounts for approximately 1-3% of patients with symptoms that initially appear to be an acute coronary syndrome. To date, the true incidence and clinical significance of left ventricular thrombus and related embolic outcomes in these patients have not been fully established. METHODS: The present systematic review aimed to report updated case series of SRC patients with left ventricular thrombus and/or cardioembolic events complicating the course of syndrome, in an attempt to summarize their demographic and clinical characteristics. RESULTS: Overall, 33 eligible studies (44 patients) were selected through the PubMed-Medline archives (December 2002-April 2009), but only 26 (36 patients) matched our inclusion criteria. Left ventricular thrombus was detected in 32 patients (89%), whereas thromboembolic events occurred in 12 (33%). Morphological characteristics of thrombi are described through the article. Women >65 years of age presenting with deep/giant negative T-waves on admission ECG seem more likely to have thrombus-related embolic complications. CONCLUSIONS: Important findings from this updated review indicate that LVT approximately occurs in 5% of the estimated worldwide SRC population, similar to historical incidence in patients with myocardial infarction. In a third of cases (approximately 1.6% of above guesstimate) nonfatal cardioembolic outcomes (brain ischemia in 75% of cases) have been documented. It is worthy considering early anticoagulant therapy, especially in patients at a higher risk of thromboembolic disease, irrespective of the presence of LVT at admission.

Just how far goes DNR?

Mr T. Ragic presented with a thrombosed limb of an aortobifemoral graft placed over 2 decades ago. He has unresectable stage VI lung cancer and do not resuscitate (DNR) orders that were suspended during the thrombectomy. A cardiac arrest resulted in him being in the intensive care unit a day later ventilator-dependent and comatose, and repeated computed tomography scans show severe cerebral edema. He has frequent ventricular dysrhythmias. His eldest daughter is about to deliver his first grandchild, which is the main reason that he requested the procedure to extend his life. In discussions with the family, they express uncertainty about the implications of his DNR order for current treatment. They ask you for your thinking on this matter.

Psychological impact of thrombosis in the young.

OBJECTIVE: Thrombosis is rare in the young, but can cause severe psychological distress that influences the quality of life and the coping capacities of these patients. This study was meant to increase the understanding of self-perception, social and family functioning and ways of coping with the disease in young patients after an episode of thrombosis. METHODS: Seven questionnaires spanning social and family functioning and ways of coping with disease were completed by 50 patients < or = 45 years of age after a first episode of venous or arterial thrombosis. Data were compared with those of 39 healthy individuals with similar age, sex and level of education. RESULTS: Compared to healthy controls, young patients with thrombosis had lower self-esteem, showed higher impairment in social activities and in familial relationships, and used more frequently coping strategies. Most patients used all coping strategies, preferring the more active ones, but more patients than controls used the passive ones, particularly "avoidance" and "religiosity". A correlation was found between the frequency of use of passive or negative coping strategies and some of the psychological, social and familial dimensions that scored more negatively. Greater psychological impairment and differences in coping styles were found in women compared with men and in individuals < 34 years compared with those > or = 34 years. CONCLUSIONS: Young individuals with thrombosis develop psychological changes that influence their behaviour, quality of life and coping. This is particularly evident in women and in young patients. Physicians dealing with thrombosis should be aware of this situation and offer psychological support.

[Effects of nutritional factors on haemostasis]. / Einfluss von Ernährungsparametern auf die Hämostase.

Among all exogenic factors nutrition has a most relevant impact on the haemostatic system and related cardiovascular and thrombotic disease. Whereas obesity and high-caloric diet are associated with negative changes of mostly all parameters of haemostasis, fibrinolysis and platelet reactivity, weight reduction and lifestyle modification induce respective beneficial effects. Recent studies demonstrate large evidence for the beneficial effects of a mediterranean diet in thrombotic diseases not mediated by cholesterol or weight reduction. The principal sources of fat within this diet, olive oil and omega-3 polyunsaturated fatty acids from fatty fish, nuts, seeds, and vegetables show a variety of beneficial effects on the haemostatic system in experimental and observational studies. Furthermore, for an increasing number of substances such as plant-based polyphenols and for moderate alcohol consumption attenuation of coagulation and platelet reactivity have been demonstrated. In the clinical context, mediterranean diet may exert its beneficial effects through synergistic action on haemostasis, endothelial function and vascular inflammation.

Thrombotic stroke in a child with diarrhea-associated hemolytic-uremic syndrome with a good recovery.

A boy aged 3.5 years with post-diarrheal hemolytic-uremic syndrome (HUS) was referred to our hospital because of convulsion and stupor. He had been admitted to a regional hospital with a 3-day history of bloody diarrhea, colic abdominal pain and fever. Two days later, he had complained of generalized seizures and oliguria. On admission, he developed anuria, and serum blood nitrogen and creatinine increased to 56 mg/100 ml and 2.8 mg/100 ml, respectively. Platelets decreased to 42,000/microl. Under the diagnosis of HUS, a continuous hemodiafiltration treatment had to be instituted. Computed tomography of his head at hospital day 5 revealed abnormal low density area of infarction with edema in both the basal ganglia involving with the posterior limb of internal capsule. Serum titer of IgM antibody to Escherichia coli O157 showed positive value. Although his anuria and stupor persisted over 10 days, he recovered without serious complications. These clinical observations may indicate that patients with similar lesions do not necessarily have serious morbidity.

Cardiovascular risks: perception versus reality.

The high estrogen doses in the original oral contraceptive (OC) formulations were associated with an increased risk of cardiovascular events. Since then the steroid doses in OC have been reduced steadily, so that current low-estrogen-dose (< or = 35 micrograms) combination OC are associated with a lower risk of arterial and venous events than occurs with higher-estrogen-dose formulations. Based on the currently available epidemiologic evidence, the following conclusions can be made regarding the cardiovascular disease risks associated with use of low-dose OC by healthy, nonsmoking women: there is no increased risk of myocardial infarction (MI) or hemorrhagic or ischemic stroke; and there is a three- to fourfold increased risk of venous thrombosis and embolism (VTE). This risk is about half that associated with pregnancy. Smoking is the most important independent risk factor for MI, and is synergistic with OC use. Women smokers should be advised strongly to stop smoking, but those aged < 35 years may use any OC containing < or = 35 micrograms of estrogen. Women smokers aged > or = 35 years should be advised to use a nonestrogen or nonhormonal contraceptive method.

Dimensions of quality of life and self-monitoring therapy with oral anticoagulants--still research or everyday practice?

In correlation with increased life expectancy of patients, quality of life (QOL) has become a factor of increasing interest by the patient himself and also of importance in health-care planning and recruitment of financial resources. In this context, self-monitoring of long-term anticoagulant treatment might be a strategy that could mean a step forward in health-related as well as general life satisfaction for patients participating in self-monitoring programs. Also, the new strategy of increased home-control of anticoagulant treatment illustrates the complexity of multiple factors that can lead to changes in the subjective feeling and objective aspects of QOL. Our intention in a pilot study was to probe the feasibility of QOL research and relevant factors of influence by retrospectively evaluating data from two groups of outpatients seen in a large treatment center. The high frequency (n = 8 in sample 2) of disturbed sleep as a simple screening indicator stresses the probable importance of undetected depression, which might require treatment and could confound research as to QOL. Instruments to measure QOL in oral anticoagulation self-monitoring should therefore be adapted to the heterogeneous structure of factors in the target population, and include psychological parameters, especially in regard to health-related locus of control and mood.