Atrial fibrillation and psychological factors : a systematic review

BACKGROUND: Psychological factors have been suggested to have an influence in Atrial Fibrillation (AF) onset, progression, severity and outcomes, but their role is unclear and mainly focused on anxiety and depression. METHODS: A systematic electronic search had been conducted to identify studies exploring different psychological factors in AF. The search retrieved 832 articles that were reviewed according to inclusion criteria: observational study with a control/comparison group; use of standardized and validated instruments for psychological assessment. Results were summarized qualitatively and quantitatively by effect size measure (Cohen's d and its 95% confidence interval). Cochrane Collaboration guidelines and the PRISMA Statement were adopted. RESULTS: Eight studies were included in the systematic review. Depression was the most studied construct/ but only one study showed a clear link with AF. The remaining studies showed small and non-significant (95% CI [-0.25-1.00]) differences between AF and controls, no differences in frequency of depression history (95% CI [-0.14-0.22]) or in case frequency (95% CI [-0.50-0.04]). Miscellaneous results were found as far as anxiety: AF patients showed higher levels when compared to healthy subjects (95% CI [2.05-2.95]), but findings were inconsistent when compared to other heart diseases. Considering personality and life-events preceding AF, we respectively found a large (95% CI [1.87-2.49]) and a moderate to large effect (95% CI [0.48-0.98]). DISCUSSION: The small number of studies does not allow to draw clear-cut conclusions on the involvement of psychological factors in AF. Promising lines of research are related to personality and adverse life-events, and to the increase of longitudinal design studies. Some methodological problems could be overcome by including clinical psychologists in the implementation of research protocols

Why does ticagrelor induce dyspnea?

In studies that compared the reversible P2Y12 inhibitor ticagrelor with the irreversible inhibitor clopidogrel, dyspnea was observed more frequently among ticagrelor-treated patients than among clopidogrel-treated patients. Because dyspnea was not associated with acidosis, pulmonary or cardiac dysfunction, alterations in the mechanisms and pathways of the sensation of dyspnea may be involved in its pathogenesis. It has been hypothesised that the sensation of dyspnea in ticagrelor-treated patients is triggered by adenosine, because ticagrelor inhibits its clearance, thereby increasing its concentration in the circulation. However, dipyridamole, a much stronger inhibitor of adenosine clearance than ticagrelor, usually does not cause dyspnea. We hypothesise that inhibition of P2Y12 on sensory neurons increases the sensation of dyspnea, particularly when reversible inhibitors are used. We base our hypothesis on the following considerations: 1) cangrelor and elinogrel, which, like ticagrelor, are reversible P2Y12 inhibitors, also increase the incidence of dyspnea; 2) it is biologically plausible that inhibition of P2Y12 on sensory neurons increases the sensation of dyspnea; 3) inhibition of P2Y12 on platelets (which do not have a nucleus) by clopidogrel is permanent, despite the once daily administration and the short plasma half-life of the inhibitor; 4) in contrast, inhibition of P2Y12 on neurons by clopidogrel may be temporary and transient, because neurons have a nucleus and can therefore rapidly replace the inhibited receptors with newly synthetised ones; 5) inhibition of P2Y12 on neurons by reversible inhibitors is permanent, because the plasma drug concentration is maintained high by repeated dosing, in order to ensure permanent inhibition of platelet P2Y12

Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity.

We have investigated the composition and function of membrane microparticles released from platelets exposed to the C5b-9 proteins of the complement system. Gel-filtered human platelets were incubated with sub-lytic amounts of the purified C5b-9 proteins and the distribution of surface antigens was analyzed using monoclonal antibodies and flow cytometry. C5b-9 assembly caused secretory fusion of the \u3b1-granule membrane with the plasma membrane and the release of membrane vesicles (approximately 0.1-\u3bcm diameter) that contained the plasma membrane glycoproteins (GP) GP Ib and GP IIb-IIIa as well as the \u3b1-granule membrane protein GMP-140. These microparticles were highly enriched in the C9 neoantigen of the C5b-9 complex. The apparent surface density of C5b-9 on the microparticles was approximately 103-fold higher than on the platelet itself, suggesting that the vesicles were selectively shed from the plasma membrane at the site of C5b-9 insertion. C5b-9 induced the expression of an activation-dependent epitope (recognized by monoclonal antibody, PAC1) in GP IIb-IIIa on the platelet surface but not in GP IIb-IIIa on the microparticles. The surface of the microparticles was also highly enriched in \u3b1-granule-derived coagulation factor V (or Va), accounting for nearly half of all the membrane-bound factor V detected. The number of potential membrane binding sites for factor Va was probed by adding saturating concentrations of factor Va light chain. Under these conditions, the density of factor Va binding sites on the microparticle surface exceeded that on the C5b-9-treated platelet by three to four orders of magnitude. Moreover, the microparticles provided most of the membrane surface for conversion of prothrombin to thrombin by VaXa. These studies demonstrate that the microparticles shed by C5b-9-treated platelets (and not the platelets themselves) provide the principal binding sites for coagulation factor Va and the principal catalytic surface for the prothrombinase complex. Platelet-derived microparticles formed during complement activation in vivo could provide a membrane surface that facilitates the assembly and dissemination of procoagulant enzyme complexes

The factor V HR2 haplotype and the risk of venous thrombosis : a meta-analysis.

Background and Objectives. A complex haplotype of factor V gene (FV HR2) has been recently reported. FVHR2 possesses decreased co-factor activity to APC in the degradation of FVIIIa, and an increased ratio of the more procoagulant isoform FV1 compared to FV2. Contrasting results on whether the haplotype induces a significant risk of venous thromboembolism (VTE) have been reported. Design and Methods. It has been surmised that FVHR2 enhances the risk of VTE carried by FV Leiden. We carried out a meta-analysis of the reported studies on the role of HR2 haplotype in inducing a risk of VTE and the influence of the polymorphism on the risk carried by patients with FV Leiden. Results. Eight studies were analyzed for the estimation of the risk of VTE. A total of 338 out of 2,696 cases (12.5%; range 7.8 to 18.5%) and 885 out of 7,710 controls (11. 5%; range 8.1 to 12.1%) were HR2 positive. The odds ratio for VTE associated with HR2 haplotype was not statistically significant (OR 1.15; 95% C.I. 0.98-1.36). The OR for the association between FV Leiden and FV HR2 and the risk of VTE in cases and controls was largely heterogeneous as to OR and 95% C.I. and no statistical significant difference was observed. Interpretation and Conclusions. The data from the present meta-analysis suggests that FVHR2 could be a very mild prothrombotic factor. The association of FV Leiden and HR2 haplotype seems not to increase significantly the risk of VTE carried by isolated heterozygosity for FV Leiden. However, well-designed clinical studies are needed to clarify this issue definitely

Association of factor V deficiency with factor V HR2

Background and Objectives. Factor V HR2 possesses decreased co-factor activity to activated protein C and an increased ratio of factor V1 to factor V2. Factor V HR2 is associated with a mild increase in the risk of venous thromboembolism although not all studies concur on this point. Design and Methods. Inconsistencies in results of the epidemiological studies may stem from a failure to identify other variables in factor V which might contribute to an increased risk of thrombosis in selected HR2 carriers. The aim of this study was to establish whether factor V deficiency increases the risk of venous thromboembolism when associated with HR2. Results. Four hundred and ninety-seven patients with venous thromboembolism and 498 controls were studied. HR2 was present in 12.5% of patients and 10.4% of controls. Factor V deficiency was associated with HR2 in 4.6% of patients and 1.0% of controls. The OR for venous thromboembolism in individual with HR2 alone was 1.2 (95% Cl 0.8-1.8), while it was 4.7 (95% Cl 1.8-12.5) for those with HR2 plus factor V deficiency. Interpretation and Conclusions. Patients with HR2 and factor V deficiency developed a thrombotic event earlier (median age 35 years) than patients with HR2 alone (median age 43 years, p = 0.018). Double heterozygosity for HR2 and a factor V defect, including factor V deficiency, increased the thrombotic risk afforded by HR2