4246 Hypercoagulability promotes atrial fibrosis and fibrillation

Background: It is well known that atrial fibrillation (AF) induces a hypercoagulable state, which significantly increases stroke risk in patients with AF contributing to morbidity and mortality in these patients. Active coagulation factors can also provoke diverse cellular responses through stimulation of protease-activated receptors (PARs). In the heart and vessels, coagulation factor mediated PAR activation may provoke and mediate pro-inflammatory and tissue remodeling responses, potentially contributing to organ damage. We hypothesized that the onset and progression of AF, may be affected by hypercoagulability-mediated cell signaling responses, in the heart. Methods and results: To study the potential role of PARs in the structural remodeling process that renders the atria more prone to AF we first investigated whether thrombin or factor Xa could induce atrial fibroblast remodeling. In isolated rat cardiac fibroblasts, thrombin enhanced the phosphorylation of the pro-fibrotic signaling molecules Akt and Erk, and increased expression of TGFβ1 (2.7 fold) and the pro-inflammatory factor monocyte chemo-attractant protein-1 (6.1 fold). Thrombin also increased the incorporation of 3H-proline suggesting enhanced collagen synthesis by cardiac fibroblasts (2.5 fold). Differentiation towards myofibroblasts was indicated by increased expression of smooth muscle actin (2 fold). All effects could be prevented by the direct thrombin inhibitor dabigatran and comparable results were obtained for stimulation with factor Xa and inhibition with rivaroxaban, respectively. Next we studied whether enhanced stimulation of PARs by chronic elevation of thrombin levels would lead to an enhanced vulnerability to AF in transgenic mice. In mice with enhanced thrombin activity due to a mutation in the thrombomodulin gene resulting in impaired thrombin inhibition (TMpro/pro), inducibility of AF episodes provoked by burst pacing was higher (6 out of 10 versus 1 out of 10 in wild type) and the duration of AF episodes was longer (episodes >2s in 6 out of 10 versus 0 out of 10 in wild type). Finally, we showed that inhibition of the coagulation cascade attenuated the development of AF in a goat model of AF. In 6 goats with persistent AF and treated with the anticoagulant nadroparine (4 weeks, 150 IU/kg twice daily) the complexity of the AF substrate was less pronounced compared to control animals. The conduction heterogeneity and block were 33% shorter in the nadroparine treated animals (maximal conduction time 23.3±3.1ms in control versus 15.7±2.1ms in nadroparine,

Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia

International audienceBACKGROUND:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain.OBJECTIVE:The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients.METHODS:We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders.RESULTS:Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy.CONCLUSION:Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias