Clinical aspects and molecular mechanisms of inflammation-driven arrhythmic risk

Increasing evidence indicates systemic inflammation as a new potential cause of acquired LQTS and Torsade de Pointes and a strong predictor of Atrial Fibrillation, via cytokine-mediated changes in cardiomyocyte ion channels and in gap-junction. We hypothesised that systemic inflammation may represent a novel risk factor contributing to TdP development in the general population and can promotes atrial electric remodelling in-vivo, as a result of cytokine-mediated changes in connexins expression. For this reason, two population studies have been designed to confirm these hypotheses. In the first study, forty consecutive patients who experienced TdP (TdP cohort) were consecutively enrolled and circulating levels of C-reactive protein and proinflammatory cytokines (IL-6, TNFα and IL-1) were compared with patients with active rheumatoid arthritis (RA), comorbidity or healthy controls. An additional 46 patients with different inflammatory conditions and elevated CRP (inflammatory cohort) were prospectively enrolled, and corrected QT and cytokine levels were measured during active disease and after a CRP decrease of >75% subsequent to therapy. In the TdP cohort, 80% of patients showed elevated CRP levels (median: ~3 mg/dL). In these subjects, IL-6 was ~15–20 times higher than in controls, and comparable to RA patients. In the inflammatory cohort, where QTc prolongation was common, CRP reduction was associated with IL-6 level decrease and significant QTc shortening. In the second study, fifty-four patients with different inflammatory diseases and elevated C-reactive protein (CRP) levels were prospectively enrolled, and electrocardiographic P-wave dispersion indices, pro-inflammatory cytokine levels (IL-6, TNFα, IL-1), and connexin expression (connexin40, connexin43) were measured during active disease and after reducing CRP by >75%. In addition, peripheral blood mononuclear cells (PBMC) and atrial tissue specimens from 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. In patients with active inflammatory diseases, P-wave dispersion indices are increased, but rapidly decreased within days when CRP normalizes and IL-6 levels decline. In inflammatory disease patients both P-wave dispersion indices and IL-6 changes are inversely associated with circulating connexins levels, and a positive correlation between connexins expression in PBMC and atrial tissue was demonstrated. Moreover, in-vitro incubation of mouse atrial cardiomyocytes with IL-6 significantly reduces connexins expression. The data are first to show that systemic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence. Furthermore, these data suggest that regardless of specific aetiology and organ localization, systemic inflammatory activation, via elevation of IL-6 levels, rapidly induces atrial electrical remodelling by down-regulating cardiac connexins.