Do elevated levels of interleukin-6 activated through PICSO intervention promote structural regeneration in heart failure patients?

Objectives: Circulating interleukin (IL-) 6 increases with the severity of heart failure and it can be also regarded as a prognostic factor. In contrast, recent studies show that temporary elevation of this marker is associated with beneficial effects through survivor activating factor enhancement (SAFE) pathway induction. We hypothesized that this mechanism might also account for the observed experimental and clinical benefits including the pronounced reduction of myocardial infarct size mediated by pressure-controlled coronary sinus occlusion (PICSO).

Methods: 32 patients undergoing cardiac resynchronization therapy (CRT) by device implantation (diagnosis: predominantly ischemic and dilated cardiomyopathy) were included into a prospective non randomized study (8 interventional/24 control group). PICSO was performed for 20 minutes by introducing a balloon catheter into the coronary sinus and after positioning of the left ventricular electrode. Hemodynamic data were obtained through the LIDCO System and PICSO catheter (coronary sinus pressure (CSP)). Coronary venous blood samples were taken and IL-6 and NT-proBNP measured before and after PICSO. Mean patients follow up was 34 months.

Results: IL-6 secretion increased significantly after PICSO in comparison to controls (p=0.009). There was no significant linear correlation between the percentage increase of IL-6 and hemodynamic data including the maximal developed coronary venous pressure during PICSO. In long term follow up, we assessed a mortality risk reduction by 80 percent (RR=0.199, CI (95%)=0.002–1.642, p=0.302). Also a trend towards a survival benefit was observed. This benefit particularly included severely diseased patients with NT-proBNP levels above 1500 pg/ml (p=0.080).

Conclusion: These results support our hypothesis of SAFE pathway induction through PICSO and are in accordance with prior experimental analyses showing enhanced expression of vascular endothelial growth factor and heme oxygenase 1. Therefore, it can be assumed that one major component of PICSO is the initiation of mechanotransduction by the applied stimuli of pulsatile stretch and shear stress. This intervention could be the link to molecular corresponding factors that improve survival, reduce the risk for re-infarction and decrease adverse cardiac events after myocardial infarction as observed in previous trials.