No prominent role for complement C1-esterase inhibitor in Marfan syndrome mice.

Marfan syndrome (MFS) is a connective tissue disorder causing aortic aneurysm formation. Currently, only prophylactic aortic surgery and blood pressure-lowering drugs are available to reduce the risk of aortic rupture. Upon whole genome sequencing of a Marfan family, we identified a complement gene C1R variant (p.Ser152Leu), which is associated with severe aortic patients. Therefore, we assessed the role of complement activation in MFS aortic tissue. Expression of various complement genes and proteins was detected in human and murine MFS aneurysm tissue, which prompted us to study complement inhibition in MFS mice. Treatment of the Fbn1C1041G/+ MFS mice with human plasma-derived C1-esterase inhibitor Cetor® resulted in reduced complement deposition, decreased macrophage influx in the aorta, and lower circulating TNFα levels. However, in line with previous anti-inflammatory treatments, complement inhibition did not change the aortic dilatation rate in this MFS mouse model. Thus, while complement factors/component 3 activation were detected in human/murine MFS aorta, Cetor® had no effect on aortic dilatation in MFS mice, indicating that complement inhibition is not a suitable treatment strategy in MFS.

Real-life use of left ventricular circulatory support with Impella in cardiogenic shock after acute myocardial infarction: 12 years AMC experience.

AIMS: Mortality in cardiogenic shock patients remains high. Short-term mechanical circulatory support with Impella can be used to support the circulation in these patients, but data from randomised controlled studies and 'real-world' data are sparse. The aim is to describe real-life data on outcomes and complications of our 12 years of clinical experience with Impella in patients with cardiogenic shock after acute myocardial infarction and to identify predictors of 6-month mortality. METHODS: We describe a single-centre registry from October 2004 to December 2016 including all patients treated with Impella for cardiogenic shock after acute myocardial infarction. We report outcomes and complications and identify predictors of 6-month mortality. RESULTS: Our overall clinical experience consists of 250 patients treated with Impella 2.5, Impella CP or Impella 5.0. A total of 172 patients received Impella therapy for cardiogenic shock, of which 112 patients had cardiogenic shock after acute myocardial infarction. The mean age was 60.1±10.6 years, mean arterial pressure was 67 (56-77) mmHg, lactate was 6.2 (3.6-9.7) mmol/L, 87.5% were mechanically ventilated and 59.6% had a cardiac arrest before Impella placement. Overall 30-day mortality was 56.2% and 6-month mortality was 60.7%. Complications consisted of device-related vascular complications (17.0%), non-device-related bleeding (12.5%), haemolysis (7.1%) and stroke (3.6%). In a multivariate analysis, pH before Impella placement is a predictor of 6-month mortality. CONCLUSIONS: Our registry shows that Impella treatment in cardiogenic shock after acute myocardial infarction is feasible, although mortality rates remain high and complications occur.

Effect of remote ischemic conditioning on atrial fibrillation and outcome after coronary artery bypass grafting (RICO-trial).

BACKGROUND: Pre- and postconditioning describe mechanisms whereby short ischemic periods protect an organ against a longer period of ischemia. Interestingly, short ischemic periods of a limb, in itself harmless, may increase the ischemia tolerance of remote organs, e.g. the heart (remote conditioning, RC). Although several studies have shown reduced biomarker release by RC, a reduction of complications and improvement of patient outcome still has to be demonstrated. Atrial fibrillation (AF) is one of the most common complications after coronary artery bypass graft surgery (CABG), affecting 27-46% of patients. It is associated with increased mortality, adverse cardiovascular events, and prolonged in-hospital stay. We hypothesize that remote ischemic pre- and/or post-conditioning reduce the incidence of AF following CABG, and improve patient outcome. METHODS/DESIGN: This study is a randomized, controlled, patient and investigator blinded multicenter trial. Elective CABG patients are randomized to one of the following four groups: 1) control, 2) remote ischemic preconditioning, 3) remote ischemic postconditioning, or 4) remote ischemic pre- and postconditioning. Remote conditioning is applied at the arm by 3 cycles of 5 minutes of ischemia and reperfusion. Primary endpoint is the incidence AF in the first 72 hours after surgery, detected using a Holter-monitor. Secondary endpoints include length-of-stay on the intensive care unit and in-hospital, and the occurrence of major adverse cardiovascular events at 30 days, 3 months and 1 year.Based on an expected incidence in the control group of 27%, 195 patients per group are needed to detect with 80% power a reduction by 45% following either pre- or postconditioning, while allowing for a 10% dropout and at an alpha of 0.05. With the combined intervention expected to be stronger, we need 75 patients in this group to detect a reduction in incidence of AF of 60%. DISCUSSION: The RICO-trial (the effect of Remote Ischemic Conditioning on atrial fibrillation and Outcome) is a randomized controlled multicenter trial, designed to investigate whether remote ischemic pre- and/or post-conditioning of the arm reduce the incidence of AF following CABG surgery. TRIAL REGISTRATION: ClinicalTrials.gov under NCT01107184.