S-nitrosation of macrophage migration inhibitory factor (MIF) has been shown to be cytoprotective in myocardial ischaemia/reperfusion (I/R) injury. Since the exact mechanism of action is unknown, we here characterise the cardioprotective effects of targeted intracellular accumulation of MIF in myocardial I/R injury. We used different in vivo, ex vivo and in vitro models of myocardial I/R and hypoxia/reoxyge-nation (H/R) injury to determine MIF levels by immunoblots and ELISA in different phases of reperfusion and reoxygenation, respectively. We discovered a rapid decrease of cardiac MIF that was specific to the early phase of reperfusion. Posttranslational modification of MIF via S-nitrosation – proofed by a modified version of the Biotin Switch Assay – prevented this rapid decrease, leading to a targeted intracellular accumulation of MIF in the early phase of reperfusion. Intracellular MIF accumulation preserved the intracellular ability of MIF to reduce oxidative stress as shown by hydrogen peroxide and aconitase activity measurements. Infarct size measurements by TTC staining showed an overall enhanced cardioprotective effect of this protein by reduction of reperfusion injury. In summary, we have unravelled a novel mechanism of MIF-mediated cardioprotection. Targeted intra-cellular accumulation of MIF by S-nitrosation may offer a novel therapeutic approach in the treatment of myocardial I/R-injury.

Although the effect of infections with multidrug-resistant bacteria (MDRB) in left ventricular assist device (LVAD) recipients is well characterized, the influence of perioperative colonization on the development of infections in this patient cohort remains unknown. The study evaluated the effect of MDRB colonization on patient outcomes after LVAD implantation. We retrospectively analyzed the microbiological screening studies of nasal, throat, wound, and rectal swabs in 82 consecutive patients who received an LVAD at our center between 2010 and 2015. Four categories of MDRB were determined: methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and Gram-negative bacterium resistant to three or four of four predefined pharmacologic categories of antibiotics. We also compared the long-term outcome of patients with and without colonization. There were 28 patients (34.1%) diagnosed as being colonized with at least 1 species of an MDRB. MDRB colonization was associated with the occurrence of fatal infections from any pathogen (MDRB positive, 63.2%; MDRB negative, 34.4%; p = 0.04) and fatal MDRB-specific infections (MDRB positive, 31.6%; MDRB negative, 6.3%; p = 0.04), significantly longer intensive care unit stay (p < 0.0001), and longer cumulative hospital stay (p = 0.04). Our study demonstrates that the colonization with MDRB is a highly prevalent risk factor for infection-associated death in the vulnerable LVAD population. Routine screening for MDRB before and after LVAD implantation should be considered to identify high-risk individuals and facilitate effective prevention of infectious complications.

Background: Prognostication in heart failure with preserved ejection fraction (HFpEF) is challenging and novel biomarkers are urgently needed. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays a crucial role in cardiovascular and various inflammatory diseases. Whether MIF is involved in HFpEF is unknown. Methods and results: Sixty-two patients with HFpEF were enrolled and followed up for 180 days. MIF plasma levels as well as natriuretic peptide (NP) levels were assessed. High MIF levels significantly predicted the combined end-point of all-cause death or hospitalization at 180 days in the univariate analysis (HR 2.41, 95% CI 1.12–5.19, p = 0.025) and after adjustment for relevant covariates in a Cox proportional hazard regression model (HR 2.35, 95% CI 1.05–5.27, p = 0.0374). Furthermore, MIF levels above the median were associated with higher pulmonary artery systolic pressure (PASP) as assessed by echocardiography (PASP 31 mmHg vs 48 mmHg in the low- and high-MIF group, respectively, p = 0.017). NPs significantly correlated with MIF in HFpEF patients (BNP p = 0.011; r = 0.32; NT-proBNP p = 0.027; r = 0.28). Conclusion: MIF was associated with clinical outcomes and might be involved in the pathophysiology of pulmonary hypertension in patients with HFpEF. These first data on MIF in HFpEF should stimulate further research to elucidate the role of this cytokine in heart failure. Trial registration NCT03232671

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory protein and contributes to several different inflammatory and ischemic/hypoxic diseases. MIF was shown to be cardioprotective in experimental myocardial ischemia/reperfusion injury and its expression is regulated by the transcription factor hypoxia-inducible factor (HIF)-1α. We here report on MIF expression in the failing human heart and assess myocardial MIF in different types of cardiomyopathy. Myocardial tissue samples from n = 30 patients were analyzed by quantitative Real-Time PCR. MIF and HIF-1α mRNA expression was analyzed in myocardial samples from patients with ischemic (ICM) and non-ischemic cardiomyopathy (NICM) and from patients after heart transplantation (HTX). MIF expression was elevated in myocardial samples from patients with ICM compared to NICM. Transplanted hearts showed lower MIF levels compared to hearts from patients with ICM. Expression of HIF-1α was analyzed and was shown to be significantly increased in ICM patients compared to patients with NICM. MIF and HIF-1α mRNA is expressed in the human heart. MIF and HIF-1α expression depends on the underlying type of cardiomyopathy. Patients with ICM show increased myocardial MIF and HIF-1α expression.

We aimed to evaluate whether therapy with immune checkpoint inhibitors (ICI) leads to changes in electrocardiogram (ECG) parameters in melanoma patients. We retrospectively examined 41 patients (46% women, age 61 ± 12years) with advanced melanoma (stage III/IV) before and during ICI treatment from our “Essen Cardio-oncology Registry” (ECoR). ECGs were analyzed before and 4–12 weeks after therapy started (follow-up, 90 ± 51 days). Heart rate, PR time, QRS duration and duration of the corrected QT (QTc) interval were recorded. QT dispersion (QTd) was calculated. Heart rate, PR time, QRS and QTc did not differ when comparing values before and after therapy started. QTd was prolonged after therapy started (32 ± 16 ms vs. 47 ± 19 ms, n = 41, p < 0.0001). Subgroup analyses revealed prolonged QTd in patients that received a combination immunotherapy with ipilimumab and nivolumab (31 ± 14 ms vs. 50 ± 14 ms, n = 21, p < 0.0001), while QTd in patients with anti–programmed death 1 (PD-1) inhibitor monotherapy did not change after therapy started. QTd is prolonged in patients under ICI combination therapy, potentially signaling an increased susceptibility to ventricular arrhythmias.