Showing papers by "Heart and Diabetes Center North Rhine-Westphalia published in 2018"

Empagliflozin directly improves diastolic function in human heart failure

Abstract: Aims Empagliflozin, a clinically used oral antidiabetic drug that inhibits the sodium-dependent glucose co-transporter 2, has recently been evaluated for its cardiovascular safety. Surprisingly, empagliflozin reduced mortality and hospitalization for heart failure (HF) compared to placebo. However, the underlying mechanisms remain unclear. Therefore, our study aims to investigate whether empagliflozin may cause direct pleiotropic effects on the myocardium. Methods and results In order to assess possible direct myocardial effects of empagliflozin, we performed contractility experiments with in toto-isolated human systolic end-stage HF ventricular trabeculae. Empagliflozin significantly reduced diastolic tension, whereas systolic force was not changed. These results were confirmed in murine myocardium from diabetic and non-diabetic mice, suggesting independent effects from diabetic conditions. In human HF cardiomyocytes, empagliflozin did not influence calcium transient amplitude or diastolic calcium level. The mechanisms underlying the improved diastolic function were further elucidated by studying myocardial fibres from patients and rats with diastolic HF (HF with preserved ejection fraction, HFpEF). Empagliflozin beneficially reduced myofilament passive stiffness by enhancing phosphorylation levels of myofilament regulatory proteins. Intravenous injection of empagliflozin in anaesthetized HFpEF rats significantly improved diastolic function measured by echocardiography, while systolic contractility was unaffected. Conclusion Empagliflozin causes direct pleiotropic effects on the myocardium by improving diastolic stiffness and hence diastolic function. These effects were independent of diabetic conditions. Since pharmacological therapy of diastolic dysfunction and HF is an unmet need, our results provide a rationale for new translational studies and might also contribute to the understanding of the EMPA-REG OUTCOME trial.

Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart.

Abstract: Aims In heart failure (HF), enhanced persistent Na+ current (I-NaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. However, the underlying regulatory mechanisms remain unclear. Our aim was to potentially investigate the regulation and electrophysiological contribution of neuronal sodium channel Na(V)1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy Methods and results By western blot, we found that Na(V)1.8 protein expression is significantly up-regulated, while of the predominant cardiac isoform Na(V)1.5 is inversely reduced in human HF. Furthermore, to investigate the relation of Na(V)1.8 regulation with the cellular proarrhythmic events, we performed comprehensive electrophysiology recordings and explore the effect of Na(V)1.8 on I-NaL, action potential duration (APD), Ca2+ spark frequency, and arrhythmia induction in human failing cardiomyocytes. Na(V)1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased I-NaL, abbreviated APD and reduced cellular-spontaneous Ca2+-release and proarrhythmic events in human failing cardiomyocytes. Consistently, in mouse cardiomyocytes stressed with isoproterenol, pharmacologic inhibition and genetically knockout of Na(V)1.8 (SCN10A(-/-)), were associated with reduced I-NaL and abbreviated APD Conclusion We provide first evidence of differential regulation of Na(V)1.8 and Na(V)1.5 in the failing human myocardium and their contribution to arrhythmogenesis due to generation of I-NaL. We propose inhibition of Na(V)1.8 thus constitutes a promising novel approach for selective anti-arrhythmic therapy in HF.

Vitamin D Status, Supplementation and Cardiovascular Disease.

Abstract: This review was conducted to assess the dose-response relationship between vitamin D and cardiovascular disease (CVD) outcomes in humans: Prospective cohort studies indicate a multivariable-adjusted non-linear increase in CVD events at levels of circulating 25-hydroxyvitamin D [25(OH)D] of less than 50 nmol/l. However, Mendelian randomization studies do not support these findings. Although meta-analyses of randomized controlled trials (RCTs) do not rule out small beneficial vitamin D effects on surrogate parameters of CVD risk, such as arterial stiffness, at vitamin D doses equivalent to 1,000-5,333 IU daily, other meta-analyses of RCTs show no reduction in CVD events by vitamin D supplementation. Notably, some cohort studies and a recent RCT provide evidence for harmful effects of vitamin D on CVD outcomes at 25(OH)D levels in excess of 100 nmol/l. In conclusion, more studies in individuals with a deficient 25(OH)D level (i.e. <30 nmol/l) are needed, but caution is necessary regarding supplementation with vitamin D doses achieving a 25(OH)D level which exceeds 100 nmol/l.

Homozygous XYLT2 variants as a cause of spondyloocular syndrome.

Abstract: Spondyloocular syndrome (SOS) is a rare autosomal recessive skeletal disorder. Two recent studies have shown that it is the result of biallelic sequence variants in the XYLT2 gene with pleiotropic effects in multiple organs including retina, heart muscle, inner ear, cartilage, and bone. The XYLT2 gene encodes xylosyltransferase 2, which catalyzes the transfer of xylose (monosaccharide) to the core protein of proteoglycans (PG) leading to initiating the process of proteoglycan assembly. SOS was originally characterized in two families A and B of Iraqi and Turkish origin, respectively. Using DNA from affected members of the same two families we performed whole exome sequencing, which revealed two novel homozygous missense variants (c.1159C>T, p.Arg387Trp) and (c.2548G>C, p.Asp850His). Our findings extend the body of evidence that SOS is caused by homozygous variants in the XYLT2 gene. In addition, this report has extended the phenotypic description of SOS by adding follow-up data from five affected individuals in one of the two families, presented here.

Validation and Reference Values for Three-Dimensional Echocardiographic Right Ventricular Volumetry in Children: A Multicenter Study.

Abstract: Background Functional assessment of the right ventricle using real-time three-dimensional echocardiography (RT3DE) has fundamental relevance in young patients with congenital heart disease. Reference values for the pediatric population are scarce. This multicenter study was designed to (1) validate new evaluation software for RT3DE and (2) establish pediatric reference values. Methods For validation, right ventricular (RV) end-diastolic volume (EDV) and end-systolic volume (ESV) were determined from real-time three-dimensional echocardiographic data sets of 38 subjects (n = 17 healthy individuals and n = 21 patients with congenital heart disease) using new dedicated evaluation software (RV-Function 2.0) and compared with cardiac magnetic resonance investigations of the same patient cohort. In a prospective multicenter design, 360 real-time three-dimensional echocardiographic data sets of healthy children (172 girls) were analyzed. To create reference centiles, the cohort was subdivided into group I (children Results Using RT3DE, RV volumes were slightly higher than using cardiac magnetic resonance (EDV, 0.8 ± 5.8% [limits of agreement, −10.8% to 12.5%; r = 0.993]; ESV, 2.0 ± 13.1% [limits of agreement, −24.2% to 28.2%; r = 0.989). Reproducibility was promising (intraobserver variability, 3.9 ± 11.4% for EDV and −1.7 ± 13.4% for ESV [intraclass correlation coefficient range, 0.94–0.98]; interobserver variability, 1.9 ± 11.8% for EDV and −0.3 ± 22.8% for ESV [intraclass correlation coefficient range, 0.85–0.96]). Regarding functional parameters, no significant gender differences were found among children in group I. In contrast, children in groups II and III differed in RV volumes, dimensional parameters, and tricuspid annular plane systolic excursion (P Conclusions RT3DE yields accurate and reproducible RV volumes. The calculated percentile curves may facilitate the clinical use of RT3DE to analyze RV function in children.

Real-Time Three-Dimensional Echocardiography of the Left Ventricle-Pediatric Percentiles and Head-to-Head Comparison of Different Contour-Finding Algorithms: A Multicenter Study.

Abstract: Background Real-time three-dimensional echocardiography (RT3DE) is a promising method for accurate assessment of left ventricular (LV) volumes and function, however, pediatric reference values are scarce. The aim of the study was to establish pediatric percentiles in a large population and to compare the inherent influence of different evaluation software on the resulting measurements. Methods In a multicenter prospective-design study, 497 healthy children (ages 1 day to 219 months) underwent RT3DE imaging of the LV (ie33, Philips, Andover, MA). Volume analysis was performed using QLab 9.0 (Philips) and TomTec 4DLV2.7 (vendor-independent; testing high (TomTec 75 ) and low (TomTec 30 ) contour-finding activity). Reference percentiles were computed using Cole's LMS method. In 22 subjects, cardiovascular magnetic resonance imaging (CMR) was used as the reference. Results A total of 370/497 (74.4%) of the subjects provided adequate data sets. LV volumes had a significant association with age, body size, and gender; therefore, sex-specific percentiles were indexed to body surface area. Intra- and interobserver variability for both workstations was good (relative bias ± SD for end-diastolic volume [EDV] in %: intraobserver: QLab = −0.8 ± 2.4; TomTec 30 = −0.7 ± 7.2; TomTec 75 = −1.9 ± 6.7; interobserver: QLab = 2.4 ± 7.5; TomTec 30 = 1.2 ± 5.1; TomTec 75 = 1.3 ± 4.5). Intervendor agreement between QLab and TomTec 30 showed larger bias and wider limits of agreement (bias: QLab vs TomTec 30 : end-systolic volume [ESV] = 0.8% ± 23.6%; EDV = −2.2% ± 17.0%) with notable individual differences in small children. QLab and TomTec underestimated CMR values, with the highest agreement between CMR and QLab. Conclusions RT3DE allows reproducible noninvasive assessment of LV volumes and function. However, intertechnique variability is relevant. Therefore, our software-specific percentiles, based on a large pediatric population, serve as a reference for both commonly used quantification programs.

Carbamazepine-Mediated Adverse Drug Reactions: CBZ-10,11-epoxide but Not Carbamazepine Induces the Alteration of Peptides Presented by HLA-B∗15:02.

Abstract: Among patients treated with the anticonvulsive and psychotropic drug carbamazepine (CBZ), approximately 10% develop severe and life-threatening adverse drug reactions. These immunological conditions are resolved upon withdrawal of the medicament, suggesting that the drug does not manifest in the body in long term. The HLA allele B∗15:02 has been described to be a genomic biomarker for CBZ-mediated immune reactions. It is not well understood if the immune reactions are triggered by the original drug or by its metabolite carbamazepine-10,11-epoxide (EPX) and how the interaction between the drug and the distinct HLA molecule occurs. Genetically engineered human B-lymphoblastoid cells expressing soluble HLA-B∗15:02 molecules were treated with the drug or its metabolite. Functional pHLA complexes were purified; peptides were eluted and sequenced. Applying mass spectrometric analysis, CBZ and EPX were monitored by analyzing the heavy chain and peptide fractions separately for the presence of the drug. This method enabled the detection of the drug in a biological situation post-pHLA assembly. Both drugs were bound to the HLA-B∗15:02 heavy chain; however, solely EPX altered the peptide-binding motif of B∗15:02-restricted peptides. This observation could be explained through structural insight; EPX binds to the peptide-binding region and alters the biochemical features of the F pocket and thus the peptide motif. Understanding the nature of immunogenic interactions between CBZ and EPX with the HLA immune complex will guide towards effective and safe medications.

Impact of Donor Core Body Temperature on Graft Survival After Heart Transplantation.

Abstract: BACKGROUND A previous donor intervention trial found that induction of mild therapeutic hypothermia in the brain-dead donor reduced the dialysis requirement after kidney transplantation. Consequences on the performance of cardiac allografts after transplantation were not explored to date. METHODS Cohort study investigating 3-year heart allograft survival according to spontaneous core body temperature (CBT) assessed on the day of organ procurement. The study is nested in the database of the randomized trial of donor pretreatment with low-dose dopamine (ClinicalTrials.gov identifier: NCT000115115). RESULTS Ninety-nine heart transplant recipients who had received a cardiac allograft from a multiorgan donor enrolled in the dopamine trial were grouped by tertiles of the donor's CBT assessed by a mere temperature reading 4 to 20 hours before procurement (lowest, 32.0-36.2°C; middle, 36.3-36.8°C; highest, 36.9-38.8°C). Baseline characteristics considering demographics of donors and recipients, concomitant donor treatments, donor hemodynamic, and respiratory parameters as well as underlying cardiac diseases in recipients, pretransplant hemodynamic assessments, including pretransplant inotropic/mechanical support, urgency, and waiting time were similar. A lower CBT was associated with inferior heart allograft survival (hazard ratio, 0.53; 95% confidence interval, 0.31-0.93, per tertile; P = 0.02, and hazard ratio, 0.68; 95% confidence interval, 0.50-0.93°C; P = 0.02) when CBT was included as continuous explanatory variable in the Cox regression analysis. CONCLUSIONS A lower CBT in the brain-dead donor before procurement may associate with an unfavorable clinical course after heart transplantation. More research is required, before therapeutic hypothermia can routinely be used in multiorgan donors when a cardiac transplantation is intended.

Electrical cardioversion of patients with implanted pacemaker or cardioverter-defibrillator: results of a survey of german centers and systematic review of the literature.

Abstract: A relevant number of patients presenting for electrical cardioversion carry a pacemaker (PM) or ICD. Case reports suggest a potential hazard of external cardioversion/defibrillation. The incidence of shock related device complications is unknown. No guidelines or recommendations by international medical societies for a cardioversion protocol of cardiovascular implantable electronic device (CIED) patients exist. We conducted a nationwide survey to gather real-world clinical data on the current clinical approach towards these patients during electrical cardioversion and to estimate the incidence of shock-related complications. Ninety hospitals with > 380 ECV in 2014 were identified from mandatory hospital quality reports and 60 were randomly selected. All centers were provided with a standardized questionnaire on the general proceedings and complications during electrical cardioversion of pacemaker, ICD and CRT patients (CIED patients). Thirty-two centers (53%) participated in the survey. In total, 16,554 ECV were reported (534 ± 314 per center). Biphasic cardioversion with a first shock energy of ≥ 150 J via adhesive patches in antero-posterior orientation was preferred by most centers (78%). Eleven percent (n = 1809) of pts were reported to carry a PM/ICD. The ECV protocol was heterogeneous among centers. Complications associated with electrical cardioversion were reported in 11/1809 patients (0.6%), all were transitory elevations of pacing thresholds. In this nationwide snapshot survey of cardioversion procedures in Germany, approximately 11% of patients presenting for elective electrical cardioversion were pacemaker or ICD carriers. Cardioversion protocols in these patients are heterogeneous throughout centers and mostly not in accordance with recommendation of the German Cardiac Society. Complications associated with external electrical cardioversion are rare. Controlled trials and large registries are necessary to provide evidence for future recommendations.

Synthesis, radiosynthesis, in vitro and first in vivo evaluation of a new matrix metalloproteinase inhibitor based on γ-fluorinated α-sulfonylaminohydroxamic acid

Abstract: To study MMP activity in vivo in disease, several radiolabeled MMP inhibitors functioning as radiotracers have been evaluated by means of SPECT and PET. Unfortunately, most of them suffer from metabolic instability, mainly hepatobiliary clearance and insufficient target binding. The introduction of a fluorine atom into MMPIs could contribute to target binding, enhance the metabolic stability and might shift the clearance towards more renal elimination. Recently developed α-sulfonylaminohydroxamic acid based γ-fluorinated inhibitors of MMP-2 and -9 provide promising fluorine interactions with the enzyme active site and high MMP inhibition potencies. The aim of this study is the (radio)synthesis of a γ-fluorinated MMP-2 and -9 inhibitor to evaluate its potential as a radiotracer to image MMP activity in vivo. Two new fluorine-containing, enantiomerically pure inhibitors for MMP-2 and -9 were synthesized in a six step sequence. Both enantiomers exhibited equal inhibition potencies in the low nanomolar and subnanomolar range. LogD value indicated better water solubility compared to the CGS 25966 based analog. The most potent inhibitor was successfully radiofluorinated. In vivo biodistribution in wild type mice revealed predominantly hepatobiliary clearance. Two major radioactive metabolites were found in different organs. Defluorination of the radiotracer was not observed. (Radio)synthesis of a CGS based γ-fluorinated MMP inhibitor was successfully accomplished. The (S)-enantiomer, which normally shows no biological activity, also exhibited high MMP inhibition potencies, which may be attributed to additional interactions of fluorine with enzyme’s active site. Despite higher hydrophilicity no significant differences in the clearance characteristics compared to non-fluorinated MMPIs was observed. Metabolically stabilizing effect of the fluorine was not monitored in vivo in wild type mice.

Shock efficacy of single and dual coil electrodes-new insights from the NORDIC ICD Trial.

Abstract: Aims Dual coil (DC) electrodes are preferred to single coil (SC) electrodes because of an assumed higher shock efficacy. However, DC-electrodes may be associated with an increased difficulty and risk of lead extraction. We aimed to compare SC- and DC-electrodes with respect to the first shock efficacy (FSE) after implantable cardioverter defibrillator (ICD) implantation. Methods and results One thousand and seventy-seven patients of the NORDIC ICD trial were randomly assigned to first time ICD implantation with or without defibrillation (DF) testing. The electrode configuration was determined before randomization. One thousand and sixty-seven patients eventually received an ICD, 516 (48.4%) with a SC- and 551 (51.6%) with a DC-electrode. DC-electrodes were preferentially selected in older patients, renal failure, atrial fibrillation, dual chamber, Cardiac Resynchronization Therapy (CRT) devices, angiotensin-converting-enzyme (ACE) inhibitors/angiotensin (AT) receptor blockers and without Sotalol. However, the preference of the investigational site was dominant over clinical parameters. The DF energy at the final electrode position was higher in SC-electrodes (adjusted difference +1.15 J; P = 0.005; only patients tested). Less patients with DC-electrodes required intra-operative system reconfiguration (adjusted difference -3.9; P = 0.046; only patients tested). Using mixed logistic regression, the FSE was 92.6% in SC- and 97.8% in DC-electrodes (adjusted odds ratio 4.3 (95% confidence interval [1.9, 9.8]; P < 0.001)). Conclusion Dual coil-electrode selection mainly depends on the preference of the investigational site and seems to be preferred in older patients, renal failure, atrial fibrillation, dual chamber, and CRT devices. Patients with DC-electrodes required less intraoperative system reconfigurations. Dual coil-electrodes provided a substantially higher FSE during follow-up. Mortality rates were not significantly different in patients with DC- and SC-electrodes. (Less)

Carotid strain measurement in patients with pseudoxanthoma elasticum - Hint for a different pathomechanism?

Abstract: Pseudoxanthoma Elasticum (PXE), caused by autosomal-recessive mutations in the ATP-binding cassette transporter (ABCC6) gene, is known for high prevalence of atherosclerosis. A novel method investigating elastic properties of arteries in atherosclerotic patients is vascular strain analysis. We compared 44 PXE patients with peripheral artery disease (PXE+PAD group) with 50 control patients, each 25 without (control group) and with PAD (PAD group). All participants underwent an angiological examination including ankle-brachial index (ABI) and were examined with speckle-tracking based vascular strain analysis of common carotid arteries, measuring radial displacement (r.Dis), radial velocity (r.Vel), radial strain (r.Str), circumferential strain (c.Str), radial strainrate (r.SR) and circumferential strainrate (c.SR). We found significant lower ABI in patients with PXE compared to all other groups (each p < 0.01). The vascular strain analysis resulted in significantly decreased values in the PAD group compared to PXE with PAD (each p ≤ 0.01) and controls without PAD (each p ≤ 0.05), whereas no significant difference could be found between PXE+PAD and controls without PAD. We found significant negative correlations between low strain values and a higher prevalence of PAD in non-PXE patients (r.Str r = -0.34; c.Str r = -0.35; r.SR: r = -0.51; c.SR: r = -0.53). In conclusion, PXE patients had similar values for arterial stiffness compared to controls without PAD in vascular strain analysis. In this group, arterial stiffness parameters were significantly higher compared to non-PXE PAD patients. It is worth to discuss whether PAD-like manifestations in PXE are a different kind of disease and might need another strategy in diagnostics and therapy.

Foetal thymus size in pregnancies after assisted reproductive technologies.

Abstract: The aim of our study was to compare thymus sizes in foetuses conceived using assisted reproductive technologies (ART) to those conceived naturally (control group). Sonographic foetal thymus size was assessed retrospectively in 162 pregnancies conceived using ART and in 774 pregnancies conceived naturally. The anteroposterior thymic and the intrathoracic mediastinal diameter were measured to calculate the thymic–thoracic ratio (TT-ratio). The ART cases were subdivided into two groups: (1) intracytoplasmic sperm injection (ICSI; n = 109) and (2) in vitro fertilisation (IVF; n = 53). The TT-ratio was smaller in pregnancies conceived using ART (p < 0.001). In both ART subgroups (ICSI and IVF), the TT-ratio was lower compared to the control group (p < 0.001). However, no difference between the two subgroups could be detected (p = 0.203). Our data show reduced thymus size in foetuses conceived using ART compared to controls. These findings indicate that the use of ART may lead to certain deviations in organogenesis.

Fetal brain development in diabetic pregnancies and normal controls.

Abstract: Abstract Objective: To compare the fetal brain structures assessed in routine sonographic scans during the second and third trimesters in diabetic and normal pregnancies. Methods: In this retrospective study, we measured the head circumference (HC), the transversal diameter of the cerebellum (TCD) and the sizes of the cisterna magna (CM), the cavum septi pellucidi (CSP) and the lateral ventricles (LV) in stored sonographic scans between 20 and 41 weeks of gestation. We compared 231 fetuses of diabetic mothers (diabetic group) to 231 fetuses of normal pregnancies (control group) matched by gestational age. The diabetic group was divided into three subgroups: pre-existing maternal diabetes, diet-controlled gestational diabetes and insulin-dependent gestational diabetes. Results: The mean widths of the CSP and LV were larger in fetuses of diabetic mothers in comparison with the controls (P<0.001, P<0.001; respectively). The sizes of HC, CM and TCD were similar in both groups. These results were consistent across the three subgroups. Conclusions: Diabetes is associated with altered fetal brain development. We would like to introduce the increased widths of CSP and LV as potential markers for gestational diabetes.

The transverse four-chamber view for the assessment of atrial tissue deformation in the fetus.

Abstract: Aims To determine if atrial tissue deformation (peak strain, PS) and time to peak strain (TTPS) can be assessed in the fetus, with identification of best echocardiographic plane. Materials and methods Pulsed-wave tissue Doppler study of a longitudinal and a transverse four-chamber view (FCV) in each of 20 healthy fetuses. Determination of PS and TTPS in regions of interest (ROI), viz., lateral walls of the right and left atria (RA, LA); comparison of values depending on section plane, with results-based discussion of the physiology of fetal atrial deformation and of possible clinical uses. Results PS and TTPS could be determined on transverse FCV in 91% of subjects and in 61% on longitudinal FCV. Transverse PS and TTPS were significantly higher than longitudinal (p = 0.0001). Transverse PS was significantly higher in RA than in LA (26.9% vs. 17.3%, p = 0.034), and transverse TTPS was significantly shorter in RA than in LA (p = 0.034). Conclusion Atrial radial PS and TTPS determinations are possible in the fetus. The transverse FCV is best suited for these. The highest PS values and shortest TTPS values are found in ROI representing the RA. Our findings may contribute to detailed intrauterine assessment of atrial and ventricular myocardial function.

Use of prothrombin complex concentrate containing heparin for emergency reversal of bivalirudin anticoagulation: a word of caution:

Abstract: We read with great interest the case reported by Dr. Hassen and colleagues describing the management of severe bleeding associated with bivalirudin in a patient with acute heparin-induced thrombocytopenia (HIT) undergoing emergent complex cardiac surgery.1 Acute renal failure serves as an explanation for the persisting anticoagulant effect observed in this case as, in dialysis patients, the half-life of bivalirudin can be prolonged up to 3.5 hours.2 Uncontrollable diffuse bleeding is a challenging scenario for cardiac surgical teams. In this case report, Hassan et al. used a multimodal approach to manage haemorrhage, which also included the administration of 4-factor prothrombin complex concentrate (PCC) containing heparin. Based on this single-case experience, the authors suggested an algorithm for the management of patients with comparable clinical conditions. Although the long-term course of the patient was fortunately uneventful, the management strategy promoted by the authors should be interpreted with caution. It is well accepted that even small amounts of heparin may trigger HIT reactions. Refaai et al. reported a case of HIT-associated venous thromboembolism and cerebral venous thrombosis as the consequence of heparin ‘flushes’.3 As thrombin plays a pivotal role in HITassociated thromboembolism (TE), it can be speculated that high intraoperative concentrations of bivalirudin may have prevented/attenuated any potential manifestations of HIT that could have been induced by the heparin contained in the PCC. However, a not rare phenomenon known as ‘late onset HIT’ has also been described in the case published by Refaai et al., meaning that HIT can occur even days following heparin exposure.3 In addition, the administration of PCC itself may be considered as a risk factor for TE complications. The halflife of the pro-coagulant factors contained in the PCC ranges from approximately 6 hours for factor VII to more than 10 days for factor II, while it is approximately 2 days for the antithrombotic proteins C and S.4 The safety profile of these powerful drugs has only been assessed in small randomized or retrospective trials, most of them for the reversal of vitamin k antagonist (VKA) therapy (only approved indication).5 The incidence of TE reported in the prospective studies for VKA reversal was approximately 4%.5 However, incidences as high as 20% have been reported following the administration of PCC for major bleeding outside the context of VKA reversal.6 Considering the absence of safety data in bleeding patients and the risk of ‘delayed onset HIT’, the administration of heparin-containing PCC should not be recommended for bleeding management in patients treated with bivalirudin. Viewing the dilemma of currently available approaches in cases of diffuse microvascular bleeding in patients treated with bivalirudin, we prefer to cautiously tamponade the thorax, leave the chest open (which also prevents the bleeding associated with the placement of sternal wires during anticoagulation) and start continuous haemofiltration immediately after intensive care unit admission. Using such a strategy, the chest can usually be closed within 24 hours when laboratory parameters have normalized and diffuse bleeding has stopped. The underlying risk for preoperative TE complications is not increased. As outlined by Dr. Hassan et al., our experience with bivalirudin anticoagulation during cardiac surgery and, Use of prothrombin complex concentrate containing heparin for emergency reversal of bivalirudin anticoagulation: a word of caution