The utility of temporal trends of blood biomarkers as predictors for bloodstream infections in left ventricular assist device recipients.

BACKGROUND: Temporal trends of routinely obtained parameters may provide valuable information for predicting BSIs, but this association has not yet been established in LVAD patients. METHODS: This retrospective analysis included data from 347 consecutive recipients of three rotary LVAD types. Study endpoints included the incidence of BSI, the association of temporal trends of routinely obtained blood biomarkers with the development of BSIs, the incidence of BSIs, and survival on LVAD support. RESULTS: During follow-up, 47.8% (n = 166) of the patients developed BSI. In multivariate analyses, the development of BSI was a significant predictor of mortality (HR 5.78, 95% CI 4.08-8.19, p < 0.0001). In univariate analyses, after adjusting for potential confounders, albumin (SHR 0.94, 95% CI 0.91-0.97, p < 0.00010), creatinine (SHR 1.49, 95% CI 1.03-2.15, p = 0.033), and C-reactive protein (SHR 1.19, 95% CI 1.08-1.32, p = 0.0007) significantly predicted the development of BSIs during LVAD support. Notably, the strength of the association of parameter changes with the prediction of BSIs demonstrated a time-dependent correlation in the cases of albumin (p = 0.045) and creatinine (p = 0.003). CONCLUSION: Bloodstream infections are highly prevalent among LVAD recipients and are independent predictors of mortality. Temporal biomarker trends significantly predict the development of BSIs. These findings suggest opportunities for interventions aiming to reduce the incidence of BSIs.

Matched comparison of decellularized homografts and bovine jugular vein conduits for pulmonary valve replacement in congenital heart disease.

For decades, bovine jugular vein conduits (BJV) and classic cryopreserved homografts have been the two most widely used options for pulmonary valve replacement (PVR) in congenital heart disease. More recently, decellularized pulmonary homografts (DPH) have provided an alternative avenue for PVR. Matched comparison of patients who received DPH for PVR with patients who received bovine jugular vein conduits (BJV) considering patient age group, type of heart defect, and previous procedures. 319 DPH patients were matched to 319 BJV patients; the mean age of BJV patients was 15.3 (SD 9.5) years versus 19.1 (12.4) years in DPH patients (p = 0.001). The mean conduit diameter was 24.5 (3.5) mm for DPH and 20.3 (2.5) mm for BJV (p < 0.001). There was no difference in survival rates between the two groups after 10 years (97.0 vs. 98.1%, p = 0.45). The rate of freedom from endocarditis was significantly lower for BJV patients (87.1 vs. 96.5%, p = 0.006). Freedom from explantation was significantly lower for BJV at 10 years (81.7 vs. 95.5%, p = 0.001) as well as freedom from any significant degeneration at 10 years (39.6 vs. 65.4%, p < 0.001). 140 Patients, matched for age, heart defect type, prior procedures, and conduit sizes of 20-22 mm (± 2 mm), were compared separately; mean age BJV 8.7 (4.9) and DPH 9.5 (7.3) years (p = n.s.). DPH showed 20% higher freedom from explantation and degeneration in this subgroup (p = 0.232). Decellularized pulmonary homografts exhibit superior 10-year results to bovine jugular vein conduits in PVR.

Cyclic pressure induced decellularization of porcine descending aortas.

The demand for decellularized xenogeneic tissues used in reconstructive heart surgery has increased over the last decades. Complete decellularization of longer and tubular aortic sections suitable for clinical application has not been achieved so far. The present study aims at analyzing the effect of pressure application on decellularization efficacy of porcine aortas using a device specifically designed for this purpose. Fresh porcine descending aortas of 8 cm length were decellularized using detergents. To increase decellularization efficacy, detergent treatment was combined with pressure application and different treatment schemes. Quantification of penetration depth as well as histological staining, scanning electron microscopy, and tensile strength tests were used to evaluate tissue structure. In general, application of pressure to aortic tissue does neither increase the decellularization success nor the penetration depth of detergents. However, it is of importance from which side of the aorta the pressure is applied. Application of intermittent pressure from the adventitial side does significantly increase the decellularization degree at the intimal side (compared to the reference group), but had no influence on the penetration depth of SDC/SDS at both sides. Although the present setup does not significantly improve the decellularization success of aortas, it is interesting that the application of pressure from the adventitial side leads to improved decellularization of the intimal side. As no adverse effects on tissue structure nor on mechanical properties were observed, optimization of the present protocol may potentially lead to complete decellularization of larger aortic segments.

Increased Drop in Activity of Alkaline Phosphatase in Plasma from Patients with Endocarditis.

(1) Infective endocarditis is a severe inflammatory disease associated with substantial mortality and morbidity. Alkaline phosphatase (AP) levels have been shown to change significantly during sepsis. Additionally, we previously found that a higher initial AP drop after cardiac surgery is associated with unfavorable outcomes. Therefore, the course of AP after surgery for endocarditis is of special interest. (2) A total of 314 patients with active isolated left-sided infective endocarditis at the Department of Cardiac Surgery (Medical University of Vienna, Vienna, Austria) between 2009 and 2018 were enrolled in this retrospective analysis. Blood samples were analyzed at different time points (baseline, postoperative days 1-7, postoperative days 14 and 30). Patients were categorized according to relative alkaline phosphatase drop (≥30% vs. <30%). (3) A higher rate of postoperative renal replacement therapy with or without prior renal replacement therapy (7.4 vs. 21.8%; p = 0.001 and 6.7 vs. 15.6%; p = 0.015, respectively) and extracorporeal membrane oxygenation (2.2 vs. 19.0%; p = 0.000) was observed after a higher initial alkaline phosphatase drop. Short-term (30-day mortality 3.0 vs. 10.6%; p = 0.010) and long-term mortality (p = 0.008) were significantly impaired after a higher initial alkaline phosphatase drop. (4) The higher initial alkaline phosphatase drop was accompanied by impaired short- and long-term outcomes after cardiac surgery for endocarditis. Future risk assessment scores for cardiac surgery should consider alkaline phosphatase.

Human Factors Evaluation of HeartMate 3 Left Ventricular Assist Device Peripherals: An Eye Tracking Supported Simulation Study.

BACKGROUND: Despite recent design improvements, human factors issues continue to challenge left ventricular assist device (LVAD) therapy. The aim of this study was to evaluate user experience of former non-HeartMate 3 (HM3) LVAD patients post heart transplantation (HTX) and laypersons (LP) with HM3 LVAD peripherals in simulated everyday and emergency scenarios. METHODS: This single center cohort study included untrained HTX and LP. Seven scenarios, including battery exchanges (without alarm, advisory alarm, dim light, consolidated bag), change of power supply, driveline dis-/reconnection and controller exchange were simulated. Subjects' gaze behavior was recorded using eye tracking technology. Success rate, pump-off-time, duration to success (DTS), percental fixation duration per areas of interest and post-scenario-survey results were defined as outcome measures. RESULTS: Thirty subjects completed 210 scenarios, initially solving 82.4% (HTX vs. LP, p = 1.00). Changing power supply revealed highest complexity (DTS = 251 ± 93s, p = 0.76): 26.7% succeeded at first attempt (p = 0.68), 56.7% at second attempt, with significantly more LP failing (p = 0.04), resulting in 10 hazards from driveline disconnections (pump-off-time 2-118s, p = 0.25). Comparison on initial success showed differences in fixation durations for seven areas of interest (p < 0.037). Decreasing DTS during battery exchanges (p < 0.001) indicate high learnability. Exchanging batteries within the bag took longer (median DTS = 75.0 (IQR = 45.0)s, p = 0.09), especially in elderly subjects (r = 0.61, p < 0.001). Subjects with less initial success were more afraid of making mistakes (p = 0.048). CONCLUSION: This eye tracking based human factors study provided insights into user experiences in handling HM3 peripherals. It highlights unintuitive and hazardous characteristics, providing guidance for future user-centered design of LVAD wearables.

Extracorporeal Photopheresis With Low-Dose Immunosuppression in High-Risk Heart Transplant Patients-A Pilot Study.

In severely ill patients undergoing urgent heart transplant (HTX), immunosuppression carries high risks of infection, malignancy, and death. Low-dose immunosuppressive protocols have higher rejection rates. We combined extracorporeal photopheresis (ECP), an established therapy for acute rejection, with reduced-intensity immunosuppression. Twenty-eight high-risk patients (13 with high risk of infection due to infection at the time of transplant, 7 bridging to transplant via extracorporeal membrane oxygenation, 8 with high risk of malignancy) were treated, without induction therapy. Prophylactic ECP for 6 months (24 procedures) was initiated immediately postoperatively. Immunosuppression consisted of low-dose tacrolimus (8-10 ng/ml, months 1-6; 5-8 ng/ml, >6 months) with delayed start; mycophenolate mofetil (MMF); and low maintenance steroid with delayed start (POD 7) and tapering in the first year. One-year survival was 88.5%. Three patients died from infection (POD 12, 51, 351), and one from recurrence of cancer (POD 400). Incidence of severe infection was 17.9% (n = 5, respiratory tract). Within the first year, antibody-mediated rejection was detected in one patient (3.6%) and acute cellular rejection in four (14.3%). ECP with reduced-intensity immunosuppression is safe and effective in avoiding allograft rejection in HTX recipients with risk of severe infection or cancer recurrence.

The Prognostic Impact of Anti-thrombotic Treatment Strategies After Biological Aortic Valve Replacement.

PURPOSE: Optimal antithrombotic therapy in patients who underwent surgical biological aortic valve replacement (AVR) represents an issue of ongoing discussion. Additionally, the prognostic impact of anti-thrombotic treatment strategies after biological AVR and real-life data on anticoagulation strategies (AC) of patients presenting with short-term postoperative atrial fibrillation (POAF) has not clearly been investigated so far. Therefore, this study aimed to investigate the impact of therapeutic AC after biological AVR on patient outcome and whether the presence of POAF affects decision making on anti-thrombotic management. METHODS: Within this prospective observational study, 200 individuals that underwent biological AVR surgery were enrolled. Participants were followed prospectively until the primary study endpoint was reached. Multivariate logistic regression analysis was performed to elucidate the effect of therapeutic AC on outcome. RESULTS: Overall, 106 individuals received therapeutic AC at the time of discharge. The fraction of patients presenting with POAF was balanced between individuals receiving AC and the non-AC subgroup (p = 0.617). After a median follow-up time of 1418 days, 31 (15.5%) individuals died, referring to 15 (13.9%) POAF-free patients and 16 (17.4%) with POAF. We observed a strong inverse association of therapeutic AC and cardiovascular mortality, which remained stable after adjustment for potential confounders showing a HR of 0.437 (95% CI 0.202-0.943; p = 0.035), while bleeding risk was comparable (p = 0.680). CONCLUSION: Within this investigation, therapeutic AC showed a strong and independent inverse association with long-term mortality in patients that underwent biological AVR. Although POAF is associated with thromboembolic adverse events, the development of this arrhythmia did not affect decision-making of the anti-thrombotic management.

Platelet activation and aggregation in different centrifugal-flow left ventricular assist devices.

Left-ventricular assist devices (LVADs) improve outcomes in end-stage heart failure patients. Two centrifugal-flow LVAD systems are currently approved, HeartMate 3 (HM3) and Medtronic/Heartware HVAD (HVAD). Clinical findings suggest differences in thrombogenicity between both systems. We compared markers of platelet activation and aggregation between HM3 and HVAD. We prospectively included 59 LVAD patients (40 HM3, 19 HVAD). Platelet P-selectin expression, activated glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregates (MPA) were assessed by flow-cytometry. Platelet aggregation was measured by light-transmission aggregometry (LTA) and multiple-electrode aggregometry (MEA). Von-Willebrand factor (VWF) antigen (VWF:Ag), VWF activity (VWF:Ac), and VWF multimer pattern analysis were determined. Soluble P-selectin (sP-selectin) was measured with an enzyme-linked immunoassay. P-selectin, GPIIb/IIIa and MPA levels in vivo and in response to arachidonic acid, adenosine diphosphate, and thrombin receptor activating peptide were similar between HM3 and HVAD (all p > .05). Likewise, agonist-inducible platelet aggregation by LTA and MEA did not differ between HM3 and HVAD (all p > .05). VWF:Ag levels and FVIII:C were similar between both systems (both p > .05), but patients with HVAD had significantly lower VWF:Ac (p = .011) and reduced large VWF multimers (p = .013). Finally, sP-selectin levels were similar in patients with HVAD and HM3 (p = .845). In conclusion, on-treatment platelet activation and aggregation are similar in HM3 and HVAD patients. Potential clinical implications of observed differences in VWF profiles between both LVAD systems need to be addressed in future clinical trials.

Inflow cannula position as risk factor for stroke in patients with HeartMate 3 left ventricular assist devices.

BACKGROUND: A relation between the left ventricular assist device inflow cannula (IC) malposition and pump thrombus has been reported. This study aimed to investigate if the pump position, derived from chest X-rays in HeartMate 3 (HM3) patients, correlates with neurological dysfunction (ND), ischemic stroke (IS), hemorrhagic stroke (HS) and survival. METHODS: This analysis was performed on routinely acquired X-rays of 42 patients implanted with a HM3 between 2014 and 2017. Device position was quantified in patients with and without ND from frontal and lateral X-rays characterizing the IC and pump in relation to spine, diaphragm or horizontal line. The primary end-point was freedom from stroke and survival one-year after HM3 implantation stratified by pump position. RESULTS: The analysis of X-rays, 33.5 (41.0) days postoperative, revealed a significant smaller IC angle of HM3 patients with ND versus no ND (0.1° ± 14.0° vs. 12.9° ± 10.1°, p = 0.005). Additionally, the IC angle in the frontal view, IS: 4.1 (20.9)° versus no IS: 13.8 (7.5)°, p = 0.004 was significantly smaller for HM3 patients with IS. Using receiver operating characteristics derived cut-off, IC angle <10° provided 75% sensitivity and 100% specificity (C-statistic = 0.85) for predicting IS. Stratified by IC angle, freedom from IS at 12 months was 100% (>10°) and 60% (<10°) respectively (p = 0.002). No significant differences were found in any end-point between patients with and without HS. One-year survival was significantly higher in patients with IC angle >10° versus <10° (100% vs. 71.8%, p = 0.012). CONCLUSIONS: IC malposition derived from standard chest X-rays serves as a risk factor for ND, IS and worse survival in HM3 patients.

Impacts of Telomeric Length, Chronic Hypoxia, Senescence, and Senescence-Associated Secretory Phenotype on the Development of Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) is an age-related and life-threatening vascular disease. Telomere shortening is a predictor of age-related diseases, and its progression is associated with premature vascular disease. The aim of the present work was to investigate the impacts of chronic hypoxia and telomeric DNA damage on cellular homeostasis and vascular degeneration of TAA. We analyzed healthy and aortic aneurysm specimens (215 samples) for telomere length (TL), chronic DNA damage, and resulting changes in cellular homeostasis, focusing on senescence and apoptosis. Compared with healthy thoracic aorta (HTA), patients with tricuspid aortic valve (TAV) showed telomere shortening with increasing TAA size, in contrast to genetically predisposed bicuspid aortic valve (BAV). In addition, TL was associated with chronic hypoxia and telomeric DNA damage and with the induction of senescence-associated secretory phenotype (SASP). TAA-TAV specimens showed a significant difference in SASP-marker expression of IL-6, NF-κB, mTOR, and cell-cycle regulators (γH2AX, Rb, p53, p21), compared to HTA and TAA-BAV. Furthermore, we observed an increase in CD163+ macrophages and a correlation between hypoxic DNA damage and the number of aortic telocytes. We conclude that chronic hypoxia is associated with telomeric DNA damage and the induction of SASP in a diseased aortic wall, promising a new therapeutic target.

The Role of Telocytes and Telocyte-Derived Exosomes in the Development of Thoracic Aortic Aneurysm.

A hallmark of thoracic aortic aneurysms (TAA) is the degenerative remodeling of aortic wall, which leads to progressive aortic dilatation and resulting in an increased risk for aortic dissection or rupture. Telocytes (TCs), a distinct type of interstitial cells described in many tissues and organs, were recently observed in the aortic wall, and studies showed the potential regulation of smooth muscle cell (SMC) homeostasis by TC-released shed vesicles. The purpose of the present work was to study the functions of TCs in medial degeneration of TAA. During aneurysmal formation an increase of aortic TCs was identified in human surgical specimens of TAA-patients, compared to healthy thoracic aortic (HTA)-tissue. We found the presence of epithelial progenitor cells in the adventitial layer, which showed increased infiltration in TAA samples. For functional analysis, HTA- and TAA-telocytes were isolated, characterized, and compared by their protein levels, mRNA- and miRNA-expression profiles. We detected TC and TC-released exosomes near SMCs. TAA-TC-exosomes showed a significant increase of the SMC-related dedifferentiation markers KLF-4-, VEGF-A-, and PDGF-A-protein levels, as well as miRNA-expression levels of miR-146a, miR-221 and miR-222. SMCs treated with TAA-TC-exosomes developed a dedifferentiation-phenotype. In conclusion, the study shows for the first time that TCs are involved in development of TAA and could play a crucial role in SMC phenotype switching by release of extracellular vesicles.

The impact of volume substitution on post-operative atrial fibrillation.

BACKGROUND: Post-operative atrial fibrillation (POAF) represents a common complication after cardiac valve or coronary artery bypass surgery. While strain of atrial tissue is known to induce atrial fibrillating impulses, less attention has been paid to potentially strain-promoting values during the peri- and post-operative period. This study aimed to determine the association of peri- and post-operative volume substitution with markers of cardiac strain and subsequently the impact on POAF development and promotion. RESULTS: A total of 123 (45.4%) individuals were found to develop POAF. Fluid balance within the first 24 hours after surgery was significantly higher in patients developing POAF as compared to non-POAF individuals (+1129.6 mL [POAF] vs +544.9 mL [non-POAF], P = .044). Post-operative fluid balance showed a direct and significant correlation with post-operative N-terminal pro-brain natriuretic peptide (NT-ProBNP) values (r = .287; P = .002). Of note, the amount of substituted volume significantly proved to be a strong and independent predictor for POAF with an adjusted odds ratio per one litre of 1.44 (95% CI: 1.09-1.31; P = .009). In addition, we observed that low pre-operative haemoglobin levels at admission were associated with a higher need of intraoperative transfusions and volume-demand. CONCLUSION: Substitution of larger transfusion volumes presents a strong and independent predictor for the development of POAF. Via the observed distinct association with NT-proBNP values, it can reasonably be assumed that post-operative atrial fibrillating impulses are triggered via increased global cardiac strain. Optimized pre-operative management of pre-existing anaemia should be considered prior surgical intervention in terms of a personalized patient care.

The adapted Heart Donor Score.

The Heart Donor Score (HDS) predicts donor organ discard for medical reasons and survival after heart transplantation (HTX) in the Eurotransplant allocation system. Our aim was to adapt the HDS for application in the United Network for Organ Sharing (UNOS) registry. To adjust for differences between the Eurotransplant and UNOS registries, the "adapted HDS" was created (aHDS) by exclusion of the covariates "valve function," "left-ventricular hypertrophy," and exclusion of "drug abuse" from the variable "compromised history." Two datasets were analyzed to evaluate associations of the aHDS with donor organ discard (n = 70 948) and survival (n = 19 279). The aHDS was significantly associated with donor organ discard [odds ratio 2.72, 95% confidence interval (CI) 2.68-2.76, P < 0.001; c-statistic: 0.937). The score performed comparably in donors <60 and ≥60 years of age. The aHDS was a significant predictor of survival as evaluated by univariate Cox proportional hazards analysis (hazard ratio 1.04, 95% CI 1.01-1.07, P = 0.023), although the association lost significance in a multivariable model. The aHDS predicts donor organ discard. Negative effects of most aHDS components on survival are likely eliminated by highly accurate donor selection processes.

Left ventricular assist device driveline infections in three contemporary devices.

Driveline infections (DLI) are common adverse events in left ventricular assist devices (LVADs), leading to severe complications and readmissions. The study aims to characterize risk factors for DLI readmission 2 years postimplant. This single-center study included 183 LVAD patients (43 HeartMate II [HMII], 29 HeartMate 3 [HM3], 111 HVAD) following hospital discharge between 2013 and 2017. Demographics, clinical parameters, and outcomes were retrospectively analyzed and 12.6% of patients were readmitted for DLI, 14.8% experienced DLI but were treated in the outpatient setting, and 72.7% had no DLI. Mean C-reactive protein (CRP), leukocytes and fibrinogen were higher in patients with DLI readmission (P < .02) than in outpatient DLI and patients without DLI, as early as 60 days before readmission. Freedom from DLI readmission was comparable for HMII and HVAD (98% vs. 87%; HR, 4.52; 95% CI, 0.58-35.02; P = .15) but significantly lower for HM3 (72%; HR, 10.82; 95% CI, 1.26-92.68; P = .03). DLI (HR, 1.001; 95% CI, 0.999-1.002; P = .16) or device type had no effect on mortality. DLI readmission remains a serious problem following LVAD implantation, where CRP, leukocytes, and fibrinogen might serve as risk factors already 60 days before. HM3 patients had a higher risk for DLI readmissions compared to HVAD or HMII, possibly because of device-specific driveline differences.

Extra-anatomic aortic bypass with aortic-, mitral-, and tricuspid surgery in a 53-year old: A single-stage approach for complex coarctation associated with triple valve pathology.

Coarctation is rare in patients over 50 years of age; however, if present, it can be associated with complex intracardiac pathologies and represent a formidable surgical challenge. Herein, we report a single-stage approach for surgical repair of coarctation associated with aortic, mitral, and tricuspid valve pathology using an ascending-to-descending aortic bypass with posterior pericardial access.

Outcomes of coronary artery bypass grafting in patients with human immunodeficiency virus infection.

BACKGROUND: With early and effective antiretroviral therapy and improved survival for persons living with human immunodeficiency virus infection (PLHIV), this patient population now faces an increasingly elevated risk of cardiovascular disease. However, the data on outcomes after coronary artery bypass grafting (CABG) for revascularization of coronary artery disease (CAD) in HIV+ patients is limited. METHODS: We conducted a retrospective analysis of 16 patients undergoing isolated CABG at the Medical University of Vienna from 2005 to 2018, who were HIV+ on admission. The primary endpoint of the study was survival. Secondary endpoints included the components of major adverse cardiac and cerebrovascular events (MACCE): cardiovascular death, stroke, myocardial infarction (MI), and repeat revascularization. RESULTS: Patients were followed for a median of 49 months (range, 7-142 months). Survival was 100% and 90% at 1 and 3 years after CABG, respectively. There were no strokes. MI and subsequent repeat revascularization were observed in two patients. CONCLUSION: CABG provides excellent short- and midterm survival and freedom from MACCE in HIV+ patients with CAD requiring revascularization.

Randomized trial of ticagrelor vs. aspirin in patients after coronary artery bypass grafting: the TiCAB trial.

AIMS: The antiplatelet treatment strategy providing optimal balance between thrombotic and bleeding risks in patients undergoing coronary artery bypass grafting (CABG) is unclear. We prospectively compared the efficacy of ticagrelor and aspirin after CABG. METHODS AND RESULTS: We randomly assigned in double-blind fashion patients scheduled for CABG to either ticagrelor 90 mg twice daily or 100 mg aspirin (1:1) once daily. The primary outcome was the composite of cardiovascular death, myocardial infarction (MI), repeat revascularization, and stroke 12 months after CABG. The main safety endpoint was based on the Bleeding Academic Research Consortium classification, defined as BARC ≥4 for periprocedural and hospital stay-related bleedings and BARC ≥3 for post-discharge bleedings. The study was prematurely halted after recruitment of 1859 out of 3850 planned patients. Twelve months after CABG, the primary endpoint occurred in 86 out of 931 patients (9.7%) in the ticagrelor group and in 73 out of 928 patients (8.2%) in the aspirin group [hazard ratio 1.19; 95% confidence interval (CI) 0.87-1.62; P = 0.28]. All-cause mortality (ticagrelor 2.5% vs. aspirin 2.6%, hazard ratio 0.96, CI 0.53-1.72; P = 0.89), cardiovascular death (ticagrelor 1.2% vs. aspirin 1.4%, hazard ratio 0.85, CI 0.38-1.89; P = 0.68), MI (ticagrelor 2.1% vs. aspirin 3.4%, hazard ratio 0.63, CI 0.36-1.12, P = 0.12), and stroke (ticagrelor 3.1% vs. 2.6%, hazard ratio 1.21, CI 0.70-2.08; P = 0.49), showed no significant difference between the ticagrelor and aspirin group. The main safety endpoint was also not significantly different (ticagrelor 3.7% vs. aspirin 3.2%, hazard ratio 1.17, CI 0.71-1.92; P = 0.53). CONCLUSION: In this prematurely terminated and thus underpowered randomized trial of ticagrelor vs. aspirin in patients after CABG no significant differences in major cardiovascular events or major bleeding could be demonstrated. CLINICALTRIALS.GOV IDENTIFIER: NCT01755520.

Early inhibition of endothelial retinoid uptake upon myocardial infarction restores cardiac function and prevents cell, tissue, and animal death.

Physiologically, following myocardial infarction (MI), retinoid levels elevate locally in the infarcted area. Whereas therapeutic systemic application of retinoids was shown to reduce the progression of ventricular dilatation and the onset of heart failure, the role of acute physiologically increased retinoids in the infarction zone is unknown to date. To reveal the role of local retinoids in the MI zone is the central aim of this study. Using human cell culture and co-culture models for hypoxia as well as various assays systems, lentivirus-based transgene expression, in silico molecular docking studies, and an MI model in rats, we analysed the impact of the retinoid all-trans retinoic acid (ATRA) on cell signalling, cell viability, tissue survival, heart function, and MI-induced death in rats. Based on our results, ATRA-mediated signalling does aggravate the MI phenotype (e.g. 2.5-fold increased mortality compared to control), whereas 5'-methoxyleoligin (5ML), a new agent which interferes with ATRA-signalling rescues the ATRA-dependent phenotype. On the molecular level, ATRA signalling causes induction of TXNIP, a potent inhibitor of the physiological antioxidant thioredoxin (TRX1) and sensitizes cells to necrotic cell death upon hypoxia. 5ML-mediated prevention of ATRA effects were shown to be based on the inhibition of cellular ATRA uptake by interference with the cholesterol (and retinol) binding motif of the transmembrane protein STRA6. 5ML-mediated inhibition of ATRA uptake led to a strong reduction of ATRA-dependent gene expression, reduced ROS formation, and protection from necrotic cell death. As 5ML exerted a cardioprotective effect, also independent of its inhibition of cellular ATRA uptake, the agent likely has another cardioprotective property, which may rely on the induction of TRX1 activity. In summary, this is the first study to show i) that local retinoids in the early MI zone may worsen disease outcome, ii) that inhibition of endothelial retinoid uptake using 5ML may constitute a novel treatment strategy, and iii) that targeting endothelial and myocardial retinoid uptake (e.g. via STRA6 inhibition) may constitute a novel treatment target in acute MI.

To Be Or Not to Be: the "Smoker's Paradox" - An in-Vitro Study.

BACKGROUND/AIMS: Clinical studies have reported a better outcome of smokers after myocardial infarction compared to non-smokers. The data are controversial, as some clinical studies did not observe this effect. The cell biological processes involved, which might account for a 'Smoker's Paradox', have not been investigated yet. Therefore, the aim was to elucidate the effect of cigarette smoke on the viability of cardiomyocytes in the context of hypoxia and reperfusion. METHODS: HL-1 cells were incubated with different concentrations of cigarette smoke extract (CSE) and subjected to hypoxia/reperfusion to further evaluate influence of CSE on viability of HL-1 cells using flow cytometry analyses, Western Blot and immunofluorescence staining. RESULTS: Incubation with CSE led to a concentration-dependent reduction in HL-1 viability. Adding hypoxia as a stressor enhanced cell death. Caspase-independent apoptosis was the observed type of cell death partly induced by P53 and apoptosis-inducing-factor. Yet a significant increase in LDH release in cardiomyocytes incubated with 4%, 8% and 16% CSE suggests necrosis with rapid DNA depletion. Interestingly, after hypoxia a decreased LDH release under lower CSE concentrations was observed. Moreover, a concentration-dependent increase in proliferation and a trend for increased ATP availability under hypoxic conditions was shown. CONCLUSIONS: The trend for less LDH release in hypoxia after low-level CSE incubation might represent a switch from necrosis to apoptosis, which in combination with the increase in metabolic activity and ATP availability might account for the 'Smoker's Paradox'. These findings could partly explain inconsistent results of previous clinical studies as the data showed strong evidence for the crucial relevance of the amount of cigarettes smoked. We are in need of future studies distinguishing between different types of smokers to finally verify or falsify the 'Smoker's Paradox'.

A Standardized Telephone Intervention Algorithm Improves the Survival of Ventricular Assist Device Outpatients.

Ventricular assist devices (VADs) are an established therapeutic option for patients with chronic heart failure. Continuous monitoring of VAD parameters and their adherence to guidelines are crucial to detect problems in an early stage to optimize outcomes. A telephone intervention algorithm for VAD outpatients was developed, clinically implemented and evaluated. During the phone calls, a structured inquiry of pump parameters, alarms, blood pressure, INR, body weight and temperature, exit-site status and heart failure symptoms was performed and electronically categorized by an algorithm into 5 levels of severity. VAD outpatient outcomes without (n = 71) and with bi-weekly telephone interviews in their usual care (n = 25) were conducted using proportional hazard Cox regression, with risk adjustment based on a propensity score model computed from demographics and risk factors. From February 2015 through October 2017, 25 patients (n = 3 HeartMate II, n = 4 HeartMate 3 and n = 18 HeartWare HVAD) underwent 637 telephone interventions. In 57.5% of the calls no problems were identified, 3.9% were recalled on the next day because of alarms. In 26.5% (n = 169), the VAD Coordinator had to refer to the physician due to elevated blood pressure (n = 125, >85 mm Hg), INR < 2.0 or > 4.0 (n = 24) or edema (n = 10), 11.9% of the calls led to a follow-up because of equipment or exit-site problems. Propensity-adjusted 2-year survival (89% vs. 57%, P = 0.027) was significantly higher for the telephone intervention group. Continuous, standardized communication with VAD outpatients is important for early detection of upcoming problems and leads to significantly improved survival.