Pre-Operative Continued Oral Anticoagulation Impact on Early Outcomes after Transcatheter Aortic Valve Implantation

Considering that there is a lack of evidence and guideline-based recommendations on the best preoperative oral anticoagulation management (OAC) for transcatheter aortic valve implantation (TAVI), this cohort study aimed to evaluate bleeding, access site complications, and early safety in patients undergoing TAVI on continued OAC therapy vs no-OAC therapy. Three-hundred forty-four patients submitted to a TAVI procedure (66.3% no-OAC vs 33.7% OAC) were consecutively enrolled. Primary endpoint was defined as in-hospital VARC-2 life-threatening or disabling bleeding. Secondary endpoints were in-hospital VARC-2 major vascular complications and VARC-2 early safety at 30 days. Propensity score matching analysis was performed to reduce potential distribution bias, resulting in 2 well-balanced groups (92 patients in each arm). In the overall cohort, mean age, median EuroScore II, and STS-score were 78.7±7.6 years, 2.9% (1.7-5.9), and 2.3% (1.6-3.6), respectively. Despite being older (78 ± 8 vs 80 ± 6, p = 0.004) and having higher STS score (2.1 vs 2.6, p = 0.001), patients on OAC had similar incidence of in-hospital VARC-2 life-threatening or disabling bleeding (1.3% vs. 0.9%, p = 0.711), major vascular complications (4.8% vs 5.2%, p = 0.888), and VARC-2 early safety at 30 days (10.1% vs 12.1%, p = 0.575). No significant differences in the main outcomes were observed when propensity score matching was applied. In conclusion, the management of patients on OAC submitted to a TAVI procedure is challenging and requires balancing the risk of bleeding with the risk of thromboembolic events. The present study suggests that continued OAC was not associated with increased in-hospital VARC-2 life-threatening or disabling bleeding, major vascular complications, and VARC-2 early safety at 30 days

Determinants of axonal growth and their role in the injured adult nervous system

Verletzungen des adulten zentralen Nervensystems ziehen schwerwiegende klinische Konsequenzen nach sich, da die Möglichkeiten zur funktionellen Kompensation minimal sind. Auch spontane Zellerneuerung, regeneratives axonales Wachstum und Wiederherstellung von synaptischen Kontakten werden kaum je festgestellt. Das Wissen über das sich entwickelnde und über das adulte Nervensystem wächst rasch, und während der letzten Jahrzehnte hat sich unser Verständnis von Neuropathologie gewandelt. Wir wissen nun, dass die fehlende funktionelle Erholung nach Verletzungen des Zentralnervensystems teilweise von Molekülen abhängt, welche die Nervenzellen umgeben. Dabei sind vor allem die Myelin- assoziierten, inhibierenden Moleküle zu erwähnen. Ausserdem fehlt verletzten Neuronen die Fähigkeit, ein Genexpressionsmuster zu aktivieren, das ihnen erlaubt, Axone zum Wachstum zu veranlassen. In dieser Dissertation werden bestimmende Faktoren des axonalen Wachstums untersucht und besprochen. Eine Möglichkeit, die mit dem Myelin zusammenhängende Wachstumshemmung teilweise zu überwinden, ist, die Bindung eines inhibitorischen Myelinbestandteils, Nogo-A, an seine neuronalen Rezeptoren zu blockieren, indem ein monoklonaler Antikörper, IN-1, verabreicht wird. Um die Effekte von IN-1 detailliert zu untersuchen, benutzen wir ein Tiermodell bei welchem wir Ratten den Kortikospinaltrakt einseitig durchtrennen. Wie früher gezeigt wurde, verstärken sich dabei strukturelle Plastizität und funktionelle Erholung. Wir zeigen zum ersten Mal auf der elektronenmikroskopischen Ebene, dass neu auswachsende Nervenfasern im verletzten adulten Zentralnervensystem fähig sind, histologisch intakte Synapsen zu bilden. Die intrazellulären Mechanismen, die es Neuronen erlauben, Axone auswachsen zu lassen, werden nach wie vor schlecht verstanden. Wir versuchen hier anhand von Gen-Chip-Analysen einen weiten Überblick über die Anpassung der Transkription nach axonalen Verletzungen zu gewinnen. Wir untersuchen die Genexpression von lumbalen dorsalen Ganglienzellen der adulten Ratte nach Verletzung der peripheren und auch der zentralen Nervenfasern. Die so gewonnenen Resultate vergleichen wir mit der Genexpression derselben Neuronenpopulation während der Embryonalentwicklung. Die periphere und die zentrale Axotomie lösen klar unterscheidbare Antworten im Zellkörper aus. Für beide Verletzungsmuster gilt, dass die Expression von mehr als 50 Genen reguliert wird. Im Vergleich mit der Embryonalenwicklung stellen wir fest, dass für die Regeneration von peripheren Nerven keine vollständige Rekapitulation des embryonalen Expressionsmusters nötig ist. Wir untersuchen auch die durch eine Verletzung ausgelösten Änderungen der Gen- und Protein-Expression genauer, dies anhand von zwei Genen, Glypican-1 und dem peripheren Benzodiazepin-Rezeptor (PBR). Unsere Resultate zeigen, dass sich die Antwort des Zellsomas auf Verletzungen nicht nur auf der Ebene der Transkription und Translation zeigt, sondern vielmehr auch in der Lokalisierung und im Transport der Proteine. Im Falle von Glypican-1 legen unsere Resultate nahe, dass dem Protein im Rahmen des axonalen Wachstums und der Richtungszuweisung von auswachsenden Neuriten, zum Beispiel durch die Beeinflussung von Slit-Robo-Interaktionen, eine Rolle zukommt. Wir liefern eine erste detaillierte Beschreibung der Expression der Mitglieder der Slit- und Robo-Familien in verletzten und unverletzten adulten dorsalen Ganglienzellen. Ebenso zeigen wir mit verschiedenen histologischen Techniken zum ersten Mal die Induktion von PBR nach einer Axotomie in dorsalen Ganglien, und zwar spezifisch in kleinkalibrigen Neuronen. Wir demonstrieren das Vorhandensein des intakten PBR mit Hilfe von Liganden-Bindungsversuchen. Zusammengefasst zeigen die in dieser Dissertation präsentierten Resultate, dass in Neuronen des adulten verletzten Nervensystems die Fähigkeit zur strukturellen Reorganisation und zum Aufbau von synaptischen Verbindungen erhalten bleibt, wenn ihre Umgebung es erlaubt. Wir beschreiben die Genexpression im Zellkörper, welche eine bestimmende Grösse der neuronalen Wachstumskapazität ist, nach neuronalen Verletzungen. Ausserdem zeigen wir, dass diese Antwort nicht auf die Transkription beschränkt bleibt, sondern auch post-transkriptionelle Mechanismen beinhaltet. The clinical consequences of adult central nervous system injuries are extremely severe since there is only a minor capability for functional compensation and an almost complete absence of cell renewal and axonal re-growth and re-connection. The understanding of the developing and adult nervous system is progressing rapidly. In the past decades the growing comprehension has been continuously extended onto neuropathological conditions. We know now that the lack of recovery following injuries of the central nervous system is partly due to environmental, most importantly myelin- associated inhibitory factors, and partly to the inability of injured neurons to mount a gene expression profile that allows axonal growth. In this thesis determinants of axonal growth are examined and discussed. A way to partially overcome myelin-derived growth inhibition, is to prevent Nogo-A from binding to neuronal receptors by applying monoclonal antibody IN-1. To further investigate the effect of IN-1, rats with unilaterally injured cortical spinal tract were treated with IN-1. This approach was previously shown to enhance structural plasticity and functional recovery in the treated rats. Using light- and electron-microscopy, we show for the first time that outgrowing nerve fibers can form new, ultrastructurally intact synaptic contacts in the adult nervous system following an identical model as described above. The intracellular mechanisms that enable neurons to grow axons are poorly understood. Microarray analysis offers a way to screen for transcriptional adaptations following axonal injury. We investigate gene expression in lumbar dorsal root ganglia of the adult rat following central or peripheral nerve injury and compare the results with the developmental gene expression in the same population of neurons. Peripheral and central axotomy induce clearly distinguishable cell body responses. For both injury paradigms the expression for more than 50 genes is regulated. The comparison to developmental stages, when axonal outgrowth occurs, reveals that a complete recapitulation of a developmental gene expression pattern is not necessary for the regeneration of peripheral nerves. We further investigate injury-induced transcriptional and post-transcriptional changes, exemplified by two genes, glypican-1 and the peripheral benzodiazepine receptor (PBR). Our results show that the cell body response to injury is not restricted to changes in transcription and translation, but also involves post-translational effects, such as protein localization and transport. For glypican-1 the presented results support functions in axonal growth and guidance, e.g. by involvement in slit-robo interactions. We provide a first detailed description of the expression of slit and robo family members in the adult injured and non-injured dorsal root ganglion. Using different histological techniques we show for the first time the induction of the PBR specifically in small-diameter dorsal root ganglion neurons after nerve injury. Ligand binding studies indicate the presence of correctly assembled PBR following injury. In summary, the results reported in this study show evidence that neurons in the adult nervous system retain capacities for structural reorganization and re-connection following injury if faced with a permissive environment. We characterize the transcriptional cell body response of neurons to injury, an important determinant of the neuronal growth capacity. Additionally, we show that the cell body response is not simply regulated at the level of transcription but is specified by post-transcriptional mechanisms

Nonbacterial thrombotic endocarditis presenting as intracerebral hemorrhage.

Nonbacterial thrombotic endocarditis is a rare cause of valvular heart disease, most commonly associated with advanced malignancy. The morbidity of this kind of endocarditis lies in its tendency to embolize, while the valve function is usually preserved. The central nervous system is the most common site of embolization, leading to ischemic stroke. We report a case of nonbacterial thrombotic endocarditis complicated by intracerebral hemorrhage as the first manifestation of adenocarcinoma of the lung. The endocarditis led to severe aortic regurgitation. In view of the advanced stage of lung cancer, the patient refused further therapy. He passed away 3 weeks after first diagnosis of the adenocarcinoma

Basic concepts of heart-lung interactions during mechanical ventilation.

Critically ill patients with the need for mechanical ventilation show complex interactions between respiratory and cardiovascular physiology. These interactions are important as they may guide the clinician's therapeutic decisions and, possibly, affect patient outcome. The aim of the present review is to provide the practicing physician with an overview of the concepts of heart-lung interactions during mechanical ventilation. We outline the basic cardiac and respiratory physiology during spontaneous breathing and under mechanical ventilation. The main focus is on the interaction between positive pressure ventilation and its effects on right and left ventricular pre- and afterload and ventricular interdependence. Further we discuss different modalities to assess volume responsiveness, such as pulse pressure variation. We aim to familiarise the reader with cardiovascular side effects of mechanical ventilation when experiencing weaning problems or right heart failure

Heart-lung interactions during neurally adjusted ventilatory assist

Introduction Assist in unison to the patient’s inspiratory neural effort and feedback-controlled limitation of lung distension with neurally adjusted ventilatory assist (NAVA) may reduce the negative effects of mechanical ventilation on right ventricular function. Methods Heart–lung interaction was evaluated in 10 intubated patients with impaired cardiac function using esophageal balloons, pulmonary artery catheters and echocardiography. Adequate NAVA level identified by a titration procedure to breathing pattern (NAVAal), 50% NAVAal, and 200% NAVAal and adequate pressure support (PSVal, defined clinically), 50% PSVal, and 150% PSVal were implemented at constant positive end-expiratory pressure for 20 minutes each. Results NAVAal was 3.1 ± 1.1cmH2O/μV and PSVal was 17 ± 2 cmH20. For all NAVA levels negative esophageal pressure deflections were observed during inspiration whereas this pattern was reversed during PSVal and PSVhigh. As compared to expiration, inspiratory right ventricular outflow tract velocity time integral (surrogating stroke volume) was 103 ± 4%, 109 ± 5%, and 100 ± 4% for NAVAlow, NAVAal, and NAVAhigh and 101 ± 3%, 89 ± 6%, and 83 ± 9% for PSVlow, PSVal, and PSVhigh, respectively (p < 0.001 level-mode interaction, ANOVA). Right ventricular systolic isovolumetric pressure increased from 11.0 ± 4.6 mmHg at PSVlow to 14.0 ± 4.6 mmHg at PSVhigh but remained unchanged (11.5 ± 4.7 mmHg (NAVAlow) and 10.8 ± 4.2 mmHg (NAVAhigh), level-mode interaction p = 0.005). Both indicate progressive right ventricular outflow impedance with increasing pressure support ventilation (PSV), but no change with increasing NAVA level. Conclusions Right ventricular performance is less impaired during NAVA compared to PSV as used in this study. Proposed mechanisms are preservation of cyclic intrathoracic pressure changes characteristic of spontaneous breathing and limitation of right-ventricular outflow impedance during inspiration, regardless of the NAVA level

P106 Methodological issues for the determination of mean systemic filling pressure at the end of life

Introduction: Mean systemic filling pressure (MSFP) is the elastic recoil pressure of the systemic circulation at zero blood flow and it reflects the stressed volume [1, 2]. Clinical estimation models have been developed [1] and values reported from dead ICU patients [2]. The time course of vascular pressure equilibration at the end of life has not been reported. Methods: In eight pigs, HES was infused to expand estimated blood volume (6% body weight) by 15% [1]. Pressures were measured in the aortic arch and both venae cavae (PSVC and PIVC). MSFPRAO was estimated by occlusion of the right atrium with an inflatable balloon and averaged from 9 to 12 seconds into the venous pressure plateau. The animals were then killed with potassium chloride in deep anesthesia without relaxation [1]. Circulatory standstill was defined as loss of pulmonary flow (ultrasonic flow probe). MSFPearly was visually identified at a venous plateau similar to MSFPRAO, MSFPequil at the meeting point of aortic and central venous pressures and MSFPlate after complete cessation of pressure drift. Pressures were averaged over 3 seconds from PIVC and PSVC. Data are average (range) and analyzed by repeated measurements ANOVA. Results: MSFPRAO was 16.4 (11.5–20.9), MSFPearly 13.3 (9.7–16.7), MSFPequil 19.6 (15.7–23.8), MSFPlate 14 (9.6–20.1) mmHg (p = 0.007). The time from standstill to MSFPearly [8.5 (2–19) sec] to MSFPequil [104 (21–91) sec] and MSFPlate [277 (94–506) sec, p < 0.001] was accompanied by an aortic pressure drop of 14.9 (5.3–29.5) mmHg. Conclusions: The venous standstill pressure after death changes dynamically with clinically relevant magnitude over a considerable time. From initial standstill, it increases to an early venous plateau, then further increases to arterio-venous equilibrium, after which all pressures decline together. The equilibrium pressure is not stable. This should be taken into account when MSFP is estimated after cardiac arrest [2]. References 1. Berger D et al. Effect of PEEP, blood volume, and inspiratory hold maneuvers on venous return. American journal of physiology Heart and circulatory physiology 2016, 311(3):H794–806. 2. Repesse X et al. Value and determinants of the mean systemic filling pressure in critically ill patients. American journal of physiology Heart and circulatory physiology 2015, 309(5):H1003–1007

Nonejecting Hearts on Femoral Veno-Arterial Extracorporeal Membrane Oxygenation: Aortic Root Blood Stasis and Thrombus Formation-A Case Series and Review of the Literature.

OBJECTIVES Cardiogenic shock constitutes the final common pathway of cardiac dysfunction associated with tissue hypoperfusion and organ failure. Besides treatment of the underlying cause, temporary mechanical circulatory support serves as a supportive measure. Extracorporeal membrane oxygenation can effectively prevent hypoxemia and end-organ dysfunction, but knowledge about patient selection, risks, and complications remains sparse. DATA SOURCES Clinical observation. STUDY SELECTION Case report and review of the literature. DATA EXTRACTION Relevant clinical information. Online databases, including PubMed, Web of Science, Scopus, and OVID, were searched for previous publications. DATA SYNTHESIS We report six cases of patients in refractory cardiogenic shock receiving emergency femoral veno-arterial extracorporeal membrane oxygenation support complicated by echocardiographic evidence of absent blood flow, sedimentation, and thrombus formation in the aortic root. CONCLUSIONS Patients in cardiogenic shock who require femoral veno-arterial extracorporeal membrane oxygenation support are at risk of developing a state of nonejecting heart with thrombus formation in the aortic root. Echocardiography is the cornerstone of diagnosis and documentation of treatment effects. Depending on the likelihood of the presence of clinically relevant thrombotic material in the aortic root, we propose a treatment algorithm for this group of high-risk patients

Single baseline serum creatinine measurements predict mortality in critically ill patients hospitalized for acute heart failure

BACKGROUND: Acute heart failure (AHF) is a leading cause of death in critically ill patients and is often accompanied by significant renal dysfunction. Few data exist on the predictive value of measures of renal dysfunction in large cohorts of patients hospitalized for AHF. METHODS: Six hundred and eighteen patients hospitalized for AHF (300 male, aged 73.3 ± 10.3 years, 73% New York Heart Association Class 4, mean hospital length of stay 12.9 ± 7.7 days, 97% non‐ischaemic AHF) were included in a retrospective single‐centre data analysis. Echocardiographic data, serum creatinine/urea levels, estimated glomerular filtration rate (eGFR), and clinical/laboratory markers were recorded. Mean follow‐up time was 2.9 ± 2.1 years. All‐cause mortality was recorded, and univariate/multivariate analyses were performed. RESULTS: Normal renal function defined as eGFR > 90 mL/min/1.73 m(2) was noted in only 3% of AHF patients at baseline. A significant correlation of left ventricular ejection fraction with serum creatinine levels and eGFR (all P < 0.002) was noted. All‐cause mortality rates were 12% (90 days) and 40% (at 2 years), respectively. In a multivariate model, increased age, higher New York Heart Association class at admission, higher total cholesterol levels, and lower eGFR independently predicted death. Patients with baseline eGFR < 30 mL/min/1.73 m(2) had an exceptionally high risk of death (odds ratio 2.80, 95% confidence interval 1.52–5.15, P = 0.001). CONCLUSIONS: In a large cohort of patients with mostly non‐ischaemic AHF, enhanced serum creatinine levels and reduced eGFR independently predict death. It appears that patients with eGFR < 30 mL/min/1.73 m(2) have poorest survival rates. Our data add to mounting data indicating that impaired renal function is an important risk factor for non‐survival in patients hospitalized for AHF

Safety and efficacy of resolute zotarolimus-eluting stents compared with everolimus-eluting stents: a meta-analysis.

BACKGROUND Although new-generation drug-eluting stents represent the standard of care among patients undergoing percutaneous coronary intervention, there remains debate about differences in efficacy and the risk of stent thrombosis between the Resolute zotarolimus-eluting stent (R-ZES) and the everolimus-eluting stent (EES). The aim of this study was to evaluate the safety and efficacy of the R-ZES compared with EES in patients undergoing percutaneous coronary intervention. METHODS AND RESULTS A systematic literature search of electronic resources was performed using specific search terms until September 2014. Random-effects meta-analysis was performed comparing clinical outcomes between patients treated with R-ZES and EES up to maximum available follow-up. The primary efficacy end point was target-vessel revascularization. The primary safety end point was definite or probable stent thrombosis. Secondary safety end points were cardiac death and target-vessel myocardial infarction. Five trials were identified, including a total of 9899 patients. Compared with EES, R-ZES had similar risks of target-vessel revascularization (risk ratio [RR], 1.06; 95% confidence interval [CI], 0.90-1.24; P=0.50), definite or probable stent thrombosis (RR, 1.26; 95% CI, 0.86-1.85; P=0.24), cardiac death (RR, 1.01; 95% CI, 0.79-1.30; P=0.91), and target-vessel myocardial infarction (RR, 1.10; 95% CI, 0.89-1.36; P=0.39). Moreover, R-ZES and EES had similar risks of late definite or probable very late stent thrombosis (RR, 1.06; 95% CI, 0.53-2.11; P=0.87). No evidence of significant heterogeneity was observed across trials. CONCLUSIONS R-ZES and EES provide similar safety and efficacy among patients undergoing percutaneous coronary intervention

Baseline serum bicarbonate levels independently predict short-term mortality in critically ill patients with ischaemic cardiogenic shock

Background: Cardiogenic shock is a feared complication of acute myocardial infarction with high mortality rates. Data on the predictive role of acid base dysregulation in this clinical setting are sparse. We therefore embarked on investigating the predictive role of serum bicarbonate in critically ill intensive care unit (ICU) patients with cardiogenic shock. Methods: A total of 165 ischaemic cardiogenic shock patients (118 men, aged 68.4 years (interquartile range 59.0–77.4), APACHE II score 26.0 (interquartile range 21.0–29.0), after percutaneous coronary intervention were included in a single-centre analysis. Percutaneous coronary intervention-related data such as left ventricular ejection fraction and laboratory indices were recorded and routine clinical follow-up was obtained at hospital discharge and at one year. All-cause mortality was assessed and data were analysed using univariate and multivariate models. Results: All-cause mortality was highest (17%) during the first 48 hours following ICU admission (28-day mortality rate 43%). In a multiple regression model, age (hazard ratio (HR) 1.035, 95% confidence interval (CI) 1.011–1.059, P=0.004), APACHE II score (HR 1.036, 95% CI 1.002–1.072, P=0.037) and baseline serum bicarbonate levels (HR 0.93, 95% CI 0.866–0.998, P=0.046) independently predicted 28-day mortality (overall model fit χ2 22.9, P<0.0001). The HR for patients in the lowest baseline serum bicarbonate tertile for 365-day mortality was HR 2.06 (95% CI 1.20–3.53). Conclusions: In a large cohort of consecutive cardiogenic shock patients hospitalised in the ICU, low serum bicarbonate levels at admission independently predicted mortality. Given the widespread availability of blood gas analysers in ICUs, we propose baseline serum bicarbonate levels as an additional biomarker for identification and stratification of cardiogenic shock patients at risk