Inzidenz und Ursache der sekundären Zyanoseentstehung nach Palliation des Univentrikels mittels Fontan-Operation

Einleitung: Seit 1971 können angeborene univentrikuläre Herzfehler durch eine Kreislauftrennung mittels Fontan-Operation palliativ therapiert werden. Durch eine weltweit wachsende Erfahrung in der Chirurgie und Therapie des univentrikulären Herzfehlers ist ein Erreichen des Erwachsenenalters für Kinder mit univentrikulärer Physiologie heutzutage möglich. Neben der Volumenreduktion des Univentrikels ist die Zyanosebeseitigung dabei eines der wesentlichen Ziele der Fontan-Operation. Ob dieses Ziel erreicht wird und welche Ursachen und Folgen der Zyanose benannt werden können, soll durch die vorliegende Arbeit untersucht werden. Methodik: Dafür wurden 350 Patienten, die zwischen 1986 und 2015 eine moderne Modifikation der Fontan-Operation (totale cavopulmonale Verbindung, TCPC) erhalten haben und über einen medianen Beobachtungszeitraum von 4,6 [0,1-27,8] Jahren am Deutschen Herzzentrum Berlin nachbetreut wurden, retrospektiv betrachtet. Zyanose wurde definiert als arterielle Sättigung 93 % und transkutan mittels Pulsoxymetrie gemessen. Zu definierten Zeitpunkten (präoperativ (t0), postoperativ (t1), bei gegebener Herzkatheter- (t2) sowie der letzten Nachuntersuchung (t3)) wurde die Inzidenz der Zyanose ermittelt und beeinflussende Faktoren, wie intraoperativ angelegte Überlaufventile (ÜLV) oder venovenöse Kollateralen (VVK) identifiziert. Durch einen Gruppenvergleich zyanotischer versus azyanotischer Patienten wurden anatomische, chirurgische und hämodynamische Parameter als weitere Ursachen für postoperative Zyanoseentstehung getestet und mögliche Korrelationen mit dem Langzeitergebnis nach TCPC untersucht. Statistisch signifikante Ergebnisse wurden mittels logistischer Regression überprüft. Ergebnisse: Die Inzidenz der Zyanose beträgt 100 % zu t0, 50 % zu t1, 72 % zu t2 und 41 % zu t3. Signifikant beeinflussende Faktoren sind ÜLV (p < 0,001) und VVK (p = 0,02). Ebenfalls in erhöhter Korrelation mit Zyanose zeigen sich im Gruppenvergleich zyanotischer versus azyanotischer Patienten ein rechter Systemventrikel, die intrakardiale Fontantechnik sowie ein prä- und postoperativ schlechter entwickeltes Pulmonalgefäßbett. Chronische Zyanose ist assoziiert mit dem Eiweißverlustsyndrom im Rahmen des Fontanversagens und korreliert zu allen Zeitpunkten signifikant mit einer erhöhten Mortalität (logRank p (t1-t3) jeweils 0,02). In einer Risikoanalyse für die Entstehung von Zyanose bestätigen sich nach multivariater Regression ÜLV und VVK mit einer 4-10fachen Risikoerhöhung sowie ein im Vergleich zu den azyanotischen Patienten präoperativ höherer Pulmonalarteriendruck (Risk Ratio = 1,2). Zusammenfassung: Zyanosebeseitigung durch TCPC wird häufig nicht erreicht. ÜLV und entstehende VVK sind wesentliche Gründe dafür. Ein präoperativ erhöhter Pulmonal-arteriendruck zeigt sich als mögliche zusätzliche Ursache. Da die Auswirkungen der Zyanose von chronischem Fontanversagen bis zu einer erhöhten Mortalität reichen, bleibt ein standardisiertes Nachsorgeprotokoll zur Identifikation und ursächlichen Abklärung von Zyanose als demaskierendem Symptom einer insuffizienten Fontan-Hämodynamik unabdingbar, um einem irreversiblen Fontanversagen möglichst rechtzeitig therapeutisch entgegenwirken zu können.Introduction: Since 1971 congenital univentricular heart defects can be treated palliatively with Fontan operation. Experience with surgery and therapy of univentricular heart defects has grown across the globe. Today, it is possible that children with univentricular physiology reach adulthood. Apart from a volume reduction of the single ventricle, the objective of a Fontan operation is improvement of cyanosis. This thesis assesses whether this particular objective can be attained and identifies causes and consequences of cyanosis. Methods: 350 patients who underwent a modern modification of the Fontan operation (total cavopulmonary connection, TCPC) between 1986 and 2015 and received postoperative care over a median observation period of 4.6 [0.1-27.8] years at the German Heart Centre were studied retrospectively. Cyanosis was defined as arterial oxygen saturation 93 % and transcutaneously determined via pulse oximetry. The incidence of cyanosis was determined at specified moments (preoperative (t0), postoperative (t1), cardiac catheter examination (t2) and last follow-up (t3)) and contributing factors were identified, such as intraoperative fenestration or venovenous collaterals (VVC). In order to identify anatomical, surgical and haemodynamical parameters that are associated with the occurrence of cyanosis a group comparison of cyanotic and acyanotic patients was used and correlated with long-term results after TCPC. Statistically significant results were verified using logistic regression. Results: The incidence of cyanosis is 100 % at t0, 50 % at t1, 72 % at t2 and 41 % at t3. Statistically significant factors are fenestration (p < 0.001) and VVC (p = 0.02). In the group comparison, right ventricular morphology, intracardiac fontan procedure and a pre- and postoperative weak pulmonary vascular bed also show statistically relevant correlation with cyanosis. Chronic cyanosis is associated with protein losing enteropathy in the context of fontan failure and significantly correlates with higher mortality at all times (logRank p (t1-t3) 0.02). Using multivariate regression, fenestration and VVC increase the risk of cyanosis by 4-10times while elevated levels of preoperative pulmonary artery pressure show a 1.2-fold higher risk of cyanosis. Conclusion: Often the goal of improving cyanosis through TCPC cannot be achieved. Fenestration and VVC are the main reasons. Elevated preoperative pulmonary artery pressure is a potential additional cause. The consequences of cyanosis reach from chronic fontan failure to higher mortality rates. Hence, a standard protocol for postoperative care is required for identification and causal clarification of cyanosis as a demasking symptom of an insufficient fontan hemodynamic in order to counteract irreversible fontan failure as early as possible

Präzisionsmedizin in der Kinder- und Erwachsenenkardiologie - klinische Anwendung bildbasierter in silico Modellierung

Die richtige Therapie zum richtigen Zeitpunkt, nichtinvasiv und patientenindividuell zu identifizieren, ist das Ziel der Präzisionsmedizin. Durch den stetigen Fortschritt sowohl im Bereich der Bildgebung als auch in mathematischen Modellierungstechniken sowie einer zunehmenden Verfügbarkeit von leistungsstarker Informationstechnologie, gewinnen in silico (angelehnt an das Lateinische „in silicio“, also „in silicium“ bzw. im übertragenden Sinne im Computer ablaufende) Modellierungsverfahren eine immer größere Bedeutung auch im Bereich der kardiovaskulären Medizin. Die bildbasierte in silico Modellierung von Hämodynamik und Funktion des Herzens kann dabei einerseits helfen, die diagnostische Aussagekraft unterschiedlicher Bildgebungsmodalitäten zu erweitern, andererseits aber auch, verschiedene Parameter der postinterventionellen bzw. postoperativen Funktion vorherzusagen und so das geeignetste patientenindividuelle Therapieverfahren zu identifizieren. Im Bereich der pädiatrischen Kardiologie, insbesondere bei Patient*innen mit komplexen angeborenen Herzfehlern, ist eine individualisierte Therapieplanung zudem von ganz besonderer Bedeutung. Da die Anatomie des kardiovaskulären Systems in diesem Patientenkollektiv hoch individuell ist, gibt es häufig keine für das jeweilige Krankheitsbild einheitliche Therapie. Die virtuelle Behandlungsplanung bietet hier ein großes Potential für die multimodale Therapiefindung. Die Translation solcher Modellierungsansätze in die Klinik stellt jedoch eine große Hürde dar. Einerseits muss die Genauigkeit der jeweiligen Simulationsmethode quantifiziert und die Methode selbst validiert werden. Dafür benötigt es in der Regel eine hohe Anzahl an Patientendaten, die insbesondere in der Kinderkardiologie, aber auch aufgrund zunehmend strengerer Datenschutzrichtlinien häufig nicht zur Verfügung stehen. Andererseits sind die Simulationsverfahren sehr komplex und verlangen neben einer hohen technischen Expertise auch beachtliche Rechenkapazitäten und -laufzeiten, wodurch sich ihr routinemäßiger Einsatz in der Klinik ebenfalls verkompliziert. Das Problem der hohen Komplexität könnte durch den Einsatz künstlicher Intelligenz (KI) überwunden werden. Fehlende klinische Daten wiederum könnten mittels synthetischer Patientenkohorten augmentiert werden, sodass sowohl für mögliche Validierungsstudien als auch zum Trainieren des maschinellen Algorithmus‘ ein ausreichend großer Datensatz zur Verfügung stünde. In der vorliegenden Habilitationsschrift werden die Inhalte von fünf wissenschaftlichen Arbeiten zum Thema Präzisionsmedizin in der Kinder- und Erwachsenenkardiologie auf Grundlage bildbasierter in silico Modellierung vorgestellt. Dabei wird in Form einer Proof of Concept Studie die prinzipielle Durchführbarkeit der bildbasierten in silico Modellierung am Beispiel verschiedener Parameter der aortalen Hämodynamik gezeigt sowie die Validierung der Methodik gegen den klinischen Goldstandard des Herzkatheters präsentiert. An komplexen Patient*innen aus dem Bereich der Kinderkardiologie wird die bildbasierte in silico Modellierung für eine konkrete klinische Fragestellung angewandt. Zuletzt werden zwei Optimierungsansätze vorgestellt, die einerseits den komplexen Arbeitsablauf der bildbasierten in silico Modellierung mittels KI vereinfachen sowie andererseits das Problem der existierenden klinischen Datenlücken überwinden sollen

Modelling blood flow in patients with heart valve disease using deep learning: A computationally efficient method to expand diagnostic capabilities in clinical routine

Introduction: The computational modelling of blood flow is known to provide vital hemodynamic parameters for diagnosis and treatment-support for patients with valvular heart disease. However, most diagnosis/treatment-support solutions based on flow modelling proposed utilize time- and resource-intensive computational fluid dynamics (CFD) and are therefore difficult to implement into clinical practice. In contrast, deep learning (DL) algorithms provide results quickly with little need for computational power. Thus, modelling blood flow with DL instead of CFD may substantially enhances the usability of flow modelling-based diagnosis/treatment support in clinical routine. In this study, we propose a DL-based approach to compute pressure and wall-shear-stress (WSS) in the aorta and aortic valve of patients with aortic stenosis (AS). Methods: A total of 103 individual surface models of the aorta and aortic valve were constructed from computed tomography data of AS patients. Based on these surface models, a total of 267 patient-specific, steady-state CFD simulations of aortic flow under various flow rates were performed. Using this simulation data, an artificial neural network (ANN) was trained to compute spatially resolved pressure and WSS using a centerline-based representation. An unseen test subset of 23 cases was used to compare both methods. Results: ANN and CFD-based computations agreed well with a median relative difference between both methods of 6.0% for pressure and 4.9% for wall-shear-stress. Demonstrating the ability of DL to compute clinically relevant hemodynamic parameters for AS patients, this work presents a possible solution to facilitate the introduction of modelling-based treatment support into clinical practice

Hemodynamic Modeling of Biological Aortic Valve Replacement Using Preoperative Data Only

Objectives: Prediction of aortic hemodynamics after aortic valve replacement (AVR) could help optimize treatment planning and improve outcomes. This study aims to demonstrate an approach to predict postoperative maximum velocity, maximum pressure gradient, secondary flow degree (SFD), and normalized flow displacement (NFD) in patients receiving biological AVR. Methods: Virtual AVR was performed for 10 patients, who received actual AVR with a biological prosthesis. The virtual AVRs used only preoperative anatomical and 4D flow MRI data. Subsequently, computational fluid dynamics (CFD) simulations were performed and the abovementioned hemodynamic parameters compared between postoperative 4D flow MRI data and CFD results. Results: For maximum velocities and pressure gradients, postoperative 4D flow MRI data and CFD results were strongly correlated (R 2 = 0.75 and R-2 = 0.81) with low root mean square error (0.21 m/s and 3.8 mmHg). SFD and NFD were moderately and weakly correlated at R 2 = 0.44 and R 2 = 0.20, respectively. Flow visualization through streamlines indicates good qualitative agreement between 4D flow MRI data and CFD results in most cases. Conclusion: The approach presented here seems suitable to estimate postoperative maximum velocity and pressure gradient in patients receiving biological AVR, using only preoperative MRI data. The workflow can be performed in a reasonable time frame and offers a method to estimate postoperative valve prosthesis performance and to identify patients at risk of patient-prosthesis mismatch preoperatively. Novel parameters, such as SFD and NFD, appear to be more sensitive, and estimation seems harder. Further workflow optimization and validation of results seems warranted

Serum dihydrotestosterone is associated with adverse myocardial remodeling in patients with aortic valve stenosis before and after aortic valve replacement

AIMS: Animal studies show a pivotal role of dihydrotestosterone (DHT) in pressure overload induced myocardial hypertrophy and dysfunction. The aim of our study was to evaluate the role of DHT levels and myocardial hypertrophy and myocardial protein expression in patients with severe aortic valve stenosis (AS). METHODS AND RESULTS: 43 patients (median age 68 (41-80) years) with severe AS and indication for surgical aortic valve replacement (SAVR) were prospectively enrolled. Cardiac magnetic resonance imaging including analysis of left ventricular muscle mass (LVM), fibrosis and function and laboratory tests including serum DHT levels were performed before and after SAVR. During SAVR left ventricular (LV) biopsies were performed for proteomic profiling. Serum DHT levels correlated positively with indexed LVM (LVMi, R=0.64, p<0.0001) and fibrosis (R=0.49, p=0.0065) and inversely with LV function (R=-0.42, p=0.005) in patients with severe AS. DHT levels were associated with higher abundance of the hypertrophy (moesin (R=0.52, p=0.0083)) and fibrosis (vimentin (R=0.41, p=0.039)) associated proteins from LV myocardial biopsies. Higher serum DHT levels preoperatively were associated with reduced LV function (ejection fraction: R=-0.34, p=0.035, circulatory efficiency: R=-0.46, p=0.012, global longitudinal strain: R=0.49, p=0.01) and increased fibrosis (R=0.55, p=0.0022) after SAVR. CONCLUSIONS: Serum DHT levels were associated with adverse myocardial remodeling and higher abundance in hypertrophy and fibrosis associated proteins in patients with severe AS. DHT may be a target to prevent or attenuate adverse myocardial remodeling in patients with pressure overload due to AS

Disease- and sex-specific differences in patients with heart valve disease: a proteome study

Pressure overload in patients with aortic valve stenosis and volume overload in mitral valve regurgitation trigger specific forms of cardiac remodeling; however, little is known about similarities and differences in myocardial proteome regulation. We performed proteome profiling of 75 human left ventricular myocardial biopsies (aortic stenosis = 41, mitral regurgitation = 17, and controls = 17) using high-resolution tandem mass spectrometry next to clinical and hemodynamic parameter acquisition. In patients of both disease groups, proteins related to ECM and cytoskeleton were more abundant, whereas those related to energy metabolism and proteostasis were less abundant compared with controls. In addition, disease group-specific and sex-specific differences have been observed. Male patients with aortic stenosis showed more proteins related to fibrosis and less to energy metabolism, whereas female patients showed strong reduction in proteostasis-related proteins. Clinical imaging was in line with proteomic findings, showing elevation of fibrosis in both patient groups and sex differences. Disease- and sex-specific proteomic profiles provide insight into cardiac remodeling in patients with heart valve disease and might help improve the understanding of molecular mechanisms and the development of individualized treatment strategies

CT-based comparison of porcine, ovine, and human pulmonary arterial morphometry

To facilitate pre-clinical animal and in-silico clinical trials for implantable pulmonary artery pressure sensors, understanding the respective species pulmonary arteries (PA) anatomy is important. Thus, morphological parameters describing PA of pigs and sheep, which are common animal models, were compared with humans. Retrospective computed tomography data of 41 domestic pigs (82.6 ± 18.8 kg), 14 sheep (49.1 ± 6.9 kg), and 49 patients (76.8 ± 18.2 kg) were used for reconstruction of the subject-specific PA anatomy. 3D surface geometries including main, left, and right PA as well as LPA and RPA side branches were manually reconstructed. Then, specific geometric parameters (length, diameters, taper, bifurcation angle, curvature, and cross-section enlargement) affecting device implantation and post-interventional device effect and efficacy were automatically calculated. For both animal models, significant differences to the human anatomy for most geometric parameters were found, even though the respective parameters’ distributions also featured relevant overlap. Out of the two animal models, sheep seem to be better suitable for a preclinical study when considering only PA morphology. Reconstructed geometries are provided as open data for future studies. These findings support planning of preclinical studies and will help to evaluate the results of animal trials.ISSN:2045-232

Can Left Atrioventricular Valve Reduction Index (LAVRI) Predict the Surgical Strategy for Repair of Atrioventricular Septal Defect?

Despite improved survival, surgical treatment of atrioventricular septal defect (AVSD) remains challenging. The optimal technique for primary left atrioventricular valve (LAVV) repair and prediction of suitability for biventricular approach in unbalanced AVSD are still controversial. We evaluated the ability of our recently developed echocardiographic left atrioventricular valve reduction index (LAVRI) in predicting LAVV reoperation rate and surgical strategy for unbalanced AVSD. Retrospective echocardiographic analysis was available in 352 of 790 patients with AVSD treated in our institution and included modified atrioventricular valve index (mAVVI), ventricular cavity ratio (VCR), and right ventricle/left ventricle (RV/LV) inflow angle. LAVRI estimates LAVV area after complete cleft closure and was analyzed with regard to surgical strategy in primary LAVV repair and unbalanced AVSD. Of the entire cohort, 284/352 (80.68%) patients underwent biventricular repair and 68/352 (19.31%) patients underwent univentricular palliation. LAVV reoperation was performed in 25/284 (8.80%) patients after surgical correction of AVSD. LAVRI was significantly lower in patients requiring LAVV reoperation (1.92 c

Computed Tomography-Based Assessment of Transvalvular Pressure Gradient in Aortic Stenosis

Background: In patients with aortic stenosis, computed tomography (CT) provides important information about cardiovascular anatomy for treatment planning but is limited in determining relevant hemodynamic parameters such as the transvalvular pressure gradient (TPG). Purpose: In the present study, we aimed to validate a reduced-order model method for assessing TPG in aortic stenosis using CT data. Methods: TPG(CT) was calculated using a reduced-order model requiring the patient-specific peak-systolic aortic flow rate (Q) and the aortic valve area (AVA). AVA was determined by segmentation of the aortic valve leaflets, whereas Q was quantified based on volumetric assessment of the left ventricle. For validation, invasively measured TPG(catheter) was calculated from pressure measurements in the left ventricle and the ascending aorta. Altogether, 84 data sets of patients with aortic stenosis were used to compare TPG(CT) against TPG(catheter). Results: TPG(catheter) and TPG(CT) were 50.6 ± 28.0 and 48.0 ± 26 mmHg, respectively (p = 0.56). A Bland-Altman analysis revealed good agreement between both methods with a mean difference in TPG of 2.6 mmHg and a standard deviation of 19.3 mmHg. Both methods showed good correlation with r = 0.72 (p < 0.001). Conclusions: The presented CT-based method allows assessment of TPG in patients with aortic stenosis, extending the current capabilities of cardiac CT for diagnosis and treatment planning