This research paper highlights the significance of mock circulatory loops in aiding the development and testing of left ventricle assist devices (LVADs). Heart disease is the leading cause of death in America, and LVAD offers an effective solution to patients with severe coronary artery disease who are not eligible for heart transplants. However, before testing LVADs in-vivo, extensive performance and reliability testing is required as per Food and Drug Administration guidelines. Mock circulatory loops are useful for simulating the cardiac cycle and capturing pressure and flow meter readings. The research focused on developing and testing a mock circulatory loop that accurately captures pressure and flow meter readings. The team experimented with various silicone elastomers and a urethane-based material, ClearFlex 30, to create a transparent phantom. The report highlights the importance of surface roughness for optical clarity, with an average surface roughness of 0.186 μ being ideal for optimal clarity achieved with 800-grit sandpaper. The impact of pressure differences between the aortic and mitral inlet/outlets was also studied, and it was found that the loop's resistance can be modified to achieve elevated pressure in the aortic outlet. The report further emphasized the importance of refractive index matching to perform particle image velocity. Matching the refractive index of the phantom with the medium is critical to avoid distortion and refraction of the light. Glycerol water was found to be an effective medium for refractive index matching. Overall, the successful testing of the mock circulatory loop provides valuable insights into the flow structure within the heart, aiding in the development of future LVADs. This research is significant in advancing the cardiology field and will potentially benefit many patients suffering from heart disease. / Master of Science / This research paper focuses on developing and testing left ventricle assist devices (LVADs) using a mock circulatory loop tool. Heart disease is a leading cause of death in America, and LVADs provide an effective solution for patients with severe coronary artery disease who are not eligible for heart transplants. However, before testing LVADs on humans, extensive performance and reliability testing is required as per Food and Drug Administration guidelines. Mock circulatory loops are a tool that helps simulate the cardiac cycle and capture pressure and flow meter readings. The researchers developed and tested a mock circulatory loop that could accurately capture pressure and flow meter readings. They used various materials to create a transparent phantom that allowed them to see inside the loop. The researchers found that the surface roughness of the phantom was important for optical clarity, and they achieved optimal clarity using 800-grit sandpaper. They also studied the impact of pressure differences between the aortic and mitral inlet/outlets. They found that the loop's resistance can be modified to achieve elevated pressure in the aortic outlet. To study the flow structure within the heart, the researchers used a technique called particle image velocity. They emphasized the importance of refractive index matching, which helps avoid distortion and refraction of light. The researchers found that glycerol water was an effective medium for refractive index matching. Overall, the successful testing of the mock circulatory loop provides valuable insights into the flow structure within the heart, aiding in the development of future LVADs. This research has significant implications for advancing the cardiology field and potentially benefitting many patients suffering from heart disease.

Congestive heart failure (CHF) is a debilitating condition that afflicts 4.8 million Americans with an increasing incidence. Each year, there are an estimated 400,000 new cases. The incidence is on the rise as the age of the population is increasing and because most people are surviving their first heart attack. Pharmacological therapies are improving, yet many patients still reach end-stage heart failure and there are too few donor hearts available. This thesis is presented as a first small step in a long process in the design and development of a novel cardiac assist device that would ultimately heal a diseased heart by the process of ventricular recovery. The device acts to restore the kinematics of a diseased heart by modulating the extra ventricular displacements. The first surgery / trial were conducted on a bovine at the Veterinary School at Texas A&M University. Main objectives of the surgery were to test the method of attachment of the device and power requirements of the device. Details regarding the design and construction of the device have been presented in the thesis.

This thesis project examined the interactive fluid dynamics between a blood pump and the univentricular Fontan circulation. 2-D particle image velocimetry (PIV) measurements were conducted on an idealized total cavopulmonary connection (TCPC) with an axial pump prototype in the inferior vena cava (IVC). Fluid velocity profiles were examined under various physiologic conditions for Fontan patients. The velocity profiles for all cases demonstrated the shunting of flow from the IVC toward the right pulmonary artery. A rotational component in the pump outflow was observed forcing flow to the periphery as compared to the flow profile without a pump present in the IVC. The inclusion of the pump provides a pressure rise of 3 to 9 mmHg. These results demonstrate the ability of the intravascular blood pump to support a Fontan circulation and support the continued optimization and development of the pump.

Este trabalho apresenta a implementação de um sistema de velocimetria de imagens de partícula (VIP) para estudo do escoamento do sangue em um dispositivo de assistência ventricular para uso pediátrico (DAVP). O sistema VIP implementado é constituído por uma fonte de iluminação composta por um par de lasers de Nd:YAG (pulso de aproximadamente 18mJ de energia e duração de 5ns), um sistema óptico contendo duas lentes convergentes, uma câmera CCD e uma câmara para visualização. O DAVP estudado foi construído em acrílico transparente e é constituído de uma câmara de sangue e uma câmara pneumática, divididas por uma membrana flexível. A câmara sanguínea possui dois orifícios dotados de válvulas de tecido biológico para a entrada e saída de sangue. A câmara pneumática é conectada a um gerador de pulsos de pressão positiva. O fluido foi semeado com esferas de poliestireno (10 \"mu\" de diâmetro). Foram determinadas as distribuições de velocidades instantâneas nas freqüências de batimento de 80, 100 e 120 bpm em três campos (65 mm x 65mm) da câmara paralelos à membrana e um campo situado no canal de entrada do DAVP, usando correlação cruzada com base na transformada rápida de Fourier. Um gerador de pulsos foi utilizado para sincronizar a detecção das imagens pelo sistema VIP com as fases de interesse no ciclo de bombeamento. Na freqüência de batimentos de 80 bpm as velocidades máximas foram de 1,94 m/s no canal de entrada durante o período de enchimento e 1,66 m/s nas regiões próximas à membrana durante o período de ejeção. Em 100 bpm, as velocidades máximas foram de 1,68 m/s no canal de entrada e 1,15 m/s nas regiões próximas a membrana. As distribuições de velocidades instantâneas mostram a ocorrência de pequenos vórtices, principalmente durante a fase de enchimento. Estes vórtices apresentam grande variabilidade ciclo-a-ciclo produzindo turbulências no fluxo e tensões de Reynolds elevadas. No ciclo a 80 bpm, ) parte da energia cinética turbulenta é dissipada devido à desaceleração do fluxo na câmara sanguínea antes do inicio da fase de ejeção. Isto ocorre para as freqüências de 100 e 120 bpm. A máxima tensão de Reynolds foi observada no canal de entrada do DAVP no valor de 222 N/m2 durante o enchimento, persistindo por 25 ms. No plano da membrana a maior tensão encontrada foi igual a 250 N/m2 durante o enchimento, persistindo por 25 ms. O campo de velocidades media contém vórtices permanentes durante a fase de enchimento que influenciam significativamente o fluxo na câmara e cujo numero aumenta com a freqüência de batimentos, provocando aumento de turbulências. Estes resultados indicam que existe maior possibilidade de ocorrer o processo de hemólise durante o enchimento do que durante a ejeção. Vetores com baixas velocidades foram observados na região compreendida entre os canais de entrada e saída do fluxo na câmara sanguínea no período de ejeção, sugerindo a possibilidade de ocorrer à formação de trombos nesta. / --

The objectives of the present body of work were 1) to evaluate the Personal Lift-Assist Device (PLAD) in terms of its effect on lifting technique, interjoint coordination, and whether sex modulates these effects and 2) to explore the use of principal component analysis (PCA) as a method to investigate lifting waveforms. Thirty participants (15M, 15F) completed a freestyle, symmetrical lifting protocol during which three-dimensional kinematics of the ankle, knee, hip, and lumbar and thoracic spine were collected using a two-camera Optotrak 3020 system. There were four testing conditions: a) with and b) without wearing the PLAD; and c) 0% load and d) 10% of maximum back strength load. All data were evaluated using PCA. In the first analysis, the relationship between the PLAD and lifting technique under a loaded condition was explored. Results showed that 8 PCs were significantly different between the PLAD/No PLAD conditions yet there were no significant effects of sex on any of the PCs. It was concluded that wearing the PLAD encourages a lifting technique that is reflective of a squat lift, independent of sex. In the second analysis, the PLAD’s effect on interjoint coordination patterns under both loaded and unloaded conditions was examined using the relative phase angle (RPA). It was found that there were no significant differences between device, sex, or load conditions on any of the PCs retained in the model. A novel approach to enhance interpretability of PCs was developed during this study. Finally, when the PLAD was not worn, male and female differences were further investigated under loaded and unloaded conditions. It was determined that when the load is individualized to personal strength characteristics, sex differences in lifting technique are negligible. This is a contradictory finding from previous research. Overall, the major contributions of this research are: support for the use of the PLAD in industry; the recommendation that load be selected based on individual strength characteristics for lifting research experimental design; the use of PCA as a method to effectively evaluate lifting waveforms; and the development of a novel approach to aid in the interpretation of principal components. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2010-08-18 09:35:19.142

Implantation of a left ventricular assist device (LVAD) is a potential treatment in terminal heart failure. Right ventricular (RV) failure is a severe complication in these patients and sometimes requires additional placement of a right ventricular assist device (RVAD). RVAD implantation, however, is an invasive treatment associated with both increased mortality and morbidity. The aim of this thesis was to study whether partial volume exclusion of the RV through a modified Glenn shunt or cavoaortic shunt could treat severe RV failure. The ultimate goal would be to use it as an alternative to a RVAD in RV failure during LVAD therapy. Swine were used as the model animal in all studies. In Study I, experimental RV failure was induced by ischemia, and verified by hemodynamic measurements and genetic expression. Treatment with a modified Glenn shunt reduced venous stasis and improved hemodynamics in general. In Study II, experimental RV failure was induced by the same method as in Study I. Treatment with a cavoaortic shunt in addition to LVAD therapy proved to reduce venous stasis and improved hemodynamics in general, which was feasible with preserved oxygen delivery despite cyanotic shunting. In Study III, experimental RV failure was induced by pulmonary banding, and verified by hemodynamic measurements and genetic expression. Treatment with a modified Glenn shunt reduced venous stasis but did not improve hemodynamics in general compared with a control group. In Study IV, the effects of LVAD therapy and subsequent treatment with a modified Glenn shunt on the normal RV function were studied. It demonstrated that LVAD therapy can put strain on the RV by increasing stroke work and end-diastolic volume, and that these effects can be reversed by treatment with a modified Glenn shunt during LVAD therapy. In conclusion, partial volume exclusion through a modified Glenn shunt or cavoaortic shunt is a feasible treatment of experimental RV failure. Thus, it could potentially be used as an alternative treatment to a RVAD in severe RV failure during LVAD therapy.

At an annual cost of over thirty billion dollars annually, the diagnosis and management of heart failure is one of the most significant public health concerns of the twenty first century, as nearly twenty percent of Americans will develop some form of heart failure in their lifetime. The incidence of newly diagnosed heart failure has remained stable over the last several years at approximately 650,000 diagnoses per year; however, due to several contributing factors the prevalence has continued to rise despite substantial advancements in interventional therapies. The three most significant contributing factors to the rising heart failure prevalence have been identified as 1) significant advancements in technology and medical intervention have dramatically improved the survival rate of those experiencing acute coronary events. This has resulted in a greater number of patients who then progress to chronic heart failure. 2) The management of those with chronic heart failure has been dramatically improved which has allowed those with the disease to live longer and 3) heart failure is in large part a disease associated with advancing age. As the population in the United States and other developed countries continue to grow, such a strong association will inevitably result in a rapidly increasing prevalence. Current clinically therapies for managing heart failure can be categorized into three major groups: pharmaceutical therapy, mechanical circulatory support, or cell-based therapy. Pharmaceutical therapies are used in the earlier stages of disease progression or to manage symptoms and comorbidities of later stage heart failure. Mechanical circulatory support is often implemented when the disease progresses to a more severe state, where volume and / or pressure overload of the ventricles is present. Many modalities of mechanical circulatory support serve as a bridge to transplant, as the only long-term treatment of advanced decompensated heart failure is cardiac transplantation. The third category of treatments for HF is cell-based or stem cell therapies. These therapies are still in their infancies but hold significant potential of cardiac regeneration and reversal of the pathologic remodeling associated with heart failure. While the management of the early stages of heart failure have improves, addressing end-stage failure remains a significant obstacle in resolving the U.S. of the heart failure epidemic. The use of ventricular assist devices (VADs) has improved the management of end-stage failure over the last few decades, but VADs serve mostly as a bridge to transplant, so eventually a donor organ and cardiac transplantation is required. As the population continues to grow, the number of patients in need of a donor heart will increase, leading to an even larger discrepancy between the number of donor organs available and those in severe need. While advancements in VAD technology have reduced potential complications and increased the duration and effectiveness of the mechanical circulatory support, a long-term permanent treatment is still very much in need. Cell-based cardiac therapy or cardiac stem cell therapy holds the greatest potential to solving this age-old problem. The ability to not only regenerate dead or damaged tissue in the heart but also reverse pathologic remodeling due to heart failure could cure millions of patients of heart failure, returning them to a healthy, fully functioning state. The last decade has shed much light on the potential of stem cell therapies, but also has illuminated significant barriers to creating a clinically acceptable treatment. While these barriers seem tall, it is crucial that much time and resources be invested into stem cell therapies for cardiac applications as they hold the greatest potential to being able to effectively treat, rather than manage, those with heart failure. In addition to regenerating dead of damaged myocardium, stem cell technology has the potential to grow an entire organ that is patient specific in its origin, and would fully alleviate having to wait for an available donor organ. The ability to grow an entire organ in the lab, which can later be transplanted, would forever change the way medicine is practiced, while saving millions if not billions of lives worldwide.

Este trabalho apresenta a implementação de um sistema de velocimetria de imagens de partícula (VIP) para estudo do escoamento do sangue em um dispositivo de assistência ventricular para uso pediátrico (DAVP). O sistema VIP implementado é constituído por uma fonte de iluminação composta por um par de lasers de Nd:YAG (pulso de aproximadamente 18mJ de energia e duração de 5ns), um sistema óptico contendo duas lentes convergentes, uma câmera CCD e uma câmara para visualização. O DAVP estudado foi construído em acrílico transparente e é constituído de uma câmara de sangue e uma câmara pneumática, divididas por uma membrana flexível. A câmara sanguínea possui dois orifícios dotados de válvulas de tecido biológico para a entrada e saída de sangue. A câmara pneumática é conectada a um gerador de pulsos de pressão positiva. O fluido foi semeado com esferas de poliestireno (10 \"mu\" de diâmetro). Foram determinadas as distribuições de velocidades instantâneas nas freqüências de batimento de 80, 100 e 120 bpm em três campos (65 mm x 65mm) da câmara paralelos à membrana e um campo situado no canal de entrada do DAVP, usando correlação cruzada com base na transformada rápida de Fourier. Um gerador de pulsos foi utilizado para sincronizar a detecção das imagens pelo sistema VIP com as fases de interesse no ciclo de bombeamento. Na freqüência de batimentos de 80 bpm as velocidades máximas foram de 1,94 m/s no canal de entrada durante o período de enchimento e 1,66 m/s nas regiões próximas à membrana durante o período de ejeção. Em 100 bpm, as velocidades máximas foram de 1,68 m/s no canal de entrada e 1,15 m/s nas regiões próximas a membrana. As distribuições de velocidades instantâneas mostram a ocorrência de pequenos vórtices, principalmente durante a fase de enchimento. Estes vórtices apresentam grande variabilidade ciclo-a-ciclo produzindo turbulências no fluxo e tensões de Reynolds elevadas. No ciclo a 80 bpm, ) parte da energia cinética turbulenta é dissipada devido à desaceleração do fluxo na câmara sanguínea antes do inicio da fase de ejeção. Isto ocorre para as freqüências de 100 e 120 bpm. A máxima tensão de Reynolds foi observada no canal de entrada do DAVP no valor de 222 N/m2 durante o enchimento, persistindo por 25 ms. No plano da membrana a maior tensão encontrada foi igual a 250 N/m2 durante o enchimento, persistindo por 25 ms. O campo de velocidades media contém vórtices permanentes durante a fase de enchimento que influenciam significativamente o fluxo na câmara e cujo numero aumenta com a freqüência de batimentos, provocando aumento de turbulências. Estes resultados indicam que existe maior possibilidade de ocorrer o processo de hemólise durante o enchimento do que durante a ejeção. Vetores com baixas velocidades foram observados na região compreendida entre os canais de entrada e saída do fluxo na câmara sanguínea no período de ejeção, sugerindo a possibilidade de ocorrer à formação de trombos nesta. / --

Preterm infants are at risk for respiratory distress syndrome (RDS) due to immature lungs, leading to notable neonatal mortality. About 10% of US births are premature. While mechanical ventilation is a common RDS treatment, it can cause complications. If it fails, extracorporeal membrane oxygenation (ECMO) is employed, but standard ECMO devices are not suited for preterm babies. The limitations of hollow fiber membrane oxygenators used in ECMO have spurred interest in an artificial placenta that connects to the umbilical cord and supports lung growth. Microfluidic blood oxygenators, with their biomimetic designs, have being explored for this purpose. This thesis advances microfabrication techniques for Lung Assist Devices (LADs), focusing on two main objectives: I. Improving Throughput for Elevated Blood Flow Rates: This section delves into refining Microfluidic Blood Oxygenators (MBOs) to accommodate greater blood flow rates. By combining parallel units, we increased throughput and optimized LAD designs. Newly designed MBOs, with an expanded gas exchange surface area, can manage blood flow rates up to 60 mL/min. Using these enhanced MBOs, we constructed a novel LAD achieving superior oxygenation compared to predecessors. Our in vitro tests confirmed that this LAD can sustain blood flow rates of up to 150 ml/min, elevating oxygen saturation by approximately 20%—equivalent to an oxygen transfer of 7.48 mL/min, a leading figure for AP-type devices. II. Hierarchically Designed Microchannels: The second objective revolves around developing microchannels with a hierarchical layout to mitigate stagnation and high shear stress regions. Traditional photolithography poses challenges at channel intersections, inducing clotting risks. We pioneered alternative microfabrication methods, yielding diverse microchannels and intricate hierarchical designs that emulate natural vascular networks devoid of dead zones. These advancements have propelled the microfabrication domain for artificial placenta-like LADs. Utilizing our method, we produced channels varying from hundreds to a few microns in height with a single exposure and an opal diffuser. Thin membranes (~60 µm top and ~45 µm bottom) were amalgamated, culminating in a total depth of about 200 µm. Such oxygenators excel in oxygenating blood even at intense flow rates of up to 15 mL/min per unit. Leveraging these hierarchically designed MBOs, we crafted a LAD supporting a flow rate of 100 mL/min, offering an oxygen transfer of 5.21 mL/min. Both LADs developed in this research proficiently support premature neonates weighing up to 2 kg. Notably, the priming volume of the LAD using the enhanced MBOs has been substantially minimized, underscoring its advancements over earlier models. Realizing these objectives can transform neonatal care, addressing respiratory challenges in premature neonates and bolstering their chances for a healthier life. / Thesis / Master of Science (MSc)

Ziel dieser Arbeit war es, neue Therapieprinzipien zu entwickeln und zu überprüfen, ob diese geeignet sind, ein Rechtsherzversagen nach Implantation eines LVAD bei Patienten mit terminaler Herzinsuffizienz zu verhindern. Bei Patienten mit chronischem Linksherzversagen erhöht sich der pulmonalvaskuläre Widerstand. Als Ursache wird eine Dysregulation des pulmonalen Gefäßendothels verstanden, die mit einer gestörten Freisetzung von NO und einer erhöhten Expression von Endothelin einhergeht und die bei längerem Bestehen auch strukturelle Veränderungen der Lungenstrombahn nach sich zieht. Bei Patienten mit chronischem Linksherzversagen führt dies zu einer sekundären pulmonalen Hypertonie, die direkt die rechtsventrikuläre Funktion beeinträchtigt und durch eine Vasodilatantientherapie zunächst noch reversibel ist. Nach LVAD-Implantation bei terminaler Herzinsuffizienz steigt häufig der pulmonalvaskuläre Widerstand unter anderem infolge der extrakorporalen Zirkulation weiter an, so daß bei vielen Patienten ein Rechtsherzversagen aufgund der sekundären pulmonalen Hypertonie mit hoher Morbidität und Mortalität auftritt. Weder positiv inotrope Pharmaka noch systemische Vasodilatantien oder gar die sekundäre Implantation eines RVAD konnten das Problem bisher lösen. Einen völlig neuen Therapieansatz stellt die inhalative Verabreichung von NO dar, welches durch die direkte Wirkung auf die glatte Gefäßmuskulatur eine selektive Vasodilatation in der pulmonalen Zirkulation bewirkt und somit konsekutiv die rechtsventrikuläre Nachlast senkt, ohne dabei den systemischen Widerstand zu beeinflussen. Zunächst wurden die klinischen Effekte einer inhalativen NO-Therapie bei Patienten untersucht, die nach Implantation eines LVAD aufgrund einer rechtsventrikulären Dysfunktion bei sekundärer pulmonaler Hypertonie ein postoperatives low-cardiac-output-Syndrom entwickelt hatten. Im ersten Teil der Untersuchungen konnte gezeigt werden, daß die ausgeprägtesten hämodynamischen Wirkungen bei einer individuellen NO-Dosis zwischen 25 und 40 ppm NO erreicht werden. Bis zu 40 ppm nahmen der pulmonalvaskuläre Widerstand und der pulmonalarterielle Mitteldruck progredient ab, während der Cardiac Index dosisabhängig signifikant stieg, ohne daß dabei eine Änderung der systemischen Druck- und Widerstandsverhältnisse zu bemerken war. Die pulmonalvaskuläre Selektivität der inhaltiven NO-Therapie sowie die teils dramatische hämodynamische Verbesserung waren somit bestätigt. Auch unter Dauerapplikation der jeweils individuell ausgetesteten optimalen NO-Dosierung zeigte sich über den gesamten Behandlungszeitraum die oben beschriebene signifikante hämodynamische Verbesserung mit Abnahme der rechtsventrikulären Nachlast bei gleichzeitiger Zunahme des Cardiac Index. Zusätzlich wurde mittels TEE ein stetiger Anstieg der RVEF und ein Abfall des RVEDV dokumentiert. Somit konnte bei den Patienten unter NO-Therapie zunächst die Katecholamingabe deutlich reduziert und die NO-Behandlung ausgeschlichen werden. Im Verlauf der Therapie kam es weder durch eine abrupte Unterbrechung der NO-Zufuhr bei täglich durchgeführten NO-Auslassversuchen noch bei Beendigung der Therapie zu einer hämodynamischen Verschlechterung, was indirekt die Erholung des rechten Ventrikels belegt. Trotz der insgesamt eindrucksvollen hämodynamischen Verbesserung unter Beatmung mit NO gab es einige Patienten, bei denen trotz hochdosierter Katecholamintherapie und adäquatem Volumenersatz die rechtsventrikuläre Dysfunktion persistierte. Dies wurde darauf zurückgeführt, daß durch Zunahme des Cardiac Index und somit des venösen Rückstromes nach LVAD-Implantation eine Erholung der Rechtsherzfunktion nicht möglich war. Um die Erholung der Rechtsherzfunktion über eine Minimierung der rechtsventrikulären Schlagarbeit zu ermöglichen, wurde ein zu sämtlichen anderen Therapiestrategien kontroverses Konzept entwickelt, das sowohl der rechtsventrikulären Vorlast und Nachlast als auch der inotropen Therapie Rechnung trägt. Statt wie bisher einen hohen Cardiac Index anzustreben wurde jetzt untersucht, ob nicht bei einem postoperativ recht niedrigen Cardiac Index von 2.5 L/min/m2 (( 2.3 L/min/m2 und ( 2.8 L/min/m2) mit daraus folgender Verminderung der Schlagarbeit eine Erholung des rechten Ventrikel möglich ist, ohne dabei jedoch die Organperfusion zu gefährden. Dies beinhaltete neben einer frühzeitig eingeleiteten NO-Beatmung eine minimale Katecholamintherapie und einen restriktiven Volumenersatz. Deshalb wurde mit der NO-Beatmung bereits intraoperativ bei Abgang vom kardiopulmonalen Bypass begonnen. Ein Cardiac Index von circa2.5 L/min/m2 erwies sich bei den analgosedierten und beatmeten Patienten für eine adäquate Organperfusion als ausreichend und zeigte sich darüber hinaus als geeignet, ein Rechtsherzversagen zu verhindern und eine Restitution der rechtsventrikulären Funktion sicherzustellen. Die inhalative NO-Therapie wurde auch hier bei allen Patienten ohne Auftreten eines Rebound-Phänomen beendet. Bekannt ist, daß Endothelin-1 als potenter endogener Vasokonstriktor (Produktion als auch Elimination hauptsächlich in der Lunge) eine pulmonale Hypertonie auslösen kann und damit als Antagonist zum wichtigsten endothelialen Mediator der pulmonalen Vasodilatation, dem NO, betrachtet wird. Zur Klärung weiterer pathophysiologischer Grundlagen wurden die Plasmaspiegel von ET-1 und Big ET-1 unter NO-Therapie nach LVAD-Implantation gemessen. Die präoperativen ET-1- und Big ET-1-Plasmaspiegel waren, wie bei terminaler Herzinsuffizienz zu erwarten, deutlich erhöht und korrelierten mit dem pulmonalvaskulären Widerstand. Dass die höchsten Plasmakonzentrationen von ET-1 intraoperativ gemessen wurden steht in Einklang mit anderen Untersuchungen und wurde mit einer durch den kardiopulmonalen Bypass ausgelösten endothelialen Dysfunktion erklärt. Unter inhalativer NO-Therapie fielen die Plasmaspiegel von ET-1 und Big ET-1 signifikant ab und waren nach Beendigung der Therapie am niedrigsten. Es bestand eine signifikante, inverse Korrelation zwischen der mittleren inhalativen NO-Dosis und den Plasmaspiegeln von ET-1 und Big ET-1. Simultan mit dem Abfall der Plasmaspiegel der Endotheline verbesserte sich die Hämodynamik. Der Abfall des pulmonalarteriellen Druckes korrelierte mit dem Abfall der ET-1-Plasmaspiegel. Die Ergebnisse lassen darauf schließen, daß eine inhalative NO-Therapie, welche die bei sekundärer pulmonaler Hypertonie pathophysiologisch defiziente endogene NO-Produktion ausgleicht, neben einer pulmonalselektiven Vasodilatation auch zu einer NO-vermittelten Inhibition der Endotheline ET-1 und Big-ET-1 führt. Da auch die Linksherzinsuffizienz durch die mechanische Entlastung mit einem LVAD suffizient behandelt ist, kann sich erneut ein physiologisches Gleichgewicht zwischen den Antagonisten NO und Endothelin in der Lungenstrombahn einstellen, das eine Dysfunktion des pulmonalen Gefäßendothels behebt. Dies erklärt, dass eine NO-Beatmung nur vorübergehend erforderlich ist und nach Beendigung der NO-Inhalation ein Rebound-Phänomen mit Wiederanstieg des pulmonalvaskulären Widerstands und konsekutiver Rechtsherzbelastung ausbleibt. Zur Unterstützung der rechtsventrikulären Funktion nach Implantation eines LVAD wurden folgende Therapieprinzipien etabliert: - Eine inhalative NO-Therapie sollte frühzeitig bereits zum Abgang vom kardiopulmonalen Bypass eingesetzt werden. - Eine intraindividuelle Dosistitration von NO ist sinnvoll um einen optimalen Behandlungseffekt mit der geringst möglichen Dosis zu erzielen. - Die inhalative NO-Therapie senkt selektiv den pulmonalvaskulären Widerstand und verursacht keine systemische Hypotension. Die rechtsventrikuläre Nachlast fällt ab, ohne dass die linksventrikulären Füllungsdrucke pathologisch ansteigen, da der linke Ventrikel durch das LVAD entlastet ist. - Tritt trotz NO-Beatmung eine rechtsventrikuläre Dysfunktion auf, so ist zur weiteren Entlastung des rechten Ventrikels ein niedriger Cardiac Index von circa 2.5 L/min/m2 angezeigt, um den venösen Rückstrom gering zu halten. - Dies ist durch eine minimale Katecholamintherapie und einen restriktiven Volumenersatz zu erzielen. Die Reduktion der rechtsventrikulären Schlagarbeit erlaubt eine Erholung der rechtsventrikulären Funktion. - Die ET-1- und Big-ET-1-Plasmaspiegel fallen um so rascher ab, je langsamer die NO-Dosis reduziert wird, da zwischen den Plasmaspiegeln der Endotheline und der mittleren inhalativen NO-Dosis eine inverse Korrelation gefunden wurde. Daher ist eine schrittweise Entwöhnung der inhalativen NO-Therapie erforderlich, um ein Rebound-Phänomen zu verhindern. - NO-Auslaßversuche sind geeignet, um in kritischen Fällen die Abhängigkeit von einer NO-Beatmung in der Entwöhnungsphase zu überprüfen. - Da eine Dysfunktion des pulmonalen Gefäßendothels nach Beendigung der inhalativen NO-Therapie offensichtlich nicht mehr fortbesteht, ist im weiteren klinischen Verlauf in der Regel nicht mit einer erneuten Rechtsherzbelastung durch einen Anstieg des pulmonalvaskulären Widerstands zu rechnen. / This thesis aimed to develop and evaluate new therapeutic principles to prevent right ventricular failure following LVAD implantation in patients with end-stage heart failure. Pulmonary vascular resistance increases in patients with chronic left ventricular failure. The mechanism is thought to be a dysregulation of the pulmonary vascular endothelium with an impaired release of NO and increased expression of endothelin, which in the long term leads to structural changes in the pulmonary circulation. In patients with chronic left ventricular failure this causes secondary pulmonary hypertension, directly compromising right ventricular function, but initially this is not fixed and is still reversible by vasodilator therapy. Following LVAD implantation in end-stage heart failure, pulmonary vascular resistance may further increase, partially due to cardiopulmonary bypass, and many patients develop frank right ventricular failure due to aggravation of secondary pulmonary hypertension, which is associated with a high morbidity and mortality. Neither positive inotropic drugs nor systemic vasodilators or even the secondary implantation of a RVAD were able to solve the problem. A novel therapeutic approach is the administration of inhaled NO, which directly acts on vascular smooth muscle cells causing selective pulmonary vasodilation and therefore decreases right ventricular afterload without altering systemic vascular resistance. The clinical effects of NO inhalation therapy were first studied in patients presenting with postoperative low cardiac output syndrome after LVAD implantation due to secondary pulmonary hypertension and right ventricular dysfunction. In this first study the greatest hemodynamic effects were demonstrated at individually titrated doses of 25 to 40 ppm NO. The pulmonary vascular resistance and the mean pulmonary artery pressure progressively decreased with increasing doses up to 40 ppm NO, as the cardiac index significantly increased dependent on dosage and without any noticeable change of the systemic arterial pressure or systemic vascular resistance. Thus a selective pulmonary vasodilating effect of inhaled nitric oxide along with a hemodynamic improvement, which in some patients was dramatic, was demonstrated. During continuous administration with the individually titrated optimal dose significant beneficial effects were shown during the entire treatment period with a decrease of the right ventricular afterload and a consequent increase of the cardiac index. In addition, a steady increase of the RVEF and a decrease of the RVEDV were demonstrated by TEE. This permitted us to first lower the catecholamine dose in these patients and then to wean them of the NO therapy. In the course of NO therapy hemodynamic deterioration was provoked neither by acute interruption of NO administration at daily performed "NO-off-trials", nor after weaning of NO therapy, which indirectly proved regeneration of the right ventricle. Although an overall impressive hemodynamic improvement was demonstrated with NO inhalation there were some patients in whom right ventricular dysfunction persisted despite maximal inotropic support and adequate volume replacement. This was thought to be due to the increase in cardiac index and thereby venous return after LVAD implantation preventing restoration of right ventricular function. To permit improvement of right ventricular function by minimizing right ventricular stroke work, a comprehensive concept contradictory to all other treatment strategies was developed, taking right ventricular preload, afterload and inotropic therapy into account. Instead of the intention being to generate a high cardiac index, it was studied whether a relatively low postoperative cardiac index of 2.5 L/min/m2 (= 2.3 L/min/m2 and = 2.8 L/min/m2) which decreases stroke work, enables the right ventricle to regenerate without compromising perfusion to vital organs. This meant early administration of inhaled NO, minimal catecholamine support and restrictive volume replacement. NO inhalation was initiated intraoperatively as soon as weaning from cardiopulmonary bypass had taken place. A cardiac index of 2.5 L/min/m2 proved to be sufficient in the analgosedated and ventilated patients to ensure sufficient organ perfusion and in addition proved to be successful in preventing right ventricular failure and permitting restitution of right ventricular function. Inhaled NO therapy was weaned successfully without rebound phenomena. The potent endogenous vasoconstrictor endothelin-1 (produced and eliminated primarily in the lungs) has been shown to cause pulmonary hypertension and is an antagonist of the most important endothelial mediator of pulmonary vasodilation, NO. To further elucidate the pathophysiology, plasma levels of ET-1 and big ET-1 were measured during NO therapy following LVAD implantation. As expected in end-stage heart failure, the preoperative ET-1 and big ET-1 plasma levels were considerably increased and correlated with the pulmonary vascular resistance. The highest plasma concentrations of ET-1 were measured intraoperatively, which is in keeping with other studies and has been explained by an endothelial dysfunction triggered by cardiopulmonary bypass. Plasma levels of ET-1 and big ET-1 fell significantly during NO therapy and were lowest after termination of inhaled NO. A significant inverse correlation was found between the mean inhaled NO dose and the ET-1 and big ET-1 plasma levels. Hemodynamics improved simultaneously with the drop in plasma levels of the endothelins. The decrease of the pulmonary artery pressures correlated with the decrease of the ET-1 plasma levels. It can be derived from the results that inhaled NO not only induces pulmonary selective vasodilation by replacing a deficient endogenous NO production in secondary pulmonary hypertension, but inhaled NO also inhibits the endothelins ET-1 and big ET-1. In addition, left ventricular failure is effectively treated by mechanical unloading through the LVAD, thus permitting a new physiologic balance to develop between the antagonists NO and endothelin in the pulmonary circulation and ameliorating dysfunction of the pulmonary vascular endothelium. This explains why NO inhalation is needed only as an intermediate therapy and the fact that a rebound phenomenon with increases in pulmonary vascular resistance and consecutive right ventricular constraint does not occur. To support right ventricular function after LVAD implantation, the following therapeutic principles have been established: - Inhaled NO therapy should be started early on weaning from cardiopulmonary bypass. - Intraindividual dose titration is useful to ensure maximal effects with minimal doses. - Inhaled NO selectively decreases pulmonary vascular resistance without inducing systemic hypotension. Right ventricular afterload decreases without pathologically increased left ventricular filling pressures, as the left ventricle is unloaded by the LVAD. - If right ventricular dysfunction presents despite NO inhalation, venous return should be lowered to relieve the right ventricle, by keeping the cardiac index low at around 2.5 L/min/m2. - This is accomplished by minimal inotropic support and restrictive volume replacement. Regeneration of right ventricular function is made possible by a reduction of right ventricular stroke work. - The slower the inhaled NO dose was lowered, the faster the ET-1 and big ET-1 plasma levels fell, as an inverse correlation was found between the plasma levels of the endothelins and the mean inhaled NO dose. Therefore stepwise weaning of inhaled NO therapy is essential in preventing rebound phenomena. - "NO-off-trials" are useful to monitor inhaled NO dependency during weaning from NO therapy in critical cases. - As dysfunction of the pulmonary vascular endothelium obviously does not persist after cessation of inhaled NO therapy, as a rule right ventricular compromise due to an increase in pulmonary vascular resistance does not occur during the further clinical course.