Mechanical circulatory support (MCS) is a viable therapy for end stage heart failure. However, despite clinical success, the ability to compare MCS devices in vitro and perform training scenarios is extremely limited. Comparative studies are limited as different devices cannot be interchanged in a patient due to the surgical nature of implant. Further, training and failure scenarios cannot be performed on patients with devices as this would subject a patient to a failure mode. A need exists for a readily available mock system that can perform comparative testing and training scenarios with MCS devices. Previously, our group has fabricated a well characterized mock circulation system consisting of a SynCardia temporary Total Artificial Heart (TAH) and Donovan Mock Circulation tank (DMC tank). Further, utilizing this system with the TAH operating in reduced output mode, a heart failure model was developed. In the present study, three ventricular assist devices (VADs) were independently attached to the heart failure model to compare device performances over a range of preloads and afterloads. In addition, specific clinical scenarios were created with the system to analyze how VAD-displayed waveforms from the system correlate with clinical scenarios. Finally, each VAD was powered off while attached to the heart failure model to compare fluid flow through the VAD in a pump-failure scenario. We demonstrated that this system can successfully be utilized to compare MCS devices (i.e. ventricular assist devices) and for successful training of patients and clinicians.

Bei der Entwicklung von Herzunterstützungssystemen oder Systemen für den totalen Herzersatz muss untersucht werden, ob ein definierter Blutfluss gewährleistet werden kann und entsprechende Druckdifferenzen erzeugt werden können. Zudem ist eine möglichst geringe Blutschädigung von großer Bedeutung.  Zur Untersuchung der Förderleistung wird der erzeugte Volumenstrom bei verschiedenen Leistungsaufnahmen (Stromstärken) ermittelt. Es zeigt sich ein linearer Zusammenhang zwischen Leistungsaufnahme (A) und erzeugtem Fluss (l/min), da der erzeugte Druckgradient der Kraft des Kolbens proportional ist. Im Weiteren werden Druck- und Flussbeziehungen bei maximaler Leistungsaufnahme gemessen und dargestellt. Hier zeigt sich, dass bis zu einer Nachlast von 120 mmHg die maximale Flussrate von 11 l/min erzielt wird.  In weiteren Versuchsreihen wird das Ausmaß der Hämolyse bestimmt, indem die lineare Blutpumpe mit einem klinisch etablierten System (Medos-HIA-Ventrikel) verglichen wird. Dafür wird der normierte Hämolyse Index (NIH) bestimmt. Die vergleichende Untersuchung im Modellkreislauf ergibt, dass für die lineare Blutpumpe der Index 0,078 g/100l zwar höher liegt, als bei dem klinisch etablierten Medos-Ventrikel 0,0037 g/100l, die Erythrozyten-, Thrombozyten- und Leukozytenzahl sowie der Hkt bleiben aber unverändert über sechs Stunden. Die hier vorgestellte lineare Blutpumpe besitzt neben ausreichender Leistungsfähigkeit und neuartigen Regulationsmöglichkeiten eine dem Entwicklungsstand nach geringe blutschädigende Wirkung. Die lineare Blutpumpe stellt damit einen geeigneten neuen Lösungsansatz zur Konstruktion eines pulsatilen Geräts zu Herzunterstützung als auch totalem Herzersatz dar.

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Heart disease is the developed world's biggest killer, and the shortage of donor hearts has accelerated the development of mechanical alternatives. Scientists, engineers and clinicians have attempted to replicate the human heart with a mechanical device for over 50 years. Although a number of pulsating devices have been developed, and in some cases worked briefly, they have invariably failed to match the success of heart transplantation. In an attempt to produce a suitable alternative, current research is focused on devices that do not replace the heart; but rather work along side it to assist its function. Many of these devices help the failing left ventricle; however some patients require the additional implantation of a second device to assist a failing right ventricle. This increases implantation time and associated risk, and because of the size of the current devices, reduces the access of smaller patients to this vital technology. The overall thesis objective focuses on the progressive design, development and preliminary evaluation of two novel centrifugal type ventricular assist devices, a bi-left ventricular device (Bi-LVAD) and a single bi-ventricular assist device (Bi-VAD). The devices have the respective capability to assist either the left ventricle, or both ventricles of a failing heart. The current concept for each VAD employs both magnetic and hydrodynamic suspension techniques to float a rotating double impeller, a technique that aims to reduce blood damage and component wear, two of the major problems encountered with current generation devices. Each VAD design was developed by conducting experimentation and drawing conclusions from a variety of engineering research fields, such as flow visualization, rotary pump design and testing, fluid dynamics, hemodynamics and heart failure, and magnetic motor bearing design. In order to evaluate pump prototype designs, it was necessary to design and develop a novel pulsatile systemic and pulmonary mock circulation loop capable of reproducing the hemodynamics of heart failure in the systemic and pulmonary circuits. The investigation then specifically examined the static hydraulic forces on the impeller of a centrifugal blood pump during operation in this mock circulation loop. The recorded magnitude and direction of radial and axial thrust then influenced the selection of magnetic and hydrodynamic bearing configurations to minimise impeller touchdown in the intended hemodynamic environment. This research required the development of correctly designed impeller (semi-open/closed) and volute (single, double, circular) components for each ventricular assist application and a unique test facility to isolate impeller hydraulic forces in addition to the mock circulation loop. The proposed Bi-LVAD incorporates symmetrical blade designs on each side of the double sided impeller. The device assists the function of the left ventricle only with symmetrical axial pressure distribution and elimination of stagnant regions beneath the impeller. These features improve axial touchdown capacity and reduce thrombus formation respectively. The proposed Bi-VAD incorporates different blade designs on each side of the double impeller to augment the function of both the left and right cardiac chambers. The design has the additional potential to act as a total artificial heart (TAH). To date there is no Bi-VAD/TAH system available that incorporates an LVAD and RVAD in one rotary pump. Successful development of each innovative VAD will provide an alternative to heart transplantation, potentially saving lives of many terminal heart patients each year. No longer would heart transplant candidates need to wait for the untimely death of a donor to provide a suitable heart. Instead, this new generation device would be available immediately, and be almost universally compatible with all patients. It has the potential to dramatically increase a patient’s expected lifetime, and to deliver them a higher quality of life.

For the last two decades heart disease has been the highest single cause of death for the human population. With an alarming number of patients requiring heart transplant, and donations not able to satisfy the demand, treatment looks to mechanical alternatives. Rotary Ventricular Assist Devices, VADs, are miniature pumps which can be implanted alongside the heart to assist its pumping function. These constant flow devices are smaller, more efficient and promise a longer operational life than more traditional pulsatile VADs. The development of rotary VADs has focused on single pumps assisting the left ventricle only to supply blood for the body. In many patients however, failure of both ventricles demands that an additional pulsatile device be used to support the failing right ventricle. This condition renders them hospital bound while they wait for an unlikely heart donation. Reported attempts to use two rotary pumps to support both ventricles concurrently have warned of inherent haemodynamic instability. Poor balancing of the pumps’ flow rates quickly leads to vascular congestion increasing the risk of oedema and ventricular ‘suckdown’ occluding the inlet to the pump. This thesis introduces a novel Bi-Ventricular Assist Device (BiVAD) configuration where the pump outputs are passively balanced by vascular pressure. The BiVAD consists of two rotary pumps straddling the mechanical passive controller. Fluctuations in vascular pressure induce small deflections within both pumps adjusting their outputs allowing them to maintain arterial pressure. To optimise the passive controller’s interaction with the circulation, the controller’s dynamic response is optimised with a spring, mass, damper arrangement. This two part study presents a comprehensive assessment of the prototype’s ‘viability’ as a support device. Its ‘viability’ was considered based on its sensitivity to pathogenic haemodynamics and the ability of the passive response to maintain healthy circulation. The first part of the study is an experimental investigation where a prototype device was designed and built, and then tested in a pulsatile mock circulation loop. The BiVAD was subjected to a range of haemodynamic imbalances as well as a dynamic analysis to assess the functionality of the mechanical damper. The second part introduces the development of a numerical program to simulate human circulation supported by the passively controlled BiVAD. Both investigations showed that the prototype was able to mimic the native baroreceptor response. Simulating hypertension, poor flow balancing and subsequent ventricular failure during BiVAD support allowed the passive controller’s response to be assessed. Triggered by the resulting pressure imbalance, the controller responded by passively adjusting the VAD outputs in order to maintain healthy arterial pressures. This baroreceptor-like response demonstrated the inherent stability of the auto regulating BiVAD prototype. Simulating pulmonary hypertension in the more observable numerical model, however, revealed a serious issue with the passive response. The subsequent decrease in venous return into the left heart went unnoticed by the passive controller. Meanwhile the coupled nature of the passive response not only decreased RVAD output to reduce pulmonary arterial pressure, but it also increased LVAD output. Consequently, the LVAD increased fluid evacuation from the left ventricle, LV, and so actually accelerated the onset of LV collapse. It was concluded that despite the inherently stable baroreceptor-like response of the passive controller, its lack of sensitivity to venous return made it unviable in its present configuration. The study revealed a number of other important findings. Perhaps the most significant was that the reduced pulse experienced during constant flow support unbalanced the ratio of effective resistances of both vascular circuits. Even during steady rotary support therefore, the resulting ventricle volume imbalance increased the likelihood of suckdown. Additionally, mechanical damping of the passive controller’s response successfully filtered out pressure fluctuations from residual ventricular function. Finally, the importance of recognising inertial contributions to blood flow in the atria and ventricles in a numerical simulation were highlighted. This thesis documents the first attempt to create a fully auto regulated rotary cardiac assist device. Initial results encourage development of an inlet configuration sensitive to low flow such as collapsible inlet cannulae. Combining this with the existing baroreceptor-like response of the passive controller will render a highly stable passively controlled BiVAD configuration. The prototype controller’s passive interaction with the vasculature is a significant step towards a highly stable new generation of artificial heart.

Introdução: A utilização de dispositivos de assistência ventricular esquerda (DAVE) proporciona melhor manejo dos pacientes que necessitam de métodos alternativos como ponte para o transplante cardíaco. Parcela significativa dos pacientes sob uso de DAVE desenvolve falência de ventrículo direito (VD), com elevada mortalidade. Propusemos estudo experimental para desenvolvimento de método de descompressão do VD em pacientes sob assistência mecânica esquerda e disfunção biventricular. Método: Foi realizado estudo experimental em cães adultos, com disfunção biventricular em fibrilação ventricular, mantidos em uso de DAVE com bomba centrífuga. Os animais foram divididos em dois grupos. No Grupo A, foi realizada descompressão do VD através de anastomose cavo-pulmonar, com anastomose da veia cava superior na artéria pulmonar direita. No grupo B, não foi realizado o \"shunt\". Após o preparo inicial foi iniciada assistência circulatória átrio esquerdo-aorta. Foram realizadas medidas hemodinâmicas e laboratoriais no momento inicial e aos 30, 60 e 90 minutos de assistência nos dois grupos. Resultados: Os dados hemodinâmicos e laboratoriais iniciais foram semelhantes nos dois grupos. No Grupo A, houve melhora da pressão arterial media (p<0,0001) durante a assistência. O fluxo pulmonar também foi maior no grupo A (p<0,0001), resultando em maior fluxo na bomba centrífuga, principalmente aos 90 min(1,2L/min X 0,5L/min, p<0,0001). A dosagem de lactato sérico no último momento de estudo foi menor no grupo A (27,6mg/dL versus 47,6mg/dL, p<0,05). Conclusão: Concluímos que a anastomose cavo-pulmonar promove descompressão do VD em modelo de disfunção bi-ventricular aguda sob assistência circulatória isolada do ventrículo esquerdo. A descompressão do VD leva a aumento do fluxo pulmonar e melhor desempenho hemodinâmico da assistência ao ventrículo esquerdo. / Introduction: The use of Left Ventricular Assist Devices promotes better clinical handling of patients in the need of alternative methods as bridge to heart transplant. A significant part of them develop right ventricle failure, leading to high death incidence. We have proposed an experimental study for the development of a method to decompress the right ventricle in biventricular failure patients under Left Ventricular Assist Devices . Method: Experimental study with adult dogs with acute biventricular failure in ventricular fibrillation under left assist device by centrifugal pump. The animals were divided in 2 groups. In Group A decompression of RV was made by cavo-pulmonary anastomosis between superior vena cava and right pulmonary artery. In Group B the anastomosis was not performed. After initial preparation left atrium-aorta circulatory support begun. Hemodinamic and laboratory measures were taken at start time and at 30, 60 and 90 minutes of circulatory support. Results: Initial laboratory and haemodinamic data were similar in both groups. Group A had better mean arterial pressure during support(p<0,0001). Pulmonary blood flow was higher in Group A resulting in higher pump flow, mainly at 90 minutes(1,2L/minX0,5L/min, p<0,0001). Serum lactate was lower at 90 minutes in Group A(27,6mg/dL x 47,6mg/dL, p<0,05). Conclusion: We conclude that the cavo-pulmonary anastomosis led to right ventricle decompression in an experimental model of acute biventricular failure under isolated left ventricle circulatory support. The right ventricle decompression generated enhancement in pulmonary blood flow and better circulatory support performance.

Background: Temporary mechanical circulatory support device without sternotomy has been highly advocated for severe cardiogenic shock patient but little is known when coupled with amniotic stem cell therapy. Case presentation: This case reports the first dual therapy of temporary left ventricular extracorporeal device CentriMag with distal banding technique and human amniotic stem cell injection for treating a severe refractory cardiogenic shock of an 68-year-old female patient. A minimally-invasive off-pump LVAD was established by draining from the left ventricle and returning to the right axillary artery with distal arterial banding to prevent right upper extremity hyperperfusion. Amniotic stem cells were injected intramyocardially at the left ventricular apex, lateral wall, inferior wall, and right subclavian vein. Conclusion: The concomitant use of the temporary minimally-invasive off-pump CentriMag placement and stem cell therapy not only provided an alternative to cardiopulmonary bypass and full-median sternotomy procedures but may have also synergistically enhanced myocardial reperfusion and regeneration.

Heart failure (HF) is a widely prevalent state in developing countries, especially among people over 65, with percentages up to 10% of the population in the US. In all developed countries the expenditure related to congestive heart failure consists of a high percentage of the total health care expenditure, reaching 60% in the UK (1991 1). One of the main strategies for dealing with HF is the use of cardiac assist devices. Among these the most widely used device is the Intra-Aortic balloon pump (IABP). The IABP has as the main aims to increase coronary flow during inflation, and decrease end diastolic pressure and ventricular afterload during deflation. The device was introduced for the first time into clinical practice over 40 years ago, but open issues still remain with the performance of the device. In fact, both inflation and deflation effectiveness are compromised when the balloon operates at an angle to the horizontal, which is often the operating position of the device in intensive care units. The main aim of the work described in this thesis is to investigate the IABP in order to improve the efficacy of this therapy, in terms of IAB design and IABP timing effectiveness. For this purpose the balloon was first filmed in an experimental set-up to visualize its wall-motion with a high speed camera. The results of this investigation were the input for the development of different designs of balloon, tested at horizontal and angled positions. Both, inflation and deflation effectiveness were augmented using different shaped balloons in an experimental set-up characterized by static pressure as well as in one characterized by physiological pressure waveform. The improved performance was associated to an improved clinical outcome on a PV diagram. In addition different pumps and pump settings were studied in an experimental set-up, characterized by physiological aortic pressure waveform, in order to estimate the influence of different pump manufacturers and triggers on the performance of the device. In this case one of the pumps (Teleflex), with the new technology for pressure measurement via a fibre optic sensor, showed to best trigger the IAB after inflation onset, while the highest number of assisted beats was obtained when this pump was set on electrocardiogram (ECG) triggering. Nonetheless a first development of multi-dimensional computational model of the IAB counterpulsation was realized with the aim of establishing the effect of this therapy on relevant areas, such as aortic root, and in order to have an insight on the 3-D flow field in the surrounding of IAB: these information can be crucial for the optimisation of the balloon’s shape. In conclusion, the key finding was that a change in balloon shape influences both, inflation and deflation mechanics at horizontal and semi-recumbent positions, and this strategy can be used for maximising the IABP clinical benefits. With the aid of the computational model it will be possible to further develop the already tested balloon different shapes. Not less important, IABP therapy was demonstrated to be crucially influenced by the pump setting and mode (triggering inflation and deflation onsets), hence the clinical operator is addressed to change the pump mode of operation according to the patient’s condition to maximise the potential benefit of this therapy.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13428号 / 論医博第2232号 / 新制||医||1053(附属図書館) / (主査)教授 湊谷 謙司, 教授 佐藤 俊哉, 教授 福田 和彦 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

This study evaluates the impact of untreated preoperative severe mitral valve regurgitation (MR) on outcomes after left ventricular assist device (LVAD) implantation. Of the 234 patients who received LVAD therapy in the Heart Center Leipzig during a 6-year period, we selected those who had echocardiographic images of good quality and excluded those who underwent mitral valve replacement prior to or mitral valve repair during LVAD placement. The 128 patients selected were divided into 2 groups: Group A with severe MR (n = 65) and Group B with none to moderate MR (n = 63, 28 with moderate MR). We evaluated transthoracic echocardiography preoperatively [15 (7–28) days before LVAD implantation; median (interquartile range)] and postoperatively up to the last available follow-up [501 (283–848) days after LVAD]. We collected mortality, complications and clinical status indicators of the patient cohort. We observed a significant decrease in the severity of MR after LVAD implantation (severe MR 51% pre- vs 6% post-LVAD implantation, P < 0.001). There was no difference between groups in terms of right heart failure, rate of urgent heart transplantation, pump thrombosis or ventricular arrhythmias. There was no difference in 1-year survival and 3-year survival (87.7% vs 88.4% and 71.8% vs 66.6% for Groups A and B, respectively, P = 0.97). We concluded that preoperative severe MR resolves in the majority of patients early on after LVAD implantation and is not associated with worse clinical outcomes or intermediate-term survival.:Inhaltsverzeichnis Abkürzungsverzeichnis 3 1. Einführung 4 2. Formatierte Publikation 12 3. Zusammenfassung der Arbeit 19 4. Literaturverzeichnis 23 5. Anlagen 28 5.1. Statistical analysis of echocardiographic parameters in follow-up 28 5.2. Statistical Models Used 30 Darstellung des eignen wissenschaftlichen Beitrages 32 Erklärung über die eigenständige Abfassung der Arbeit 33 Lebenslauf 34 Publikationen 37 Danksagung 38