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.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13651号 / 論医博第2333号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 尾野 亘, 教授 浅野 雅秀, 教授 長船 健二 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Pump thrombosis is the epitome of left ventricular assist device dysfunction for end-stage heart failure patients. With the increased utilization of implantable, long-term, left ventricular assist devices (LVADs), understanding the implications associated with device orientation and interaction with the body is exceedingly important. Components associated with pump thrombosis in the Thoratec© HeartMate II™ (HMII) and the HeartWare© HVAD® devices include the inflow cannula, the outflow graft, and the pump elements as well as pump pocket depth for the HMII specifically. Several studies have been conducted to analyze these interactions with the HMII, however there is minimal to no data available analyzing how the device orientation of the HeartWare HVAD affects hemodynamics and a patient’s risk for developing pump thrombosis. Therefore, the purpose of this pilot study is the simulate the hemodynamic implications associated with Sub-optimal cannula angulation of the HVAD. Using Solidworks 2016 Ed., a simplified, hemo-static model of the left side of the heart was created. Dimensions for the atria, ventricle, and mitral valve were determined through the combination of Trans-Esophageal Echo cardiogram data as well as literature references. Three different inflow cannula angle scenarios were developed including a Control, a Clinically Optimal, and a Sub-optimal. Assumptions included body temperature, no accumulation within the ventricle, and no ejection or contraction. The model consists of static continuous flow set to 5 liters per minute with the assumption that the HeartWare HVAD is completely supporting the left ventricle. The results include both qualitative and quantitative data. Flow trajectory plots for each cannula scenario depict the hemodynamic flow patterns for different time points. Results show visible changes in the Sub-optimal orientation when compared to both the Control and the Clinically Optimal scenario. Additionally, it was determined that there were no statistically significant differences in the velocity vectors for any of the scenarios however, the shear stress values were determined to be significantly different for all time points, p < 0.001 for all scenarios when compared to Control. Though there are several limitations of this study, with sub-optimal inflow cannula angulation, there is a potential increased risk of hemolysis due to increased shear stress.

Background: Right ventricular failure is a serious complication after left ventricular assist device placement. Case Presentation: A 70-year-old male in decompensated heart failure with right ventricular failure after the placement of a left ventricular assist device. A single dual-lumen PROTEKDuo cannula was inserted percutaneously via the internal jugular vein to draw blood from the right atrium and return into the pulmonary artery using the CentriMag system, by passing the failing ventricle. The patient was successfully weaned from right ventricular assist device. Conclusions: In comparison to two-cannula conventional procedures, this right ventrivular assist device system improves patient rehabilitation and minimizes blood loss and risk of infection, while shortening procedure time and improving clinical outcomes in right ventricular failure.

Background: Aortic valve insufficiency (AI) at the time of left ventricular assist device (LVAD) insertion needs to be corrected, however there is little known about how to manage bioprosthetic valvular AI. Case presentation: A 55-year-old female with dilated cardiomyopathy who previously had a bioprosthetic aortic valve replacement needed a LVAD as a bridge to transplant. Her left ventricular ejection fraction was 10% and had mild to moderate transvalvular AI. She underwent a HeartWare HVAD insertion along with aortic valvular coaptation stitch repair (Park's stitch) to the bioprosthetic valve. Conclusion: Her AI improved to trivial with minimal ejection through the bioprosthetic valve. She was transplanted 6 months following the surgery. A Park's stitch to the bioprosthetic aortic valve with more than mild AI might be a good option for bridge to transplant patient.

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.

Heart failure is a progressive condition that affects over 5.7 million Americans and costs associated with heart failure account for 2-3 % of the national health care budget. The high rates of morbidity and mortality along with increased costs from readmissions associated with advanced heart failure have led to the exploration of advanced treatments such as left ventricular assist devices (LVADs). LVADS have demonstrated morbidity and mortality benefit but cost remains extensive with costs per quality-adjusted years > $400,000. With this in mind, it is important to identify those who are most likely to benefit from an LVAD to avoid unfavorable outcomes and cost. Although general guidelines and criteria for patient eligibility have been established, choosing patients for LVAD implantation remains challenging. A new focus on patient selection involves the presence of frailty. While frailty has been studied in the elderly population and in patients undergoing cardiac surgery, frailty in patients undergoing left ventricular assist device (LVAD) remains controversial. The purpose of this dissertation was to examine measures of frailty in patients undergoing LVAD implantation. The specific aims of this dissertation were to: (1) identify a feasible frailty measure in adults with end-stage heart failure who underwent LVAD implantation by testing the hypothesis that frailty would predict 30 day rehospitalization rates using Fried’s criteria, Short Physical Performance Battery test, handgrip strength, serum albumin and six minute walk test (2) Determine whether frailty measures improve 3 months post LVAD implantation (3) compare sensitivity of these three measures to change in frailty. Surgical approaches, including heart transplantation and LVAD implantation, for patients with end-stage heart failure was discussed in this dissertation. Data from two subsets of participants who underwent LVADS at the University of Kentucky between 2014 and 2017 were included in the analysis for this dissertation. In the first study, we found that none of the measures are good predictors of frailty in patients with advanced heart failure who undergo LVAD implantation. Handgrip was the only marker of frailty that predicted 30 day readmission but the relationship was a negative association. In the second study, six-minute walk and low serum albumin levels reflect short-term improvement in frailty. These simple measures may be used to determine those patients who are responsive to LVAD implantation. The findings of these studies filled some gaps in our understanding of markers of frailty in patients undergoing LVADs. We gained a better understanding of which markers of frailty are likely to improve in most people after LVAD implantation and thus frailty should not preclude candidate selection for an LVAD. Subsequently, more research is needed to investigate these markers and outcomes.

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.

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