Cardiac Surgery Research

Prof.
Francesco Maisano, MD
Director Department of
Cardiac Surgery

Organization

Valvular heart-disease and heart failure

Valvular heart-disease and heart failure represent a major cause of mortality around the globe. Both entities are interdependent. The therapy options for affected patients with valvular heart disease are currently undergoing rapid changes and in addition to conventional, surgical valve operations on heart lung machine representing the standard of care since several decades, transcatheter techniques have entered the clinical-routine representing an efficient alternative for the treatment of elderly high-risk patients. Given sufficient long- term safety, it can be predicted that these minimally-invasive techniques may have a major impact on the treatment strategy of patients with VHD and will further be expanded to a broader and younger patient population. Recent trials suggest higher safety profile of transcatheter aortic valve implantation as compared to surgery in patients with low-risk profile. As a result, catheter based procedures are becoming first line option in patients above 70 years. To further expand indications and to improve long term durability and sustainability of the procedures, research and development and collaboration with industry partners is fundamental. On this background, the research of the department of cardiovascular surgery has a broad translational and multidisciplinary approach covering the ground from cellular and molecular biology to preclinical research to first in man and large scale clinical studies. Conceputally, we develop novel minimally invasive or transcatheter devices and treatment strategies for patients with valve and heart failure, involving the latest technologies in devices and imaging. To that end, our experimental research lines are as follows:

Novel Models and treatments for Heart Failure
Valve regurgitation is a pathological state where a unidirectional heart valve has become insufficient in its function and allows s blood to leak back. In consequence, the downstream blood ejection volume decreases, while the regurgitant blood volume causes overload in the upstream heart chamber. The upstream heart chamber undergoes morphological and cellular changes which can cause dysfunction and heart failure. The left ventricle undergoes thinning of the ventricular wall and remodeling of cardiac cellular structures attributed to prolonged stress caused by volume overload. These changes are believed to be irreversible and are involved in several features of heart failure. However, the exact mechanisms behind these adaptive phenomena of the left ventricle are still poorly understood. On this background, we develop and validate a novel animal model to study morphological and cellular changes in subacute left ventricular volume overload and afterload mismatch. This model allows to identify functional parameters and early biomarkers specific to left ventricular volume overload and remodeling; to investigate blood and tissue biomarkers known to be elevated in chronic left ventricular remodeling at early stages of left ventricular volume overload; to investigate early changes in myocardial fiber architecture as well as myocardial metabolism by means of Dynamic Nuclear Polarization and Diffusion Tension Imaging, to study cellular, subcellular and metabolic characteristics of early signaling and response.
Another concept involves the concept of fluid-structural interaction between global and regional wall motion and the intracavitary blood stream (vortex). The ideal interaction happens in healthy hearts by exact synchronization of wall motion, valve function and flows, as demonstrated by several MRI and blood speckle tracking studies. Using a device specially developed for this task (a rotating disk mitral prosthesis), we investigate the role of flow redirection in the inflow of the left ventricle as a potential factor involved in the determination of heart failure. The study involves intraprocedural LV loops and MRI studies of fluid-structure interactions.
Heart failure is a multifactorial disease, with a large spectrum of clinical presentations. As a consequence, there is a large opportunity to investigate new targets of therapy. We investigate the role of respiratory mechanics in heart failure, by diaphragm stimulation in a novel animal model to precisely analyse the role of the interaction between chest dynamics and right ventricular hemodynamics and left ventricular diastolic properties. In this project new, old techniques like auscultation have been rejuvenated by integrating them in sophisticated imaging and monitoring modalities, inspiring new opportunities for clinical monitoring and early diagnosis.

Next generation bioengineered implants
Congenital heart defects represent a major cause of death around the globe. Although current therapy strategies have rapidly developed over the last decades, the currently used artificial prostheses are still considered to be suboptimal. They do not promote regeneration, physiological remodeling or growth (particularly important aspects for children) as their native counterparts. This leads to the continuous degeneration and subsequent failure of such substitutes which is associated to an increased morbidity and the need for multiple re-interventions. To overcome this problem, the concept of regenerative medicine comprising of tissue-, bio-engineering and hybrid technologies has been suggested as a next generation approach to enable native like cardiovascular replacements with regenerative and growth capacities, amendable to young adults and children. However, despite promising data from preclinical and first clinical pilot trials, the translation and clinical relevance of such technologies is still very limited. The reasons for that are multifaceted and comprise of scientific, logistical, infrastructural and regulatory challenges that need to be systematically addressed in order to facilitate clinical translation of such next generation cardiovascular substitutes.

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Figure 1:
Simulation-based Research and Development of new procedures is today a viable alternative to animal experiments, particularly in the early stage of the research. It is also the best solution for physician training and education. In this picture, a multidisciplinary team is testing a new catheter based tricuspid annuloplasty system, with multimodality imaging.

Development of Novel Devices, training and education


Development of novel devices is frequently performed in collaboration with industry partners and often based on own intellectual property. We investigate feasibility and safety in the porcine model, and work towards optimization of device characteristics, investigating hemodynamics, ventricular and device function in detail and assessing long-term effects in order to prepare for translation into clinical application. Various devices designed to allow for minimally invasive or percutaneous treatment of mitral valve regurgitation, tricuspid valve regurgitation, chordae replacement, leaflet augmentation and ventricular aneurysm were evaluated.
Progressively, this field evolved in direction of ex-vivo and in vitro testing. Our laboratory is becoming more and more specialized in non-animal testing using the facility resources (imaging, instrumentation, etc.) to develop new technologies, implants and instruments to an advanced level before being tested in liging animals. This is achieved using sophisticated dynamic simulators which can be used under X rays and replicated the exact intraprocedural conditions to develop the devices and optimize and standardize the procedures minimizing the need of animal experiments.
This experience has also induced a strong investment in training simulators, to eliminate the need for physician training with living animals. Simulation training experimentation using physical simulators is a very active field of investigation, using augmented reality and artificial intelligence methodologies to improve the assessment methodology of skill and competence training.

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Figure 2:
A state of the art animal lab allow the use of latest imaging technologies to develop new procedures, test and improve the standard operating procedures in the late phase of the preclinical testing. Here the multidisciplinary team is testing the same catheter based tricuspid annuloplasty system, with multimodality imaging as shown in figure 1, but in an animal model of tricuspid regurgitation.

Development of novel strategies for procedural planning and guidance

A novel minimally invasive device typically asks for specific procedural planning and intra-operative, imaging based guidance. This is especially true as the heart is a 3D moving structure and many technologies that allow for real-time imaging are restricted to 2D visualization, while others, such as MRI and CT are not available for the operator in the hybrid operation room and/or not suited to allow for direct manipulation with therapeutic devices. We focus on developing new approaches for the fusion of several imaging techniques, such as MRI, CT and echocardiography with fluoroscopy in real time in or- der to optimize catheter based procedures, to reduce X-ray contrast volume and radiation exposure.
We also work in the field of machine learning and automation of procedures, integrating this process in our device development programs.

Collaborations

  • Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, USA
  • Department of Biomedical Engineering, Technical University Eindhoven, The Netherlands
  • Center for Integrative Human Physiology, University of Zurich, Switzerland
  • Department of Materials, Federal Institute of Technology, Zurich, Switzerland
  • Department of Biochemistry, University of Zurich, Switzerland
  • Department of Mathematics, Federal Institute of Technology, Zurich, Switzerland
  • Department of Computational Science, Federal Institute of Technology, Zurich, Switzerland
  • Department of Veterinary Surgery, MSRU Vetclinics, University of Zurich, Switzerland
  • Department of Cardiac Surgery, Children‘s Hospital, Harvard Medical School, Boston, MA, USA
  • Department of Pathology, Brigham and Women‘s Hospital, Harvard Medical School, Boston, MA, USA
  • Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
  • Laboratory for Tissue Engineering, German Heart Centre, Berlin, Germany
  • Department of Cardiology, Medical University of Vienna, Austria
  • Institute of Nuclear Medicine, University of Debrecen, Hungary
  • Institute of Chemistry and Applied Biosciences, Federal Institute of Technology Zurich, Switzerland
  • Institute of Anatomy, University of Bern, Switzerland
  • Human Genetics Laboratory, Genetica AG, Zurich, Switzerland
  • Departments of Pathology, Neurosurgery, Cardiology, and Laboratory for Transplantation Immunology, UniversityHospital, Zurich, Switzerland
  • Randall Division of Cell and Molecular Biophysics, King’s College London, UK