Non-pharmacological heart failure therapies : evaluation by ventricular pressure-volume loops

In this thesis, we evaluated the acute and chronic hemodynamic effects of non-pharmacological heart failure therapies. In particular, the effects of surgical treatment and biventricular pacing therapy were investigated by left ventricular pressure-volume loop analyses. We demonstrated that restrictive mitral annuloplasty effectively restored mitral leaflet coaptation without inducing significant acute changes in ventricular function. This indicates that this procedure can be safely applied in patients with heart failure. Surgical ventricular restoration was shown to achieve acute normalisation of left ventricular volumes, improved systolic function, and decreased left ventricular wall stress and mechanical dyssynchrony. At the expense of a higher diastolic pressure resulting from altered diastolic properties, stroke work and cardiac output were not importantly altered, but mechanical efficiency was significantly improved. Chronically, surgical therapy resulted in improved clinical status evidenced by improved NYHA class, quality of life score, and 6-min walking distance. Left ventricular function and dyssynchrony remained significantly improved at 6 months follow-up. In addition, we observed a decrease in pulmonary artery pressure, right ventricular reverse remodeling and reduced tricuspid regurgitation. Acute and chronic hemodynamic effects of cardiac resynchronization therapy (biventricular pacing) were demonstrated by pressure-volume loop analysis. Hemodynamic improvements, previously only shown in acute studies, were shown to be maintained at 6 months follow-up. In addition, ventricular-arterial coupling, mechanical efficiency, and chronotropic responses were improved. In conclusion, the acute and chronic hemodynamic effects of these non-pharmacological heart failure therapies were demonstrated by ventricular pressure-volume analysis. These findings provide insight in the underlying mechanisms and help to explain improved functional status achieved with these therapies.UBL - phd migration 201

Echocardiography

The book "Echocardiography - New Techniques" brings worldwide contributions from highly acclaimed clinical and imaging science investigators, and representatives from academic medical centers. Each chapter is designed and written to be accessible to those with a basic knowledge of echocardiography. Additionally, the chapters are meant to be stimulating and educational to the experts and investigators in the field of echocardiography. This book is aimed primarily at cardiology fellows on their basic echocardiography rotation, fellows in general internal medicine, radiology and emergency medicine, and experts in the arena of echocardiography. Over the last few decades, the rate of technological advancements has developed dramatically, resulting in new techniques and improved echocardiographic imaging. The authors of this book focused on presenting the most advanced techniques useful in today's research and in daily clinical practice. These advanced techniques are utilized in the detection of different cardiac pathologies in patients, in contributing to their clinical decision, as well as follow-up and outcome predictions. In addition to the advanced techniques covered, this book expounds upon several special pathologies with respect to the functions of echocardiography

Partitioned Solution of Geometrical Multiscale Problems for the Cardiovascular System:Models, Algorithms, and Applications

The aim of this work is the development of a geometrical multiscale framework for the simulation of the human cardiovascular system under either physiological or pathological conditions. More precisely, we devise numerical algorithms for the partitioned solution of geometrical multiscale problems made of different heterogeneous compartments that are implicitly coupled with each others. The driving motivation is the awareness that cardiovascular dynamics are governed by the global interplay between the compartments in the network. Thus, numerical simulations of stand-alone local components of the circulatory system cannot always predict effectively the physiological or pathological states of the patients, since they do not account for the interaction with the missing elements in the network. As a matter of fact, the geometrical multiscale method provides an automatic way to determine the boundary (more precisely, the interface) data for the specific problem of interest in absence of clinical measures and it also offers a platform where to study the interaction between local changes (due, for instance, to pathologies or surgical interventions) and the global systemic dynamics. To set up the framework an abstract setting is devised; the local specific mathematical equations (partial differential equations, differential algebraic equations, etc.) and the numerical approximation (finite elements, finite differences, etc.) of the heterogeneous compartments are hidden behind generic operators. Consequently, the resulting global interface problem is formulated and solved in a completely transparent way. The coupling between models of different dimensional scale (three-dimensional, one-dimensional, etc.) and type (Navier-Stokes, fluid-structure interaction, etc.) is addressed writing the interface equations in terms of scalar quantities, i.e., area, flow rate, and mean (total) normal stress. In the resulting flexible framework the heterogeneous models are treated as black boxes, each one equipped with a specific number of compatible interfaces such that (i) the arrangement of the compartments in the network can be easily manipulated, thus allowing a high level of customization in the design and optimization of the global geometrical multiscale model, (ii) the parallelization of the solution of the different compartments is straightforward, leading to the opportunity to make use of the latest high-performance computing facilities, and (iii) new models can be easily added and connected to the existing ones. The methodology and the algorithms devised throughout the work are tested over several applications, ranging from simple benchmark examples to more complex cardiovascular networks. In addition, two real clinical problems are addressed: the simulation of a patient-specific left ventricle affected by myocardial infarction and the study of the optimal position for the anastomosis of a left ventricle assist device cannula

The Effects of Adult Progenitor Cell Transplantation on Recipient Cardiomyocyte Excitation-Contraction Coupling

Cell transplantation is a promising strategy for treating heart failure but the mechanisms effecting functional improvements remain unknown. The hypothesis that cell transplantation influences the contractile properties and excitation-contraction (EC) coupling of recipient cardiomyocytes by paracrine mechanisms was tested. Adult rats underwent myocardial infarction and subsequently developed chronic heart failure. They then received intra-myocardial injections of either skeletal myoblasts or bone marrow mononuclear cells which were harvested from transgenic rats constitutively expressing green fluorescent protein. Four weeks after injection, both cell types increased ejection fraction and reduced cardiomyocyte size. Isolated cardiomyocytes emitted low levels of green fluorescence, indicating that they originated from the recipient heart. The cardiomyocytes were then studied using sarcomere length measurements, indo-1 fluorescence and whole-cell patch-clamping techniques. Injection of either bone marrow cells or skeletal myoblasts normalized the impaired contractile performance and the prolonged time-to-peak of the Ca2+ transients that were observed in failing cardiomyocytes. The smaller and slower L-type Ca2+ current observed in heart failure returned to normal values after skeletal myoblast, but not bone marrow mononuclear cell, transplantation. Analysis of Ca2+ sparks in isolated cardiomyocytes using confocal microscopy revealed that SR Ca2+ leak had increased in failing cardiomyocytes, but was normalized by skeletal myoblast transplantation. In order to test the hypothesis that these effects observed in vivo are mediated by paracrine substances secreted from the transplanted cells further experiments were performed. Cardiomyocytes were isolated from failing hearts and cultured for 48 hours. Co-culturing with either skeletal myoblasts or bone marrow mononuclear cells during this period improved cardiomyocyte contraction and Ca2+ handling. This effect was maintained even when the different cell populations were mechanically separated by means of a porous membrane, demonstrating that cell-to-cell contact was not required and that soluble substances mediated the effect. Analysis of the supernates obtained from these co-culture experiments identified four candidate substances as possible mediators, but confirmation of their importance requires further experimental investigation. In addition to the work described above, experiments were performed during the preparation of the whole-cell patch-clamping system. The system was tested by measuring the Na+/Ca2+ exchanger current densities in cardiomyocytes isolated from normal rat hearts. Using this system the acute effects of various -adrenergic agonists was assessed. The results obtained from this separate study are presented in Chapter 6

Incremental value of advanced cardiac imaging modalities for diagnosis and patient management : focus on real-time three-dimensional echocardiography and magnetic resonance imaging

Advanced cardiac imaging modalities play a crucial role in the diagnostic process and clinical management of patients with different cardiac diseases, including heart failure, valvular heart disease, myocardial infarction and atrial fibrillation. RT3DE has made an important transition from a research tool to a clinically applicable imaging technique and has been demonstrated to provide important advantages over conventional 2D echocardiography, such as a more accurate quantification of cardiac chamber size and function and the possibility of unlimited image plane orientations for better understanding of valvular heart diseases. Contrast-enhanced echocardiography should be performed in every patient with suboptimal acoustic window, especially with RT3DE. Importantly, in patients underwent primary percutaneous coronary intervention, perfusion analysis can provide an accurate estimate of myocardial infarction size, which is crucial information for the patient management, together with more sophisticated assessment of LV mechanics. Myocardial deformation imaging has witnessed an enormous development in the last years and is now considered an accurate tool for a more sensitive assessment of LV regional and global function and for a more detailed assessment of LV mechanics and dyssynchrony. CMR represents the reference imaging modality for the quantification of LV volumes and function and for the identification of myocardial scar/fibrosis. It should be therefore considered for a comprehensive evaluation of heart failure patients, including more novel and sophisticated assessments of transvalvular flow and LV dyssynchrony. Advanced cardiac imaging modalities can be applied in heart failure patients referred for CRT to explore novel physiopathological aspects, such as the effect on LV rotation mechanics, on functional mitral regurgitation and cerebral blood flow.Philips Healthcare, Meda Pharma, Boehringer Ingelheim, Roche, Servier, Biotronik, Boston Scientific Nederland BV and ServierUBL - phd migration 201

Heart failure syndrome and predicting response to cardiac resynchronisation therapy.

Heart failure results from the heart pumping insufficient quantities of blood to meet the body’s metabolic requirements. This condition affects around 600,000 people in the United Kingdom and carries with it a significant morbidity and mortality. Patients typically complain of reduced exercise capacity and a poor quality of life. Whilst there are various pharmaceutical options available to clinicians, none directly augment cardiac function. Cardiac resynchronisation therapy (CRT) is proven to reverse the progression of left ventricular systolic dysfunction, the most common cause of heart failure. The device resynchronises inefficient cardiac function, reducing symptoms and improving stroke volume and life expectancy. However, only two thirds of patients typically derive benefit from this pacemaker, it being unclear why. Finding a sensitive and specific predictor of response would be invaluable, preventing potential harm to patients, reducing waste and targeting the patient groups who will derive benefit. In this body of work, the heart failure syndrome is delineated; the evidence underpinning CRT discussed and the difficulties in defining response outlined. There are 2 main research themes in this body of work, measuring and predicting response to CRT. In the former, the role of patient specific three-­‐dimensional computational models and biophysical properties are investigated, and, in the latter, the influence of CRT on the heart failure syndrome using biomarkers. It is concluded that CRT response can be predicted using patient specific computational models of the left ventricle, but they are too complex for routine clinical use. Biophysical markers have more merit in the immediate future, being simper and quicker, with measures of endothelial and skeletal muscle function, demonstrating promise in a small cohort of patients. Finally, there exists a significant level of undiagnosed pathology in this patient group, such as hyperuricaemia and hyperparathyroidism, but it remains unclear what impact CRT has on this comorbidity