In this cluster our research activities have focussed on
- Improvement of left ventricular (LV) pump function in patients with heart failure
- Stem cell therapy in patients with untractable ischemia, in patients with heart failure and in mice with (sub)acute myocardial infarction
- Surgical treatment of heart failure
- Predisposition of cardiac disease in rats that were treated with glucocorticosteroids in the neonatal stage
- The effects of cardiomyocyte stretch on gene expression, cellular signal transduction and cellular function
Improvement of left ventricular (LV) pump function: Cardiac resynchronization therapy
In patients with heart failure, LV dilatation is often accompanied by conduction delays that lead to asynchronous contraction of LV segments and inefficient pump performance. Resynchronization therapy using a biventricular pacemaker (BVP) with a RV apical pacing electrode and a LV lateral pacing electrode results in rapid improvement of LV pump function. Our research with patients with heart failure who had a BVP implanted aims at
- finding selection criteria for identifying patients that will benefit from this therapy
- assessing echocardiographic parameters to quantify improvement of synchronized LV contraction
- assessing pacemaker parameters including AV and VV timing to quantify improvement of synchronized LV contraction
- evaluating long-term hemodynamic effects by pressure-volume loops
- finding criteria for simultaneous implantation of a defibrillator device (ICD)
- measurement of plasma markers (ANP, BNP) of LV overload
- finding plasma markers of ventricular remodeling and reverse remodeling, and
- detecting improvement of heart rate variability.
Surgical treatment of heart failure
In collaboration with the Department of Thoracic Surgery we contribute to the ACORN CorCap trial, an international, multi-center study that uses a biocompatible, mesh-like support device that opposes further dilatation of the ventricular chambers of patients with a dilated heart (left ventricular end-diastolic dimension ≥ 30 mm/m2) and NYHA functional class III-IV. Objective and subjective criteria of improvement of cardiac performance, including echocardiography, 6-min walking test and quality of life questionaire, are collected during 6 months postsurgical follow-up.
A second protocol focusses on patients with heart failure who have mitral valve regurgitation. This protocol investigates the acute and chronic effects of mitral valve repair using an undersized ring. A third protocol aims at reconstruction of a remodelled left ventricle by endoventricular circular patch plasty (DOR procedure). In this protocol improvement of left ventricular function is analysed by pressure-volume loop analysis and echocardiography.
Improvement of left ventricular (LV) pump function: Stem cell therapy
Basic stem cell research
Stem cell therapy for cardiac disease is a relatively new field of research that offers opportunities to repair damaged myocardium through the generation of new cardiomyocytes and new blood vessels. Although the concept of differentiation of stem cells into cardiomyocytes, endothelial cells and smooth muscle cells has been demonstrated, the observed efficiencies with which these processes occur are low. This hampers the successful application of stem cells for clinical therapies. Our basic stem cell research group investigates whether stem cells may be forced to differentiate towards the cardiomyocyte phenotype through the introduction of cardiogenic transcription factors by infecting the stem cells with vectors containing various transcription factors, including the human variants of Myocardin, Nkx 2.5, GATA-4, MEF2C and others. After transfection, the differentation of human bone marrow-derived mesenchymal stem cells (MSCs), peripheral blood-derived mononuclear cells, and cord blood mononuclear cells is studied by assessing the expression pattern of cardiospecific genes using RT-PCR, as well as using reporter genes assays. Immunohistochemistry is then used to study the presence and distribution of cardiospecific proteins.
In addition, a myocardial ischemia/reperfusion model in NOD/SCID mice is used to test the effects of intramyocardial injection of transfected human stem cells. In these experiments the number and state of differentiation of the embedded cells are determined. Cardiac mechanical performance is studied using a miniature pressure conductance catheter that allows real-time measurement of the pressure-volume relationship (PV-loops). Micro Magnetic Resonance Imaging (MRI) is used to serially study the anatomic and functional characteristics of infarcted mice hearts and the effect of stem cell injection on these parameters.
Clinical stem cell research
At the moment we have several clinical protocols in progress in which stem cell therapy in patients is studied. In 2003 a clinical protocol has started to test the safety and feasibility of injection of autologous bone marrow cells into the myocardium of no-option patients with ischemia upon myocardial perfusion scintigraphy. In this procedure, bone marrow is aspirated from the iliac crest in the morning. The cells are then transferred to the Stem Cell Laboratory, a GMP facility, where suitable cells are isolated in a process that takes approximately three hours. Then, the patient is transferred to the heart catheterization laboratory where the cells are injected using a special steerable injection catheter and the NOGA system, which setup allows targeted injection of the bone marrow cells into ischemic myocardium. A total of 25 patients have been treated and analysed for left ventricular function, left ventricular perfusion, and ischemic symptoms. In a second protocol, patients with refractory severe heart failure (NYHA Class III and IV) receive intramyocardial injections of bone marrow derived mononuclear cells. To date, 21 patients have been included.
A third protocol has been started to investigate –in a randomised way- stem cell therapy in no-option patients with ischemia.
Predisposition of cardiac disease in rats that were treated with glucocorticosteroids in the neonatal stage
Prematurely born babies often suffer from impaired lung function due to subnormal surfactant content. Current therapy is glucocorticosteroid treatment, but there is growing evidence that this treatment leads to cardiac disease at adult age and reduced life expectancy. The long-term negative effects include hypertension and deterioration of myocyte structure and performance. In collaboration with the Department of Neonatology of the University Medical Center Utrecht we have started a prospective study to evaluate the long-term effects of neonatal glucocorticosteroid treatment on LV function in rats. At various stages (juvenile, young adults, middle age) the effects in terms of histopathological and molecular changes of the heart, cardiac performance and hemodynamics, and changes in β-receptor responsiveness are investigated.
The effects of cardiomyocyte stretch on gene expression, cellular signal transduction and cellular function
Stretch of cardiomyocytes leads, in the acute situation to an increase of force development and, if continued, to augmented growth resulting in myocardial hypertrophy. To investigate the mechanisms that “sense” stretch and the mechanisms that convert this “sensing” into cellular signals leading to changes in gene expression and changes in function we have studied stretch-induced activation of integrins, i.e. cell membrane receptors that bind to extracellular matrix proteins. Once activated by stretch, the integrins initiate myocardial nitric oxide production that stimulates Ca2+ release from the sarcoplasmic reticulum. Elevated cellular Ca2+ and NO levels release may depress myocardial function by increased protease (calpain and matrix metalloproteinases (MMPs)) activity that causes proteolysis of cytoskeletal, contractile and ion channel proteins, as well as extracellular matrix components. Research now focusses on integrin stimulation-induced release of troponin-I from vital cardiomyocytes. In addition, in an animal model of right ventricular failure right ventricular myocardium is investigated for signalling events and activation of enzymes (e.g. MMP-2) that are responsible for right ventricular remodelling. Results obtained in this preparation will be used to find serum markers of ventricular remodeling and reverse remodeling.