Cardiovascular diseases are the most common cause of death and disability in the developed world, costing millions of dollars annually.
Reducing the incidence of cardiovascular disease can be attained by identifying and educating people at risk. However, new modalities such as individually tailored drugs, devices and ultimately gene therapy are needed to really make a major difference.
The rapid advances in understanding the basic mechanisms responsible for normal function of the cardiovascular system have provided a multiple-facetted approach to study the pathophysiology of cardiovascular disease. Nevertheless, much remains to be done.

Rationale

The tools of the modern researcher are remarkable. Success in today's research environment therefore requires an entirely new system of interactions between biomedical scientists, bringing together skills and talent of many investigators in order to find answers to ever more complex questions.
The human genome project has ushered in a new era in medical research. By understanding the genetic basis of a disease, which is responsible for its aberrant biochemical pathways and mechanisms, one can predict what protein it produces and try to develop a drug that will block it. Genetic diagnosis will ideally help to tailor regimens for each patient individually, taking into consideration age, sex and race.

Molecular and genetic approaches allow us to more deeply understand the cellular functions of e.g., cardiac myocytes, smooth muscle cells, or endothelial cells, thereby revealing their modes of intercellular signaling. This in turn provides us with the means to develop treatments that are targeted directly to the diseased area. On the other hand, the discovery of a growing number of DNA-polymorphisms in the human genome that can directly be connected to a higher risk of developing cardiovascular diseases, provides the means to identify patients at much earlier stages and under more benign conditions when drug therapy presents fewer risks than surgery.

A: Molecular Cardiac Research Facility
B: Physiology-Cardiac Research Facility
C: Interventional Cardiology Research Facility
D: Echocardiography Research Facility
E: Clinical Cardiac Research Facility

Research Program

We plan to develop a state-of-the-art research program in the Molecular Cardiac Research Facility that will include an inter-disciplinary approach to the understanding of cardiovascular disorders on the molecular level focusing on the genetics of cardiovascular disease, molecular pharmacology and ischemic injury. Some examples of research projects that will be carried out include the following:

1. Angiogenesis, the process by which new blood vessels grow, is crucial in the treatment of cardiovascular disease. In order to understand what makes blood vessels grow where needed and how tissues "know" the number of blood vessels required, genes involved in the regulation of vessel growth and blood flow will have to be manipulated. Results may lead to treatments by which blood flow can be controlled, or by which blood clots can be circumvented by growing new vessels.

2. A major challenge is the delivery of drugs directly to the injured area. Many different methods have been attempted, such as lipid-encoated molecules. We propose a gene therapy approach using a unique DNA-vector, which has shown to be very promising. SV40, a DNA-virus can be used to deliver and express foreign genes, its host range is very wide and it has never been shown to have any side effects in humans. The cDNAs coding for a number of cytokines, growth factors etc. can be packaged in vitro (in the test tube), into recombinant SV40 particles and be delivered to the site of injury where they will be expressed.

3. Many drugs administered for the treatment of non-vascular related diseases may have side effects leading to cardiac dysfunction. A prominent example is Herceptin, given to women with Her-2/neu positive breast cancer. Although this drug has been shown to substantially prolong the lives of affected women, cardiac dysfunction was diagnosed in up to 27% of patients. We intend to study the action of Herceptin on the heart in order to understand its mechanism. Results should help to improve currently used protocols for treatment of women with this highly malignant form of breast cancer.

4. The population of Israel consists of a number of different subpopulations, some of which have immigrated only recently (e.g., Ethiopians), or have not inter-married (e.g. Arabs). This unique situation allows an analysis of genetic risk factors to be made for each ethnic group, giving a molecular profile of the entire Israeli community. Results from a genetic study will subsequently enable the early identification of high-risk groups to either prevent the development of cardiovascular disease or ensure its treatment at a very early stage.

5. The natriuretic peptides, e.g. atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are secreted by the heart and act as hormones causing vasodilatation, diuresis and natriuresis. Comparing the actions of different natriuretic peptides (ANP, BNP, CNP, DNP) on cultured cardiac myocytes and further defining their influence on apoptosis will be studied. The mechanism on the molecular level will be analyzed by studying the different effects of these peptides on gene expression in myocytes from neonatal and adult animals.
This project will be carried out in collaboration with the Physiology-Cardiac Research Facility.

6. Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Neoangenesis within the infarcted tissue is an integral component of the remodeling process, however, the capillary network is unable to support the greater demands of the hypertrophied myocardium. Bone marrow (BM) cells are a natural source of multiple factors involved in angiogenesis e.g., fibroblast growth factors1, 2 and VEGF. Dr. Shmuel Fuchs (who will soon join the Department) has already shown that BM, when injected transendocardialy, can augment collateral perfusion and myocardial function in ischemic myocardium. He will continue his work by studying the effect of BM injection in an animal model of experimental myocardial ischemia. In addition, the use of BM for the delivery of therapeutic genes (gene-therapy) will be studied.

Research Program

In the Physiology-Cardiac Research Facility, we intend to concentrate on the study of physiological changes in response to cardiac insults, vascular injury and micro-environmental effects. Some of the projects will be carried out in collaboration with the Molecular Cardiac Research Facility.

1. The timing of surgery in patients with chronic mitral regurgitation is problematic. Although the ventricle seems to contract extremely well as tested by echocardiograms, an examination of single cells from these ventricles (by force-frequency relationships) show that the cells are phenotypically failing. We will study the events taking place over time, and try to find a non-invasive marker of impending failure for affected
patients by analyzing changes in:

a. Function (whole ventricle by end-systolic pressure-volume relationship, echocardiography),
b. Tissue composition (apoptosis, intracellular signaling mechanisms, extra cellular matrix and MMPs), and

c. The general "milieu," involving the activation of "inflammatory" factors (TNF, IL-6) and neuro-humoral factors (BNP, Angiotensin, ET-1, etc.).

3. The experiments connected with all the physiological aspects of the Clinical Cardiac Research Facility, described in the molecular section, will be carried out by concentrating on the comparison of the effects of the natriuretic peptides and endothelin on myocytes from the left and the right ventricle. The current hypothesis is that the better compliance of the right ventricle is, at least partially, due to a higher natriuretic peptide effect (peptide content, receptor density and/or post-receptoral factors). These aspects will be tested.

Research Program

We plan to place major emphasis in the Interventional Cardiology Research Facility on discovering innovative ways for preventing vascular injury and restenosis post-percutaneous coronary intervention. Priority will be given to projects that may help to improve the clinical outcome after intervention.

1. Coronary restenosis post-percutaneous coronary intervention is still a major problem for which no definitive answers have yet been found. We are planning to combine two facts, namely that:

a. Nitric oxide (NO) plays a critical role in the maintenance of vascular homeostasis and is depleted after coronary angioplasty and ensuing endothelial denudation, and
b. Anti-oxidants have been shown to be vital in the preservation of endothelium-dependent functions, being beneficial for cell proliferation and arterial remodeling. A unique approach of combining anti-oxidants and NO-donors to partially restore endothelial function after vascular injury will be investigated.

2. Vascular damage and the resulting healing processes play a major role in the pathogenesis of coronary atheroscelerosis and vascular healing after coronary intervention. The study of the inflammatory response post-vascular surgery and the possible value of immunomodulation for the prevention of its sequela will be studied

3. Prevention or reduction of restenosis may be achieved by coating stents with different molecules such as polymers. In collaboration with Prof. S. Ben-Sasson of the Hebrew University we will test a coating system in a rat model. The polymers to be tested bind to FGFR instead of Heparin leading to a inhibition of smooth muscle proliferation by preventing auto-phosphorylation. Results of these studies should provide insights on the possible use of these stents in clinical trials. These will be carried out in collaboration with the Clinical Cardiac Research Facility.

Research Program

Echocardiography (cardiac ultrasound) is to date the most important tool for assessing cardiac structure, anatomy and function. Its value consists not only in the information and understanding gained, but especially in its non-invasive nature. In the Echocardiography Research Facility we will use the most advanced equipment, incorporating cutting-edge technology, to address a number of scientific topics. We will study the mechanisms of myocardial and valvular dysfunction in acquired and congenital heart disease in both adult and pediatric patients. Special emphasis will be placed on the study of genetic diseases and cardiac abnormalities in special populations.

1. Echocardiography, due to its non-invasive character, is especially suited for elderly individuals. We will study the characteristics of heart failure in this growing group of patients in order to improve early diagnosis and evaluate the impact of therapy on the quality of life.

2. Patients with amyloid heart disease frequently experience renal failure. The comparison of heart rate variability and myocardial echoradiographic parameters in patients with and without renal failure will help in developing an improved treatment for affected patients.

3. Echocardiography will be used as a non-invasive means to assess atrial and ventricular electromechanical coupling and atrioventricular time intervals.

4. Fetal echocardiography is one of the most important means for determining fetal heart disease. We will concentrate, e.g., on improving the application by optimizing the fetal kinetocardiogram.

5. Pre-natal counseling has reduced the incidence of patients with thalassemia, nevertheless children suffering from this hematologic disease are still being born, although in low numbers. We plan to evaluate left ventricular function using echocardiography as a predictor of survival in thalassemic patients.

6. Echocardiography is today one of the most important tools to assess the success of treatments in experimentally induced heart disease in animal models.

Research Program

In the Clinical Cardiac Research Facility, major emphasis will be placed on the prevention, prognosis and treatment of patients.
1. We will primarily be involved in initiating clinical studies in the intensive care units. Innovative approaches will be used for the assessment and evaluation of patients with acute cardiac symptoms, their prognosis and long-term follow-up.
2. We will initiate the establishment of a computerized database to assess the risk factors in women with coronary artery disease as a means to optimize primary and secondary prevention programs.
3. We will participate in contracted clinical studies, with the major aim of testing new drugs and their long-term effects.
4. An additional range of services will be introduced, comprising early clinical research with fully monitored beds (phase I and IIa), through participation in late-phase (IIb-IV) clinical research as a site coordination and monitoring facility.