Research Topics

Exploring platelet signalling and metabolism to identify new predictive markers of arterial thrombosis

The major physiological role of platelets is to ensure integrity of vessels, primary hemostasis and coagulation. Platelet activation and aggregation are also involved in pathological processes like arterial thrombosis, fearsome complication of atherosclerosis, which can lead to coronary occlusion and myocardial infarction. Cardiovascular diseases have become the leading cause of death in industrialized countries and are therefore a key public health issue.

Research in our group aims at identifying new molecular mechanisms responsible for controlling platelet function and metabolism. The experimental approach is based on preparation and ex vivo treatment of human platelets taken from healthy volunteers, or platelets from mice, the latter providing genetic evidences through the use of transgenic models. The mixed basic/clinical nature of our team also highlights a translational approach that supports experimental data obtained in the lab by clinical evidences obtained in the patient.

In addition to measurement of platelet aggregation, our experimental approach involves the use of various biochemical and molecular biology techniques (expression and phosphorylation of proteins, enzymatic assays, evaluation of metabolic processes, FACS, PCR and qRT-PCR, microarray analysis), microscopy (thrombus analysis through intravital microscopy) and physiology (animal model of atherothrombosis).

Cardiac fibroblasts as a target to limit ventricular remodelling and heart failure

The various phenotypic changes that accompany the left ventricular (LV) response to myocardial infarction are a phenomenon referred to as LV remodelling. Remodelling is supported by progressive cellular and molecular changes, eventually resulting in altered myocardial functional properties and heart failure. Our laboratory is particularly interested in the role of cardiac fibroblasts in this adverse process. We aim at further substantiating their role in the pathogenesis of LV remodelling and more particularly at identifying new potential intracellular therapeutic targets. These aims are carried out through the use of human cardiac fibroblasts in culture, mouse models of myocardial infarction or hypertrophy as well as human models of LV remodelling.

The experimental approach involves various techniques of biochemistry, cellular and molecular biology (cell culture, expression and phosphorylation of proteins, enzyme assays, FACS, immunohistology immunocytology, PCR and qRT-PCR, microarray analysis).

Targeting AMPK to prevent lethal complications during sepsis

The barrier function of endothelium derives from the integrity of the endothelial structure that is provided by membrane intercellular junctions connected to the actin cytoskeleton and cell attachment to extracellular matrix and basement membrane. An alteration of these junctions and/or of the cytoskeleton organization/contraction promotes vascular hyper-permeability to fluid and solutes and can contribute significantly to the damage associated with a variety of pathological states such as sepsis. Sepsis is characterized by a systemic inflammatory response that occurs during severe infection. Increased microcirculatory permeability is a major complication in sepsis and contributes to end-organ dysfunction. Enhanced permeability can induce tissue oedema, impairing organ function by increasing the distance required for the diffusion of oxygen and by compromising microvascular perfusion because of increased interstitial pressure. From the above, the pivotal role of the microvascular barrier as a therapeutic target in sepsis seems obvious. A better understanding of the molecular basis of endothelial barrier function might lead to new molecular targets for therapies. The project, focused on the AMPK pathway, aims to evaluate how the modulation of endothelial permeabilty can affect the cardiovascular pathophysiology. Its feasibility is supported by the availability of key cellular and mouse models, pharmacological reagents, as well as characterized cohorts of patients.

Valvular Heart Disease

Valvular Heart Disease are becoming more and more frequent in developed countries.

Our hospital benefits from a top level valve surgery and we developed a valvular heart clinic to follow patients with various valve disease.

We follow outcomes of patients with valve disease before and after surgery in a prospective registry (SALVARE) and study predictors of natural history and postoperative outcome. Also are particularly interested in cardiac imaging, by echocardiography, cardiac MR and cardiac CT to better characterize the pathophysiology of valvular heart disease and to study predictors of outcome

Aortic Stenosis

Aortic stenosis is the most common acquired heart disease. It is mainly degenerative and affects elderly patients due to calcareous invasion of the aortic valve leaflets. In calcific aortic stenosis, the valve cusps become gradually thickened and fibrosed, with calcified lesions.

increasing valve rigidity, decreasing cusp excursion, and gradually causing valve-orifice narrowing and obstruction to the ejection of blood from the left ventricle to the aorta. This leads to rising in left ventricular systolic pressure and increase in left ventricular parietal stress, compensated by concentric myocardial hypertrophy. This condition is initially well tolerated, but when it progresses, may lead to development of angina, heart failure or sudden death. Therefore severe aortic stenosis requires replacement of the valve.

Our research focuses on studying the pathophysiology of hypertrophy and development of myocardial fibrosis by cardiac MR and pathology in calcific aortic stenosis. We also evaluated prevalence of aortic stenosis in elderly populations, and evaluated predictors of outcome and indications for surgical valve replacement in aortic stenosis. Further, we evaluated the use of new less invasive surgical techniques making use of catheter-based valve replacement (TAVR) and new techniques to resect the calcified valve.

Mitral regurgitation

Mitral regurgitation is another common valve disease. It most often results from degenerative changes to the leaflets and cordae, with development of valve prolapse due to leaflet elongation and rupture of cordae. It leads to reflow of blood from the left ventricle to the left atria, causing volume and pressure overload in the pulmonary circulation. Our surgical team is expert in repair of mitral valve regurgitation and developed minimal invasive robotic techniques for valve repair (Da Vinci).

Our research focusses on defining optimal indications for valve repair by studying natural history and postoperative outcome of patients undergoing mitral regurgitation in a multicenter registry (Mitral Regurgitation International Database).

Aortic regurgitation

In aortic regurgitation, blood flows back from the aorta to the leaking valve to the left ventricle. It is often caused by dilatation of the aortic root or by prolapse of dysfunctional (bicuspid) valves. Our center has leadership in surgical repair of aortic regurgitation.

Our research focusses on improving surgical repair techniques, on predicting outcomes and failures in this novel type of surgery. Furthermore we also study left ventricular remodeling and fibrosis development in this disease.

Cardiac Imaging

Cardiac Imaging is one of the keystones of the CARD unit.

It is a translational technique, which we use both for clinical imaging to characterize the patholphysiology of human pathology, but also in basic research to exlore the phenotypic expression of knock-out gene models of human disease.

Our group is particularly expert in multimodality cardiac imaging. Indeed we use all types of cardiac imaging and performed many cross-modality studies employing different imaging modalities.

Cardiac Imaging modalities

Echocardiography

• Cardiac MRI More info

• Nuclear Imaging
• Positron Emission Tomography
• Cardiac CT