Lipids and heart attacks

For the past five years, UCL professors Sandrine Horman and Christophe Beauloye have been studying one of the major players in thrombosis: blood platelets. Under certain conditions, they can become ‘hyper’ reactive and more easily form clots that clog our arteries. The professors’ recent publication in the prestigious journal Blood highlights the key role of lipids in the deregulation of our platelets, a major discovery that could ultimately help identify and treat patients at higher risk of heart attack.

Each year 15,000 people die of cardiovascular events. The cause is often arterial thrombosis. ‘It can lead to myocardial infarction’, explains Sandrine Horman, an FNRS professor and researcher at the UCL Institute of Experimental and Clinical Research (IREC). ‘Thrombosis is a blood clot that develops in a vessel. When such a clot occurs in one of the coronary arteries, it prevents the arrival of blood in an area of the heart, which can be critical for its proper functioning. These arteries supply the heart with oxygen and nutrients. However, when part of the heart is cut off from what feeds it, it eventually dies, causing a heart attack.’

Research conducted by IREC’s Cardiovascular Research Center (CARD) targets cell metabolism, that is, how cells use and synthesise energy substrates to live and function. More specifically, for many years the laboratory has been one of the few research groups in the world specialised in studying cell and heart muscle metabolism. But Prof. Horman’s group has become interested in the perpetrators of arterial thrombosis: platelets circulating in our blood.

Studying heart attacks from another perspective

‘Only a handful of research groups are currently studying platelet metabolism’, Prof. Horman says. Platelets play a major role in heart disease. Moreover, the main clinical treatments are antiplatelet treatments. Aspirin or Clopidogrel (also known as Plavix), for example, are such treatments. They seek to prevent the formation of clots that create the ‘clogged vessel’, by targeting the platelets that aggregate (stick to each other) and trigger thrombosis, causing a potentially fatal heart attack. To prevent it, platelet aggregation must be inhibited.

‘The problem is that not all patients are the same when it comes to treatment’, Prof. Horman explains. ‘In addition, some are at greater risk than others of having a heart attack because their platelets work differently.’ With Prof. Beauloye, Prof. Horman directed the research of three young PhD students: Sophie Lepropre, Shakeel Kautbally and Marie Octave. The objective was to identify the factors responsible for the change in platelets that makes them react differently.

An enzyme involved in platelet aggregation

‘We wanted to target the enemy rather than focus on the victim’, Prof. Horman says. The enemy is the triggering of platelet aggregation, in which lipids are of major importance. ‘They play an important role in platelet structure, but that’s not all: they also feed them and control their function.’

This is where the IREC researchers’ discovery comes in. In their work, they focused on lipids within the platelet. Their main conclusion is that platelets are able to synthesise lipids. ‘Platelets are lipogenic’, Prof. Horman says.

They then sought to modulate an enzyme that allows platelets to synthesise lipids. ‘We have shown that if we modify this enzyme’s activity, we can modify platelet lipid content. More than 800 lipids in the platelet have been screened in order to identify those that play a key role in controlling its function.’

Interestingly, not all lipids are affected in the same way: it’s mainly those that promote arterial thrombosis that are produced when this enzyme is active. “This is the central discovery of our work: when the activity of this enzyme, Acetyl-CoA Carboxylase or ACC, is changed, platelet lipids are modified, promoting activation of platelets and consequently thrombosis”.

Marie Dumas

Interview

Sandrine Horman is a professor and FNRS research associate at UCL. She works at IREC’s CARD, a laboratory in which she co-directed the research that led to publication in Blood.

What are the prospects for the CARD laboratory’s work?
The long-term prospects are clear: “we want to apply these results in hospital. Of course, we conduct fundamental research. But we must make the link between what we discover in the laboratory and what we can apply to the patient”. This link is made thanks to Professor Christophe Beauloye, who, in addition to being a UCL professor of cardiovascular physiology, is also a clinical cardiologist. For two years now, he has been head of the Cardiology Department at Saint-Luc University Hospital. He still devotes a lot of his time to research, as evidenced by this discovery. “It’s he who allows us to easily make this obvious link with the hospital”.

More directly, what are the next steps of your research?

We recently analysed the platelets of patients at risk of thrombosis or at risk of heart attack, and they have modified ACC and lipid metabolism. Our future research will focus on this pathway of control of lipid metabolism, firstly for therapeutic purposes, in order to evaluate whether, by targeting this enzyme, certain treatments may have an influence on the activity of platelets and therefore the risk of clot formation, and secondly for diagnostic purposes, to find new biomarkers capable of identifying patients at risk of thrombosis and heart attack. One of the objectives will be to study whether these platelets with modified metabolism release easily detectable markers in the blood. The measurement of this (these) blood biomarker(s) would help identify patients at risk and administer the appropriate treatment, to prevent the occurrence of myocardial infarction and reduce mortality.

A glance at Sandrine Horman's bio

1992, begins university study in biological sciences, Université Libre de Bruxelles (ULB)
1994, Bachelor’s Degree in Biological Sciences, ULB
1994–99, PhD in Biological Sciences, Cytology and Experimental Oncology Laboratory (Prof. P. Galand), ULB
2000–07, Postdoctoral Researcher, Hormones and Metabolism Unit (HORM, Prof. L. Hue), de Duve Institute, UCL
2007, FNRS Research Associate, Cardiovascular Research Center, Institute of Experimental and Clinical Research (IREC), UCL
2012, Part-time Associate Professor, UCL
2016, Professor, UCL

A glance at Christophe Beauloye's bio

1992, begins university study in medicine, Faculté universitaire Notre Dame de la Paix, Namur
1996, PhD in Surgical Medicine and Childbirth, UCL
1996 –2004, Assistant Physician Candidate Specialising in Internal Medicine and Cardiology
1998–2002, FNRS Candidate, PhD in Biomedical Sciences, Hormones and Metabolism Unit (HORM, Prof. L. Hue), de Duve Institute, UCL
2004, DES (a post-graduate degree) in Cardiology, UCL
2004–05, DES in Intensive Care, UCL
2005–06, Fellowship, Interventional Cardiology, OLVZ, Aalst
2006, Deputy Head of Clinic, Cardiology Department, Saint-Luc University Hospital
2009, Clinical Associate Professor, UCL
2014, Clinical Professor, UCL
2010–17, FNRS Postdoctoral Research Clinician, Cardiovascular Research Center, Institute of Experimental and Clinical Research (IREC), UCL
2016, Head of Cardiology Department, Saint-Luc University Hospital