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Heart Researcher Will Use Mass Spec to Hunt Protein Signatures in Sudden Death Syndrome

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Antonio
López-Farré
Head, cardiovascular research unit
Hospital Universitario Clínico San Carlos
Name: Antonio López-Farré
 
Position: Head of the cardiovascular research unit and coordinator of research of the Hospital Universitario Clínico San Carlos, Madrid; associate professor, medicine, Complutense University, Madrid
 
Background: PhD, biological sciences, Universidad Autónoma de Madrid
 
Last month, a symposium was held in Madrid, Spain, focusing on the molecular analysis of sudden death syndrome in soccer players after reports surfaced in the media of several young men dying suddenly while participating in sporting events.
 
Sudden cardiac death syndrome, sometimes called Long QT Syndrome, is a disorder affecting the heart’s electrical system. Specifically, the ailment affects the length of time it takes for the electrical system to recharge after a heartbeat.
 
Those who need longer recharging times are vulnerable to a very fast, abnormal heart rhythm, which inhibits the amount of blood pumped from the heart, depriving the brain of oxygen, which can lead to sudden loss of consciousness and death.
 
Genetic factors are one cause of the ailment, though because they have no symptoms they make diagnosing sudden death syndrome especially challenging. One of the focuses of the Madrid meeting was to push for development of diagnostic tests for sudden death syndrome.
 
Presenting at the symposium was Antonio López-Farré, a cardiovascular research scientist at Hospital Universitario Clínico San Carlos, who is using both genomics and proteomics methods to study causes of the disease.
 
ProteoMonitor spoke with López-Farré recently about his work. Below is an edited version of the conversation.
 

 
Tell me about the work you’ve been doing.
 
We are using proteomics to detect new biomarkers [in] patients [with] acute coronary syndrome to treat and [better understand] the molecular mechanisms involved in acute coronary syndrome.
 
We recently published a paper in the [Journal of the American College of Cardiology] showing that in acute coronary syndrome, there are some proteins that are missing during the acute phase of the coronary event, such as alpha1-antitrypsin … and we also saw differences in patients during acute myocardial infarction and patients with unstable angina [who showed higher levels] in the plasma of apolipoprotein A, which is not shown in the patients with acute myocardial infarction.
 
The focus of our research was to detect biomarkers in patients who are resistant to aspirin treatment. In this way, all the patients, after a coronary event, must be treated with aspirin, but about 20 percent of them are resistant to aspirin treatment. The consequence of resistance is the patient may have a new coronary event. From a clinical point of view, it is very important but very difficult to detect such types of patients and we are looking for biomarkers in plasma and in platelets that may allow us to detect them.
 
Recently, we published [an article] in the Journal of Proteome Research [showing] that the patients with coronary infarction and with resistance to aspirin have in their plasma high levels of a protein [named] DBP [or vitamin D binding protein]. Nobody has found previously that this protein may interfere with the anti-platelet effect of aspirin.
 
We observed that patients with higher levels of DBP are resistant to aspirin. We have [also] performed new experiments showing that DBP blocks the ability of aspirin to inhibit thromboxane A2 production by platelets. Taken together, DBP may influence the ability of aspirin to prevent thromboxane A2 production by platelets and this may be a new mechanism to explain aspirin resistance.
 
And now we are performing experiments analyzing whether aspirin-resistance syndrome is not only for aspirin [but] also for other antithrombotic agents and antithrombotic drugs, and in this way, we are looking for differences in protein content in the platelets between the patients [who are] not resistant to aspirin and [those] who are resistant to aspirin treatment.
 
How does this tie in with what you’re doing with sudden death syndrome?
 
We are [currently] performing genetic experiments, not proteomic experiments on sudden death syndrome. … We are performing genetic analysis of [players from] football clubs here in Spain in the first league division of soccer.
 
And in the next year, we are performing new protocols to try to detect differences in proteomics for people at high risk for sudden death syndrome and patients with no risk. We are preparing new protocols to detect in plasma some proteins and in blood cells such as leukocytes. Sudden death is many times provoked by a defect in genes and in proteins involved in ion channels … and we are thinking [that] leukocytes or platelets might be targets [for detecting] sudden death syndrome. Maybe we can perform new research, but actually [at the moment] it’s only an idea.
 
Do you suspect the biomarkers for sudden death syndrome will be very similar to the biomarkers you’re finding so far for myocardial infarction and ischemia?
 
It is difficult to say because sudden death syndrome is very specific to the myocardiocytes while in acute coronary syndrome, other cells — platelets and leukocytes — are involved. It is difficult for the early detection of sudden death, particularly in apparently healthy individuals. Currently, the classical cardiological clinical test to detect patients with cardiological pathologies associated with sudden death is by genetic study.
 
The problem is that in many cases, the morphological changes in the myocardium cannot be detected by the electrocardiogram or by the echocardiogram. The only way to detect disease associated with sudden death such as long QT, short QT, right ventricular arrhythmogenic dysplasia, Brugada syndrome, and hypertrophy myocardiopathy is by genetic study.
 
If you’re saying that sudden death syndrome is primarily a genetic disease, what role would proteomics have in expanding our understanding it?
 
That is difficult to answer. Maybe in a specific pathology such as right ventricular arrhythmogenic dysplasia — in which specific areas with the right and in some cases also in the left ventricle myocardiocytes are substituted by fibro-fatty tissue [and] it is not well known the genesis of this substitution — proteomics may be a useful tool to know more in-depth such pathology associated with sudden death.
 
[With] proteomics we can detect changes in specific proteins. After that, we can develop a specific kit to analyze only these proteins … by antibodies or any other way … but we have to develop more pathways or mechanisms to detect the proteins.
 
[We may develop] an ELISA or a western blot … maybe a blood-based test.
 
What kind of interest have you received from the sporting world for your work?
 
The sporting world is a very interesting field [for such a test], not only for professional [athletes] but also the people who play sports [casually]. It would be interesting to know if they are at risk for sudden death syndrome or any other cardiologic pathology.
 
In this way the [control group of patients] is very important and probably preferred [to be those] at a young age. It is not well-known — the pathologies and molecular mechanisms involved in all these cardiologic pathologies.
 
For this it’s very important … to use new technologies like proteomics and also genetics to [learn] more about that.
 
Have any sporting organizations, for example the Fédération Internationale de Football Association [FIFA] expressed any interest in what you’re doing?
 
We are now performing genetic analysis [on players with] Atlético de Madrid, a very important football club in Spain. … Other organizations like FIFA could be interested in it.
 
Has FIFA contacted you about what you’re doing?
 
We have not been contacted about that …but maybe in the future, we will. We are [studying players from] two football clubs here in Spain.

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