Francisco Fernández-Avilés, MD, PhD, FESC, FACC - Circulation

European Perspectives
Circulation. 2009;119:f127-f132
doi: 10.1161/CIRCULATIONAHA.109.192206
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Circulation June 9, 2009
On other pages...
European Perspectives in Cardiology
Spotlight: Francisco Fernández-Avilés,
MD, PhD, FESC, FACC
Leading Translational Research With Stem Cells
to Prevent and Treat Postinfarction Heart Failure
Francisco Fernández-Avilés, chair of the Department of Cardiology,
University Hospital Gregorio Marañón, Madrid, Spain,
talks to Barry Shurlock, MA, PhD.
The Department of Cardiology at the University Hospital
Gregorio Marañón, Madrid, Spain, is the largest heart
centre in Spain, and it plays a leading role in the studies of
stem cell techniques for repairing heart tissue. Like other
cardiology departments in Spain, it sends its experienced
cardiologists to business school but still puts the patient at
the centre, according to Fernández-Avilés, MD, PhD, FESC,
FACC, chief and professor of medicine at Complutense
University, Madrid, Spain.
“I Decided to be a Doctor Before I Was 10 Years Old
Because I Had the Experience of Seeing Close Relatives
Who Were Sick”
Professor Fernández-Avilés was born in Cuenca, Spain,
about 50 miles (80 kilometres) from Madrid. Cuenca is a
small historic town that is now a World Heritage Site and a
tourist destination. His father died when he was very young,
and his mother took him to live in Madrid, which almost
makes him a “Madrileño.” He says, “I decided to be a doctor
before I was 10 years old because I had the experience of
seeing close relatives who were sick and I considered the
work of medicine to be marvellous. I was the first to go to
university. It was fantastic! I was very, very lucky.” He
studied medicine at Complutense University and the
University Hospital Gregorio Marañón.
Complutense University is widely regarded as the premier
university in Spain. First founded as a studium generale
by a Castilian monarch at the end of the 13th century (1293),
it was refounded by papal edict in the early 16th century
(papal bull 1499, opened 1509). In 1836, it moved to central
Madrid. Among its famous sons are Santiago Ramón y
Cajal, MD (1852–1934), who won a Nobel Prize in 1906 for
his work on the fine structure of the nervous system and gave
his name to Cajal cells. His name is commemorated in a city
centre hospital in Madrid. He also made many contributions
to tumour biology, although they are little known to non-
Spanish speakers. More recently, in 1959, the Nobel Prize
for Medicine was shared by the Spanish physician and biochemist
Severo Ochoa, MD (1905–1993). Ochoa studied in
Madrid and worked in several cities in Germany and the
United Kingdom before emigrating to the United States,
where he studied the enzymatic mechanisms of oxidative
metabolism and helped to unravel the biological synthesis of
RNA and DNA.
By 1990, Professor Fernández-Avilés had performed
more than 1000 angioplasties and overseen 50 cases as the
Centre of Excellence: Department of Cardiology,
University Hospital Gregorio Marañón, Madrid, Spain
Francisco Fernández-Avilés, MD, PhD, FESC, FACC, chair of the Department of Cardiology,
University Hospital Gregorio Marañón, Madrid, Spain, describes the Department and its ambitious
research programme with a budget of $6 million and major research projects on heart failure, coronary
syndromes, cardiac valve disease, cardiovascular imaging, arrhythmias, and stem cell therapy.
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Aerial view of the University Hospital Gregorio Marañón,
Madrid, Spain, where Professor Fernández-Avilés is chair of
the Department of Cardiology. The hospital is named after the
celebrated endocrinologist, Gregorio Marañón y Posadillo, MD
(1887–1960), a writer, philosopher, and brilliant all-round intellectual.
Photograph courtesy of Professor Fernández-Avilés.
coordinator of the heart transplantation programme. In that
year, at the relatively young age of 37, he was appointed to
head the Department of Cardiology at the University
Hospital, Valladolid, Spain, a city of half a million people
and about 130 miles (200 kilometres) north of the Spanish
capital. Once favoured by the Spanish court and containing
one of the houses where Cervantes, the author of Don
Quixote, lived, it is now the economic hub of its region and
a venue for a prestigious international film festival. At the
University Hospital, Valladolid, Professor Fernández-Avilés,
while running his own department, was able to spread his
wings and pursue influential studies of poststent restenosis and
postinfarct reperfusion in general. A key platform for his work
was the Institute of Heart Sciences [Instituto de Ciencias del
Corazon] at Valladolid, which he created in 1998 and directed
until 2006 when he took up his present appointments in
Madrid. He has 160 articles in peer-reviewed journals and,
from a long list of prizes, is particularly proud of the Order of
Merit in Civil Health [Orden del Mérito Civil en Sanidad], the
highest award of its kind in Spain, presented to him in 2004 by
the Spanish Minister of Health.
“Every Year in the Last 5 Years, We Have Sent About
12 to 15 Cardiologists Around the Age of 40 to the
Escuela Superior de Administración y Dirección de
Empresas Business School in Madrid”
In the early 1990s, Professor Fernández-Avilés started to win
awards at the annual meetings of the Spanish Society of
Cardiology—for example, “Best Abstract of the Year,”
“Young Investigator Award,” and “Best Original Article” in
the prestigious Revista Española de Cardiologia, the official
Spanish Society of Cardiology journal, of which he was
editor-in-chief for 6 years (from 1991 to 1997).
In 1993, he made an unusual choice for a cardiologist—for
1 week every month, he flew off to Barcelona to attend courses
at the Escuela de Alta Dirección y Administración Business
School to obtain a diploma in the Direction and Management
of Medical Departments. He comments, “I needed it! Now
the Novartis Cardiovascular Institute and the Foundation
Miguel Servet (named after a Spaniard who described pulmonary
circulation before William Harvey), with the advice
of chiefs of the most prestigious cardiology departments in
Spain, have decided to promote the teaching of business skills
for cardiologists. Every year in the last 5 years, we have sent
about 12 to 15 cardiologists (from throughout Spain) around
the age of 40 to the Escuela Superior de Administración y
Dirección de Empresas Business School in Madrid. When we
started, there were many negative answers from all the potential
candidates, and we had to work hard to convince them to
attend. Now there is a waiting list—we get about 50 applications
each year!”
“More Than 70% of Patients in the World
Do �ot Have Access to Primary Percutaneous
Coronary Intervention”
One of the most enduring legacies of Professor Fernández-
Avilés’ period in Valladolid is the multicentre Spanish study
group, Group for the Analysis of Acute Ischemic Heart
Disease [Grupo de Análisis de la Cardiopatía Isquémica
Aguda] (GRACIA), 1,2 which he founded in 1999. GRACIA
has made major contributions to postinfarct reperfusion by
piecing together the optimal strategy for the key therapeutic
elements—thrombolysis, angiography, angioplasty, primary
percutaneous coronary intervention (PCI), facilitated stenting
(with thrombolysis with tenectplase and enoxaparin and
thienopiridines), and conservative management.
The outcomes of the GRACIA-1 trial, 1 published in the
Lancet in 2004, and other data made it necessary to rewrite
the European Society of Cardiology (ESC) guidelines for
PCI, which were published in the European Heart Journal in
2005. 3,4 According to Professor Fernández-Avilés, “More
than 70% of patients in the world do not have access to
primary PCI. If primary angioplasty cannot be done, postthrombolysis
PCI is mandatory. The logistics of acute
myocardial infarction (AMI) therapy with PCI is being further
studied with GRACIA-3, which is now complete and
has compared restenosis with a paclitaxel-eluting stent versus
a bare stent; it has also determined the effect of the
antiplatelet agent, tirofiban, administered before PCI but
after thrombolysis.” GRACIA-4 will study what Professor
Fernández-Avilés calls “the following day strategy” or “rescue
PCI” in cases without evidence of reperfusion after lysis.
“In 2001, I Founded the Terapia Celular Aplicada al
Miocardio Group to Develop Translational Research
With Stem Cells to Prevent and Treat
Postinfarction Heart Failure”
Professor Fernández-Avilés’ experimental and clinical
studies on ischaemia and reperfusion now span more than 25
years. For much of that time, he has sought to reduce
mortality after myocardial infarction by what he calls (in an
article presented at the ESC Congress in 2005) “definitive
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Circulation June 9, 2009
1994 team photograph of the
Department of Cardiology,
University Hospital, Valladolid.
Professor Fernández-Avilés was
appointed head of the Department
in 1990. Left to right, top
row: Dr Enrique Guillén; Juan
Carlos Muñoz; Dr Luis de la
Fuente; middle row: Dr Benigno
Ramos; Dr Joaquín Alonso; Dr
Jerónimo Rubio; Professor
Fernández-Avilés; Dr Zulema
Sainz (fellow from Bolivia); Dr
Lolita Diurzaeva (fellow from
Russia); bottom row: Dr Jose
Luis Vega; Dr José Bermejo; Dr
Federico Gimeno; Dr Justo
Torres; Dr Miguel Casado.
Photo courtesy of Professor
Fernández-Avilés.
mechanical repair of the culprit artery,” but more recently he
has focused on postinfarct sequelae. He explains, “I realised
after GRACIA-2 2 and other trials that reperfusion after AMI
is not enough, and we must now consider how to improve
left-ventricular function after an infarct. Even with optimal
PCI and thrombolysis, many patients will develop heart failure
and die. My main interest now, after the mechanical
approach [of reperfusion] has done what it can for the patient
acutely, is to use biological strategies [such as the use of
stem cells] to avoid heart failure. The future of cardiology is
the chronic patient because we are doing very well in the
acute setting, but [in the process] are creating many, many
chronic patients!”
One of the key events of Professor Fernández-Avilés’
time at Valladolid was his creation, in 2001, of the Stem
Cell Therapy for Myocardial Repair [Terapia Celular
Aplicada al Miocardio] (TECAM) project. He recalls, “In
2001, I founded the TECAM group to develop translational
research with stem cells to prevent and treat postinfarction
heart failure. 5 We have a number of AMI trials ongoing,
including 1 with 4 arms, comparing autologous mononuclear
bone marrow transplantation, resynchronisation, or
both, with conventional reperfusion therapy. For the more
difficult scenario of chronic myocardial infarction, the
PRECISE (adiPose-deRived stEm Cells In the treatment
of patients with non revaScularisable ischaEmic
myocardium) trial is currently in progress. This is a doubleblind,
randomised clinical trial of adipose-derived stem and
regenerative cells in the treatment of patients with nonrevascularisable
ischaemic myocardium. Adipose-derived
stem and regenerative cells will be injected into the left
ventricle and the outcomes of safety and feasibility will be
measured. The position and function of these cells will be
guided and assessed with a variety of imaging modalities,
including electromagnetic mapping with NOGA, magnetic
resonance imaging, single photon emission computed
tomography, and echocardiography.”
“Good Opportunities for the Use of Stem Cells in the
Myocardium, and for AMI There Is Already Enough
Evidence to Perform Large-Scale Clinical Trials”
In 2003, after TECAM, Professor Fernández-Avilés, on his
own initiative, held the first International Symposium on
Stem Cell Therapy and Cardiovascular Innovations
(http://www.cardiovascularcelltherapy.com), which has
become an annual fixture in Madrid and is attended by about
400 specialists from around the world, with a strong faculty
from Europe and the United States. In 2004, buoyed up with
the success of the first symposium and keen to spread news
of a new area of cardiovascular research, Professor
Fernández-Avilés presented a key lecture to delegates at the
ESC Congress in Munich, Germany, titled, “Cell
Therapy—The Genie Is Out of the Bottle.” Four years later,
in 2008, the message had moved on. When he addressed the
4th International Symposium on Stem Cell Therapy, held in
New York, NY, his lecture was titled, “Reconstructing the
Heart—Strategies for the Next Decade. Adipose-Derived
Cells for Chronic Myocardial Infarction.”
Commenting on the use of stem cells in cardiac repair,
Professor Fernández-Avilés says, “There are good opportunities
for the use of stem cells in the myocardium, and for
AMI there is already enough evidence to perform largescale
clinical trials. Several centres in Germany are almost
ready to start, although it will take 5 years before we have
any results. For chronic disease, we need to reinnervate
cardiac muscle, and for that we need very plastic stem
cells, such as induced pluripotent stem cells. However,
there are safety issues, principally the prevention of
tumours, which will have to be addressed before we can
consider clinical use.”
“Leading the Way Forward”
Since 2000, Professor Fernández-Avilés has served the
ESC in a variety of positions. He holds a silver medal of the
society and served as a vice-president between 2002 and
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Photograph of participants at the first meeting on February 7, 2007, of the Spanish Cooperative Cardiovascular Disease Research �etwork
(RECAVA). Professor Fernández-Avilés is the chair of RECAVA, which is run by the Spanish Ministry for Science and Innovation and integrates
about 700 researchers and 50 basic and clinical research groups from around Spain. Photograph courtesy of Professor Fernández-Avilés.
2004. He is editor-in-chief of European Heart Journal
supplements, a member of working groups on coronary circulation
as well as thrombosis and platelets, and also part of
the ESC Task Force on Stem Cells and Repair of the Heart,
founded in 2004. He says, “One of the main purposes of the
task force is to make proposals on the methodology of
clinical research with stem cells, to consider the types of
cardiovascular studies that need to be carried out, and to
define the types of end points that need to be achieved.” He
also belongs to the ESC European Relations Committee and
has been charged with writing a “White Paper” on cardiovascular
research for presentation to the European Union.
His national commitments have also grown. In addition to
chairing the Spanish Cooperative Cardiovascular Disease
Research Network [Red Temática de Investigación
Cooperativa en Enfermedades Cardiovasculares], which is
run by the Spanish Ministry for Science and Innovation and
integrates about 700 researchers and 50 basic and clinical
research groups from around the country, he advises the
Spanish government on national plans for cardiology in general,
including biomedical research, cardiac transplantation,
catheterisation laboratories, and other matters. He is a member
of the Spanish National Commission for the Specialty of
Cardiovascular Medicine and a board member of the Centre
for Transplants and Regenerative Medicine [Centro de
Transplantes y Medicina Regenerativa].
In addition, Professor Fernández-Avilés has been active at
the European level as a member of the European Union
Health Research Advisory Group, setting priorities for the
7th Framework Programme for Research and Technological
Development, which runs to 2013. He is also a board member
of the International Society for Cardiovascular
Translational Research, created in 2007.
Professor Fernández-Avilés has a busy life. During the
summer, he spends time catching up with his family, who
gather at Cadiz in the Adalusian region of Spain, where he
has a second home. Here he can indulge his passion for
natural history (Darwin is one of his heroes). He says, “In
my spare time, I love to read─and sometimes I play golf. I
am really bad─my handicap is 24!”
References
1. Fernández-Avilés F, Alonso J, Castro-Beiras A, Vázquez N, Blanco J,
Alonso-Briales J, López-Messa J, Fernández Vazquez F, Calvo I, Martínez-
Elbal L, San Román A, Ramos B. Routine invasive strategy within 24 hours
of thrombolysis versus ischaemia-guided conservative approach for acute
myocardial infarction with ST-segment elevation (GRACIA-1): a randomised
controlled trial. Lancet. 2004 ;364:1045–1054.
2. Fernandez-Aviles F, Alonso J, Peña G, Blanco J, Alonso-Briales J, López-
Messa J, Fernandez-Vázquez F, Moreu J, Hernández R, Castro-Beiras A,
Gabriel R, Sanchez PL. Primary angioplasty versus early routine post-fibrinolysis
angioplasty for acute myocardial infarction with ST-segment elevation:
the GRACIA 2 non-inferiority, randomised, controlled trial. Eur
Heart J. 2007;28:949–960.
3. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task
Force for the Redefinition of Myocardial Infarction, Jaffe AS, Apple FS,
Galvani M, Katus HA, Newby LK, Ravkilde J, Chaitman B, Clemmensen
PM, Dellborg M, Hod H, Porela P, Underwood R, Bax JJ, Beller GA,
Bonow R, Van der Wall EE, Bassand JP, Wijns W, Ferguson TB, Steg PG,
Uretsky BF, Williams DO, Armstrong PW, Antman EM, Fox KA, Hamm
CW, Ohman EM, Simoons ML, Poole-Wilson PA, Gurfinkel EP, Lopez-
Sendon JL, Pais P, Mendis S, Zhu JR, Wallentin LC, Fernández-Avilés F,
Fox KM, Parkhomenko AN, Priori SG, Tendera M, Voipio-Pulkki LM,
Vahanian A, Camm AJ, De Caterina R, Dean V, Dickstein K, Filippatos G,
Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem
U, Silber S, Tendera M, Widimsky P, Zamorano JL, Morais J, Brener S,
Harrington R, Morrow D, Lim M, Martinez-Rios MA, Steinhubl S, Levine
GN, Gibler WB, Goff D, Tubaro M, Dudek D, Al-Attar N.Universal definition
of myocardial infarction. Circulation. 2007;116:2634–2653.
4. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation
Acute Coronary Syndromes of European Society of Cardiology, Bassand
JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, Fox
KA, Hasdai D, Ohman EM, Wallentin L, Wijns W. Guidelines for the diagnosis
and treatment of non-ST-segment elevation acute coronary syndromes.
Eur Heart J. 2007;28:1598–1660.
5. Fernández-Avilés F, San Roman A, García-Frade J, Fernández ME.
Peñarrubia MJ, de la Fuente L, Gómez-Bueno M, Cantalapiedra A,
Fernández J, Gutierrez O, Sanchez P.L, Hernández C, Sanz R, García-Sancho
J, Sanchez A. Experimental and clinical regenerative capability of human
bone marrow cells after myocardial infarction. Circ Res. 2004 ;95:742–748.
Barry Shurlock is a freelance medical journalist.
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Circulation June 9, 2009
Centre of Excellence: Department of Cardiology,
University Hospital Gregorio Marañón,
Madrid, Spain
An Ambitious Research Programme with a Budget of $6 Million and Major
Research Projects on Heart Failure, Coronary Syndromes, Cardiac Valve Disease,
Cardiovascular Imaging, Arrhythmias, and Stem Cell Therapy
Francisco Fernández-Avilés, MD, PhD, FESC, FACC, chair of the Department of Cardiology,
University Hospital Gregorio Marañón, Madrid, Spain, describes the Department and its work to
Barry Shurlock, MA, PhD.
Team photo May 2007. Department of Cardiology. University Hospital Gregorio Marañón, Madrid, Spain. The Department of Cardiology
has 4 divisions—clinical, noninvasive, invasive, and research, innovation, and education—with a medical staff of 30, about 25 fellows
and newly qualified specialists, and an ever-changing contingent of about 20 visiting researchers. Photograph courtesy of Professor
Fernández-Avilés.
In Madrid, Francisco Fernández-Avilés, MD, PhD, FESC,
FACC, runs a large Department of Cardiology at the
University Hospital Gregorio Marañón, Madrid, Spain.
With origins in 1567, when King Phillip II founded the
hospital, it now belongs to the Public Heath Service of
Madrid and receives more than 65000 admissions a year in
all departments. Every year, more than 35000 cardiac
patients pass through the 7 outpatient clinics, and more
than 5000 are admitted to the 51-bed cardiology ward
and/or the 11-bed coronary care unit. They are served by 4
catheterisation laboratories, 2 focused on intervention plus
another for electrophysiology and a multifunction laboratory.
A large imaging centre with 11 echocardiographs produces
more than 20000 scans (echos) each year. The department
performs nearly 1000 electrophysiology studies a year, of
which about 75% are therapeutic.
Despite a considerable administrative load, Professor
Fernández-Avilés manages to spend about half his time with
patients or doing research. He explains, “I love my department!
I am an interventional cardiologist and I love it! But I
also love to be close to the patient and receive input from the
patient. I believe that everything should be based on the
patient. I am not fond of administration—but it’s very important:
If you want to improve the situation of patients, staff,
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An endovascular percutaneous implantation of a prosthetic aortic
valve perfomed by Professor Fernández-Avilés at the Department
of Cardiology at the University Hospital Gregorio Marañón,
Madrid, January 31, 2009. This type of procedure, which is performed
using a simple groin puncture and local anaesthesia,
avoids the need for open heart surgery and has revolutionised the
field of cardiac valve replacement. Photograph courtesy of
Professor Fernández-Avilés.
fellows, and students, you must fight for it, and that means
lots of administration! To achieve goals, you need to spend
time—you have to have a meeting, then another meeting,
and another. So, although one very important focus is the
patient, the other is the team. As ‘the boss,’ you need to create
a framework and have goals, and you need to be firm.
But you also need to allow people to ‘roam’ with freedom, to
be free and autonomous, otherwise the team will fragment.”
“Working in Another Country Is Essential”
Professor Fernández-Avilés clearly values working abroad,
although he never managed to do so himself. In 1982, after
completing his PhD, he planned to work at the Montreal
Heart Institute, Quebec, Canada, but his plans were thwarted
when his mother fell ill and he decided to stay home. He comments,
“For young cardiologists, working in another country
is essential. It’s almost obligatory for my young fellows to go
abroad. They normally come back and then try to incorporate
the knowledge they have gained into their clinical practice.
But it’s not only for clinical and scientific knowledge that
they go─they also get new ideas on life and culture.”
In line with this philosophy, the Department of
Cardiology has close relations with a number of major institutions,
including the Mayo Clinic, Rochester, Minn, the
Mount Sinai Heart Centre, New York, NY, and the Texas
Editor: Helmut Drexler, MD, FESC
Managing Editor: Lindy van den Berghe, BMedSci, BM, BS
We welcome comments. E-mail lindy@circulationjournal.org
Heart Institute, Houston, Tex. It also runs a “Meet With the
Cardiovascular Experts” programme, where senior specialists
from top cardiac centres in the world spend 2 days every
month in the University Hospital Gregorio Marañón giving
lectures and sharing their experiences with staff members.
“We Are Focusing on Translational Research”
The Department of Cardiology has an ambitious research
programme with a budget of $6 million and major research
projects on heart failure, coronary syndromes, cardiac
valve disease, cardiovascular imaging, arrhythmias, and
stem cell therapy. 1–3
All cardiovascular interventions are performed, including
heart transplantations, left-ventricular support procedures,
and stem cell therapy. Emphasising that the Department of
Cardiology has one of the largest cardiovascular caseloads in
the whole of Spain, Professor Fernández-Avilés says, “We
want to cure, so we need to know more. In other words, in
our research the idea is to put the patient at the centre of the
work, both in clinical and basic studies. We are focusing on
translational research, trying to reduce the impact of the
main cardiovascular pathologies through biomedical innovation.WearepartofanorganisationofwhichIamthe
national chair, namely, the Spanish Cooperative
Cardiovascular Disease Research Network [Red Temática de
Investigación Cooperativa en Enfermedades Cardiovasculares],
which is run by the Spanish Ministry for
Science and Innovation and integrates about 700 researchers
and 50 basic and clinical research groups from around the
country. We are mainly concerned with heart failure,
ischaemic heart disease, and arrhythmias—trying to improve
knowledge and therapy. Our main research areas include
molecular biology, imaging, stem cell therapy, and electrophysiology.
A major priority is to reduce the detrimental
impact of myocardial infarction on left-ventricular function by
reperfusion, myocardial protection, and stem cell therapy.”
References
1. Cortina C, Bermejo J, Yotti R, Desco MM, Rodríguez-Pérez D, Antoranz
JC, Rojo-Alvarez JL, Garcia D, García-Fernández MA, Fernández-Avilés
F. Noninvasive assessment of the right ventricular filling pressure gradient.
Circulation. 2007;116:1015–1023.
2. Bratos-Pérez MA, Sánchez PL, García de Cruz S, Villacorta E, Palacios
IF, Fernández-Fernández JM, Di Stefano S, Orduña-Domingo A,
Carrascal Y, Mota P, Martín-Luengo C, Bermejo J, San Roman JA,
Rodríguez-Torres A, Fernández-Avilés F; Grupo AORTICA (Grupo de
Estudio de la Estenosis Aórtica). Association between self-replicating
calcifying nanoparticles and aortic stenosis: a possible link to valve calcification.
Eur Heart J. 2008;29:371–376.
3. Datino T, Almendral J, González-Torrecilla E, Atienza F, García-Fernández
FJ, Arenal A, Atea L, Fernández-Avilés F.Rate-related changes in QRS
morphology in patients with fixed bundle branch block: implications for
differential diagnosis of wide QRS complex tachycardia. Eur Heart J.
2008;29:2351–2358.
Barry Shurlock is a freelance medical journalist.
The opinions expressed in Circulation: European Perspectives
in Cardiology are not necessarily those of the editors or of
the American Heart Association.
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