Spotlight: Christian Seiler, MD, FESC, FACC - Circulation

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Spotlight: Christian Seiler, MD, FESC, FACC - Circulation

European Perspectives

Circulation. 2010;121:f73-f78

doi: 10.1161/CIR.0b013e3181d9ce57

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Circulation April 6, 2010

On other pages...

European Perspectives in Cardiology

Spotlight: Christian Seiler, MD, FESC, FACC

Pioneer of a �onivasive Method to Measure Coronary Blood Flow

and Bio Bypasses as an Alternative to Surgical Bypasses

Christian Seiler, co-chairman of cardiology at the University Hospital, Bern,

Switzerland, and president of the Swiss Society of Cardiology,

talks to Jennifer Taylor, BSc, MSc, MPhil.

Professor Christian Seiler, MD, FESC, FACC, co-chairman

of cardiology, University Hospital, Bern,

Switzerland, and president of the Swiss Society of

Cardiology (until June 2010) started his working life as a

cartographer. Despite

enjoying the meticulous

nature of cartography,

Seiler desired more

interaction with people,

so he trained in

medicine at Bern medical

school—chosen

because it allowed students

contact with

patients earlier in their

studies than other

medical schools in

Switzerland. He graduated

in 1985, and his

subsequent chosen specialty

of cardiology, which involves making measurements

and physics, enabled him to maintain a link with his former

life as a cartographer.

For the past 20 years, Professor Seiler’s primary

research interest has been coronary circulation and his

research has been mainly funded by the Swiss National

Research Foundation and the Swiss Heart Foundation.

Measuring Blood Flow in Heart Muscle in ml/min/g

Using Contrast Echocardiography

Professor Seiler’s interest in coronary circulation began

when he was a research fellow at the University of Texas in

Houston, Tex, between

1990 and 1992. His mentor

at that time, coronary

physiologist and clinical

cardiologist Professor

Lance Gould, MD, is

according to Professor

Seiler, “a cool intelligent

guy who is meticulous in

his research.” He vividly

recalls Professor Gould

telling him that probably

the most important thing

in research is to let the

Professor Seiler as a subject in one of his own studies. He says, “You get an impres- data speak for itself. By

sion of how the study affects your patients.” Photograph courtesy of Professor Seiler.

just observing the data,

another hypothesis might arise, or something unexpected

might emerge that falsifies the initial hypothesis. This idea

of learning by looking at the data was an important lesson.

Professor Seiler’s main task in Texas was to mathematically

model the coronary circulation of the heart. The

group showed that human coronary circulation could be

modelled mathematically and that the model could be

Spotlight: Ulrich Martin, PhD

Ulrich Martin, head of the Leibniz Research Labs for Biotechnology and

Artificial Organs, Hannover, Germany, and professor of cardiorespiratory tissue

engineering at Hannover Medical School, says, “Proper vascularisation,

including in vitro generation of large blood vessels, is the key technology

essential for the future generation and implantation of larger dimension tissue.”

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Circulation April 6, 2010

verified using coronary angiography. 1 On the basis of the

model it was possible to detect stenotic lesions and diffuse

coronary artery disease. On his return to Switzerland,

Professor Seiler secured grants to focus on coronary circulation,

and coronary collateral circulation in particular.

The first aim was to measure collateral circulation. The

first measurement in humans was published in JACC in

1998. Professor Seiler and his colleagues simultaneously

compared 2 methods to measure flow through collateral

circulation. 2 Then in 2005, they showed that contrast

echocardiography could be used to measure blood flow in

the heart muscle in absolute terms, in ml/min/g. 3 Professor

Seiler says, “With the exception of positron emission

tomography, there is no other means to measure heart muscle

blood flow.” The method is not widely used, mainly

because industry needs engineers who can incorporate the

measurements into their machines so that the algorithm can

be used automatically. Professor Seiler is negotiating with

industry to take the method forward. He believes that cardiologists

would benefit from being able to use the method

in the noninvasive diagnosis of coronary artery disease.

Currently, echocardiography is used to detect coronary

artery disease but is not quantitative: a patient is stressed on

an ergometer, for example, and then echocardiography is

used to look for wall motion abnormalities in the left ventricle.

Professor Seiler’s method measures the amount of

blood flow during exercise. If it is below normal, the investigation

provides valuable information in the detection of

coronary artery disease and is more precise than observing

wall motion. He says, “It would help in deciding whether a

patient should undergo coronary angiography and from

there on whether it is necessary to dilate any stenosis

found.”

Bio Bypasses: an Alternative to Surgical Bypasses

Professor Seiler’s group is now looking at therapeutic

aspects and how bio bypasses can be created as an alternative

to surgical bypasses. They have been testing ways to

improve collateral function and found that they could

promote collateral growth using the growth factor granulocyte-macrophage

colony-stimulating factor (GM-CSF), a

substance that oncologists have used for years to turn on

the production of white blood cells. 4 It was the first time a

growth factor had been tested in humans to induce collateral

growth. A second growth factor, granulocyte colony-stimulating

factor (G-CSF), was also effective and patients did

not have the flu-like side effects experienced with GM-

CSF. 5 The aim is for natural bypasses, called bio bypasses,

to become a third pillar in the strategy to treat coronary

artery disease, after angioplasty and coronary bypass grafting,

but the quest remains to find which method is best.

Professor Seiler’s group has also found a physical way

of improving collateral growth—external counter pulsation.

Cuffs are put around the legs and pumped up simultaneously

to the heart beat, which improves blood flow in coronary

circulation and collateral circulation. Another method is

physical exercise training. Professor Seiler was a subject in

this study, in which he performed endurance exercise for

several months and had a coronary angiogram at the start

and end of the study. His collateral function increased substantially.

6 Professor Seiler has been a subject in his own

studies several times. He explains, “You get an impression

of how this study affects your patients.”

In collateral circulation research, Professor Seiler’s most

important mentor has been Professor Wolfgang Schaper,

MD, in Bad Nauheim, Germany, and they meet every couple

of months. Professor Schaper has been engaged in the

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Circulation April 6, 2010

Left (page f74) and above. Group photograph (taken in 2008) of experts in arteriogenesis (called collateralogists by Professor Seiler)

who meet in Sils-Maria, close to St. Moritz, Switzerland, every 2 years. Professor Seiler organises the meeting, and his mentor, Professor

Wolfgang Schaper, is far left in the photograph above. Photograph courtesy of Professor Seiler.

field of collateral research for the past 45 years and was

probably the first person to study the topic in depth. “He is

not engaged in clinical cardiology but he’s really a brilliant

physiologist and a very honest researcher, which I find very

important. You can trust him,” says Professor Seiler.

Advocate of Screening for PFO in Professional Divers

Sports cardiology is another field of interest for Professor

Seiler as a result of his own marathon running and because

his daughter used to be a diver. She was 1 of his first subjects

when he was studying the relevance of patent foramen

ovale (PFO) in divers in whom PFO is a risk factor for

strokes when they surface from 40m below surface: a lowering

in ambient pressure causes small air bubbles to develop

in the blood that can cross the border between the right and

left atria in patients with PFO. 7

Professor Seiler’s group made a similar discovery in

mountaineers with PFO, who have an increased risk for high

altitude pulmonary oedema. 8 It is not clear whether the finding

in mountaineers is of relevance, but Professor Seiler

advocates screening for PFO in professional divers. Some

diver organisations, including the police diving school in

central Switzerland, have sent people to him for screening,

but the practice is not commonplace.

Another aspect of sports cardiology that interests him is

the left ventricular hypertrophy and increased myocardial

mass sometimes developed in endurance exercise. This

physiological form of hypertrophy can be distinguished

from the pathological hypertrophy seen in hypertensive

patients using myocardial contrast echocardiography.

References

1. Seiler C, Gould KL, Kirkeeide RL. Basic structure-function relations of

the coronary vascular tree. The basis of quantitative coronary arteriography

for diffuse coronary artery disease. Circulation. 1992;85:

1987–2003.

2. Seiler C, Fleisch M, Garachemani A, Meier B: Coronary collateral

quantitation in patients with coronary artery disease using intravascular

flow velocity or pressure measurements. JACC. 1998;32:1272–1279.

3. Vogel R, Indermühle A, Reinhardt J, Meier P, Siegrist P, Namdar M,

Kaufmann P, Seiler C. The quantification of absolute myocardial perfusion

in humans by contrast echocardiography: Algorithm and validation.

JACC. 2005;45:754–762.

4. Seiler C, Pohl T, Wustmann, Hutter D, Nicolet PA, Windecker S, Eberli

FR, Meier B. Promotion of collateral growth by granulocytemacrophage

colony-stimulating factor in patients with coronary artery

disease: a randomised, double-blind, placebo-controlled study.

Circulation. 2001;104:2012–2017.

5. Meier P, Gloekler S, de Marchi SF, Indermuehle A, Rutz T, Traupe T,

Steck H, Vogel R, Seiler C. Myocardial salvage through coronary collateral

growth by granulocyte-colony stimulating factor in chronic

coronary artery disease: a controlled randomized trial. Circulation.

2009;120:1355–1363.

6. Zbinden R, Zbinden S, Windecker S, Meier B, Seiler C. Direct demonstration

of coronary collateral growth by physical endurance exercise in

a healthy marathon runner. Heart. 2004;90:1350–1351.

7. Schwerzmann M, Seiler C, Lipp E, Guzman R, Lövblad KO, Kraus M,

Kucher N. Relation between directly detected patent foramen ovale and

ischemic brain lesions in sport divers. Ann Intern Med. 2001;134:21–24.

8. Allemann Y, Hutter D, Lipp E, Sartori C, Duplain H, Egli M, Cook S,

Scherrer U, Seiler C. Patent foramen ovale and high-altitude pulmonary

edema. JAMA. 2006;296:2954-2958.

Contact details for Professor Seiler:

E-mail: Christian.seiler@insel.ch

Jennifer Taylor is a freelance medical journalist.

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Spotlight: Ulrich Martin, PhD

“In Vitro Generation of Large Blood Vessels Is the Key Technology

for the Generation and Implantation of Larger Dimension Tissue”

Ulrich Martin, head of the Leibniz Research Labs for Biotechnology and Artificial

Organs, Hannover, Germany, and professor of cardiorespiratory tissue engineering

at Hannover Medical School, talks to Judy Ozkan, BA.

Born in Lehrte, a small town to the east of Hannover,

Germany, in 1967, Professor Ulrich Martin, PhD, head

of the Leibniz Research Labs for Biotechnology and

Artificial Organs (LEBAO), Hannover, Germany, and professor

of cardiorespiratory tissue engineering at Hannover

Medical School, had an early introduction to the lab environment

thanks to his mother, who worked as a technician.

From the age of 3, he was planning his research career,

although his aim at that time was focused on protecting big

game animals in Africa. At school he was interested in and

excelled at science, as well as sports and geography. He

was fairly clear that when he left high school at the age of

18 that he would go into a career involving his favourite

subjects of chemistry and biology. Thus, after compulsory

military service, he entered the Technical University of

Hannover to study biology. He then progressed through the

veterinary and medical schools and started an early specialisation

in molecular biology and lab sciences.

After graduating in 1990, Martin worked on his doctoral

thesis, which he presented in 1997 on the cloning of the

human C3a receptor and the first characterisation of its

expression pattern. His PhD supervisor, microbiologist

Andreas Klos, MD, PhD, was an inspiring scientist and

teacher. Professor Martin says that Professor Klos’ advice

on the importance of being critical in the evaluation of data

has proved invaluable. Another influential figure was

Gustav Steinhoff, MD, PhD, a professor and director of the

Department of Cardiac Thoracic Transplantation and

Vascular Surgery at the University of Rostock, Rostock,

Germany. Professor Martin says, “He is 1 of the most

active scientists among German heart surgeons and recruited

me to the Department of Cardiothoracic Surgery.”

Professor Steinhoff taught Martin about animal models and

their importance for preclinical developments.

Developing the Leibniz Research Labs for

Biotechnology and Artificial Organs

A notable mentor whose influence was and continues to be

important for Professor Martin is Axel Haverich, MD,

PhD, professor and director of the Department of Cardiac,

Thoracic, Transplantation, and Vascular Surgery at

Hannover Medical School. He says, “Axel has been my

great mentor for more than 12 years. He was my main

source of inspiration in terms of understanding clinical

views and needs, as well as the requirement for interdisciplinary

research and human resources management.”

Professor Haverich offered Martin 1 of the dual directorships

of the Department of Cardiac Thoracic Transplantation and

Vascular Surgery and the LEBAO.

The LEBAO, named after Gottfried Wilhelm Leibniz,

who spent 40 years of his life in Hannover and was considered

the last great polymath to highlight the benefits of

interdisciplinary research, was founded by Professor

Haverich in 1996 with funding from the Leibniz Prize

awarded by the German Research Foundation. It forms the

nucleus of the excellence cluster in regenerative medicine

(7 institutions in Germany known as REBIRTH, the

acronym for Regenerative Biology and Reconstructive

Therapies, http://www.rebirth-hannover.de/) and is closely

linked to the Department of Cardiac, Thoracic,

Transplantation, and Vascular Surgery of the Hannover

Medical School. Professor Ulrich says, “The idea was to

marry application-oriented basic research with clinical

practice under a dual leadership; in this case, Professor

Haverich on the clinical side and myself on the research

side. This close linkage facilitates better-focused research

and development and allows fast translation of innovative

therapeutic concepts into clinical practice.”

Table football at the REBIRTH halftime party. Professor Martin says,

“REBIRTH is currently funded for 5 years. After 2.5 years we had a

party for all REBIRTH members celebrating the achievements of the

first 2.5 years.” Axel Haverich (front left), REBIRTH coordinator, and

Tilman Fabian, REBIRTH manager, take on Christopher Baum (front

right), REBIRTH deputy coordinator; and Ulrich Martin, REBIRTH

deputy coordinator. Photograph courtesy of Professor Martin.

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Circulation April 6, 2010

The Leibniz Research Labs for Biotechnology and Artificial Organs (LEBAO) team in 2009. Photograph courtesy of Professor Martin.

Different aspects of regenerative medicine and organ

transplantation are investigated in this way. Current

projects at the LEBAO include the development of

bioartificial lungs led by Professor Haverich, molecular

biotechnology and stem cell research led by Professor

Martin, and tissue engineering directed by Andres Hilfiker,

PhD. Each research project aims to develop new therapies

for the treatment of cardiovascular and respiratory diseases.

The overall goal is to support cutting-edge research

in Germany and improve international competitiveness.

Projects focus the research potential at university locations

in Germany and, hence, strengthen their international visibility.

There are interconnections and close collaborations

with other projects within the Hannover Medical School

and REBIRTH, as well as commercial companies.

Professor Martin is most proud of having developed the

LEBAO from notes in the “vest pocket of a lab surgeon” to

a well-respected research institution in the field of cardiorespiratory

and regenerative medicine. He regrets not

having had the time to investigate and develop longstanding

ideas concerning embryonic stem cell-based tolerance

induction, but he plans to develop the basis for clinical

translation of their concepts for stem cell-based therapies

of cardiorespiratory diseases. His role in REBIRTH has

proved most rewarding. He says, “It was quite an achievement,

which would not have been possible without the

close interaction and excellent collaboration with colleagues

Axel Haverich and Chris Baum [MD]. It’s now a

real pleasure to realise what has developed here in

Hannover from our previous work.” Professor Martin looks

forward to reaping the benefits that will flow from the project

for many years to come.

Professor Martin sees his own strengths as a researcher

as his instincts in the interpretation of experimental results

and his persistence concerning the establishment of new

fields of research and new techniques. He is focused on the

end result and derives great satisfaction from long-term

projects that eventually deliver a successful result. One

example of this, he suggests, is the development of stem

cell-based implantable human myocardium. Of the 67 articles

he has had published so far, he says that the most

important are those on immunology, xenotransplantation,

and stem cell research. 1–5

Despite his success in getting a major project such as

REBIRTH off the ground, Professor Martin says that certain

choices in his academic career have made life more

difficult. He explains, “My decision not to follow a typical

career path by not joining a well-established research group

abroad for a postdoctoral position did not always facilitate

my career. Although the choice to stay in Hannover to build

a research team led to demanding and fascinating independent

work at quite an early stage in my career, the need

to apply for funding without sufficient work and publications

did result in sleepless nights for many years.” The

German Research Foundation and the Federal Ministry of

Education and Research have funded most of his work,

along with charitable foundations.

“A Cell Source With Almost Unlimited Potential for

Proliferation and Differentiation”

Since November 2006, Professor Martin has been deputy

coordinator of the REBIRTH excellence cluster, and since

March 2008, he has been full professor of cardiorespiratory

tissue engineering at the Hannover Medical School and

head of the LEBAO. He is also a member of the editorial

board of the World Journal of Stem Cells, a visiting professor

at the People’s Friendship University, Sochi, Russia,

and a member of the Scientific Advisory Board of the

German Stem Cell Society.

Research has long been Professor Martin’s driving interest,

but he also enjoys direct supervision and mentoring of

students. He says, “It is always nice to follow the students’

progress not only within their project but also in the long

term regarding their personality and career.” Less enjoyable

are the unnecessary administrative hurdles. He comments,

“Clearly, administrative rules are necessary; however,

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Left, Aerial view of Hannover Medical School, Hannover, Germany. The arrow indicates the Hans Borst Center for Heart and Stem Cell

Research, which includes the Leibniz Research Labs for Biotechnology and Artificial Organs (right). Photographs courtesy of Professor Martin.

research could be much more effective without this tangled

mass of regulations!”

Professor Martin advises would-be researchers: “Don’t

miss a chance to look beyond your own nose and discover

the fascination of interdisciplinary research. Despite the

increasing complexity of the world, it is still necessary to

focus on 1 topic of research.” He also suggests that,

although it can be helpful to join famous researchers

abroad, it is a matter of personal skills, effort, and your

stamina as to how successful this will be. “In the end, a certain

level of fortune is definitely important to meet the right

people at the right time and in the right place.”

Professor Martin’s work is essentially forward looking,

and he is broadly optimistic about the future clinical applicability

of induced pluripotent stem cell technology,

athough he is uncertain whether autologous-induced

pluripotent stem cell technology will be broadly applied

clinically. He says, “The high costs of patient-specific cell

preparation and the time required for reprogramming,

establishment, and selection of cell clones, cell expansion,

differentiation, and potential tissue engineering are not

available for acute diseases and injuries.”

Professor Martin believes that tolerance induction or

establishment of large worldwide stem cell banks may provide

alternatives to autologous therapies. A great advantage

of induced pluripotent stem cell technology, he says, “is

that it is ethically unproblematic and comes from a cell

source with almost unlimited potential for proliferation and

differentiation. Nevertheless, there are still major hurdles to

be overcome prior to the clinical application of engineered

myocardial tissue, including proper integration and functional

coupling of cellular transplants. However, proper

vascularisation, including in vitro generation of large blood

Editor: Christoph Bode, MD, FESC, FACC, FAHA

Managing Editor: Lindy van den Berghe, BMedSci, BM, BS

We welcome comments. E-mail lindy@circulationjournal.org

vessels, is the key technology essential for future generation

and implantation of larger dimension tissue.”

Professor Martin says his family is most important to

him in his life, and his wife and partner of 25 years is his

best advisor and counsellor. He enjoys being active and, if

time permitted, would spend more time skiing, snowboarding,

and windsurfing. He comments that his home life and

gardening provide an important balance to his work.

References

1. Haase A, Olmer R, Schwanke K, Wunderlich S, Merkert S, Hess C,

Zweigerdt R, Gruh I, Meyer J, Wagner S, Maier LS, Han DW, Glage S,

Miller K, Fischer P, Schöler HR, Martin U. Generation of induced

pluripotent stem cells from human cord blood. Cell Stem Cell.

2009;5:434–441.

2. Mauritz C, Schwanke K, Reppel M, Neef S, Katsirntaki K, Maier LS,

Nguemo F, Menke S, Haustein M, Hescheler J, Hasenfuss G, Martin U.

Generation of functional murine cardiac myocytes from induced

pluripotent stem cells. Circulation. 2008;118:507–517.

3. Gruh I, Beilner J, Blomer U, Schmiedl A, Schmidt-Richter I, Kruse

ML, Haverich A, Martin U. No evidence of transdifferentiation of

human endothelial progenitor cells into cardiomyocytes after coculture

with neonatal rat cardiomyocytes. Circulation. 2006;113:1326–1334.

4. Martin U, Kiessig V, Blusch JH, Haverich A, von der Helm K, Herden

T, Steinhoff G. Expression of pig endogenous retrovirus by primary

porcine endothelial cells and infection of human cells. Lancet.

1998;352:692–694.

5. Martin U, Bock D, Arseniev L, Tornetta MA, Ames RS, Bautsch W,

Köhl J, Ganser A, Klos A. The human C3a receptor is expressed on

neutrophils and monocytes but not on B or T lymphocytes. J Exp Med.

1997;186:199–207.

Contact details for Professor Martin:

Leibniz Research Labs for Biotechnology and Artificial

Organs (LEBAO), Carl-�euberg-Str. 1, 30625 Hannover,

Germany. E-mail: martin.ulrich@mh-hannover.de

Judy Ozkan 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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