Download Cardiac Stem Cell Trial Overview

Stem Cells for Heart
Disease: hype or hope
Robert M. Graham
Victor Chang Cardiac Research Institute and
St Vincent’s Hospital, Sydney, Australia
Australian Health Insurance Association Conference
31 Oct - 2 Nov, 2006
1 November,
2006
Cardiology – where have we been?
Cardiology: Where have we been?
• In ~ 400B.C., the time of Hippocrates, air and water
were pushed through hollow reeds or brass pipes into
the aortas of cadavers in an attempt to understand
the function of the heart valves.
• In 1651 Harvey inserted tubes into cadavers and
proved, contrary to popular opinion, that blood in the
veins flowed up to the lungs, and not down into the
legs.
Cardiology: Where have we been?
• Wren delivered the first injection into a vein of a
living subject (a dog) in 1665
• Major delivered the first injection into the vein of a
living human in 1667
• Also in 1667, Lower used the first catheter - a man
made tube inserted into the body to transfuse blood
from a sheep to a human
Earliest known cardiac
catheterisations were
performed by Hales in
1711 – inserting brass
pipes through the veins
and arteries into the
hearts of horses.
Using the wind-pipes of
geese as a connector,
the brass pipes were
connected to glass tubes
to measure pressure –
the water columns rose
to >9 feet.
The first human catheterisation
• Werner Forssmann (1904-79)
• As a 25yo medical resident wanted to give drugs directly to the
heart
• Superiors “horrified” – thought that any invasion of the heart
would be fatal – refused to allow this research
• Practiced passing bladder catheters into the hearts of cadavers
• “Gained the trust” of Gerda Ditzen, a surgical nurse, who had
access to the necessary equipment
The first human catheterisation
• In July of 1929, Ditzen (the surgical nurse) agreed to permit
Forssmann to perform the first human catheterisation on her
• Forssmann secured her to the operating table
• He then put local anaesthetic in his own forearm and passed a
bladder catheter to its full length of 65cm up his own arm
• He then released the angry nurse and together they walked to
the radiology department (up the stairs!) and made medical
history
The first human catheterisation
• Bitter criticism followed – Forssmann described by peers as
“mentally deficient”
• Fired by his superior the same day, and told “such methods are
fit for a circus, but not for a respected hospital”
• Abandoned cardiac research within 2 years, finally becoming a
urological surgeon
• Awarded the 1956 Nobel prize with other cardiac poineers,
Cournard and Richards
On February 12th 1974,
Andreas Gruentzig
performed the first
balloon dilation of a
human leg artery, and in
1977 this was then done
in the human heart.
Other important recent advances in
cardiology
• Coronary artery bypass surgery
• Awareness of the importance of diet, smoking (not!),
lifestyle and exercise
• Medical therapies – aspirin, blood pressure lowering
drugs, cholesterol lowering tablets etc.
• Coronary care units
• Cardiac transplantation
Cardiology – where are we going?
Stem cell research – future directions
for heart disease treatment
Prometheus, who was
damned to be chained to
Mount Caucasus for 30,000
years. Every day an eagle
would come down and pick
his liver, and the next day it
would have regenerated.
The hound of Zeus, the tawny eagle,
…feasting on thy liver
Till he hath gnawn it black.
- Aeschylus, Prometheus Bound
Muscle, skin, vessel
Stem cell and divides
Muscle, skin, vessel
Poss et al, Science 2002
Are there stem cells in the heart?
Old way of thinking =
– The heart can not repair itself
– After a heart attack, dead heart cells are not
replaced
There are stem cells in the heart!
What do heart stem cells do?
• Human heart contains ≈ 5,000,000,000 cells
• 3,000,000 cardiac cells become worn out and die each
day
• The heart would disappear in ≈ 4 - 5 years if these
cells were not replaced!
Heart stem cells may multiply after a heart attack
Blood vessel stem cells are also important
Heart and
blood vessel
stem cells
• We all have them
• They probably help to fix everyday wear-and-tear
• Heart stem cells try to fix things after a heart attack
– but don’t do enough!
• Our job is to find out why they don’t do much after a
heart attack and see what helps them do more
Research using stem cells in humans
Research using stem cells in human
hearts
• Already over 500 patients around the world have
had stem cell therapy to the heart
• Many cell types have been used
– Bone marrow
– Muscle stem cells
– Blood vessel stem cells
• Many different heart problems have been treated
– Days after a heart attack
– Years after a heart attack
– Reduced pumping of the heart (never had a heart attack)
Stem cell trial at St Vincent’s Hospital and
The Victor Chang Cardiac Research
Institute
Granulocyte-colony stimulating factor (G-CSF) and intracoronary endothelial progenitor cell (EPC) infusion in
patients with chronic refractory ischaemic heart disease
The stem cell team
Clinical trial at SVH and VCCRI
•
•
Investigators
David Muller
Peter Macdonald
Michael Feneley
Neil Jacobs
Helen Tao
Andrea Herbert
David Ma
John Moore
Sam Milliken
Anthony Dodds
Judy Freund
Lyn Chan
Silviu Itescu
Robert Graham
Data and Safety Monitoring Board
Roger Allan
John Rasko
Vivian Fernandez
VCCRI cardiac stem cell lab
Richard Harvey
Joan Li
Corey Heffernan
Owen Prall
Ish Ahmed
Robert Graham
G-CSF
• Typically used for bone marrow
donation or transplantation
• Given by daily skin injection for 3-5
days
• Stimulates bone marrow and causes
release of stem cells into the blood
Normal BM
BM after 5 days G-CSF
Age
62 ± 9.0 (36 - 74)
Sex
Male = 18/20, female = 2/20
Body mass index
29.8 ± 4.4 (22.1 - 39.2)
Diabetes
3/20
High cholesterol
20/20
High blood pressure
18/20
Smoking
17/20 ex, 0/20 current
Family history (1st degree relative < 55 male or < 65 female)
15/20
Number of bypass operations
1.6 ± 0.7 (1 - 3)
Number open bypass grafts
1.5 ± 1.0 (0 - 4)
Number of open heart arteries
0.7 ± 0.9
Pumping ability of the heart (LVEF)
48.7 ± 10.3% (30 - 65%)
Number of cardiac tablets per day
8.7 ± 1.4
Data presented as mean ± SD (range), or number of patients/20
Final trial results and future directions
Safe
Less chest pain
Less use of medications to get rid of chest pain
Exercise time on the treadmill improved
Quality of life improved
On the basis of this small study of 20 patients,
and with support from MBF, we are already in the
advanced planning stages for a larger study
Stem cell research – future directions for
heart disease treatment
• Important new knowledge about stem cells and the heart and vessels
• It is definitely possible to put stem cells into the human heart
• Over 500 patients have already had this around the world in
research studies
• Although stem cells are exciting, we have a long way to go!
– It took over 200 years from the first horse catheterisation in
1711 until the first human catheterisation in 1929
- It’s only taken <5 years since heart stem cells were discovered
to do the first human studies