Stem Cells for Heart Disease: hype or hope

Robert M. GrahamVictor Chang Cardiac Research Institute and

St Vincent’s Hospital, Sydney, AustraliaAustralian Health Insurance Association

Conference31 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 cardiaccatheterisations wereperformed by Hales in1711 – inserting brass

pipes through the veins

and arteries into thehearts of horses.

Using the wind-pipes of

geese as a connector,the brass pipes wereconnected to glass

tubesto 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 Gruentzigperformed 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

The hound of Zeus, the tawny eagle,…feasting on thy liverTill he hath gnawn it black. - Aeschylus, Prometheus Bound

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.

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 andblood 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)

POSITIVE

POSITIVEBORDERLINE

NEGATIVE

NEGATIVE

Stem cell trial at St Vincent’s Hospital and The Victor Chang Cardiac Research

Institute

Granulocyte-colony stimulating factor (G-CSF) and intra-coronary endothelial progenitor cell (EPC)

infusion in patients with chronic refractory ischaemic heart disease

The stem cell team

VCCRI cardiac stem cell labRichard HarveyJoan LiCorey HeffernanOwen PrallIsh Ahmed

Robert Graham

Clinical trial at SVH and VCCRI• Investigators

David MullerPeter MacdonaldMichael FeneleyNeil JacobsHelen TaoAndrea HerbertDavid MaJohn MooreSam MillikenAnthony Dodds Judy FreundLyn ChanSilviu Itescu

Robert Graham

• Data and Safety Monitoring BoardRoger AllanJohn RaskoVivian Fernandez

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

AgeSexBody mass indexDiabetesHigh cholesterolHigh blood pressureSmokingFamily history (1st degree relative < 55 male or < 65

female)

Number of bypass operationsNumber open bypass graftsNumber of open heart arteriesPumping ability of the heart (LVEF)Number of cardiac tablets per day

62 ± 9.0 (36 - 74)Male = 18/20, female = 2/20

29.8 ± 4.4 (22.1 - 39.2)3/20

20/2018/20

17/20 ex, 0/20 current15/20

1.6 ± 0.7 (1 - 3)1.5 ± 1.0 (0 - 4)

0.7 ± 0.948.7 ± 10.3% (30 - 65%)

8.7 ± 1.4

Data presented as mean ± SD (range), or number of patients/20

Final trial results and future directionsFinal trial results and future directionsSafe

Less chest painLess use of medications to get rid of chest pain

Exercise time on the treadmill improvedQuality 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