1mm minced biopsy specimen

Formation of 3D CDCs in suspension

Cardiac cells are taken from the healthy

myocardium of the same individual

CDCs are injected into the artery related to area of infarct via a catheter.

(As shown in table 2)

Figure 1. Illustrative process of Cardiosphere-derived cells (CDCs) harvesting

Miane Ng – MBBS Year 4 (London) Gordon Ng – BSc Life Sciences (Toronto)

Anti-thrombolysis • Immediate action to prevent further

deterioration, but no reversibility, therefore cannot improve cardiac function

Percutaneous coronary intervention (PCI)

• Can provide symptomatic relief but again does not regenerate lost/ damaged myocardium

Coronary artery bypass graft (CABG) • Lengthy procedure linked with high risks

of mortality

Heart transplant • Lack of eligible and available donors • High risk of immune-rejection

Stem cell therapy Cardiac progenitor cells (CPCs)

• Harvested and grown from recipients own heart tissue, ethically acceptable.

• Less likely to be rejected by host • Clinical evidence of cardiac regeneration

• The heart can contract 3.7 billion times and still be functional. That’s over 100 years if your heart were to contract at an average pace of 70 beats per minute.

• Nevertheless, though highly variable, the function of the cardiovascular system does decline with age.

• Myocardial infarction (MI) commonly known as a heart attack, kills 1 person every 6 minutes and claims 94,000 lives on average per annum in the UK.

• Though there are many preventative measures and treatments for a heart attack, there was thought to be no reversibility once the damage had been inflicted

• Recent stem cell therapy studies with focus on cardiac regeneration however, have shown benefits not only in sustaining but improving an individuals cardiac function hence quality of life after experiencing a heart attack.

Figure 3. Representative MRI and changes in scar size

Short axis MRI of the heart at baseline (77 days post-MI) (A), 6 months after in a control (B). Short axis MRI of the heart at baseline (82 days post-MI) (C), 6 months after CDC infusion (D), Infarct scar tissue appears white, whereas viable myocardium appears dark.

References • Makkar RR, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomized phase 1 trial. (2012) The

Lancet 371:895-903 • Feng Y, et al. Progenitor/ stem cell transplantation for repair of myocardial infarction: Hype or hope? (2012) NIH 1(1):65-77 • Goldspink DF, et al. Cardiomyocyte death and the ageing and failing heart. (2004) Experimental physiology 88(3):447-458 • Goldthwaite CA. Stem cells and Cardiac repair. (2005) Chapter 6Pgs 57-63 • http://www.cardiacmatters.co.uk/facts-figures-heart-disease-uk.html • http://www.hopkinsmedicine.org/stem_cell_research/cell_therapy/a_new_path_for_cardiac_stem_cells.html • http://www.stemcellnetwork.ca/index.php?page=heart-failure&hl=eng • http://abcnews.go.com/Health/stem-cell-therapy-promising-regenerating-damage-heart-muscle/story?id=15576909#.UBsmTKOaZS4

• Histological findings in mouse models and MRI studies obtained from individuals who participated in the trial both support the clinical evidence of improvement seen after 6 months of receiving CDC infusions.

• However, there were also limitations to this study owing to the small sample sizes from each of the groups which may not have been a true representation of the whole population.

• Furthermore, despite the benefits seen, the mechanism of action remains unknown. In theory, the stiffened infarct area is now replaced by more compliant material which may relieve ventricular wall stress.

Figure 2. Post-mortem studies on mouse models In initial stages of the trial, post-mortem studies on models of mice were used, the histograms above illustrate the significant reductions in scar size (A), reduction in scar mass (B) and an increase in the viable mass of the myocardial 6 months following CDC infusion in comparison to the control group which did not receive infusions.

A B

C D

Control Control

CDCs CDCs

0

10

20

30

Controls CDCs

0

10

20

30

40

50

Controls CDCs

0

100

200

300

Controls CDCs

p=0.0001 p=0.0014 p=0.0099 Scar Size Scar Mass Viable Mass

Tota

l LV

(%

)

mg mg

• CDCs contain subpopulations, including mesenchymal cells which could also play a role in cardiac repair.

• Cardiomyocytes contract in unity by signal conduction through gap junctions. We need a way of assessing synchronized contractions between the old and new cells

• Unsynchronized firing and contraction of the untrained myocytes may lead to arrhythmias and adverse cardiac events causing more harm than benefits.

• Biochemical studies on mechanism of action, o Direct – cell differentiation o Indirect – paracrine effects

Though it may not be entirely possible to re-grow a new heart, evidence suggests that what was once thought to be a post-mitotic organ, may harness the potential of regeneration to some extent. Nevertheless, this probable new lease of life would require synchronization in order to contract in unity with its surrounding myocardium.

Although this study could potentially revolutionize the field of cardiology, to assess the long term implications of CDC infusions and to ensure greater reliability of the data, a longitudinal study with recruitment of a larger cohort is necessary. It would also be beneficial to verify the mechanism of action through future biochemical studies.

Inferior (Posterior) Right Coronary Artery (RCA)

Anterior-lateral Left Coronary Artery (LCA)

Anterior-septal Left Anterior Descending (LAD)

Lateral Left Circumflex Artery (LCX)

Table 2. Artery associated with site of Myocardial infarct

Table 1. Current treatments post-myocardial infarct

3. Plate Explants

4. Cardiospheres

5. Cell infusion

1. Damaged myocardium

2. Harvest cardiac tissue