Cardiovascular diseases are the leading cause of death globally, with 17.3 million deaths in 2008. Induced pluripotent stem cells (iPSCs) offer potential treatments by generating patient-specific heart cells. iPSCs are generated through reprogramming somatic cells using genes like Yamanaka factors. Models of diseases like long QT syndrome using iPSC-derived cardiomyocytes have helped test drugs and uncover disease mechanisms. However, challenges remain in ensuring pure cardiomyocyte populations and modeling complex diseases. If addressed, iPSCs may help regenerative medicine efforts through cell transplantation and screening new drugs for cardiac toxicity.

1. Induced pluripotent stem cells in
cardiovascular diseases

2. Cardiovascular diseases (CVDs)
• An estimate shows that 17.3 million people died from CVDs in
2008, representing 30% of all global deaths.
• The number of people who die from CVDs, mainly from heart
disease and stroke, will increase to reach 23.3. million by 2030
• Group of disorders of the heart and blood vessels
 coronary heart disease -48%
 cerebrovascular disease -25%
 peripheral arterial disease-11%
 rheumatic heart disease – 6%

3. • Treatment Options
 Coronary Angioplasty
 Radiofrequency ablation
 Pacemaker insertion
 Cardiac defibrillator
 Resynchronization therapy
• Risk factors associated with various therapies includes
discomfort and bleeding, blood vessel damages, arrhthymia
Kidney damage.
• hESC therapy could potentially repair and regenerate
damaged heart tissue.

4. Induced pluripotent stem cells
• Overexpression of four genes (or ‘Yamanaka factors’) was able to
turn back the developmental clock of somatic cells .
(Yamanaka et al; Cell,2006)

5. Generating patient-specific iPSCs
• Methods to reprogramme somatic cells
 integrating methods
 non-integrating methods

6. Integrating methods
• Retoviral transduction (eg. Moloney murine leukemia virus)
• Lentiviral transduction (eg.Sendai viruse)

7. Non-integrating methods
• Minicircle vectors
• Protein transduction

8. Cardiovascular disease modelling
• Models for CVDs
 Myocardial infarction(mice)
 arterial thrombosis (rat)
 venous thrombosis (rat)
 venous stasis thrombosis (rabbit)
• Derivation of iPSCs from human somatic cells circumvent the
ethical roadblock associated with the acquisition of hESCs.
• iPSC-CMs can recapitulate the disease phenotype in
humans(Moretti et al,cell,2010) .

9. Modelling the long QT syndrome
• Autosomal dominant inheritance of a 596G/A missense
mutation in the KCNQ1 gene.
• Electrophysiological parameters in iPSC-CMs generated from
two patients with LQTS1 were compared with healthy control.
• Similarly, two other studies reported the use of iPSC-CM
disease models for LQTS2(Itzhaki et al ,Nature 2011.)

10. • The investigators further tested drugs that could either relieve
or aggravate the clinical phenotype of LQTS
• The potential therapeutic effects of nifedipine and pinacidil
was tested in this in vitro model.
• Generation of iPSC-CMs from two patients with Timothy
syndrome (LQTS8)(Yazawa et al, Nature, 2011).
• Timothy syndrome had APs that were significantly prolonged
compared with controls, while atrial and nodal Timothy
syndrome iPSC-CMs did not.

11. significant hurdles still exist in modelling the
more complex cardiovascular diseases using
iPSC technology
• Difficulty in ensuring a purified cardiomyocyte population
from iPSCs .
• The complexities of reproducing a heterogeneous disease
phenotype
• Limitations of modelling essentially adult-onset diseases using
iPSC-CMs.

12. Applications in drug testing and
discovery
• Part of the process of drug development and testing is to
demonstrate that the product does not have any significant
cardiac toxicities.
• To ascertain the cardiac response or side effects of an
individual to a new drug in vitro.
• Targeted gene modification of patient-specific iPSCs

13. Applications in regenerative medicine
Myocardial repair
• Research in regenerative medicine using these cells is still at
an early stage.
Intramyocardial
iPSC-MC delivery
Proper
engrafting
Cytoarchitecture
maintanance
Contractile
perfomance
restoration
Electrical stability
& ventricular wall
thickness
(Nelson et al ,circulation,2009)

14. Conclusion
• Mininizing the potential of transplanted undifferentiated
iPSCs to form teratomas.
• Methods ensuring a purified cardiomyocyte population from
iPSCs.
• Safe and effective methods of cell delivery and ensuring that
transplanted cells remain in the myocardium.

15. References
• Nelson TJ, Martinez-Fernandez A, Yamada S, et al. Repair of
acute myocardial infarction by human stemness factors
induced pluripotent stem cells. Circulation, 2009;120:408e16
• Moretti A, Bellin M, Welling A, et al. Patient-specific induced
pluripotent stem-cell models for long-QT syndrome. N Engl J
Med 2010;363:1397e409
• Yazawa M, Hsueh B, Jia X, et al. Using induced pluripotent
stem cells to investigate cardiac phenotypes in Timothy
syndrome. Nature, 2011;471:230e4