Cardiac Stem Cell Therapy for the Treatment of Heart Failure Brandy Weller

PICO Question Patient: Adult patients aged 18-75 with heart failure defined as an ejection fraction of less than 50% Interventions: Stem cell therapy Comparison: Medical management Outcome: Reduced morbidity/mortality and improved ejection fraction Question: In adult patients aged 18-75 with heart failure defined as an ejection fraction of less than 50% does stem cell therapy reduce morbidity/mortality, and improve ejection fraction when compared to medical management?

Heart Failure (www.MDconsult.com) Affects nearly 5 million Americans currently, > 500,000 new cases diagnosed each year Most common inpatient diagnosis in the US for patients > 65 years of age Affects 2% of the population in developing nations 12-15 million office visits per year More common in men before age 75, after equally affects both genders

Heart Failure (Ze-Wei, 2007) Irrespective of etiology classified by Cardiac hypertrophy Insufficient vascularization Loss of cardiomyoctes Reduced contractility

Diastolic Heart Failure Systolic Heart Failure Preserved EF Elevated filling pressure Systolic Heart Failure Reduced EF less than 55 % www.med.uc.edu/kranias/heart_failure.htm

Heart Failure Left sided heart failure Right sided heart failure Ischemic heart disease HTN Arrhythmias Valvular disease (AS, AI, MI) Cardiomyopathy Volume Over loaded Right sided heart failure Left sided heart failure COPD PE Pulmonary HTN Valvular disease (MS)

Heart Failure: (Gajos, 2008)

Current Treatment Beta-Blockers ACE-Inhibitors ARB Diuretic Cardiac Glycosides (digoxin) Heart Transplantation www.googleimages.com

Current Treatment Outcomes Increased morbidity and mortality Decreased quality of life (Hagege, 2006) Patients have less < 50 % survival rate after 5 yrs (Ichim, 2008) http://kidneyinthenews.files.wordpress.com/2007/10/pills1.jpg

Cardiac Myocytes Believed to be terminally differentiated Angiogenesis/arteriogenesis Collateral circulation in long standing ischemia Provides hypothesis that in-situ cardiac stem cells exist (Wollert, 2005)

Stem Cells (Wollert, 2005)

Stem Cell Therapy (Martin-Rendon, 2008; Zei-Wei, 2007; Angelini, 2005, Wollert, 2005) www.googleimages.com Initial research in mice with ischemic heart failure Cardiac myocte repair Increased EF Decreased mortality Pigs with chronic ischemia Increased collateral blood flow Increased regional contractility

Stem Cell Therapy (Martin-Rendon, 2008 ; Angelini, 2005, Barbash, 2006) By 2004 > 150 humans underwent stem cell therapy Observational studies No controls Reduction in scar tissue after MI Revascularization Reversed ischemia (75% improvement) Increased ejection fraction N=8 avg increase 8.7% in <1 yr No controls in this study

Stem Cell Therapy (Zei-Wei, 2007) Randomized Control study N=60 5% improvement in EF at 6 months No significant improvement over controls at one year. Greatest improvement seen with baseline EF less than 48%

Stem Cell Therapy (Ichim, 2007, Angelini, 2005) Improved EF Immediate vs. long term Reduction in angina Improved quality of life In a review study:

Conclusion Limited research appears to offer hope More effective than medical management alone 5-10 % improvement in EF can drastically improve quality of life Increased exercise capacity Decreased morbidity/mortality

Future Research (Barbash, 2006) Type of Donor source Bone Marrow In-situ cardiac stem cells Skeletal myoblasts Placental/mesenchymal cord blood Endothelial progenitor cells Adult stem cells Located in body tissues Reservoir for damaged and aging cells Restricted differentiation Embryonic stem cells Controversial Versatile Difficult to control & tend to form tumors

Future Research Methodology of Transplantation During CABG Intravenous infusion Transendocardial injection Transepicardial injection Transcoronary vein injection Direct injection into the ventricular wall Vary in concentration delivered, efficacy, and localization

Application With future research confirming efficacy An adjunct to medical management Reduction in infarcted tissue (Wollert, 2005) Not generally achieved with medical management alone Potential to reduce demand for heart transplantation Patients with inoperable CAD

References Angelini, P., Markwald, RR. (2005). Stem cell treatment of the heart. A review of its current status on the brink of clinical experimentation. Texas Heart Institute Journal. 32, 479-488. Barbash, IM., Leor, J. (2006). Myocardial regeneration by adult stem cells. Israeli Medical Association Journal. 8, 283-187. Hagege, AA., Marolleau J., Vilquin, J., Alheritiere, A., Peyrard, S., Duboc, D., Abergel, E., Messas, E., Mosseaux, E., Schwartz, K., Desnos, M., Menasche, P., (2006). Skeletal myoblast transplantation in ischemic heart failure. Long-term follow-up of the first phase I cohort of patients. Circulation. 114 (supplement I): 108-113. Ichim, TE., Solano, F., Brenes, R., Eduardo, G., Chang, J., Chan, K., Riordan, NH. (2007). Placental mesenchymal and cord blood stem cell therapy for dilated cardiomyopathy. Reproductive BioMedicine. 16 (6), 898-905. Martin-Rendon, E., Brunskill, S., Doree, C., Watt, S., Mathur, A., Stanworth, S. (2008). Stem cell treatment for acute myocardial infarction. Cochrane Database System Review, 4: CD006536. Wollert, KC, Drexler, H. (2005) Clinical applications of stem cells for the heart. Circulation Research. 96, 151-163. Ze-Wei, T., Long-gui, LI. (2007). Cell therapy in congestive heart failure. Journal of Zehjang University Science B. 8 (9), 647-660.