Stem Cell Therapy for Heart Attacks

Heart attacks, also known as myocardial infarctions, occur when the flow of oxygen-rich blood to a section of heart muscle suddenly becomes blocked. If blood flow isn’t restored quickly, the section of heart muscle begins to die, and healthy heart tissue may be replaced with scar tissue.

Each year, more than 1 million people in the United States have heart attacks. Many of these people die, and survivors may go on to suffer from heart failure and sudden death. Treatments include inserting small mesh tubes called stents to open blocked or narrowed coronary arteries, medications to decrease the workload on the heart muscle and reduce blood clotting, and cardiac rehabilitation, a medically supervised program that includes exercise training and education components.

What was the study?

“Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial” was published in The Lancet online February 13 and in the March 10–16, 2012, print edition. CADUCEUS is an abbreviation for CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dysfunction. (In Greek mythology, “caduceus” referred to the staff carried by Hermes, the messenger of the gods.)

The research was a “proof of principle” phase I clinical trial. In such trials, researchers test an experimental drug or treatment in a small group of people (20–80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In the CADUCEUS trial:

• Twenty-five males with an average age of 53 years were enrolled in the study 2–4 weeks after they had a heart attack.
• All patients had a left ventricular ejection fraction (LVEF) of 25–45 percent (average 39 percent). LVEF is the percentage of blood that is pumped out of the left ventricle during each contraction, and is a measure of how well the heart muscle is functioning. A normal LVEF value is 55–70 percent.
• Patients had undergone a coronary angioplasty with stent placement to open their blocked arteries. The blocked vessel was the left anterior descending coronary artery or its diagonal branch in 23 of the patients. Patients had an average scar size of 24 percent of their left ventricular mass.
• Patients were randomly assigned to receive either cardiosphere-derived cells (CDCs) or standard care, in a 2:1 ratio. Thus 17 patients received the CDCs and 8 patients received standard care, which included prescription medications, exercise recommendations, and dietary advice.
• Patients in the CDC group underwent a minimally invasive biopsy about 4 weeks after their heart attack. A catheter was inserted through a vein in the patient’s neck, and healthy heart tissue was obtained that was about half the size of a raisin. The tissue was minced and processed in a laboratory under conditions that encouraged the cells to divide and multiply, until an appropriate numbers of cells were achieved (within approximately 36 days of the biopsy).
• Patients in the CDC group received an infusion of their cells 1.5–3 months after their heart attack through an angioplasty catheter into the artery at the site of the previous blockage. Patients received a low dose (12.5 million cells, 4 patients), an intermediate dose (17.3 million cells, 1 patient), or a high dose (25 million cells, 12 patients).
• Patients were closely monitored at numerous time points to evaluate the safety of the experimental treatment. Heart muscle function was assessed by cardiac magnetic resonance imaging (MRI).

What did the study find?

• There were no complications following the heart muscle biopsy or the infusion of the CDCs into the injured part of the heart muscle.
• After 6 months, there was no statistically significant difference in the rates of serious adverse effects and arrhythmias between the patients who received the cell therapy and those who received standard care. No patients died, developed cardiac tumors, or had a major adverse cardiac event (composite of death and hospital admission for heart failure or nonfatal recurrent myocardial infarction). Five patients had serious adverse events (four in the CDC treatment group and one in the control group).
• Scar size decreased significantly in the CDC group (-7.7 percent) at 6 months, and was unchanged in the control group (0.3 percent). At 12 months, CDC patients had a 12.3 percent absolute decrease in scar size, whereas control patients had a 2.2 percent decrease. (Scar size was measured as scar mass normalized to total left ventricular mass.)
• Viable heart muscle mass increased in the CDC group by 13.0 grams, compared with 0.9 grams in the control group, at 6 months. This increase correlated with the decrease in scar mass.
• Patients in the CDC group had an increase in regional contractility in the CDC-infused segments of their heart muscle and improved systolic wall thickening in these segments at 6 months, compared with the control group.
• There were no significant changes in LVEF, end-diastolic volume, or end-systolic volume in either treatment group at 6 months.

What are the take-home messages?

• The patients who received the cell therapy showed a decrease in scar tissue and an increase in viable heart muscle tissue. These findings suggest that heart muscle scarring following a heart attack may not be permanent, and that it may be possible to restore healthy heart muscle with regenerative-based therapies.
• The experimental stem cell therapy technique was safe, suggesting it can be expanded to a phase II clinical trial. In a phase II trial, the experimental treatment is given to a larger group of people (100–300) to see whether it is effective and to further evaluate its safety.
• Supporting the promise of this treatment option, a parallel phase I study known as SCIPIO also showed benefits from treating patients with cells derived from their own hearts. Patients in this study, which was supported by the NHLBI, had chronic ischemic heart disease.
• The NHLBI is additionally supporting several projects that are examining the safety and effectiveness of adult stem cells taken from bone marrow to treat heart disease (including heart attack and heart failure). These studies are part of the Cardiovascular Cell Therapy Research Network (CCTRN). For information about participation in the CCTRN studies, view a list of CCTRN Centers to find the clinic closest to you.

Where can I learn more?

Health information

• Health Topics: Cardiac MRI, Cardiac Rehabilitation, Coronary Angioplasty, Heart Attack, Heart Failure, Heart Surgery, How the Heart Works, Clinical Trials
• Understanding Clinical Trials: Frequently Asked Questions

Research

• Makkar, R.R., Smith, R.R., Malliaras, K., … & Marbán E. (2012). Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet, 379(9819), 895–904.
• Sui, C.W., & Tse, H.F. (2012). Cardiac regeneration: messages from CADUCEUS. Lancet, 379(9819), 870–1.
• Bolli, R., Chugh, A.R., D’Amario, D., … & Anversa, P. (2011) Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet, 378(9806), 1847–57.
• Heusch, G. (2011). SCIPIO brings new momentum to cardiac cell therapy. Lancet, 378(9806), 1827–8.
• Cardiovascular Cell Therapy Research Network
• Delayed stem cell therapy following heart attack is safe but not effective(News release)

Additional study information

• The study was performed at the Cedars-Sinai Heart Institute in Los Angeles, CA, and the Johns Hopkins Hospital in Baltimore, MD.
• The study was additionally funded by the Cedars-Sinai Board of Governors Heart Stem Cell Center.

April 2012