Intramyocardial Injection of Autologous Aldehyde Dehydrogenase-Bright Stem Cells for Therapeutic Angiogenesis (FOCUS Br)

This is a phase I, double blind trial to evaluate the use of Aldehyde Dehydrogenase-Bright (ALDHbr) in ischemic cardiomyopathy patients. The study hypothesis is that transendocardial injections of autologous bone marrow cells in patients with end-stage ischemic heart disease is safe, can provide neovascularization, and can improve perfusion and myocardial contractility. The primary object of this study is to assess the safety of the ALDHbr cell injections. The efficacy will be based upon treadmill MVO2. A maximum of 60 patients will be enrolled in the study. At the end of 6 months, after the required testing has been completed, the patients will be told whether they were in the control group or not. The patients in the control group will be given the option to crossover and actually receive stem cell injection. At the time of crossover, which then becomes the baseline, patients will begin the follow-up with all testing including clinic visits for one year for a total of 18 months follow-up.

• Stem Cell Therapy (Biological), also known as NOGA Myostar catheter: Cells are injected under electromechanical guidance and delivered by the Myostar catheter after NOGA mapping.
• Control (plasma) (Other): Placebo patients receive an injection of plasma (control) containing 5 % albumin the the same quantity as the stem cell arm. A total of 15 injections of 0.2 ml to total 3.0 ml.

Primary outcomes

• Safety of Aldehyde Dehydrogenase Bright Stem Cells Versus the Control Group as Measured by Combined Early and Late Adverse Events [Baseline and 6 months]: Safety of cell injections was assessed by reviewing adverse events at 2 time points: Baseline (periprocedural period up to 2 weeks post-procedure) and at 6 months post-procedure. Major adverse events were adjudicated (hospitalization, arrhythmia, exacerbation of congestive HF \[CHF\], acute coronary syndrome, myocardial infarction, stroke, or death).

Secondary outcomes

• New York Heart Association (NYHA) Classification [Baseline and 6 months]: Clinical and functional assessment in endstage ischemic cardiomyopathy patients using New York Heart Association (NYHA)Classification and indicates extent of heart failure based on limitations in physical activity. Class I- No symptoms/limitation in ordinary physical activity (shortness of breath when walking, etc) Class II-Mild symptoms/slight limitation during ordinary activity Class III- Marked limitation in activity due to symptoms, even during less-than-ordinary activity Class IV- Severe limitations in activity/experiences symptoms while at rest (bedbound)
• Canadian Cardiovascular (CCS) Angina Score [Baseline and 6 months]: Clinical and functional assessment in endstage ischemic cardiomyopathy patients using Canadian Cardiovascular (CCS) Angina Score which indicates discomfort from angina (chest pain). Class I- Angina only during strenuous or prolonged activity Class II- Slight limitation, with angina only during vigorous physical activity Class III- Symptoms with everyday living activities (moderate limitation) Class IV- Inability to perform any activity without angina or angina at rest (severe limitation)
• Echocardiography (EF)Percent (%) [Baseline and 6 months]: Clinical and functional assessment in endstage ischemic cardiomyopathy patients using Echocardiography measures ejection fraction(EF)as a percentage(%) of blood leaving the heart with each beat or contraction. It can provide information concerning structural characteristics and blood flow in the heart and blood vessels. A normal heart pumps 50-75% of the blood with each contraction.
• Left Ventricular End-Systolic Volume (LVESV) (ml) [baseline and 6 months]: Clinical and functional assessment in endstage ischemic cardiomyopathy patients using Left Ventricular End-Systolic Volume (LVESV) when the blood moves from the ventricles to the atria during the contraction cycle. Measured as volume in milliliters (ml). Normal is approximately 60- 65 milliliters.
• Left Ventricular End-Diastolic Volume (LVEDV) [baseline and 6 months]: Clinical and functional assessment in endstage ischemic cardiomyopathy patients using Left Ventricular End-Diastolic Volume (LVEDV)which is the volume of blood inside the left ventricle when the heart has completed its filling cycle. The volume of the left ventricle is measured during contraction and relaxation. Normal heart volume inside the left ventricle is about 140 milliliters.
• Echocardiography Wall Motion Score Index (WMSI) [baseline and 6 months]: Clinical and functional assessment in endstage ischemic cardiomyopathy patients using Echocardiography Wall Motion Score Index (WMSI) as defined by the American Heart Association which allows detection of abnormalities in the heart wall or blood flowing through the heart. Using this model, the left ventricle is divided into 17 segments. Normal contracting Left Ventricle has WMSI of 1. Larger WMSI indicates higher degree of abnormalities (2 for hypokinetic, 3 for akinetic, 4 for dyskinetic, and 5 for aneurysmal). WMSI was calculated as the sum of scores divided by the total number of segments.
• Myocardial Oxygen Consumption (MVO2) [baseline and 6 months]: Clinical and functional assessment in endstage ischemic cardiomyopathy patients using Myocardial Oxygen Consumption (MVO2)which is the amount of oxygen used by the heart muscle and is indicative of heart muscle function. Normal value is 15.5 Volume %. Measured as milliliters (ml) oxygen per kilogram (kg) body weight per minute.
• Echocardiography (EF) Percent (%) [baseline and 6 months]: Clinical and functional assessment in endstage ischemic cardiomyopathy patients using Echocardiography measures ejection fraction(EF)as a percentage(%) of blood leaving the heart with each beat or contraction. It can provide information concerning structural characteristics and blood flow in the heart and blood vessels. A normal heart pumps 50-75% of the blood with each contraction.
• Total Severity Score (Stress) [baseline and 6 months]: For the stress test, cardiac SPECT polar mapping (gated dual-isotope) is used to evaluate perfusion, compared against a database with a statistically significant number of polar maps of healthy hearts based on gender, data acquisition method, stress vs rest and type of data (i.e. perfusion, wall motion or wall thickening) using a clinically validated software package (J Nucl Med Technol 2006; 34:3-17). The basal and mid-ventricle heart wall is mapped by cylindrical sampling and apex mapped by spheric, cylindric and radial sampling. Total severity score during stress is the sum of blackout pixels in the blackout polar map of myocardial perfusion during stress using cardiac SPECT imaging (adding scores in different views), weighted by the number of SDs below the mean. Total severity score varies from 0 (normal) to several thousands although the upper limit is not well defined. A score greater than 1000 indicates poor perfusion.
• Total Severity Score (Rest) [baseline and 6 months]: For the total severity score at rest, cardiac SPECT polar mapping (gated dual-isotope) is used to evaluate myocardial cardiac perfusion, compared against a database with a statistically significant number of polar maps of healthy hearts and compared based on gender, data acquisition method, stress vs rest and type of data (i.e. perfusion, wall motion or wall thickening) using a clinically validated software package (J Nucl Med Technol 2006; 34:3-17). The basal and mid-ventricle heart wall is mapped by cylindrical sampling and apex mapped by spheric, cylindric and radial sampling at rest. Total severity score at rest is the sum of blackout pixels in the rest blackout polar map of myocardial perfusion cardiac SPECT imaging (adding scores in different views), weighted by the number of SDs below the mean. Total severity score varies from 0 (normal) to several thousands although the upper limit is not well defined. A score greater than 1000 indicates poor perfusion.
• Total Severity Score (Reversible) [baseline and 6 months]: For the severity test, cardiac SPECT polar mapping (gated dual-isotope) is used to evaluate myocardial cardiac perfusion, compared against a database with a statistically significant number of polar maps of healthy hearts and compared based on gender, data acquisition method, stress vs rest and type of data (i.e. perfusion, wall motion or wall thickening) using clinically validated software package (J Nucl Med Technol 2006; 34:3-17). The basal and mid-ventricle heart wall is mapped by cylindrical sampling and apex mapped by spheric, cylindric and radial sampling at rest/stress. Total severity score is the sum of blackout pixels in rest/stress blackout polar map of myocardial perfusion cardiac SPECT imaging (adding scores in different views), weighted by number of SDs below mean. Total severity score reversible is total severity scores at rest subtracted from those during stress. The severity score varies from 0 (normal) to > 1000 (poor perfusion) but upper limit is not well defined.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Canadian cardiovascular (CV) Class II-IV angina and/or congestive heart failure (CHF) symptoms
* Ejection fraction less than or equal to 45%
* Reversible perfusion defect on single photon emission computed tomography (SPECT)
* Coronary artery disease (CAD) unable to be corrected by surgery (bypass) or intervention (stent)
* Able to walk on treadmill
* Hemodynamically stable

Exclusion Criteria:

* Age less than 18 or greater than 70
* Atrial fibrillation
* Severe valve disease
* History of cancer in last 5 years
* HIV positive; hepatitis B or C positive.
* Left ventricular wall thickness less than 8 mm
* Recent heart attack within the last 30 days

Participant flow

Outcome results

• Safety of Aldehyde Dehydrogenase Bright Stem Cells Versus the Control Group as Measured by Combined Early and Late Adverse Events (Primary), Number, participants: Control 10; Stem Cell Therapy 10
• New York Heart Association (NYHA) Classification (Secondary), Mean, NYHA Functional class: Stem Cell Therapy 2.5 +/- 0.5; Control 2.6 +/- 0.5
• Canadian Cardiovascular (CCS) Angina Score (Secondary), Mean, units on a scale: Stem Cell Therapy 2.5 +/- 0.5; Control 2.5 +/- 0.5
• Echocardiography (EF)Percent (%) (Secondary), Mean, percentage of blood: Stem Cell Therapy 36.1 +/- 10.9; Control 32.1 +/- 10.6
• Left Ventricular End-Systolic Volume (LVESV) (ml) (Secondary), Mean, ml: Stem Cell Therapy 93.2 +/- 46.1; Control 94.9 +/- 59.8
• Left Ventricular End-Diastolic Volume (LVEDV) (Secondary), Mean, ml: Stem Cell Therapy 138.3 +/- 43.0; Control 132.7 +/- 65.2
• Echocardiography Wall Motion Score Index (WMSI) (Secondary), Mean, units on a scale: Stem Cell Therapy 1.91 +/- 0.51; Control 2.13 +/- 0.38
• Myocardial Oxygen Consumption (MVO2) (Secondary), Mean, ml/kg/min: Stem Cell Therapy 15.5 +/- 6.3; Control 14.1 +/- 4.8
• Echocardiography (EF) Percent (%) (Secondary), Mean, percentage of blood: Stem Cell Therapy 38.0 +/- 17.5; Control 41.9 +/- 11.8
• Total Severity Score (Stress) (Secondary), Mean, units on a scale: Stem Cell Therapy 798.2 +/- 528.7; Control 1007.6 +/- 352.4
• Total Severity Score (Rest) (Secondary), Mean, units on a scale: Stem Cell Therapy 542.8 +/- 440.7; Control 812.4 +/- 304.5
• Total Severity Score (Reversible) (Secondary), Mean, units on a scale: Stem Cell Therapy 72.6 +/- 95.2; Control 46.5 +/- 48.5

Adverse events

Time frame: Adverse event data were collected pre-procedure, during procedure, after procedure, week 1, week 4, month 3 and month 6 post-procedure.

Serious adverse events by term

Other adverse events by term

65 more terms not shown.

Limitations and caveats: The study is a preliminary study based on a small sample size which limits the statistical rigor of the analysis.

• Perin EC, Silva GV, Zheng Y, Gahremanpour A, Canales J, Patel D, Fernandes MR, Keller LH, Quan X, Coulter SA, Moore WH, Herlihy JP, Willerson JT. Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure. Am Heart J. 2012 Mar;163(3):415-21, 421.e1. doi: 10.1016/j.ahj.2011.11.020. Epub 2012 Feb 10. PMID 22424012

• Emerson Perin, MD, PhD, Principal investigator, Texas Heart Institute