| Stem Cell Therapy in Cardiovascular Diseases | ||||||||||||||
| Phillip A Poole-Wilson | ||||||||||||||
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| Researchers around the world are investigating
a variety of approaches to myocardial regeneration
via transplantation of immature cells that have
the potential for becoming functional myocytes).1
The goals of such therapy are to improve the structural
adaptation of the heart to myocardial infarction
(MI), regenerate ischemic and scarred myocardium,
enhance cardiac function, and improve quality of
life (QOL).2 One
approach involves the intracoronary infusion of
bone-marrow-derived autologous stem cells in patients
with acute MI. Stem cells have the capacity to differentiate
into a variety of different cell types and experimental
evidence suggests that such cells “home,”
or migrate, to the infarct zone even when infused
peripherally.3 Early
clinical studies have demonstrated promising but
variable effects on infarct size, left ventricular
(LV) systolic function, and myocardial viability.3,4
Whether improvements can be attributed to differentiation
of stem cells into cardiac myocytes, angiogenesis,
or some other mechanism, is unclear. Another approach, used in patients with chronic ischemia and heart failure, is intramyocardial transplantation of autologous skeletal myoblasts. Unlike stem cells, skeletal myoblasts are predetermined to become contractile muscle. They are readily available and easily cultured in the cell laboratory. In addition, they are highly resistant to ischemia, which enables them to survive under hypoxic conditions. There have been concerns, however, about their potential pro-arrhythmic effects. In early studies, transplantation of skeletal myoblasts took place during open-chest surgery. Today, researchers are performing percutaneous endocardial injections of both skeletal myoblasts and bone-marrow-derived stem cells guided by electromechanical mapping.5 |
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 Intracoronary
Stem-cell Infusion in Acute MI |
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| At the 2005 Scientific Sessions of
the American College of Cardiology, results were
presented of the first randomized, placebo-controlled,
double-blinded study of intracoronary infusion of
autologous bone marrow cells in acute MI. The study
demonstrated a reduction in infarct size and an
improvement in ventricular remodeling with the novel
therapy. However, investigators observed no significant
improvement in LV systolic function. Stefan Janssens,
MD, PhD, University of Leuven, Belgium, and colleagues
set out to investigate the effect of intracoronary
transplantation of autologous bone marrow cells
on myocardial structure, global and regional function,
and metabolism. The study enrolled 67 patients with a cumulative ST-segment elevation > 6 mm. Only patients who arrived at the hospital at least 2 hours after onset of chest pain were eligible to participate in the study, as investigators were concerned that more rapid recanalization of the infarct-related artery might result in spontaneous recovery of the myocardium unrelated to stem-cell infusion. After successful percutaneous coronary intervention (PCI), patients underwent echocardiography and positron emission tomography (PET) to determine baseline LV function and metabolism. Within 24 hours the patients were then randomized to receive either intracoronary transplantation of 300 million bone marrow cells, half of which were mononuclear, or a placebo infusion. During a 7-day hospitalization period, patients were continuously monitored for arrhythmias and underwent magnetic-resonance (MR) perfusion and late-enhancement imaging to determine global and regional LV function and infarct size. At 4-month follow-up, PET, MR, and echocardiographic imaging were repeated. The investigators observed no increase in life-threatening arrhythmias or recurrent ischemia in the treatment group. One patient died at 2 months as a result of excessive anticoagulation. At 4-month follow-up, global LV function had improved by an average of 4%, with no significant difference between the treatment and placebo groups. There was a significantly greater reduction in infarct size in patients who received the stem-cell infusion, however. In particular, among patients treated within 6 hours of chest-pain onset, stem-cell therapy was associated with an almost 40% greater reduction in infarct size compared to the placebo group. A similar benefit was observed in patients with large infarcts (defined as >20% of LV mass index). Regional LV function, as gauged by MR systolic wall-motion index in the infarct and border zones, was no different in the stem-cell and control groups. However, end-diastolic wall thickness, a marker of remodeling, was significantly attenuated in both the infarct and remote zones in the stem-cell group. Preliminary analysis showed no significant difference between the two groups in PET indices of perfusion and metabolism. Dr. Janssens concluded that infusion of bone-marrow cells after acute MI is safe and can significantly alter the structural adaptation of the heart and enhance infarct healing, particularly in patients who receive early treatment or who have large infarcts. The associated reduction in compensatory hypertrophy of remote myocardium suggests a benefit in diastolic function as well, he said. |
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| Skeletal
Myoblast Injection During CABG |
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| A separate study focused on injection
of skeletal myoblasts at the time of coronary artery
bypass grafting (CABG) in patients with ischemic
cardiomyopathy. After more than 3 years of follow-up,
investigators found this technique to be safe and
feasible. In addition, they observed significant
improvements in symptoms, LV volumes, and LV ejection
fraction (LVEF). Nabil Dib, MD, FACC, Arizona Heart
Institute, Phoenix, reported the results of this
open-label, nonrandomized, multicenter study. Previously,
he reported that LVEF improved by 60% in patients
who underwent skeletal myoblast transplantation
in conjunction with CABG surgery after MI (AHA 2002).
At ACC 2005, he reported 3-year follow-up data for
a total of 24 patients with a mean LVEF of 28%,
all of whom had a history of MI and were scheduled
to undergo CABG. Preparation for myoblast injection included biopsy of the leg muscle. Skeletal myoblasts were then isolated in the laboratory and cultured over 4 to 6 weeks. During the bypass-surgery procedure, the first 9 patients received either 10 million, 30 million, or 100 million myoblasts, which were injected into several sites within the ischemic myocardium; then a total of 15 patients received an estimated 300 million cells. Cell delivery was 100% successful, without injection-related complications. Over a follow-up of 11 to 45 months, 2 patients developed nonsustained ventricular tachycardia that may have been related to myoblast transplantation. All other adverse events were deemed unrelated to the procedure. Patient symptoms improved significantly at 3 and 12 months compared to baseline (pre-myoblasts), as evidenced by a drop in the average New York Heart Association (NYHA) class from 2.1 to 1.4. This significant difference was not sustained at 24 months. LVEF improved from 28.2 at baseline to 34.7 at 12 months (p=0.02) and 36.2 at 24 months (p=0.01). LV end-systolic and end-diastolic volume also improved significantly from baseline to 6 months. But PET scanning revealed what Dr. Dib referred to as the most important findings of the study: Within 6 months, scar tissue was replaced by viable myocardium, as evidenced by a several-fold increase in uptake of the metabolic tracer, fluorodeoxyglucose. MR imaging confirmed a reduction in infarct size following cell transplantation. Dr. Dib concluded that the isolation and expansion of autologous skeletal myoblasts, and their surgical transplantation into infarcted myocardium at the time of CABG, is feasible and safe. Moreover, he said, PET scanning can detect the viability of engrafted tissue. (Editor’s note: Results of about half of these patients were published in early 2005.6 The article included the results of an additional six patients who underwent LV assist device implantation as a bridge to heart transplantation. The latter patients were required to donate their heart for testing at the time of transplantation. Histological analysis documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium.). |
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| Percutaneous
Endocardial Stem Cell Injection |
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| In a small study that evaluated percutaneous
endocardial injection of autologous bone marrow
cells in patients with chronic myocardial ischemia,
investigators found the procedure to be safe and
associated with improvement of symptoms, QOL, and
cardiac function. The study enrolled 15 patients
whose myocardial ischemia was inadequately managed
on optimal medical therapy and who were ineligible
for revascularization. Gated single-photon emission
computed tomography (SPECT) imaging identified areas
of ischemic myocardium in all patients. Beeres,
et al., Leiden University Medical Center, the Netherlands,
injected 30 million to 100 million autologous mononuclear
bone-marrow cells into the endocardium, guided by
electromechanical mapping. Blood tests showed no myocardial damage associated with the procedure. Echocardiography showed no pericardial effusion and no arrhythmias were recorded. Canadian Cardiovascular Society anginal class, angina frequency, and nitroglycerin use all improved significantly at 3- and 6-month follow-up. In addition, LVEF and QOL, as assessed by the Seattle Angina Questionnaire, both improved significantly. QOL improved from 52% at baseline to 70% at 3 months and 78% at 6 months, both significant differences. However, no significant changes in exercise capacity or perfusion defect size were observed. Investigators concluded that intramyocardial injection of autologous bone marrow cells is safe and improves anginal symptoms and cardiac mechanical performance. |
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| REFERENCES |
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Available Volumes
| EDITOR IN CHIEF |
| Dr.
Rajeev Gupta (MD PhD FACC) |
 |
| HON. EDITOR |
| Dr.
Soneil Guptha (MD FACC FESC) |
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