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Can cellular cardiomyoplasty cure heart failure?

Cardiomyocyte regeneration through stem cell transplantation is a promising option for patients with a loss of functioning myocardium after myocardial infarction.

Melinda Jean Johnson, MCMS, PA-C
Doreen C. Parkhurst, PA, MD, FACEP

Melinda Johnson works in the emergency department of Gulf Coast Hospital, Fort Myers, Florida. Doreen Parkhurst is Assistant Dean, School of Graduate Medical Sciences, and Program Director, PA Program, Barry University, Miami Shores, Florida. The authors have indicated no relationships to disclose relating to the content of this article.

Heart failure (HF) affects approximately 5 million people in the United States, with 550,000 new cases diagnosed each year.¹ The number of annual hospitalizations for this condition has increased from around 400,000 in 1979 to more than 1.1 million in 2004.¹ From 30% to 40% of patients with HF are hospitalized every year,² and it is the leading cause of hospitalization in adults older than 65 years.³

The most common cause of HF is MI, but uncontrolled hypertension, valvular heart disease, congenital heart disease, cardiomyopathies, myocarditis, or infectious endocarditis can also lead the heart to fail.² Given the aging of the population, HF is becoming a larger clinical issue. More than 287,000 people die from it each year,¹ and 5-year mortality rates are 60% for men and 45% for women, with the most common cause of death being progressive failure of the heart.²

FACTS ABOUT HEART FAILURE

After MI occurs, the loss of functioning myocardium initiates a process of adverse left ventricular (LV) remodeling, leading to chamber dilation and contractile dysfunction in many patients.⁴ Complete revascularization procedures help some. However, a large number of patients have poor distal vessels, total arterial occlusion, or unacceptable procedural risks due to concomitant medical conditions, making revascularization procedures an unacceptable choice.⁵

HF occurs when the heart is unable to adequately pump blood forward throughout the body. It can be classified as systolic or diastolic, high-output or low-output, and left-sided or right-sided.⁶ Systolic failure is characterized by a diminished capacity of the affected ventricle to eject blood because of impaired contractility or pressure overload. This causes the blood coming into the heart from the lungs to flow backward, leading to pulmonary vascular congestion.^2,6 Diastolic failure is characterized by impaired early diastolic relaxation, an increased stiffness of the ventricle, or both, causing vascular congestion.⁷ High-output failure results when the heart is unable to meet the abnormally elevated metabolic demands of the peripheral tissues. Low-output failure is characterized by insufficient forward output both at rest and during times of increased metabolic demand. Acute HF is typically used to describe decompensation from a state of compensated HF in a person who is completely asymptomatic. Chronic HF is the term used when symptoms are defined by the person’s level of activity.⁶

At present, HF treatment involves a combination of nonpharmacologic and pharmacologic interventions. Patients are instructed to limit sodium intake to approximately 2 g/d and to limit fluid intake. Weight reduction and supervised exercise also may help reduce the workload on the failing heart and improve cardiac function. Diuretics are the most effective therapy for symptomatic relief of pulmonary congestion and peripheral edema. Vasodilators reverse the peripheral vasoconstriction that occurs. Inotropic agents increase ventricular contractility, thereby decreasing HF symptoms. Beta-blockers produce consistent substantial rises in ejection fraction (EF) and decreases in LV size and mass.⁶

These therapies are generally effective but do not address the underlying issue of the myocardial cell death that occurs following MI, predisposing patients to HF. In addition, the only option currently available for patients with HF that is refractory despite maximal medical management is transplant. Given the rising number of cases and the economic impact on health care, it is imperative to develop newer and more effective treatment options for patients with HF.

It was once believed that the heart is incapable of self-renewal. There is increasing evidence, however, that stem cell mobilization to the heart and differentiation into cardiomyocytes is a naturally occurring process.³ Although this information is promising, these cells have limited ability to minimize the effects of infarcted myocardium and recover cardiac function. A logical next step is to introduce stem cells into the infarcted myocardium in order to stimulate regeneration of cardiomyocytes and ventricular remodeling.³ This article reviews the types of cells used in ongoing research, as well as the various forms of cell administration.

POTENTIAL DONOR CELLS

Skeletal myoblasts, adult mesenchymal cells, endothelial cells, and fetal cardiomyocytes have all been proven to be effective donor cells; however, it has not yet been determined which is the most effective. Additional studies comparing the donor cell types are needed.

Various methods are used to obtain these cells. Autologous cultured myoblasts are obtained from a patient’s muscles. Blood is aspirated from a patient’s bone marrow, and these aspirates can be injected directly into the infarcted myocardium. Mononuclear cells can be purified, ex vivo cultured, and then reinfused into the infarcted area.

Skeletal myoblasts Skeletal muscle cells are able to regenerate after injury because of the presence of satellite cells, which are reserve cells located on the surface of mature myofibers.⁸ Some advantages to this type of donor cell include their resistance to ischemia, which allows the myoblasts to survive and engraft in host myocardium; their ability to multiply after injury with a high potential for division in culture; their easy accessibility; their suitability for autologous transplantation; and their lack of immunogenicity.^3,8

The future use of skeletal myoblasts may be limited because of their association with ventricular tachyarrhythmias.³ Several patients who underwent autologous skeletal myoblast transfer experienced ventricular tachyarrhythmias within weeks of transplantation.³ Furthermore, skeletal myoblasts have two serious biological differences when compared to adult cardiomyocytes: they are arrhythmogenic and they lack gap junctions (proteinaceous tubes that connect adjacent cells and allow material to pass from one cell to the next without having to pass through the plasma membranes of the cells).

Adult mesenchymal stem cells, also known as marrow stromal cells, have the ability to colonize different tissues, replicate, and allow for autologous transplantation. They also are thought to have multilineage differentiation capacity in vitro, with the ability to differentiate into specialized tissues including cardiomyocytes, endothelial cells, and smooth muscle cells.³ In addition, adult mesenchymal stem cells lack immunogenicity, are pluripotent, and are cryopreservable for future use.³ Disadvantages include uncertainty as to their functional and electrophysiologic properties. Adult mesenchymal stem cells also may differentiate into fibroblasts after implantation in a fibrotic scar.⁸

Endothelial progenitor cells circulate in peripheral blood and contribute to neovascularization, which can salvage hibernating myocardium and inhibit the apoptosis of hypertrophied cardiomyocytes. This eventually leads to dilation of the left ventricle and improved cardiac function after MI. Endothelial progenitor cells have increased mobilization during acute MI; therefore, injecting these cells into the infarct-related artery may be clinically beneficial.³ Advantages to using endothelial progenitor cells are their lack of immunogenicity and suitability for autologous transplantation. A disadvantage to using these cells is that preparing them requires an extensive ex vivo process.

Fetal cardiomyocytes have been successfully grafted into the myocardium after in vitro expansion.⁸ They demonstrated the ability to foster electrical pathways through the formation of gap junctions, to limit scar expansion, to form new cardiac tissue, and to prevent postinfarction HF.³

Fetal cardiomyocytes, however, have some major disadvantages. First, immunosuppression is required for their use, after which cell survival is short. Second, the supply of fetal cardiomyocytes is very limited, and their use has intense political and ethical ramifications.

Embryonic stem cells Research using human embryonic stem cells is limited because federal funding for research on embryonic stem cell lines derived after August 9, 2001, is prohibited.⁹ The ethical, moral, and political issues surrounding their application; the severe restrictions on human embryonic stem cell research in the United States; and their limited supply have prompted scientists to search for alternative sources of stem cells.³

ADMINISTRATION METHODS

Several factors need to be taken into consideration when deciding which mode of delivery to use. These include the type of stem cell to be administered, the state of myocardial ischemia (chronic versus acute), patient risk factors, and whether or not a surgical procedure is already scheduled.¹⁰ Delivery methods include surgical injection, percutaneous catheter-based delivery, intracoronary balloon catheter delivery, and IV injection.

Surgical intramyocardial injection Direct myocardial injection is the preferred delivery method when patients are already scheduled for an open-heart surgical procedure.^3,10 It also may be the preferred method for patients with chronic HF because the homing process that is up-regulated during MI is decreased, and for patients receiving skeletal muscle cells because there is an increased potential for embolization when implanting a large quantity of cells.^3,10

Advantages to this delivery mode are that a smaller number of cells are needed to achieve engraftment in comparison to other methods and the procedure can be performed by direct inspection of the potential target zones. A potential disadvantage is that it may lead to “islands” of cells in the infarcted myocardium, providing a substrate for electrical instability and ventricular tachyarrhythmias. Also, not all areas can be readily accessed with this approach.^3,10

Transendocardial injection This method primarily involves the NOGA cardiac navigation system, a cardiac-catheter-based method of electromechanical navigation of the heart. Cells are implanted via catheter-based myocardial injections guided by LV electromechanical mapping.^3,10 Therapy can then be precisely targeted to nonviable areas of the myocardium. The transendocardial injection-needle catheter offers an advantage over the associated risks of more invasive surgical approaches.³

Intracoronary injection This method is a nonsurgical technique using selective intracoronary injection to an infarct-related artery with an over-the-wire balloon catheter.³ It is especially well suited for the delivery of cells to a specific coronary territory and allows all the cells to flow through the infarcted and peri-infarcted tissue during the first passage.^3,10 The retention of cells in the target area makes this procedure a good option for treating severe ischemia.¹⁰

There are still unresolved issues involving intracoronary injection. The technique may not be suitable for certain types of larger stem cells, such as skeletal myoblasts, which may be prone to embolization.¹⁰ The number of cells infused and the duration of delivery needs to be carefully monitored as they may adversely affect coronary perfusion and induce myonecrosis.³

IV injection This is the simplest and least invasive method of cell administration available. However, IV injection relies more heavily on homing for the stem cells to reach the myocardium. Many stem cells could be lost to extraction by noncardiac organs and fail to reach the infarct area because of the long circulation time.^3,10 This method will require a better understanding of dosages and duration of delivery. Several small studies have used peripheral blood stem cells and bone marrow progenitor cells, and the results were promising.

CAVEATS TO STEM CELL USE

Although no studies have correlated patients’ results with lifestyle changes, it would be logical to assume that patients with close follow-up and a healthy lifestyle would have the best and most long-term results. It is up to clinicians to educate patients on the importance of a healthy diet, exercise, smoking cessation when applicable, and close follow-up care.

Of all donor-cell sources, skeletal muscle, bone marrow, and peripheral blood stem cells are the ones most available for research. Because of the invasive nature of harvesting bone marrow and skeletal muscle cells, peripheral blood stem cells would seem to be the ideal choice. However, peripheral blood stem cells require extensive and time consuming ex vivo expansion because of their limited supply.

Published studies demonstrate promising data for using stem cell therapy to treat infarcted myocardium. But all the studies thus far dealt with small sample sizes for short periods of time, and most were phase 1 trials.

The main benefits of cellular cardiomyoplasty appear to be reduced size and fibrosis of infarct scars, limited postischemic ventricular remodeling, improved LV wall thickening and compliance (diastolic pressure-strain relationship), and increased regional myocardial contractility. The mechanism that triggers transmission and propagation of electrical impulses from the native myocardium to the engrafted cells has not been elucidated.⁸

A REVIEW OF THE STUDIES

The results of studies involving skeletal myoblasts show both promise and challenges. Skeletal muscle cell survival and differentiation into mature myofibers were confirmed in scarred myocardium, and, in one patient, an increase in small vessel formation was observed at the site of surviving myotubes in a study performed by Pagani and colleagues.¹¹ Smits and team demonstrated an increase in LVEF when compared with baseline, as well as a significant increase in wall thickening at the target areas and less wall thickening in remote areas.⁷ An increased EF and improved systolic thickening was also demonstrated in a study by Menasche and colleagues.¹² Histologic examination performed by Hagege and colleagues demonstrated formation of nondegenerated functional myotubes and a phenotypic switch towards slow-twitch fibers.¹³ The latter indicates the possibility of the grafts sustaining a cardiac workload over time.

Skeletal myoblasts can be arrhythmogenic. One patient in the Smits study required implantation of a cardioverter-defibrillator after transplantation because of asymptomatic runs of nonsustained ventricular tachycardia.⁷ Four patients in the Menasche trial showed delayed episodes of sustained ventricular tachycardia and were implanted with an internal defibrillator.¹²

All the reviewed studies involving bone marrow cells demonstrated an increased coronary perfusion to stem-cell-implanted areas on myocardial radionuclide images. Stamm and colleagues noted a gain in LVEF and improved diastolic LV dimensions.¹⁴ Global LVEF was also increased in the study done by Wollert and colleagues.⁴ Transfer of bone marrow cells did not improve LV remodeling at 6 months. Perin and colleagues noted improvement in LVEF in bone-marrow-cell-treated patients as well as a reduction in end systolic volume (ESV).¹⁵ Strauer and colleagues noted improvement with regard to stroke volume index, LVESV, and contractility.¹⁶ Tse and colleagues reported that patients had a decrease in the number of anginal episodes and nitroglycerin tablets used per week,⁵ and they demonstrated an improvement in target wall thickening and target wall motion.

Hamano and team noted that postoperative chest radiography, electrocardiography, echocardiography, and blood tests did not reveal any detrimental changes.¹⁷ Tse’s group also noted the absence of any acute procedural complications or long-term sequelae, including ventricular arrhythmia, myocardial damage, or development of intramyocardial tumor.⁵ The Stamm trial included four patients with complications.¹⁴ It was unclear whether these problems were induced by the cell therapy. Strauer’s team reported no complications or side effects from the cell therapy.¹⁶ Perin’s group reported no sustained arrhythmias and no pericardial effusions.¹⁵

In a study by Kang and colleagues involving the use of peripheral blood stem cells, improvement of functional capacity and cardiac function was demonstrated, as were improvements in LVEF and a reduction of LVESV.¹⁸ A reduction in the hypoperfused region of myocardium measured by SPECT was also noted. The researchers noted no deaths, aggravation of heart failure or angina, or substantial arrhythmias during follow-up.

In a study conducted by Assmus and team, injections of peripheral blood and autologous bone marrow cells were performed.¹⁹ There was no difference in the results. Both cell types demonstrated an increase in global LVEF, improved regional wall motion in the infarct zone, and reduced LVESV. Also, echocardiography revealed a profound enhancement of regional contractile function. Coronary blood flow reserve was significantly increased in the infarct artery. No signs of inflammatory response or malignant arrhythmias were observed.

CONCLUSION

Perhaps the future will offer more information regarding the use of embryonic stem cells. These are the most versatile of all stem cells and have the ability to undergo an undetermined number of cell doublings and differentiate into specific cell types, including cardiomyocytes.⁸ Until restrictions are lifted, scientists will have to continue the current research to find a definitive treatment option for the growing number of patients with HF.

Combining stem cell therapy with other treatments may increase therapeutic options in the future.¹⁰ The main benefits of human-autologous-serum cell expansion is that it can be performed without risk of viral, prion, or zoonoses contamination.⁸ A number of clinical difficulties remain to be solved. The best cell type and the best dose for each cell type have yet to be defined. The most optimal method for improving cell engraftment after implantation also remains to be identified.⁸

REFERENCES

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