Advances in cardiovascular treatments have resulted in a decreased mortality rate from heart attacks. Despite this, heart disease remains the leading cause of death in the United States and heart failure remains a public health issue affecting a staggering 5.7 million adults (CDC, 2017).
Of this population remains a growing category of patients who do not respond to pharmacologic, surgical or device therapies. Having exhausted current treatment possibilities, these “no-option” patients suffer daily from debilitating symptoms that negatively impact quality of life.
Cardiac stem cell therapy utilizing autologous (a patient’s own) adult stem cells is a promising innovation, offering the opportunity to address symptoms, function, and quality of life for no-option patients with heart disease and heart failure. Though not a cure for cardiovascular disease, robust clinical evidence points to cell therapy as the next phase in the evolution of cardiac care—welcome news for those previously categorized as untreatable.
Heart Failure Treatment: An Evolution
The earliest heart failure treatment options were limited to activity restrictions or bedrest while natural diuretics and homeopathic remedies were utilized as adjunctive treatment. In 1785, William Withering wrote a paper entitled, “An Account of the Foxglove and Some of its Medical Uses; With Practical Remarks on Dropsy and Other Diseases.” Dropsy is now thought to have been a manifestation of congestive heart failure, and although his methods of investigation were ethically questionable, ostensibly Withering’s experimentation with foxglove (scientifically known as digitalis) dosing ultimately led to further studies as well as the development of the drug that is utilized today (Sacks, Jarcho & Curfman, 2014). In 1972 the Food and Drug Administration (FDA) classified digoxin—derived from the leaves of the digitalis plant—as a “new drug.” However, it was not until September 1997 that digoxin in oral form gained approval for use in treating congestive heart failure (FDA, 2000).
The development of medications that dilate blood vessels (vasodilators) ushered in a greater reliance on pharmaceutical treatment for heart failure. Diuretics and digoxin continued to be widely used while positive inotrope therapy was also available to assist the practitioner in the management of heart failure by increasing the strength of muscular contraction.
In further efforts to manage symptoms, surgical procedures such as bypass grafting and stent deployment as well as implantable devices such as pacemakers were developed for use in conjunction with pharmacologic options towards the goal of maximizing cardiac efficiency, thereby increasing cardiac output (Sacks, Jarcho & Curfman, 2014).
Despite remarkable progress and early detection programs, a growing pool of patients continue to live with debilitating symptoms and a poor quality of life. Both practitioners and patients are met with challenges of the existing treatment model—adverse effects, drug-drug interactions, complications and the daunting prospect of heart transplant. For those whom the current standards of care are unsatisfactory, or for whom the transplant is unacceptable, cardiac stem cell therapy presents a new option which recruits natural repair mechanisms in a minimally-invasive way.
Early Promise of Cardiac Stem Cell Research
In April, 2003, Emerson Perin, MD, PhD from Texas Heart Institute presented to the scientific sessions audience at the American College of Cardiology meeting, discussing his findings from a small cardiac cell therapy clinical trial conducted in Rio de Janeiro (SoRelle, 2003). He reported that patients who received intramyocardial injections of adult stem cells had experienced:
- No major procedural complications
- Improved symptoms in terms of heart failure and chest pain classification
- Improvement in functional capacity
- Dramatic changes in terms of lifestyle for many
Some years later, the 2012 APOLLO cardiac trial demonstrated the safety and feasibility of using autologous adipose-derived stem cells within thirty-six hours of a heart attack to reduce the infarct size and amount of scarring and remodeling (Schulman & Hare, 2012).
In 2014, Perin et al published results from the small but rigorous PRECISE trial, which demonstrated that patients who receive adipose-derived stem cells via intramyocardial injections experienced decreased symptoms of heart failure and a slight increase in ejection fraction (EF) at 6 months post-treatment.
Cardiac Cell Therapy Today
Adult stem cells known as mesenchymal stem cells (MSCs) are repair cells that are found in many tissues of the body and have been studied comprehensively in bone marrow. As a plentiful and potent source of MSCs, adipose tissue has become a research focus for the potential to treat a variety of complex, unmet healthcare needs including heart failure (Fraser, Wulur, Alfonso & Hedrick, 2006).
Adipose-derived MSCs have demonstrated superiority to bone marrow-derived cells, an observation thought to be attributed to the fact that there are up to 2,500 more cells per gram of fat than cells per gram of bone marrow (Baer, 2014). In addition, the use of adipose stem cells circumvents the problem of age and disease-related decline in potency seen in bone marrow cells, making them an ideal harvesting source among patients in the aging population (Dimmeler & Leri, 2008).
Autologous MSCs can be harvested from an individual and returned to the same individual. Much like surgeons utilize veins from a patient’s leg to use in the heart or skin grafts from one area of a person’s body to repair another, procedures conducted in this way eliminate the issue of cell rejection as well as the need for immunosuppressant drugs. When transplanted into the human heart, autologous ADRCs have demonstrated the capacity to encourage the growth of new blood vessels and regulate inflammation and remodeling as well as fibrosis (Shah & Heldman, 2017).
Intramyocardial Injection of MSCs: Goals of Therapy
The first and foremost goal with any new line of therapy is patient safety. In the aforementioned clinical trials, intramyocardial injection of MSCs as well as the procedure necessary for stem cell harvesting has been safe and well-tolerated by most patients with minimal complications. Secondarily, goals of this therapy remain akin to predecessor treatments, targeting relief of symptoms, improvements in functional capacity and a better quality of life.
A broader understanding of factors at play in heart disease as well as the paracrine mechanisms of MSCs has enabled researchers to more deeply comprehend the opportunities for cell therapy to provide a benefit (Farini et al, 2014). For example, the role of inflammation, scarring (such as the infarct created post-heart attack) and insufficient blood flow (ischemia) in heart disease each correlate with the key capacities of MSCs, which include:
- Stimulation of new blood vessel growth (angiogenesis);
- Anti-inflammatory effects;
- Reduction in scarring (anti-fibrosis);
- Prevention of premature heart muscle cell death (anti-apoptosis); and
- The recruiting of other cells necessary for repairing or replacing damaged myocardium.
Shaping the Future of Safe, Effective Heart Disease Treatment
Published research to-date has been very encouraging towards cell therapy as the next phase in cardiac care. However, treatment accessibility remains limited in the United States except for in clinical trials which are subject to acceptance criteria geared toward a specific patient profile in order to provide a clean, focused view of the data.
Despite promising evidence, a healthy debate exists as to whether cardiac cell therapy is proven enough for patients outside of a clinical trial. While safety has been strongly established, some questions loom as to whether the many small trials provide enough evidence to treat CHF patients today, or whether further research in the setting of a multi-million dollar phase III trial is necessary before doing so. In the case of no-option heart disease, collecting observational data may be the only method for timely evaluation in this population with significantly limited lifespan. By the time a phase III trial is completed, many of these patients will have lost their lives.
Founded with the same mission as the early cardiac cell therapy researchers, Okyanos Cell Therapy is a free-standing stem cell treatment center located in Freeport, Grand Bahama. After developing treatment protocols utilizing data from the PRECISE cardiac trial, Okyanos became The Bahamas’ first licensed adult stem cell treatment facility under the nation’s Stem Cell Research and Therapy Act of 2013, and began treating patients in October, 2014.
More than 60 human cardiac cell therapy trials have been conducted since 2001, exploring different cell types and protocols collectively paving the way toward a bright future of safer and more effective care for heart disease.