Stem cells represent a new possibility for the treatment of refractory angina.

The refractory angina is coronary obstructive disease in its terminal presentation, after exhausting all possibilities of conventional treatment currently known. Patients present with recurrent intractable chest angina (chest pain), despite the drug optimization and performance of several hemodynamic procedures (angioplasty and/or stents) and surgical procedures (myocardial revascularization surgery). The greatest impact of this disease is just the quality of life of patients, which is extremely limited for the performance of all daily activities and have several episodes of rest pain.

The prevalence of refractory angina comprises 5% to 15% of patients with coronary artery disease. Despite the severity and the degree of limitation of symptoms, most patients (75%) with refractory angina have normal cardiac function.

For the daily recurrence of symptoms, these patients represent a high cost to any health system, because of hospital (including ICU) and frequent tests. The treatment of refractory angina is very complex, involving optimization of drug and heroic attempts of myocardial revascularization surgery (hemodynamic and/or surgical via); without success, in most cases, the level of resolution of angina. Until the advent of cell therapy, the only option for patients was to learn how to live with pain. With the experimental confirmation of the angiogenic effect (formation of new blood vessels) through stem cells injected into the heart, a new therapeutic option for the treatment of refractory angina emerges.

The intramyocardial injection (directly into the heart muscle) of stem cells from bone marrow promotes heart neoangiogenesis, with an improvement in cardiac perfusion (blood flow) and, consequently, of angina symptoms. Given this new therapeutic possibility, we initiated a protocol of intramyocardial injection of stem cells from bone marrow in patients with refractory angina. This protocol provides a specific formulation of stem cells, MonoCell®, and is called ReACT® (Refractory Angina Cell Therapy Protocol). Until the present date, there are now over 20 patients treated by this specific protocol, with extremely encouraging results. Most patients did not present angina after one year of clinical follow up, and many have standardization of tests that assess cardiac perfusion (muscle pain).

Interview

Dr. Nelson Américo Hossne Jr, a cardiovascular surgeon, member of Prof. Dr. Enio Buffolo staff, responsible for CellPraxis® Protocol of Cell Therapy for Class IV Angina, is the doctor responsible for carrying out the procedure of cell therapy and follow up patient and answers some questions from our readers.

1. What has encouraged you to start a cell therapy protocol?

Considering the well established angiogenic effect (formation of new blood vessels) of cell therapy in the heart, the possibility of an offer of a promising treatment for patients with refractory angina has been observed.

2. What are your expectations for Heart Cell Therapy?

In my opinion, the expectations of heart cell therapy are endless. With the results of clinical protocols for heart cell therapy, we are getting a better understanding of the behavior of heart cells. From this, theoretically, we would be enabled to rebuild a heart entirely.

3. What is the prospect of use of Umbilical Cord Blood and Placental Blood in Heart Cell Therapy?

SCUP has stem cells younger than those obtained from the bone marrow, while maintain the same theoretical advantages of cardiac neoangiogenesis. Moreover, obtaining stem cells from SCUP is painless for the patient. Thus, the prospects of using stem cells from SCUP in cardiovascular disease are enormous.

4. How do you see the interaction between university and company?

The interaction between universities and companies is a novelty in Brazil. This partnership is critical to the development of clinical research protocols in accordance with international standards of quality assurance and best practices for handling cells and tissues. The possibility of generation of new pharmaceutical products must necessarily be obtained from this interaction.

5. The protocol should generate patents and scientific articles. What is the impact of this for the university and for you as a researcher?

The generation of scientific articles and patents is one way of acquiring knowledge and intellectual property assurance to the university, the researcher and, ultimately, to Brazil. The creation of university patents in the university/company partnership guarantees royalties for both.

6. What are the advantages of having a company like Cryopraxis as a partner?

A company initially designed for the storage of umbilical cord blood has previous scientific and technical knowledge, facilitating the implementation of a protocol for clinical research in cell therapy. In addition, the expertise of the company in areas of quality assurance and data storage media are guarantors of the seriousness and integrity of a clinical protocol.

Cardiovascular diseases are among the largest global concern, given its prevalence, incidence, mortality, hospital setting and economic impact.

Angina is the main clinical manifestation of chronic coronary heart disease. Among grading classifications of angina, the most accepted worldwide is the Canadian Cardiovascular Society Angina Classification (CCSAC), which is the most reproducible classification.

METHODS

Table 1. Classification of angina pectoris (CCSAC), according to Canadian Cardiovascular Society.

Class Definition

I - Ordinary physical activities (e.g. walking, climbing stairs) do not cause angina, this occurs only after fast, prolonged and strenuous exercise during work or recreation.

II - Slight limitation to ordinary activities. Angina occurs when climbing stairs rapidly, walking uphill, walking or climbing stairs after meals, in cold weather, with wind conditions or under emotional stress, or during the first hours after waking, when walking more than two blocks on a flat surface, or climbing more than one flight of stairs at normal rhythm and conditions.

III - Significant limitation of ordinary physical activity. Angina occurs when walking one or two blocks on a flat surface or climbing a flight of stairs at normal rhythm and conditions.

IV - Inability to perform any physical activity without discomfort, symptoms of angina may be present at rest.

Despite appropriate identification, diagnosis, stratification and treatment, a subgroup of patients with coronary disease have refractory ischemic symptoms and intractability of their clinical condition, not responding both to conventional pharmacological therapy and available revascularization techniques.

Refractory Angina

Definition

The European Cardiology Society, in consensus committee, defined refractory angina pectoris as a "chronic condition characterized by the presence of angina caused by coronary insufficiency in the presence of coronary artery disease, which cannot be controlled by the combination of pharmacological therapy, angioplasty and myocardial revascularization surgery. The presence of reversible myocardial ischemia should be clinically established as the cause of symptoms. Angina classification as chronic is defined as lasting more than three months."

Two criteria need to be met before patients are diagnosed as suffering from refractory angina pectoris: Objective myocardial ischemia must produce severe anginal symptoms; and all known conventional therapies have been thoroughly tried and exhausted. The scientific literature calls them "no-option patients".

As a result of constant scientific and technological advances in the cardiovascular area, this subgroup of patients with refractory angina is growing rapidly.

More than 100,000 patients annually are diagnosed as having refractory angina. Of 500 consecutive angiograms performed in the "Cleveland Clinic" in 1998, 59 (12%) had evidence of ischemia and were not candidates for conventional revascularization techniques9. The European Society of Cardiology estimates that 15% of patients who have angina can be characterized as presenting it in refractory type11. Data from the "Mayo Clinic" of 2005 indicates that approximately 150,000 to 250,000 patients per year diagnosed with Class III and IV angina are considered refractory.

Surprisingly, and of paramount importance to the proposition of any treatment modalities, the ventricular function of patients with refractory angina remains relatively preserved despite the refractoriness of their disease.

We can conclude, then, from the above, that the greatest challenge for patients with refractory angina is the very persistent angina and poor quality of life.

Treatment

The pharmacological treatment always presents itself as a first and supportive option despite the addition of any other types of treatments. It is primary and indispensable the use of acetylsalicylic acid (ASA), beta blockers, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers and long-acting nitrates in the highest tolerated doses. Administration of sublingual nitrates (nitroglycerin) provides immediate relief of acute angina symptoms. Statins are also indicated, because they improve endothelial function, besides having anti-inflammatory activity.

Guidelines of the "American Heart Association/American College of Cardiology" provides little information about refractory angina treatment. Among guidelines, there are transmyocardial revascularization "LASER" (Class IIa, Level of Evidence A); maximized external counterpulsation (Class IIb, Level of Evidence B) and spinal cord stimulation - neuromodulation (Class IIb, Level of Evidence B). None of these treatments have sustained efficacy in randomized trials.

Interview with Mr. Rubens Turquete, patient of ReACT® (Refractory Angina Cell Therapy Protocol)

Mr. Rubens Turqueta, 72, was suffering from refractory angina, a condition that causes frequent episodes of chest pain at short intervals of time, disabling the patient for the simplest daily activities. This type of angina had no surgical, clinical or drug treatment until the onset of Heart Cells Therapy.

In his history, this patient underwent several surgical procedures (bypass surgery) and interventional procedures (stents) until the infusion of a specific formulation of stem cells in 2006. This formulation (RA001) was developed by Cryopraxis within one of its clinical study protocols (Protocol CellPraxis® of Treatment for Class IV Angina), developed in partnership with the course of Cardiac Surgery, Escola Paulista de Medicina - UNIFESP. We chatted a bit with Mr. Rubens to know what changes have occurred in his life, having been included in the protocol:

1. Mr. Rubens, how was your life before surgery?

It was hell. Having said that, I think it simplifies everything. I suffered from angina for 10 years, I felt pain everyday day and, from 15 to 15 days, had severe crises. I never stopped working and, every day, around 3 o'clock in the afternoon, I began to feel much pain and had to go home. Until midnight, one o'clock in the morning I was in great pain and taking medication. So, I can summarize my life before the surgery as a hell.

2. Why have you opted for treatment with stem cells?

First, as I said, my life was hell. Second, because, according to Dr. Enio Buffolo, I had no more other procedures to do. I have very fine coronary vessels, with no condition of undergo, for example, an angioplasty or any other type of procedure.

3. Is there any change after surgery?

There were many changes, sure. About 3 to 4 months after surgery, I started to not feel pain - I could not even believe this – those angina attacks I felt every day. And so I gradually improved and began to live in paradise. After surgery, all these symptoms disappeared. My family, who suffered with me, today is satisfied with the result and now has more confidence in everything I wanted to do.

4. Do you recommend this stem cell treatment to other patients?

I certainly think it's a great opportunity. It may be that some patients do not get the same results I got, but, certainly, I would recommend.

5. Can you leave a message for the doctors who allowed you to do this treatment?

I really annoyed Dr. Enio, as he was my doctor. When I heard of this procedure with stem cells, I went to his office wanting to know everything about it. He asked me to have patience because as soon as possible I would be among the first. There is no way to thank the attention I received from all doctors. A simple thank you, if you could see inside of me the way that "thank you" is said, I think that would be enough.

I am very grateful to them all.

Sr. Rubens Turquete

Events

- 5th International Symposium of Heart Surgery of São Paulo

- Brazilian research proving the efficacy of stem cells in refractory angina treatment was introduced to the world

- Dr. Leslie Miller, well known heart surgeon, talks about ReACT product in International Symposium of Cardiology

ReACT® – International Symposium of Heart Surgery

Cell Therapy for Refractory Angina Treatment

ReACT - Procedure

Clipping

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