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Ann Thorac Surg 2005;80:712-714
© 2005 The Society of Thoracic Surgeons

Case report

Cell Therapy Plus Transmyocardial Laser Revascularization for Refractory Angina

Luís Henrique W. Gowdak, MD, PhD * , Isolmar T. Schettert, MD, Carlos Eduardo Rochitte, MD, PhD, Luiz Augusto F. Lisboa, MD, PhD, Luís Alberto O. Dallan, MD, PhD, Luiz Antônio M. César, MD, PhD, José Eduardo Krieger, MD, PhD, José Antônio F. Ramires, MD, PhD, Sérgio A. de Oliveira, MD, PhD

Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil

Accepted for publication April 25, 2005.

* Address reprint requests to Dr Gowdak, Heart Institute (InCor), University of São Paulo Medical School, Av Dr Enéas de Carvalho Aguiar, 44, São Paulo, SP, 05403-000 Brazil (Email: luis.gowdak{at}incor.usp.br).


   Abstract
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We describe the use of autologous bone marrow cells combined with transmyocardial laser revascularization in a 74-year-old man with refractory angina. Baseline cardiac magnetic resonance imaging revealed a markedly depressed left ventricle systolic function and an extensive area of myocardial ischemia. During surgery, 11 laser shots using a CO2 Heart Laser System (PLC Medical Systems, Milford, MA) were fired and a 5-mL cell suspension containing 21.5 x 106 bone marrow cells/mL was delivered by multiple injections into the myocardium. At 6 months after the procedure, another cardiac magnetic resonance imaging showed an almost complete resolution of the perfusion defect and an improvement in left ventricular contractility.


   Introduction
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Cell therapy with adult bone marrow cells represents a promising strategy for treating ischemic heart disease [1]. Experimental studies have shown that pluripotent stem cells have the potential to differentiate in both contractile and blood vessels in ischemic tissues [2], and early accounts exist of clinical improvement in myocardial perfusion and segmental contractility in ischemic heart disease [3] after cell therapy.

Transmyocardial laser revascularization (TMLR) is a therapeutic option in patients with end-stage ischemic heart disease, and disabling symptoms that are not amenable to coronary artery bypass grafting or percutaneous coronary intervention because of the extension of the disease [4]. Besides the immediate opening of myocardial conduits through which blood can flow, angiogenic cytokines released in response to the inflammatory process triggered by TMLR can further explain the increase seen in myocardial perfusion after TMLR [5].

Because the efficacy of both of the aforementioned techniques is dependent on their angiogenic potential, it is licit to consider that a synergistic angiogenic effect may occur if those strategies are combined.

A 74-year-old man was admitted for severe ischemic heart disease. He had already had a myocardial infarction and bypass surgery 20 years prior, and a long history of hypertension and diabetes.

He was reportedly well until 3 years earlier when he noticed a shortness of breath after walking a short distance. In the past 3 months, angina and dyspnea became quite disturbing as they occurred occasionally, even at rest. He was put on maximally tolerated medical treatment with little improvement. He was diagnosed with refractory angina and severe ischemic heart disease and was referred to our hospital.

On admission, his pulse was 106 beats per minute, and his blood pressure was 112/70 mm Hg. No cardiac murmurs or extra sounds were heard; basal pulmonary rales were noted in both lungs. The liver was slightly enlarged, and peripheral edema was present. After further adjustment of his medication, he continued to have in-hospital angina even with a lower heart rate.

Myocardial ischemia was assessed by a magnetic resonance imaging examination with a 1.5T scanner (Signa CV/i, GE Medical Systems, Waukesha, WI) as described elsewhere [6]. At rest, a markedly depressed left ventricular systolic function was found (ejection fraction, 27%). During pharmacological stress with dipyridamole, an extensive area of ischemia was noted in the left ventricle, anterior, septal, and inferior walls (Fig 1).



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  		Fig 1. Left ventricle short-axis images of first-pass perfusion during dipyridamole stress at baseline (upper left) and at 6 months after transmyocardial laser revascularization plus stem-cell therapy (lower left). Arrows (upper left) indicate an almost circumferential, subendocardial dark rim compatible with myocardial ischemia, which is not seen at follow-up (lower left). Myocardial delayed enhanced images (upper/lower right) revealed an anteroseptal myocardial infarction (arrow) equally seen in both exams.

 
Coronary angiography revealed occlusion of the right and left coronary arteries. Although three patent grafts were found, multiple and diffuse lesions distally to the anastomoses were seen in all bypassed arteries. Because of the extension and severity of the lesions, an expert panel considered this a "no-option" patient and TMLR combined with intramyocardial injection of bone marrow cells was suggested. The Institutional Ethics Committee approved the procedure, and the patient provided written informed consent.

The TMLR was performed through a left anterolateral thoracotomy using a CO2 Heart Laser System (PLC Medical Systems), and laser drills were made into the left ventricle, anterior (n = 3), lateral (n = 4), and inferior (n = 4) walls.

Immediately before surgery, 100 mL of bone marrow cells were aspirated from the iliac crest, and the lymphomononuclear fraction isolated by density gradient on Ficoll-Paque Plus (Amersham Biosciences, Piscataway, NJ). Afterward a 5-mL cell suspension containing 21.5 x 106 cells/mL (lymphocytes = 26%, monocytes = 3.5%, and hematopoetic progenitor cells = 0.9%) was delivered by intramyocardial injections into the anterior, septal, and inferior walls. No complications occurred during the procedure, and the patient recovered uneventfully.

During the following 6 months, his functional status improved and he was allowed to decrease the use of medication, including short-acting nitrates. Another cardiac magnetic resonance image was performed at 6 months after the procedure, which revealed an almost complete resolution of the extensive perfusion defect previously seen and a remarkable improvement in left ventricular contractility with a left ventricular ejection fraction of 43% (Fig 2).



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  		Fig 2. End-systolic frame of left ventricle short-axis (left), 4-chamber (middle) and 2-chamber (right) views of cine magnetic resonance imaging are depicted at baseline (top) and at 6 months after the procedure (bottom). Arrows indicate the left ventricle mid anterior (left), basal anterior (middle), and anterolateral (right) segments that showed the most evident improvement in myocardial contractility defined by an increase in the end-systolic wall thickness at 6 months. Overall left ventricular functional improvement was mainly due to an increase in stroke volume (B = 48 mL versus 6 months = 77 mL), and a decrease in end-systolic volume (B = 129 mL versus 6 months = 101 mL), since there was no change in end-diastolic volume (B = 177 mL versus 6 months = 178 mL).

 

   Comment
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It is certainly beyond the scope of this report to provide any insight of the underlying mechanisms leading to the observed results. Although conflicting data exist regarding this issue, transdifferentiation of transplanted cells into vascular endothelial cells [7], the action of cytokines and growth factors released locally either after TMLR or by the injected cells themselves [8], or both, may have acted synergistically, leading to angiogenesis and subsequent functional improvement.

This report showed the feasibility of combining two different strategies (TMRL plus cell therapy) in a "no-option" patient with disabling symptoms unresponsive to medical treatment. It may further direct investigators to new lines of research in order to establish the safety profile, efficacy, potential risks, and undesirable side effects of this new therapeutic strategy in a broad number of patients.


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  1. Angoulvant D, Fazel S, Li RK. Neovascularization derived from cell transplantation in ischemic myocardium Mol Cell Biochem 2004;264:133-142.[Medline]
  2. Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival Proc Natl Acad Sci USA 2001;98:10344-10349.[Abstract/Free Full Text]
  3. Lee MS, Makkar RR. Stem-cell transplantation in myocardial infarctiona status report. Ann Intern Med 2004;140:729-737.[Abstract/Free Full Text]
  4. Frazier OH, March RJ, Horvath KA. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease N Engl J Med 1999;341:1021-1028.[Abstract/Free Full Text]
  5. Fuchs S, Baffour R, Vodovotz Y, et al. Laser myocardial revascularization modulates expression of angiogenic, neuronal, and inflammatory cytokines in a porcine model of chronic myocardial ischemia J Card Surg 2002;17:413-424.[Medline]
  6. Pennell DJ, Sechtem UP, Higgins CB, et al. Clinical indications for cardiovascular magnetic resonance (CMR)consensus panel report. Eur Heart J 2004;25:1940-1965.[Free Full Text]
  7. Kawamoto A, Tkebuchava T, Yamaguchi J, et al. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia Circulation 2003;107:461-468.[Abstract/Free Full Text]
  8. Liu Y, Guo J, Zhang P, et al. Bone marrow mononuclear cell transplantation into heart elevates the expression of angiogenic factors Microvasc Res 2004;68:156-160.[Medline]



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[Abstract] [Full Text] [PDF]

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