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Ann Thorac Surg 2000;69:1414-1419
© 2000 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Angiogenesis in ischemic human myocardium: clinical results after 3 years

^a Department of Cardiac Surgery, University Hospital Ulm, Ulm, Germany

Address reprint requests to Dr Pecher, Department of Cardiac Surgery, University Hospital Ulm, Steinhövelstr 9, D-89081 Ulm, Germany;
e-mail: peter.pecher{at}medizin.uni-ulm.de

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Using the human fibroblast growth factor we could already demonstrate the induction of neoangiogenesis in the ischemic human myocardium.

Methods. Forty patients, who were undergoing elective coronary artery bypass grafting were randomly selected and allotted either to a treatment or a control group. In 20 patients (study group) fibroblast growth factor was injected directly into the myocardium, close to the left anterior descending coronary artery. The control group comprised 20 patients who had been injected with heat denatured fibroblast growth factor. The 3-year follow-up consisted of a clinical examination, echocardiography, and selective imaging of the internal mammary artery bypass using angiography.

Results. As with the early results, a dense new capillary network could be demonstrated angiographically in the region where the factor had been injected. Echocardiography showed an increase in the left ventricular ejection fraction in the study group. We also found a more pronounced improvement in the clinical appearance of the patients with fibroblast growth factor.

Conclusions. Fibroblast growth factor, in addition to operative myocardial revascularization, may be the appropriate treatment for patients with peripheral stenosis or diffuse coronary arteriosclerosis. It is necessary to confirm these results in further studies on a larger group of patients.

	Introduction

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In industrialized countries, coronary heart disease is one of the most common serious illnesses, with 5 to 6 myocardial infarctions per 1,000 persons per year in Europe alone [1]. Despite major advances in medical treatment, in interventional cardiological methods, and in heart surgery, coronary heart disease continues to be one of the most frequent causes of death.

Since the first bridging of hemodynamically active coronary stenoses by Favaloro [2] in 1968 and by Kolossov [3] in 1967, coronary artery bypass grafting has become, within a period of 20 years, the most frequent operation on the heart. Balloon dilation of the stenosed coronary artery, introduced by Grüntzig and colleagues in 1979 [4], has become an equally common procedure for treating coronary heart disease.

Notwithstanding the extremely rapid progress in these methods, satisfactory treatment is still not available for many patients, because their coronary arteries are either diffusely calcified or very narrow throughout. An entirely new approach to treatment is offered by the induction of local angiogenesis with growth factors [5–11]. Among the substances that are capable of inducing the physiologic actions of neoangiogenesis (ie, the formation of capillary and vascular structures), the human fibroblast growth factor (FGF) is especially important [10, 12–18]. We have shown in an extensive series of experiments that new vessel formation may be induced with FGF [19], and it has been possible to confirm histologically and angiographically the development of a capillary net that rejoins the parent vessel.

After achieving unambiguous proof of neoangiogenesis in animal experiments, we used this growth factor for the first time on 20 patients with diffuse coronary artery disease [20]. These patients were given a follow-up examination 3 years after their treatment. The results of these examinations form the bulk of this communication.

	Material and methods

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Patients and operative procedure
With the consent of the Ethical Commission of the Philipps-Universität, Marburg, FGF was used clinically for the first time for the treatment of patients with coronary heart disease [20]. The study was carried out at the Department for Thoracic and Cardiovascular Surgery at Fulda Medical Center.

Of the more than 800 patients undergoing surgical treatment for coronary heart disease every year, 48 were selected, of whom 40 finally agreed to take part in the study. The details and aim of the study were fully explained to all patients willing to take part in the study, as well as the possible risks of additional investigations, and written consent was obtained from each participant. Patients were selected because they had multiple involvement of their coronary vessels, elective surgical revascularization was indicated. Study inclusion was confined to patients who showed comparable findings on coronary angiography, and it was also essential that, in addition to a proximal stenosis of the left anterior descending branch of the coronary artery (LAD) that would be revascularized surgically, another peripheral stenosis not susceptible to operative treatment, was present in the LAD or one of its branches. In all patients, stenoses involving the right coronary artery or the circumflex artery would be treated by a single venous bypass. For each of the patients selected it was intended that revascularization of the LAD would be provided by an internal mammary artery bypass. If this was not the case, that patient was excluded from the study. The patients were assigned to two equal groups of 20 each (the study group and a control group) by double-blind randomization. The actual details of the operation were the same for both groups. After completion of the distal anastomosis, FGF (0.01 mg/kg body weight) was injected directly into the myocardium alongside the peripheral segment of the LAD. In the controls, heat-denatured growth factor was used instead.

Routine laboratory tests were carried out every day on both groups of patients, and on days 1, 3, and 5, and just before discharge, the white blood cell count, erythrocyte sedimentation rate, and C-reactive protein were estimated. In addition, a final echocardiographic examination was done on every patient before discharge, and the ejection fraction of the left ventricle was assessed.

Follow-up examinations
All patients were given a follow-up examination 3 months after the operation and at yearly intervals thereafter. These included a complete clinical examination, with echocardiographic and chemical laboratory control of their progress. All follow-up examinations were carried out by physicians who did not know whether the patient came from the study group or the control group.

In addition, selective visualization of the internal mammary bypass and the LAD by transfemoral intraarterial digital subtraction angiography was done after operation. The procedure was identical in all patients: bolus administration of 20 mL of water-soluble contrast medium (Solutrast 300; Schering AG, Berlin, Germany). The angiographic catheter was introduced through the femoral artery, and the angiographic findings were recorded at exactly the same time after administration of the medium in every patient. The angiographs were then assessed by computer-assisted gray-value analysis. A defined area of 100 pixels was digitally calculated for the surgically revascularized myocardium, with or without the addition of FGF [21–24]. An identical area was used for the measurements in all the angiographic evaluations—4 cm distal to the internal mammary artery/LAD anastomosis, 1 cm in length, and 0.5 cm wide, and positioned directly lateral to the coronary vessel.

	Results

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After the random allotment of the 40 patients to either the study or the control group, the mean (standard deviation) age of the patients in the study group was 58.1 ± 4.6 years and that of the control group, 57.8 ± 3.8 years. The first group included 14 men and 6 women, and the controls 12 men and 8 women. The preoperative ejection fraction of the left ventricle was comparable in the two groups: 50.3% ± 4.1% in the study group and 51.5% ± 4.3% in the controls. In the study group one to four additional single venous bypasses were introduced into the circumflex or right coronary arteries (mean, 2.7). The corresponding average figure for the controls was 2.9 (range, 1 to 4 additional venous bypasses as in the study group).

Postoperative treatment on the ward was the same for both groups. Patients stayed in the hospital from 5 to 16 days after the operation with an average stay of 6.7 days. Myocardial ischemia that developed in any patient between admission and discharge was excluded clinically, by the laboratory tests and by echocardiography. The tightly controlled laboratory testing (white cell count, erythrocyte sedimentation rate, and C-reactive protein) revealed no sign of inflammation in either the study group or control patients. With regard to the ejection fraction of the left ventricle, the echocardiographic control before discharge revealed no difference between the two groups. After 3 months, selective visualization of the internal mammary artery/LAD bypass and the region supplied by the LAD was also possible in all 40 patients, therefore it was not necessary to exclude any patient during the course of the study. Three years after the operation, angiographic control was carried out on 31 patients, three of the study group and four of the control group patients had died. Two other patients of the study group refused further angiographic examination.

Three months after the operation, angiography of the perivascular region of the LAD where FGF had been injected showed that, in every patient of the study group, there was a significant increase in the amount of contrast medium that reached beyond the peripheral stenosis of the LAD or its affected branch. This significant enrichment was again demonstrated in all remaining 15 patients of the study group after 3 years. In none of the 20 patients of the control group, or of the 16 available for examination after 3 years, could any such increase in the deposition of the medium be demonstrated, although the internal mammary artery/LAD anastomosis could be demonstrated as in the study group (Figs 1 and 2).

View larger version (179K): [in this window] [in a new window]   Fig 1. Angiography of the internal mammary artery/left anterior descending coronary artery 3 years after application of fibroblast growth factor. Collateralization of the stenosed distal left anterior descending coronary artery through the newly grown capillaries.

View larger version (150K): [in this window] [in a new window]   Fig 2. Angiography in the control group with heat-denatured fibroblast growth factor. There is no increased accumulation of contrast medium.

The angiographically confirmed improvement in the blood supply can be correlated with the results of the echocardiographic follow-up, which showed that the ejection fraction in the study group improved from 50.3% ± 4.1% before the operation to 63.8% ± 7.8% after 3 years, whereas the equivalent figures for the control group within the same period were 51.5% ± 4.3%, with an increase of only 59.4% ± 6.1% after 3 years (Fig 3).

View larger version (19K): [in this window] [in a new window]   Fig 3. Comparison of the left ventricular function preoperatively and after 3 years by echocardiography. The patient group given fibroblast growth factor (FGF) shows benefit. (EF = ejection fraction.)

	Comment

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Encouraged by the results of our animal experiments [19], our next aim was—as already suggested by other investigators [29]—to use this growth factor for the treatment of human patients. By using it locally, we succeeded in producing and confirming the growth of new functional vessels in the ischemic human heart [20].

As in the animal experiments, 3 months after the operation, we were able to establish by angiography the presence of newly developed vascular structures filled with contrast medium. The use of human growth factor had led to the induction in situ of localized neoangiogenesis. This increase in the deposition of the contrast medium could be confirmed in all the patients of the study group by means of computer-assisted gray-value analysis [20]. A two- to threefold increase in the local blood supply of the myocardium had taken place.

To ascertain whether the patients had in fact gained a long-term functional advantage, 3 years after the operation we are carrying out follow-up examinations. Because 15 patients from the study group and 16 of the controls were available for follow-up, the results allowed us to make a satisfactory comparison with the situation as it was at 3 months. The mortality rates in the study group and the control group during the first 3 years after the operation were practically identical. However, because of the small number of patients, statistical confirmation of this statement is not possible.

Angiography of the internal mammary artery bypass was able to show—as at the examination 3 months after operation—a capillary network sprouting from the same coronary artery into the myocardium. The network continued to bridge over the additional stenoses of the LAD or its branches that could not be revascularized surgically. This effect can only be explained by assuming that the angiographically demonstrable increase in contrast medium deposition is due to the newly developed vessels, which are permanently contributing to the blood supply.

An inflammatory reaction caused by the presence of a foreign protein (here FGF), as was previously the case when Beck and colleagues introduced asbestos powder into the pericardial cavity [30], can be definitely excluded. A further proof of the presence of newly formed vessels is provided by the quantitative computer-assisted evaluation of the angiographs after 3 years. There was, as after 3 months, a similar enrichment of the contrast medium (a gray value of 65 ± 5.6 in the study group as opposed to 18 ± 2.8 in the controls) in the region where the growth factor had been injected. We accept this as additional evidence for the permanent increase in the local blood supply and collateralization.

Only this permanent improvement in the blood supply can explain the additional finding of more efficient myocardial contractility in the study group, where there was an increase in the left ventricular ejection fraction after FGF administration of 13.5% (from 50.3% before the operation to 63.8% after 3 years). In the control group, the improvement over the same period of time was about 7.9%, from 51.5% to 59.4%.

Furthermore, assessing our patients in terms of NYHA classification before and 3 years after operation clearly confirmed the more advantageous outcome for those to whom the growth factor had been administered. Two patients from the study group were shown to be two classes and 12 patients one class better, as opposed to the control group, where only 2 patients achieved improvement by a single class.

The results of the 3-year follow-up examinations have confirmed that the local administration of FGF produces a permanent and functionally active increase in the regional blood supply of the myocardium.

We have used the well-recognized and thoroughly investigated effect of FGF, as it appears during wound healing or collateralization after tissue ischemia, for the successful treatment of human heart disease. In the future, the use of FGF can lead to the acceptance of a new therapeutic approach—particularly for patients with diffuse coronary arterial disease. It is, however, certainly true that all possible techniques for administering the growth factor must be explored, and that the results achieved so far must be supported by studies on larger sample populations of patients.

	Acknowledgments

 
We express our gratitude to Thomas Stegmann, MD, for providing us with the opportunity to undertake this study at the Department for Thoracic- and Cardiovascular Surgery, Fulda Medical Center.

	References

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