Intracoronary Administration of Circulating Blood-Derived Progenitor Cells After Recanalization of Chronic Coronary Artery Occlusion Improves Endothelial Function
To the Editor:
We read with interest the letter by Dr Traverse.1 He pointed out that the beneficial effects of the therapy with circulating progenitor cells (CPC) rely on the increase in left ventricular (LV) function in CPC-treated patients as compared with a control group where LV performance did not change during the study period of 3 months.
However, we would like to use this opportunity to address a couple of questions that have been raised by Dr Traverse:
First, our study was the first randomized placebo-controlled trial ever that was designed to address the effects of an intracoronary CPC application on endothelial dysfunction after recanalization of chronic total occlusion (CTO).2 The primary end point of our study was coronary flow reserve in the reopened artery, which was found to be increased by 43% in patients of the CPC group. This was linked to an improvement in metabolism, an increase in local and global left ventricular function. In contrast, even though CTO was successfully recanalized, which results in a restoration of the antegrad flow that is clearly higher than the collateral flow, endothelial dysfunction persisted in the control group; the number of hibernating segments as well as the myocardial performance did not change significantly in these patients. These data are consistent with the hypothesis that the degree of endothelial dysfunction after recanalization of CTO is a main determinant of myocardial metabolism and LV function.2
Second, there is evidence that the suggestive observational data reported in the studies, which were cited by Dr Traverse, are partially influenced by biases.1,3 In contrast to our study, none of these previous trials were randomized, contained a control group, or were double-blind. In none of the studies, endothelial function was assessed by direct agonist stimulation, ejection fraction was not measured by MRI (which is considered to be the gold standard for the assessment of LV function), and myocardial perfusion and metabolism were not assessed by PET and SPECT. Therefore, the conclusions that can be drawn from these observations are limited. Additionally, these studies do not provide any mechanisms for the improvement in LV function seen after successful recanalization of CTO.1,3
Interestingly, recovery of myocardial function after recanalization of CTO was only observed in 41% patients with initially impaired LV function in the study by Werner et al.4 These data are in agreement with the results from our control group, in which in 5 patients a small increase in ejection fraction was observed; however, these effects were offset by the deterioration in LV function in other patients of this group. In the study by Gottschall and coworkers3 and a trial by Chung et al,5 no augmentation in ejection fraction was seen after recanalization of CTO in patients with previous myocardial infarction (MI). Given that the majority of subjects in the control group had a previous MI (9 of 11 patients with MRI measurements), the lack of improvement with regard to LV function is not surprising and is in agreement with the literature.
In the CPC group, 9 of 11 patients (in which MRI was performed) had experienced myocardial infarction before. All of them responded to the CPC treatment with an increase in ejection fraction and a reduction in infarct size. Therefore, CPC treatment is efficient and superior to recanalization of CTO alone with regard to an improvement in LV function in patients with previous MI.
Third, we agree with Dr Traverse that patients with CTO are heterogenous. Nevertheless, the patients in our control and CPC group were comparable with respect to the baseline characteristics. Collateral circulation was not assessed in our trial; however, recent studies suggest that the importance of collateral might have been overestimated in the past. This notion is supported by a recently published study of Werner et al.6 This article revealed that recovery of LV performance after recanalization of CTO is not directly related to the quality of collateral function because collateral formation did not appear to require the presence of viable myocardium. Because of the space constraint we were not able to address all of these points in the original version of our manuscript.2
Fourth, it was correctly noted that wall motion score improved significantly from 71.3±4.2 after PCI to 77.2±3.5 at 3 months in the CPC group (P<0.05 versus Control for the change, P<0.001 versus post-PCI within the CPC group; Table 2, online data supplement).2 However, wall motion score remained unchanged in the control group during the study period (76.7±2.1 after PCI, 78.4±2.1 at three months, P=0.262; Table 2, online data supplement).2
In summary, our data support the notion that intracoronary transplantation of CPCs after recanalization of CTO results in an improvement of macro- and microvascular function and contributes to the recruitment of hibernating myocardium, in particular in patients with previous myocardial infarction.
Traverse JH. CPCs as treatment for chronic total coronary artery occlusions. Circ Res. 2006; 98: e1.
Erbs S, Linke A, Adams V, Lenk K, Thiele H, Diederich KW, Emmrich F, Kluge R, Kendziorra K, Sabri O, Schuler G, Hambrecht R. Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion. Circ Res. 2005; 97: 756–762.
Werner GS, Emig U, Bahrmann P, Ferrari M, Figulla HR. Recovery of impaired microvascular function in collateral dependent myocardium after recanalisation of a chronic total coronary occlusion. Heart. 2004; 90: 1303–1309
Chung CM, Nakamura S, Tanaka K, Tanigawa J, Kitano K, Akiyama T, Matoba Y, Katoh O. Effect of recanalization of chronic total occlusions on global and regional left ventricular function in patients with or without previous myocardial infarction. Catheter Cardiovasc Interv. 2003; 60: 368–374.