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Vascular Growth Factor and Stem Cell Therapy in Ischemic Heart Disease

Yongzhong Wang


Larger randomized clinical trials with recombinant growth factor protein therapies or genes encoding VEGF-A cannot confirm the same clinical effects as in the smaller safety trials in patients with chronic ischemic heart disease. Therefore, it has been speculated that the angiogenic growth factors already were maximally expressed in human chronic ischemic myocardium. In such case, additional growth factor therapy would not make any further benefit. 

We demonstrated that both VEGF-A and VEGF-C participate in the spontaneous angiogenic response during acute ischemic conditions in the human chronic ischemic myocardium. The expressions of VEGF and VEGFR-1 and VEGFR-2 expression were not upregulated in human chronic ischemic myocardium. An increased expression of VEGF-A and –C, but no changes in VEGF receptors was found after short-term acute ischemia and reperfusion measured by real-time PCR in both nonischemic and chronic ischemic myocardium. Thus, our study indicates there is an identical change in VEGF expression in normal and chronic ischemic myocardium, but it can be further increased by acute short-term myocardial ischemia and reperfusion. These results suggest that there is a place for therapeutic exogenous administration of angiogenic growth factors to stimulate angiogenesis as an alternative treatment in chronic ischemic myocardium.  Although there are numerous experimental animal and clinical studies on the effects of BMSCs and mobilizing angiogenic factors in acute myocardial infarction, little is known about the spontaneous response of BMSCs including MSC and MSC subsets after myocardial infarction. The investigation on patients with acute STEMI treated by primary PCI demonstrated that MSC with the endothelial markers CD105 and CD31 both decreased significantly after acute STEMI. Circulating MSC levels in patients with a large infarction tended to fluctuate more in the sub acute phase after STEMI. In addition, we also demonstrated a consistent increased plasma SDF-1 level that may represent relevant upregulation of a chemo-attractant for enhancing the recruitment of circulating stem cells or progenitor cells into the infarct myocardium after STEMI. Moreover, we indicated both increased plasma VEGF level and concomitant increase of FGF-2 level in response to acute myocardial infarction. The increase in plasma VEGF-A and FGF-2, which was prolonged, might contribute to the stimulation of subacute angiogenic cascade in ischemic myocardium, lasting for a long period, and are involved in neovascularization after STEMI. The knowledge of these spontaneous sequential fluctuations in MSC and vascular growth factors after acute STEMI might provide helpful information for the planning and timing of clinical stem cell, stem cell homing and vascular growth factor therapies in patients with acute myocardial infarction treated by primary PCI. Based on the increase in vascular growth factors levels after the STEMI, the optimal time point for an additional stem cell therapy should be three weeks after myocardial infarction to obtain the maximal effects by the stimulation of endogenous growth factors on delivered stem cells. 

As an alternative treatment to the traditional invasive revascularization for the occluded coronary arteries, mobilization of stem cells from BM to the peripheral circulation by exogenous administration of G-CSF may provide a potentially effective non-invasive strategy to enhance myocardial regeneration in “no option” patients with chronic ischemic heart disease. In an investigation on the safety and efficacy of cell therapy by G-CSF mobilization, we demonstrated an improvement in angina score and a reduction in consumption of nitroglycerine in the G-CSF treated patients. The importance of numbers of mobilized stem for clinical effects was supported by the facts that treated effect was seen only in patients with an increased mobilization of CD34+ stem cells from the bone marrow into peripheral circulation after G-CSF treatment. But How G-CSF mobilizes stem cells and progenitor cells from the BM in to peripheral circulation is not fully understood. Moreover, we could not detect any improvement in myocardial perfusion, and an adverse effect on ejection fraction could not be excluded. The clinical improvement might be therefore a placebo effect. Large planned  randomised, double-blind and placebo-controlled clinical trials are considered to clarify the effectiveness of G-CSF treatment with present or higher dose in patient with severe occlusive coronary artery disease.