Background-Experimental studies suggest that transplantation of blood-derived or bone marrow-derived progenitor cells beneficially affects postinfarction remodeling. The safety and feasibility of autologous progenitor cell transplantation in patients with ischemic heart disease is unknown. Methods and Results-We randomly allocated 20 patients with reperfused acute myocardial infarction (AMI) to receive intracoronary infusion of either bone marrow-derived (nϭ9) or circulating blood-derived progenitor cells (nϭ11) into the infarct artery 4.3Ϯ1.5 days after AMI. Transplantation of progenitor cells was associated with a significant increase in global left ventricular ejection fraction from 51.6Ϯ9.6% to 60.1Ϯ8.6% (Pϭ0.003), improved regional wall motion in the infarct zone (Ϫ1.5Ϯ0.2 to Ϫ0.5Ϯ0.7 SD/chord; PϽ0.001), and profoundly reduced end-systolic left ventricular volumes (56.1Ϯ20 mL to 42.2Ϯ15.1 mL; Pϭ0.01) at 4-month follow-up. In contrast, in a nonrandomized matched reference group, left ventricular ejection fraction only slightly increased from 51Ϯ10% to 53.5Ϯ7.9%, and end-systolic volumes remained unchanged. Echocardiography revealed a profound enhancement of regional contractile function (wall motion score index 1.4Ϯ0.2 at baseline versus 1.19Ϯ0.2 at follow-up; PϽ0.001). At 4 months, coronary blood flow reserve was significantly (PϽ0.001) increased in the infarct artery. Quantitative F-18-fluorodeoxyglucose-positron emission tomography analysis revealed a significant (PϽ0.01) increase in myocardial viability in the infarct zone. There were no differences for any measured parameter between blood-derived or bone marrow-derived progenitor cells. No signs of an inflammatory response or malignant arrhythmias were observed. Conclusions-In

Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months.

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Background— Cell therapy with bone marrow–derived stem/progenitor cells is a novel option for improving neovascularization and cardiac function in ischemic heart disease. Circulating endothelial progenitor cells in patients with coronary heart disease are impaired with respect to number and functional activity. However, whether this impairment also extends to bone marrow–derived mononuclear cells (BM-MNCs) in patients with chronic ischemic cardiomyopathy (ICMP) is unclear. Methods and Results— BM-MNCs were isolated from bone marrow aspirates in 18 patients with ICMP (ejection fraction, 38±11%) and 8 healthy control subjects (controls). The number of hematopoietic stem/progenitor cells (CD34 + /CD133 + ), CD49d + (VLA-4) cells, and CXCR4 + cells did not differ between the 2 groups. However, the colony-forming capacity of BM-MNCs from patients with ICMP was significantly lower compared with BM-MNCs from healthy controls (37.3±25.0 versus 113.8±70.4 granulocyte-macrophage colony-forming units; P =0.009). Likewise, the migratory response to stromal cell–derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) was significantly reduced in BM-MNCs derived from patients with ICMP compared with BM-MNCs from healthy controls (SDF-1, 46.3±26.2 versus 108.6±40.4 cells/microscopic field, P <0.001; VEGF, 34±24.2 versus 54.8±29.3 cells/microscopic field, P =0.027). To assess the in vivo relevance of these findings, we tested the functional activity of BM-MNCs to improve neovascularization in a hindlimb animal model using nude mice. Two weeks after ligation of the femoral artery and intravenous injection of 5×10 5 BM-MNCs, laser Doppler–derived relative limb blood flow in mice treated with BM-MNCs from patients with ICMP was significantly lower compared with mice treated with BM-MNCs from healthy controls (0.45±0.14 versus 0.68±0.15; P <0.001). The in vivo neovascularization capacity of BM-MNCs closely correlated with the in vitro assessment of SDF-1–induced migration ( r =0.78; P <0.001) and colony-forming capacity ( r =0.74; P <0.001). Conclusions— BM-MNCs isolated from patients with ICMP have a significantly reduced migratory and colony-forming activity in vitro and a reduced neovascularization capacity in vivo despite similar content of hematopoietic stem cells. This functional impairment of BM-MNCs from patients with ICMP may limit their therapeutic potential for clinical cell therapy.

Abstract-Transplantation of bone marrow cells as well as circulating endothelial progenitor cells (EPC) enhancesneovascularization after ischemia. The chemokine receptor CXCR4 is essential for migration and homing of hematopoietic stem cells. Therefore, we investigated the role of CXCR4 and its downstream signaling cascade for the angiogenic capacity of cultured human EPC. Ex vivo, differentiated EPC derived from peripheral blood abundantly expressed CXCR4. Incubation of EPC from healthy volunteers with neutralizing antibodies against CXCR4 profoundly inhibited vascular endothelial growth factor-and stromal-derived factor-1-induced migration as well as EPC-induced angiogenesis in an ex vivo assay. Preincubation of transplanted EPC with CXCR4 antibody reduced EPC incorporation and impaired blood-flow recovery in ischemic hindlimbs of nude mice (57Ϯ4% of normal perfusion versus untreated EPC: 80Ϯ11%, PϽ0.001). Bone marrow mononuclear cells (BM-MNC) or EPC of heterozygous CXCR4 ϩ/Ϫ mice displayed reduced CXCR4 expression and disclosed impaired in vivo capacity to enhance recovery of ischemic blood flow in nude mice (blood flow 27Ϯ11% versus 66Ϯ25% using wild-type cells, PϽ0.01). Importantly, impaired blood flow in ischemic CXCR4 ϩ/Ϫ mice was rescued by injection of wild-type BM-MNC. Next, we investigated the role of CXCR4 for functional capacities of EPC from patients with coronary artery disease (CAD). Surface expression of CXCR4 was similar in EPC from patients with CAD compared with healthy controls. However, basal Janus kinase (JAK)-2 phosphorylation was significantly reduced and less responsive to stromal-derived factor-1 in EPC from patients with CAD compared with healthy volunteers, indicating that CXCR4-mediated JAK-2 signaling is dysregulated in EPC from patients with CAD. The CXCR4 receptor signaling profoundly modulates the angiogenic activity and homing capacity of cultured human EPC. Disturbance of CXCR4 signaling, as demonstrated by reduced JAK-2 phosphorylation, may contribute to functional impairment of EPC from patients with CAD. Stimulating CXCR4 signaling might improve functional properties of EPC and may rescue impaired neovascularization capacity of EPC derived from patients with CAD. (Circ Res. 2005;97:1142-1151.) Key Words: coronary artery disease Ⅲ endothelium Ⅲ angiogenesis Ⅲ EPC C irculating endothelial progenitor cells (EPC) play a crucial role in postnatal neovascularization. 1-3 Increasing evidence suggests that transplantation of cultureexpanded progenitor cells or bone marrow-derived progenitor cells successfully promotes therapeutic neovascularization in both ischemic hindlimbs as well as acute myocardial infarction models. 4 -7 Moreover, recent clinical pilot studies suggest that not only restoration of blood flow in peripheral artery disease but also functional regeneration and left ventricular remodeling can be enhanced after autologous transplantation of bone marrow-derived cells or cultured EPC in patients with coronary atherosclerosis. 8 -11 Further evidence indicates that no...

Background-Circulating levels of microRNA (miR) have been proposed as biomarkers for cardiovascular disease. To identify the heart as a potential source for miRs released into the circulation, we measured concentration gradients across the coronary circulation for muscle-enriched (miR-133a, miR-499, miR-208a), vascular (miR-126, miR-92a), leukocyterelated (miR-155), and platelet-enriched (miR-223) miRs. Methods and Results-Circulating miRs were measured by TaqMan polymerase chain reaction in EDTA-plasma simultaneously obtained from the aorta and the coronary venous sinus in patients without coronary artery disease (nϭ7), with stable coronary artery disease (nϭ31), and with troponin-positive acute coronary syndromes (nϭ19). Circulating levels of the muscle-enriched miR-499 (Ͼ20-fold; PϽ0.01), miR-133a (11-fold; PϽ0.01), and miR-208a (5-fold; PϽ0.01) were significantly elevated in the aorta of troponin-positive acute coronary syndrome patients compared with patients with coronary artery disease. Importantly, there was a significant increase in circulating levels of miR-499 and miR-133a across the coronary circulation in troponin-positive acute coronary syndrome patients, suggestive of a release into the coronary circulation during myocardial injury. Indeed, miR-499 concentration gradients were significantly correlated with the extent of myocardial damage as measured by high-sensitivity troponin T (rϭ0.70, PϽ0.01). In contrast, circulating levels of miR-126 (Pϭ0.16) decreased during transcoronary passage in patients with evidence of myocardial injury, suggesting consumption during transcoronary passage. Conclusions-Muscle-enriched miR-499 and miR-133a are released from the heart into the coronary circulation on myocardial injury, whereas the vascular miR-126 is consumed during transcoronary passage. The differential regulation of circulating miRs during the transcoronary passage might provide important insights to exploit their role as cardiac biomarkers. Clinical Trial Registration-URL: http://www.germanctr.de. Unique identifier:

Ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular (LV) remodeling process.

Patients undergoing TAVI with implantation of CVP are at significantly higher risk for development of AV block and subsequent need for permanent PM, particularly if RBBB preexists. Since AV block occurs in >90% within the first week after the procedure, careful monitoring should be performed for at least 7 days after TAVI.