Background— The Doppler Substudy of the randomized, double-blind, placebo-controlled Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial aimed to investigate the effects of intracoronary infusion of bone marrow–derived progenitor cells (BMCs) on coronary blood flow regulation in patients with reperfused acute myocardial infarction. Methods and Results— In a total of 58 patients (BMC group, n=30; placebo group, n=28), coronary flow reserve (CFR) in the infarct artery and a reference vessel was assessed by intracoronary Doppler at the time of study therapy (4.2±0.1 days after acute myocardial infarction) and at the 4-month follow-up. Initial CFR was reduced in the infarct artery compared with the reference vessel in both groups (BMC: 2.0±0.1 versus 2.9±0.2, P <0.05; placebo: 1.9±0.1 versus 2.8±0.2; P <0.05). At the 4-month follow-up, CFR in the infarct artery had slightly improved in the placebo group (+0.88±0.18; P <0.001 versus initial) but was markedly increased by 90% (+1.80±0.25; P =0.005 versus placebo) in BMC-treated patients, resulting in a normalization of CFR (3.8±0.2; P <0.001 versus initial and placebo at 4 months). In the infarct vessel, adenosine-induced minimal vascular resistance index declined slightly in the placebo group (from 1.77±0.12 to 1.52±0.15 mm Hg · s/cm; P <0.05) but considerably decreased by −29±6% in the BMC group (from 1.86±0.19 to 1.20±0.12 mm Hg · s/cm; P <0.05 versus initial and placebo at 4 months). Conclusions— Intracoronary BMC therapy after acute myocardial infarction restores microvascular function of the infarct-related artery, which is associated with a significant improvement in maximal vascular conductance capacity. These data provide clinical proof of concept that progenitor cell transplantation promotes vascular repair.

Background—: Attenuated peripheral perfusion in patients with advanced chronic heart failure (CHF) is partially the result of endothelial dysfunction. This has been causally linked to an impaired endogenous regenerative capacity of circulating progenitor cells (CPC). The aim of this study was to elucidate whether exercise training (ET) affects exercise intolerance and left ventricular (LV) performance in patients with advanced CHF (New York Heart Association class IIIb) and whether this is associated with correction of peripheral vasomotion and induction of endogenous regeneration. Methods and Results—: Thirty-seven patients with CHF (LV ejection fraction 24±2%) were randomly assigned to 12 weeks of ET or sedentary lifestyle (control). At the beginning of the study and after 12 weeks, maximal oxygen consumption (V o ₂ max) and LV ejection fraction were determined; the number of CD34 ⁺ /KDR ⁺ CPCs was quantified by flow cytometry and CPC functional capacity was determined by migration assay. Flow-mediated dilation was assessed by ultrasound. Capillary density was measured in skeletal muscle tissue samples. In advanced CHF, ET improved V o ₂ max by +2.7±2.2 versus −0.8±3.1 mL/min/kg in control ( P =0.009) and LV ejection fraction by +9.4±6.1 versus −0.8±5.2% in control ( P <0.001). Flow-mediated dilation improved by +7.43±2.28 versus +0.09±2.18% in control ( P <0.001). ET increased the number of CPC by +83±60 versus −6±109 cells/mL in control ( P =0.014) and their migratory capacity by +224±263 versus −12±159 CPC/1000 plated CPC in control ( P =0.03). Skeletal muscle capillary density increased by +0.22±0.10 versus −0.02±0.16 capillaries per fiber in control ( P <0.001). Conclusions—: Twelve weeks of ET in patients with advanced CHF is associated with augmented regenerative capacity of CPCs, enhanced flow-mediated dilation suggestive of improvement in endothelial function, skeletal muscle neovascularization, and improved LV function. Clinical Trial Registration—: http://www.clinicaltrials.gov . Unique Identifier: NCT00176384.

Background: Exercise training (ET) in addition to optimal medical therapy (OMT) in patients with stable coronary artery disease (CAD) has been demonstrated to be superior to percutaneous coronary interventions (PCI) with respect to the composite endpoint of death, myocardial infarction, stroke, revascularization and hospitalization due to worsening of angina. One mechanism leading to this superiority discussed in the literature is the increase in coronary collateral blood flow due to ET. Until now, data demonstrating the positive effect of ET on the collateral blood flow and the functional capacity of the coronary collateral circulation are still lacking. Methods/design: The EXCITE trial is a three-armed randomized, prospective, single-center, open-label, controlled study enrolling 60 patients with stable CAD and at least one significant coronary stenosis (fractional flow reserve ≤0.75). The study is designed to compare the influence and efficacy of two different 4-week ET programs [high-intensity interval trainings (IT) versus moderate-intensity exercise training (MT) in addition to OMT] versus OMT only on collateral blood flow (CBF). The primary efficacy endpoint is the change of the CBF of the target vessel after 4 weeks as assessed by coronary catheterization with a pressure wire during interruption of the antegrade flow of the target vessel by balloon occlusion. Secondary endpoints include the change in plaque composition as assessed by intravascular ultrasound (IVUS) after 4 weeks, myocardial perfusion as analyzed in MRI after 4 weeks and 12 months, peak oxygen uptake (V02 peak), change in endothelial function and biomarkers after 4 weeks, 3, 6 and 12 months. The safety endpoint addresses major adverse cardiovascular events (death from cardiovascular cause, myocardial infarction, stroke, TIA, target vessel revascularization or hospitalization) after 12 months. Discussion: The trial investigates whether ET for 4 weeks increases the CBF in patients with significant CAD compared to a sedentary control group. It also examines the impact of two intensities of ET on the CBF as well as the histological plaque composition. The trial started recruitment in June 2009 and will complete recruitment until June 2012. First results are expected in December 2012 (4-week follow-up), final results (12-month long-term secondary endpoint) in December 2013. Trial registration: Clinical trial registration information-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01209637