Failed Downregulation of Circulating MicroRNA-155 in the Early Phase after ST Elevation Myocardial Infarction Is Associated with Adverse Left Ventricular Remodeling.

BACKGROUND: MicroRNA are noncoding RNA that have a significant role in both inflammatory and cardiovascular diseases. AIMS: We aimed to assess whether the inflammation-related microRNA-155 is associated with the development of adverse left ventricular (LV) remodeling following ST elevation myocardial infarction (STEMI). METHODS: Peripheral blood samples were collected in the inflammatory (day 2), proliferative (day 5), and maturation phases (6 months) after STEMI (n = 20). Granulocytes, monocytes, and lymphocytes were enumerated with flow cytometry. The changes in LV volumes were assessed with 3-D echocardiography on day 1 and after 6 months. Adverse remodeling was defined as a >20% increase in end-diastolic volume. Healthy subjects were recruited as controls. RESULTS: MicroRNA-155 measured on day 5 correlated positively with the relative change in end-diastolic volume (ρ = 0.490, p = 0.028). MicroRNA-155 (day 5) was significantly higher in patients with compared to patients without adverse LV remodeling. The expression level was similar in healthy subjects (n = 8) and in patients with LV remodeling. There was a positive correlation between microRNA-155 and the amount of monocytes (day 5, ρ = 0.463, p = 0.046). CONCLUSION: Impaired downregulation of microRNA-155 during the second phase of the post- STEMI inflammatory response is a determinant of the development of adverse LV remodeling.

Cost-effectiveness of contemporary vascular closure devices for the prevention of vascular complications after percutaneous coronary interventions in an all-comers PCI population.

AIMS: The present observational case-control study assessed the cost-effectiveness of contemporary vascular closure devices (VCDs) for the prevention of vascular complications in an all-comers transfemoral percutaneous coronary intervention (PCI) population. METHODS AND RESULTS: A total of 8,292 consecutive PCI patients were enrolled from a single-centre prospective registry from January 2005 to December 2010. VCDs were available from July 2007 and, from that time point, VCDs were implanted in 1,780 of the 5,394 patients (33%). Vascular complications occurred in 221 (2.7%) patients. The use of VCDs was independently associated with a 53% risk reduction (OR 0.47, 95% CI: 0.3-0.7) in vascular complications (3.0% vs. 1.5%) and with a 65% risk reduction (IRR 0.37, 95% CI: 0.32-0.43) in the post-PCI length of hospital stay (LOS) (mean 2.8 vs. 1.5 days). Mainly due to the reduced LOS, the patients with VCDs accrued vascular direct medical costs (VCD, diagnosis and treatment of vascular complications, post-PCI LOS) that were on average 498€ less than those accrued by the non-VCD patients. The cost-effectiveness was present across all vascular risk profiles. CONCLUSIONS: In this large, all-comers transfemoral PCI population, the use of VCDs was independently associated with a reduction in the rate of vascular complications and the post-PCI length of hospital stay and proved to be cost-saving across all vascular risk profiles.

Long-term vascular responses to Resolute® and Xience V® polymer-based drug-eluting stents in a rabbit model of atherosclerosis.

OBJECTIVES: To assess the late postinterventional response to iliac stenting in atheromatous rabbits using the Xience V everolimus-eluting stent (Xience V EES; Abbott Vascular) and the Resolute zotarolimus-eluting stent (Resolute ZES; Medtronic Vascular) with the MultiLink Vision bare metal stent (BMS; Abbott Vascular) as a reference. BACKGROUND: Xience V EES and Resolute ZES were developed to overcome shortcomings of first-generation DES. METHODS: Functional and microscopic changes were assessed by organ bath experiments and histopathologic examination. Gene expression was investigated using RT-PCR. RESULTS: After 91 days, re-endothelialization was nearly complete (BMS: 93 ± 3%; Resolute ZES: 92 ± 2%; Xience V EES: 94 ± 3%; P = 0.10). Neointima thickness was similar in Resolute ZES (0.17 ± 0.08 mm) and BMS (0.17 ± 0.09 mm), and reduced in Xience V EES (0.03 ± 0.01 mm; P < 0.0001). Xience V EES had less peri-strut inflammation compared with BMS (P = 0.001) and Resolute ZES (P = 0.0001), while arterial segments distal to Xience V EES were more sensitive to acetylcholine than those distal to BMS and Resolute ZES (P = 0.02). Lectin-like oxidized receptor-1 was overexpressed in stented arteries (P < 0.001), whereas thrombomodulin was downregulated in Resolute ZES (P = 0.01) and BMS (P = 0.02) compared to unstented arteries of rabbits on regular chow. No significant changes were seen for vascular cell adhesion molecule-1, nitric oxide synthase 3, or endothelin-1. CONCLUSIONS: At 3-month follow-up, nearly complete re-endothelialization was achieved for all stent groups. Xience V EES induced greater suppression of neointimal growth and peri-strut inflammation, higher vasorelaxation to acetylcholine, and expression of thrombomodulin at the level of unstented controls.

Levels of circulating CD34+/KDR+ cells do not predict coronary in-stent restenosis.

BACKGROUND: Angiographic and clinical parameters are poor predictors of in-stent restenosis. Bone marrow-derived CD34(+) cells that coexpress a receptor for vascular endothelial growth factor (kinase insert domain receptor [KDR]) are committed to endothelial lineage. Mobilization and infusion of CD34(+)/KDR(+) cells accelerates re-endothelialization and reduces neointimal thickness in vascular injury models. Bioengineered stents capturing CD34(+) cells also show expedited re-endothelialization. We examined whether circulating CD34(+)/KDR(+) cell counts can be used to predict restenosis in a bare-metal stent (BMS). METHODS: CD34(+)/KDR(+) cells were counted by flow cytometry in 124 nondiabetic patients before BMS implantation and the relation to in-stent late luminal loss (LLL) was examined by angiography at 6 months (primary end point). Neointima was also quantified as the maximum percentage area stenosis (M%AS) and percentage volume intima hyperplasia (%VIH) on intravascular ultrasonography (secondary end points). RESULTS: Multiple linear regression analysis, taking into account implanted stent length and diameter, revealed no relation between CD34(+)/KDR(+) cell counts and LLL (partial regression coefficient b = 0.11; 95% confidence interval [CI], -0.19-0.42; P = 0.46). Similarly, no relation between CD34(+)/KDR(+) cell counts and M%AS or %VIH could be demonstrated. Moreover, the increase in CD34(+)/KDR(+) cell counts over 6 months was unrelated to LLL (b = -0.15; 95% CI, -0.42-0.12; P = 0.28), M%AS, and %VIH. CONCLUSIONS: Although our study does not exclude a pathophysiologic role for CD34(+)/KDR(+) cells in the formation of neointima, cell counts before percutaneous coronary intervention proved to be unrelated to LLL or intravascular ultrasonographically derived restenosis parameters in coronary BMSs at 6 months.

Difference in clinical target lesion revascularization between a silicon carbide-coated and an uncoated thin strut bare-metal stent: the PRO-Vision study.

BACKGROUND: Bare-metal stents trigger a foreign body reaction, resulting in neointima formation and restenosis. Silicon carbide (SiC) coating shields the metal from circulating blood and vessel wall, both potential sources of neointima smooth muscle cells. METHODS: We investigated whether SiC-coated stents (PRO-Kinetic) have lower clinical target lesion revascularization (TLR) rates than do uncoated bare-metal stents (Vision). Stents were implanted in 2731 patients during 2 consecutive 18-month periods. Clinical TLR was evaluated at 1 year. RESULTS: In the PRO-Kinetic group, TLR was significantly higher (9.0% vs 5.6%; unadjusted odds ratio, 1.61; 95% confidence interval [CI], 1.24-2.08; P < 0.001) compared with the Vision group. After adjustment for postintervention minimal luminal diameter (adjusted odds ratio [AOR], 0.56; 95% CI, 0.42-0.73), total implanted stent length (AOR, 1.01; 95% CI, 1.00-1.02), non-ST-segment elevation myocardial infarction or unstable angina at initial presentation (AOR, 1.89; 95% CI, 1.41-2.54), and triple vessel stenting (AOR, 2.68; 95% CI, 1.02-7.05), the use of PRO-Kinetic stents remained an independent predictor for revascularization (AOR, 1.57; 95% CI, 1.18-2.10; P = 0.002). Because strut thickness is lower in 2.0- to 3.0-mm PRO-Kinetic stents, a subgroup analysis (n = 2382 lesions) was performed. Even in this subgroup, PRO-Kinetic implantation proved an independent predictor of TLR (AOR, 1.62; 95% CI, 1.17-2.23; P = 0.003). CONCLUSION: In contrast to theoretical expectations, the SiC-coated PRO-Kinetic stent was associated with greater target lesion revascularization rates at 1 year compared with the uncoated Vision stent.

Atrioventricular dissociation due to pheochromocytoma in a young adult.

Atrioventricular dissociation can be a manifestation of an underlying noncardiac disease.We present a patient who underwent pacemaker implantation because of intermittent atrioventricular dissociation and medically untreatable supraventricular arrhythmias, which could not be induced by electrophysiological testing. The arrhythmias proved to be due to a pheochromocytoma. After left adrenalectomy, both the supraventricular arrhythmias and the atrioventricular dissociation disappeared. Adequate recognition and treatment of pheochromocytoma can reverse atrioventricular dissociation and may avoid unnecessary procedures such as electrophysiological testing and pacemaker implantation.

Current perspective of pathophysiological and interventional effects on endothelial progenitor cell biology: focus on PI3K/AKT/eNOS pathway.

For more than a decade, endothelial progenitor cells (EPCs) have been implicated in cardiovascular homeostasis. EPCs are believed to reside within the bone marrow in close contact with surrounding stromal cells, and, under stimulation of pro-inflammatory cytokines, EPCs are mobilized out of the bone marrow. Hereafter circulating EPCs home to peripheral tissues, undergoing further proliferation and differentiation. Under certain pathophysiologic conditions this process seems to be blunted, resulting in a reduced capacity of EPCs to engage in vasculogenesis at sites of endothelial injury or tissue ischemia. In this review, we focus on the effects of traditional cardiovascular risk factors on EPC biology and we explore whether pharmacological, dietary and lifestyle interventions can favorably restore EPC mobilization, differentiation, homing and angiogenic properties. Because the PI3K/Akt/eNOS pathway plays a pivotal role in the process of EPC mobilization, migration and homing, we specifically emphasize the involvement of PI3K, Akt and eNOS in EPC biology under these different (patho)physiologic conditions. (Pre)clinically used drugs or lifestyle interventions that have been shown to ameliorate EPC biology are reviewed. These treatment strategies remain attractive targets to restore the regenerative capacity of EPCs in cardiovascular diseases.

Quantification of circulating endothelial progenitor cells: a methodological comparison of six flow cytometric approaches.

OBJECTIVES: The validity of endothelial progenitor cells as biomarkers and their therapeutic potential depend on the accuracy of techniques used for enumeration. This study assessed the agreement between 6 flow cytometric methods and a CFU assay used for EPC quantification. METHODS: Two blood samples were obtained from 30 healthy volunteers (60 samples). CD34+/VEGFR2+ cells were analyzed with flow cytometry, starting from whole blood (A-C) or PBMC (D-F), using different gating strategies: A: lymphocyte gating; B and D: exclusion of autofluorescent cells (CD3 negative selection); C and E: exclusion of autofluorescence and cell aggregates (pulse shape analysis by FSCarea/FSCpeak); F: exclusion of autofluorescence, cell aggregates and non-nucleated cells (Draq 5). PBMC were cultured under endothelial cell conditions to assess CFU numbers. RESULTS: Moderate agreement was found between methods B-C and D-E (ICC 0.647 and 0.530). Comparison of methods B-D and C-E showed poor agreement (ICC 0.178 and 0.249). This was also the case for techniques that considerably differed with regard to gating strategies (A-B, A-F, B-F). CFU numbers did not correlate with flow cytometric quantification (all p>0.05). CONCLUSIONS: Agreement between methods for EPC quantification is moderate to poor, which may explain apparent controversies in literature. Although each protocol is highly reproducible, this study cautions against comparing study results gathered with different enumeration techniques.

A maximal exercise bout increases the number of circulating CD34+/KDR+ endothelial progenitor cells in healthy subjects. Relation with lipid profile.

Mobilization of bone marrow-derived endothelial progenitor cells (EPC) might explain exercise-induced improvement of endothelial function. We assessed whether a maximal exercise bout could alter the number of circulating EPC in healthy subjects and whether this effect is related to their cardiovascular risk profile. Additionally, we investigated possible mediators of this effect, namely nitric oxide (NO) bioavailability and vascular endothelial growth factor (VEGF) release. Healthy subjects (group 1, n = 11; group 2, n = 14) performed a symptom-limited cardiopulmonary exercise test on a bicycle ergometer. Numbers of CD34+/kinase insert domain receptor (KDR)+ cells were determined by flow-cytometric analysis, either after magnetic separation of CD34+ cells (group 1) or starting from whole blood (group 2). Serum concentrations of VEGF and NO metabolites were measured by using ELISA. Following exercise, EPC increased by 76% (15.4 +/- 10.7 cells/ml vs. 27.2 +/- 13.7 cells/ml; P = 0.01) in group 1 and by 69% in group 2 (30.9 +/- 14.6 cells/ml vs. 52.5 +/- 42.6 cells/ml; P = 0.03). The increase in EPC correlated positively with LDL and total cholesterol/HDL ratio and negatively with peak oxygen consumption and oxygen consumption at anaerobic threshold. VEGF levels increased with exercise, with a strong trend toward significance (P = 0.055). NO levels remained unchanged. The present study demonstrates that a maximal bout of exercise induces a significant shift in CD34+ cells toward CD34+/KDR+ cells. This response was larger in subjects with a less favorable lipid profile.