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Supplemental Digital Content is available in the text., Background. Endothelium-enriched microRNAs (miRs) are involved in the development of cardiac allograft vasculopathy (CAV). Recently, serum-derived miR-126-3p and -5p, known endothelial microRNAs with a crucial function in angiogenesis and re-endothelialization, provided additional predictive power for cardiac allograft vasculopathy in addition to clinical predictors. However, their myocardial expression in and relationship with CAV are still unknown. Our study aim was to investigate the expression of endomyocardial microRNA-126-3p and microRNA-126-5p levels in heart transplant recipients and their relationship with allograft vasculopathy. Methods. We studied 39 heart transplant recipients, 21 with proven allograft vasculopathy (CAV+) and 18 without allograft vasculopathy (CAV−) with serial coronary angiograms. Additionally, 8 patients with end-stage native coronary artery disease (CAD) were added to the study to investigate disease specificity of the microRNA signature. The mRNA levels of miR-126-3p and miR-126-5p were determined by qRT-PCR in the right ventricular endomyocardial biopsies obtained at baseline and during routine follow-up. Results. MiR-126-3p levels were significantly lower in the CAV+ group compared to the CAV− group at follow-up, while miR-126-5p levels were unaltered. This was in stark contrast to native CAD patients in whom miR-126-3p and -5p levels were significantly higher. qPCR levels of miR-126 targets are differentially regulated in CAV versus ischemic cardiomyopathy and are influenced by the administration of immunosuppressive agents in endothelial cells. Conclusions. Our data provide evidence for a distinct microRNA signature in heart transplantation patients with allograft vasculopathy. In contrast to CAD patients, lower miR-126-3p levels coincide with the development of cardiac allograft vasculopathy. Further studies in a larger patient population are warranted to determine if the serial measurement of myocardial microRNA-126 products could help in risk assessment and early detection of CAV.

Background Elevated serum levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and atherogenesis. In patients with suspected coronary artery disease (CAD), we assessed the correlation of serum ADMA levels with extent and functional significance of coronary atherosclerosis. Methods We enrolled 281 patients with suspected CAD undergoing coronary angiogram. Angiographic CAD severity was evaluated by Bogaty score. In patients with angiographic evidence of at least one intermediate coronary stenosis (≥50% diameter stenosis), functional significance was assessed by fractional flow reserve (FFR). Blood samples were collected in all patients prior to coronary angiography for measurement of serum ADMA levels. Results We observed across tertiles of ADMA levels increasingly higher values of both Stenosis Score (2.25±1.70 vs. 2.89±1.99 vs. 2.95±1.82, p=0.016) and Extent Index (0.52±0.32 vs. 0.61±0.39 vs. 0.72±0.47, p=0.003). The association between ADMA levels and Extent Index remained significant after multivariate adjustment (p=0.005). Patients with FFR ≤0.80 in at least one vessel (n=113) had significantly higher ADMA levels compared with patients without functionally significant CAD (0.51 [0.43–0.64] vs. 0.46 [0.39–0.58]μmol/L, p=0.005). Serum ADMA levels were independent predictors of abnormal FFR after adjustment for extent score (odds ratio 7.35, 95% confidence interval 1.05–56.76, p=0.046). Conclusions Serum ADMA levels are independent predictors of coronary atherosclerosis extent and functional significance of CAD.

BACKGROUND: Collaterals in patients with coronary artery disease (CAD) limit myocardial infarction and improve survival. Macrophage migration inhibitory factor (MIF) might play a role in collateral development. We aimed this study to evaluate the association of Macrophage migration Inhibitory Factor (MIF) with the extent of collateralization in patients with coronary occlusion. METHODS AND RESULTS: We consecutively enrolled: a) 40 patients undergoing PCI of a chronic coronary total occlusion (CTO); b) 26 patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI (pPCI) of the infarct-related artery (IRA); c) 12 control patients undergoing angiography without significant coronary artery disease (CTRL). CTO patients were grouped in high (HCG) or low collateralization group (LCG). STEMI patients were grouped in COLL+ or COLL- group depending on the presence of collaterals to the IRA. Blood sampling was performed from the arterial sheath (SYSTEMIC), and distal to the occlusion (LOCAL). SYSTEMIC and LOCAL levels were significantly different between the 3 groups. A progressive increase in MIF ratio (defined as: % (LOCAL-SYSTEMIC)/SYSTEMIC) was observed (CTRL: -0.5[-23;28] vs. CTO: 4[-19;32] vs. STEMI: 55[37;87], p

Platelet reactivity is greater in patients with stable angina and with more extensive peripheral vascular atherosclerosis. We sought to evaluate whether impaired peripheral microcirculatory endothelial function might correlate with platelet reactivity after clopidogrel and therefore predispose to an unfavorable outcome after percutaneous coronary intervention (PCI). In 52 consecutive patients with stable angina undergoing elective PCI, endothelial function was assessed by (1) endothelial peripheral arterial tonometry (measuring the "Endoscore"); (2) the von Willebrandt factor antigen level and ristocetin co-factor activity. Basal platelet reactivity was assessed by soluble P-selectin. Patients then received a 600-mg clopidogrel loading dose ≥12 hours before PCI. A blood sample was withdrawn 12 hours later, but before PCI, to assess platelet reactivity using the P2Y12 reaction unit and percentage of P2Y12 inhibition with the point-of-care VerifyNow P2Y12 assay. Troponin T was assessed 24 hours after PCI. The Endoscore inversely correlated with von Willebrandt factor antigen activity (r = -0.52, p = 0.0001) and soluble P-selectin concentration (r = -0.36, p = 0.021), suggesting greater platelet reactivity with increased impaired endothelial function. After clopidogrel, the Endoscore correlated directly with the percentage of P2Y12 inhibition (r = 0.36, p = 0.009) and inversely with the P2Y12 reaction unit (r = -0.41, p = 0.002), suggesting greater residual platelet reactivity with more impaired endothelial function. The average Endoscore was significantly lower in patients with troponin T elevation (troponin positive group 0.267 ± 0.091) than in patients without troponin T elevation (troponin negative group 0.508 ± 0.041, p = 0.015 vs troponin positive). In conclusion, an impaired endothelial response before clopidogrel was associated with greater platelet reactivity after clopidogrel. This link might explain the unfavorable PCI outcomes in patients with more severe endothelial impairment. © 2010 Elsevier Inc. All rights reserved.

Monocyte–platelet aggregates (MPA) are increased in patients with acute coronary syndrome. We investigated whether MPA are associated with the presence of functionally significant coronary stenoses or with coronary arterial endothelial dysfunction. One hundred forty five patients undergoing elective coronary angiography were prospectively enrolled. Functional significance of coronary stenosis was assessed by fractional flow reserve (FFR). Thirty randomly selected patients underwent pacing protocol to evaluate Coronary endothelium-dependent vasomotor function (CVF). Whole blood was drawn to evaluate MPA. In patients with FFR ≤ 0.8 (FFRpos, n = 75), MPA did not significantly differ from FFR >0.8 patients (FFRneg, n = 70) (38.1 % [25.7–56.6] vs 34.0 % [20.5–49.9], p = 0.08). CVF was similar in FFRpos and FFRneg patients (percent vessel diameter change, %VDC = 7.19 % [6.01–10.9] vs 8.0 % [0.81–9.80], p = 0.78). Yet, patients with abnormal CVF showed higher MPA as compared to patients with preserved CVF (28.3 % [28.8–53.4] vs 20.5 % [17.0–32.9], p = 0.01). Moreover, MPA was inversely correlated with %VDC (R 2 = 0.26, p

AIMS: Endothelium dysfunction has been reported in patients (pts) undergoing transradial catheterisation. Alterations of the hand microcirculation possibly associated with systemic inflammation have never previously been reported. We aimed at investigating possible alteration of hand endothelial microcirculation secondary to transradial heart catheterisation. METHODS AND RESULTS: We randomised 40 pts with stable angina undergoing coronary angiography to either transradial (TR, n=20) or transfemoral (TF, n=20) approach. At baseline (BL), 24 hours (24 hrs) and 30 days (FU: follow-up) after catheterisation we assessed: a) peripheral endothelial function (EndoScore [ES]) by peripheral arterial tonometry (EndoPAT); b) biomarkers of endothelial turnover (sE-Selectin) and inflammation (hs-CRP). No clinical or angiographic differences were observed between the two groups. At 24 hours, ES (BL: 0.42±0.27 vs. 24 hours: 0.27±0.19, p

Biomarkers of blood lipid modification and oxidative stress have been associated with increased cardiovascular morbidity. We sought to determine whether these biomarkers were related to functional indices of stenosis severity among patients with stable coronary artery disease. We studied 197 consecutive patients with stable coronary artery disease due to single vessel disease. Fractional flow reserve (FFR) ≤ 0.80 was assessed as index of a functionally significant lesion. Serum levels of secretory phospholipase A2 (sPLA2) activity, secretory phospholipase A2 type IIA (sPLA2-IIA), myeloperoxydase (MPO), lipoprotein-associated phospholipase A2 (Lp-PLA2), and oxidized low-density lipoprotein (OxLDL) were assessed using commercially available assays. Patients with FFR0.8 had higher sPLA2 activity, sPLA2 IIA, and OxLDL levels than patients with FFR ≤ 0.8 (21.25 [16.03-27.28] vs 25.85 [20.58-34.63] U/mL, p0.001, 2.0 [1.5-3.4] vs 2.6 [2.0-3.4] ng/mL, p0.01; and 53.0 [36.0-71.0] vs 64.5 [50-89.25], p0.001 respectively). Patients with FFR0.80 had similar Lp-PLA2 and MPO levels versus those with FFR ≤ 0.8. sPLA2 activity, sPLA2 IIA significantly increased area under the curve over baseline characteristics to predict FFR ≤ 0.8 (0.67 to 0.77 (95 % confidence interval [CI]: 0.69-0.85) p 0.01 and 0.67 to 0.77 (95 % CI: 0.69-0.84) p0.01, respectively). Serum sPLA2 activity as well as sPLA2-IIA level is related to functional characteristics of coronary stenoses in patients with stable coronary artery disease.