Carlos Cuellas Ramón

Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart.

OBJECTIVES The purpose of this study was to test the ability of insulin-like growth factor (IGF)-1/hepatocyte growth factor (HGF) to activate resident endogenous porcine cardiac stem/progenitor cells (epCSCs) and to promote myocardial repair through a clinically applicable intracoronary injection protocol in a pig model of myocardial infarction (MI) relevant to human disease. BACKGROUND In rodents, cardiac stem/progenitor cell (CSC) transplantation as well as in situ activation through intramyocardial injection of specific growth factors has been shown to result in myocardial regeneration after acute myocardial infarction (AMI). METHODS Acute MI was induced in pigs by a 60-min percutaneous transluminal coronary angiography left anterior descending artery occlusion. The IGF-1 and HGF were co-administered through the infarct-related artery in a single dose (ranging from 0.5 to 2 μg HGF and 2 to 8 μg IGF-1) 30 min after coronary reperfusion. Pigs were sacrificed 21 days later for dose-response relationship evaluation by immunohistopathology or 2 months later for cardiac function evaluation by cardiac magnetic resonance imaging. RESULTS The IGF-1/HGF activated c-kit positive-CD45 negative epCSCs and increased their myogenic differentiation in vitro. The IGF-1/HGF, in a dose-dependent manner, improved cardiomyocyte survival, and reduced fibrosis and cardiomyocyte reactive hypertrophy. It significantly increased c-kit positive-CD45 negative epCSC number and fostered the generation of new myocardium (myocytes and microvasculature) in infarcted and peri-infarct/border regions at 21 and 60 days after AMI. The IGF-1/HGF reduced infarct size and improved left ventricular function at 2 months after AMI. CONCLUSIONS In an animal model of AMI relevant to the human disease, intracoronary administration of IGF-1/HGF is a practical and effective strategy to reduce pathological cardiac remodeling, induce myocardial regeneration, and improve ventricular function.

Endothelialization of Nonapposed Stent Struts Located over the Origin of a Side Branch: Results with Different Carbofilm‐Coated Stents

OBJECTIVE To evaluate the degree of endothelialization of the nonapposed struts located at the ostia of side branches. BACKGROUND Endothelialization of coronary stents has got considerable relevance because of the phenomenon of late thrombosis. Bifurcation location and incomplete stent apposition have been linked to this complication. METHODS Domestic pigs (n = 11; weight: 25 +/- 3 kg) were anesthetized and had one stent per coronary artery implanted: one stainless steel (Tecnic), one cobalt-chromium (Chrono), and one tacrolimus-eluting stent (Janus), all of them being Carbofilm-coated (Sorin). One, three, or seven days postprocedure, the pigs were sacrificed, the hearts explanted, and longitudinal sections examined by surface electron microscopy to quantify the percentage of the strut endothelialized over the branches and in the total surface. RESULTS Forty-four side branches (25 stents) that had stent struts over their origin were evaluated. Different patterns of endothelialization were observed, from the total absence to the complete endothelialization. There were no significant differences in relation to type of stent or to the artery treated. The predictors of higher percentage of endothelialization were the ratio of metal to branch diameter (P = 0.04) and better endothelialization in the rest of the stent (P = 0.0002), only this parameter maintaining significant correlation (P = 0.03) in multivariate analysis. CONCLUSIONS Carbofilm-coated stent struts located over the origin of side branches follow the pattern of endothelialization for the rest of the stent, even in the case of tacrolimus-eluting stent.

Post-Treatment Platelet Reactivity Predicts Long-Term Adverse Events Better Than the Response to Clopidogrel in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome

Introduction and objectives Poor response to antiplatelet therapy has been associated with adverse long-term outcomes. The objective of this study is to assess the relationship between response to clopidogrel and post-treatment platelet reactivity (PPR) and 1-year major adverse cardiovascular events (MACE) in patients with non-ST segment elevation acute coronary syndrome (NSTEACS). Methods Patients with NSTEACS undergoing early coronary angiography were enrolled in this prospective, observational study. The VerifyNow® analyzer was used to measure clopidogrel response and PPR immediately before coronary angiography. Results Of the 179 patients included (97 percutaneous coronary intervention, 21 coronary artery bypass graft), 161 (90%) completed 1-year follow-up and 18 (11%) incurred MACE: 10 deaths, 6 myocardial infarctions, 2 strokes, 5 revascularizations. Lower response to clopidogrel (31±21% vs. 43±21%; P=.049) and higher PPR (204±60 vs. 155±67 platelet reaction units [PRU]; p=.006) were significantly associated with MACE occurrence. Multivariate analysis confirmed PPR (OR per 10-unit increase, 1.12, 95% CI, 1.01-1.24; P=.020) as an independent predictor of MACE. A PPR cut-off value of 175 PRU was associated with an adjusted OR for 1-year MACE occurrence of 3.9 (95% CI, 1.2-15.4; P=.024). Conclusions PPR predicts adverse long-term outcomes better than response to clopidogrel in patients with NSTEACS. Patients with PPR values above 175 PRU were identified as being at higher risk for adverse long-term events.

Incidence and prognostic implications of late bleeding events after percutaneous mitral valve repair

Objectives MitraClip is an established therapy for patients with mitral regurgitation (MR) that are considered of high-risk or inoperable. However, late bleeding events (BE) after hospital discharge and their impact on prognosis in this cohort of patients have been poorly investigated. Our purpose is to address the incidence, related factors and clinical implications of BE after hospital discharge in patients treated with MitraClip. Methods Prospective registry of all consecutive patients (n = 80) who underwent MitraClip implantation in our Institution between June 2014 and December 2017. BE were defined according to MVARC definitions. A combined clinical end-point including admission for heart failure (HF) and all-cause mortality was established to analyze prognostic implications of BE. Results During a median follow up of 523.5 days, 41 BE were reported in 21 patients. Atrial fibrillation (AF, HR 4.54, CI95% 1.20–17.10) and combined antithrombotic therapy at discharge (HR 3.52, CI95% 1.03–11.34) were independently associated with BE. In the study period, 15 (18.8%) patients died, 20 (25%) were admitted for HF and 29 (36.3%) presented the combined end-point. After multivariable adjustment BE remained independently associated with an adverse outcome (HR 3.80, CI 95% 1.66–8.72). In the subgroup of patients with AF, HAS-BLED score was higher among subjects with BE (3.1 ± 1.3 vs 2.1 ± 0.9, p = 0.003). HAS-BLED score had a significant discrimination power for the occurrence BE (AUC: 0.677 [0.507–0.848]) in this subgroup. Conclusions BE are common after MitraClip and are associated with an impaired outcome. Strategies to reduce bleeding events are paramount in this cohort of patients.