Felipe Fernández-Vázquez

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.

Effect of Early Metoprolol on Infarct Size in ST-Segment–Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) Trial

Background —The effect of β-blockers on infarct size when used in conjunction with primary percutaneous coronary intervention (PCI) is unknown. We hypothesize that metoprolol reduces infarct size when administered early (intravenously [i.v.] before reperfusion). Methods and Results —Patients with Killip-class ≤II anterior ST-segment elevation myocardial infarction (STEMI) undergoing PCI within 6 hours of symptoms onset were randomized to receive i.v. metoprolol (n=131) or not (control, n=139) pre-reperfusion. All patients without contraindications received oral metoprolol within 24 hours. The pre-defined primary endpoint was infarct size on magnetic resonance imaging (MRI) performed 5-7 days after STEMI. MRI was performed in 220 patients (81%). Mean (±SD) infarct size by MRI was smaller after i.v. metoprolol compared to control (25.6±15.3 vs. 32.0±22.2 grams; adjusted difference, -6.52; 95% confidence interval [CI], -11.39 to -1.78; P=0.012). In patients with pre-PCI TIMI flow grade 0/1, the adjusted treatment difference in infarct size was -8.02; 95% CI, -13.01 to -3.02; P=0.0029. Infarct size estimated by peak and area under the curve creatine-kinase release was measured in all study population and was significantly reduced by i.v. metoprolol. Left ventricular ejection fraction was higher in the i.v. metoprolol group (adjusted difference 2.67%; 95% CI, 0.09% to 5.21%; P=0.045). The composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block and reinfarction at 24 hours in the i.v. metoprolol and control groups respectively was 7.1% vs. 12.3%, p=0.21. Conclusions —In patients with anterior Killip-class ≤II STEMI undergoing primary PCI, early i.v. metoprolol before reperfusion reduced infarct size and increased LVEF with no excess of adverse events during the first 24 hours after STEMI. Clinical Trial Registration Information —ClinicalTrials.gov. Identifier: [NCT01311700][1] & EUDRACT Number 2010-019939-35. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01311700&atom=%2Fcirculationaha%2Fearly%2F2013%2F09%2F03%2FCIRCULATIONAHA.113.003653.atomBackground— The effect of &bgr;-blockers on infarct size when used in conjunction with primary percutaneous coronary intervention is unknown. We hypothesize that metoprolol reduces infarct size when administered early (intravenously before reperfusion). Methods and Results— Patients with Killip class II or less anterior ST-segment–elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention within 6 hours of symptoms onset were randomized to receive intravenous metoprolol (n=131) or not (control, n=139) before reperfusion. All patients without contraindications received oral metoprolol within 24 hours. The predefined primary end point was infarct size on magnetic resonance imaging performed 5 to 7 days after STEMI. Magnetic resonance imaging was performed in 220 patients (81%). Mean±SD infarct size by magnetic resonance imaging was smaller after intravenous metoprolol compared with control (25.6±15.3 versus 32.0±22.2 g; adjusted difference, −6.52; 95% confidence interval, −11.39 to −1.78; P=0.012). In patients with pre–percutaneous coronary intervention Thrombolysis in Myocardial Infarction grade 0 to 1 flow, the adjusted treatment difference in infarct size was −8.13 (95% confidence interval, −13.10 to −3.16; P=0.0024). Infarct size estimated by peak and area under the curve creatine kinase release was measured in all study populations and was significantly reduced by intravenous metoprolol. Left ventricular ejection fraction was higher in the intravenous metoprolol group (adjusted difference, 2.67%; 95% confidence interval, 0.09–5.21; P=0.045). The composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block, and reinfarction at 24 hours in the intravenous metoprolol and control groups was 7.1% and 12.3%, respectively (P=0.21). Conclusions— In patients with anterior Killip class II or less ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, early intravenous metoprolol before reperfusion reduced infarct size and increased left ventricular ejection fraction with no excess of adverse events during the first 24 hours after STEMI. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01311700. EUDRACT number: 2010-019939-35.

Spanish Registry of Cardiac Catheterization and Coronary Interventions. Thirteenth Official Report of the Working Group on Cardiac Catheterization and Interventional Cardiology of the Spanish Society of Cardiology (1990-2003)

The results of the Registry of the Working Group on Cardiac Catheterization and Interventional Cardiology of the Spanish Society of Cardiology for 2003 are presented. Data were obtained from 112 centers representing nearly all cardiac catheterization laboratories in Spain; 104 centers performed mainly adult catheterization and 8 carried out pediatric procedures only. In 2003, 105,939 diagnostic catheterization procedures were performed, including 90 939 coronary angiograms, representing a total increase of 8.5% in comparison to 2002. The population-adjusted rate was 2171 coronary angiograms per 106 inhabitants. Coronary interventions increased by 14.4% in comparison to 2002, with a total of 40,584 procedures and a rate of coronary interventions of 969 per 106 inhabitants. Coronary stents were used in 92.5% of the procedures (47,249 units implanted, for a total increase of 22% in comparison to 2002). About one fifth (20.2%) of the implanted stents were drug-eluting stents (11,699 units). A total of 6080 percutaneous coronary interventions were done in patients with acute myocardial infarction, representing an increase of 27.5% in comparison to 2002, and accounting for 14.9% of all interventional procedures. Of the noncoronary interventions recorded, we note the increase in percutaneous mitral valvuloplasties (21.6%) and atrial septal defect closures (86%), and also the increase in pediatric interventions (13.3%). In conclusion, we emphasize the high rate of reporting by laboratories, which allows the Registry to compile data that are highly representative of the activity at cardiac catheterization laboratories in Spain.

Spanish Cardiac Catheterization and Coronary Intervention Registry. 15th Official Report of the Spanish Society of Cardiology Working Group on Cardiac Catheterization and Interventional Cardiology (1990­-2005)

This article summarizes the findings contained in the 2005 registry of the Spanish Society of Cardiology Working Group on Cardiac Catheterization and Interventional Cardiology. Data were obtained from 128 centers, which comprise almost all cardiac catheterization laboratories in Spain. Of these, 118 performed catheterizations mainly in adults, while 10 carried out procedures in only pediatric patients. In 2005, 117,245 diagnostic catheterization procedures were performed, including 103,646 coronary angiograms, which was 5.9% more than in 2004. The population-adjusted rate was 2326 coronary angiograms per million inhabitants. A total of 51,689 coronary interventions were performed, which is 13.6% more than in 2004 and which corresponds to a rate of 1161 per million inhabitants. Coronary stents were used in 96% of procedures. Of the 80,569 stents implanted, 41,352 (51.3%) were drugeluting stents. Some 8341 percutaneous coronary interventions were carried out in patients with acute myocardial infarction, which is 13.8% more than in 2004. They accounted for 16.1% of all such interventions. Among the non-coronary interventions recorded, the number of percutaneous mitral valvuloplasties decreased by 7%. The number of procedures carried out to close atrial septal defects increased by 40% compared with 2004. The number of pediatric interventions increased by 1.7%. Finally, it is important to note that a large proportion of laboratories reported results, which helped to ensure that the data summarized here are highly representative of the work carried out at cardiac catheterization laboratories in Spain.

Registro Español de Hemodinámica y Cardiología Intervencionista. XV Informe Oficial de la Sección de Hemodinámica y Cardiología Intervencionista de la Sociedad Española de Cardiología (1990-2005)

Se presentan los resultados del Registro de Actividad de la Seccion de Hemodinamica y Cardiologia Intervencionista de la Sociedad Espanola de Cardiologia del ano 2005. Se recogen datos de 128 centros, casi la totalidad de los laboratorios del pais. De ellos, 118 realizaron su actividad principalmente en pacientes adultos y 10 exclusivamente en pacientes pediatricos. Se realizaron 117.245 estudios diagnosticos, con 103.646 coronariografias, lo que representa un aumento del 5,9% respecto al ano 2004 y una tasa de 2.326 coronariografias por millon de habitantes. Se efectuaron 51.689 procedimientos de intervencionismo coronario, con un incremento del 13,6% respecto al ano anterior y una tasa de 1.161 intervenciones por millon de habitantes. Se empleo stent intracoronario en el 96% de los procedimientos, con 80.569 unidades utilizadas, de las cuales, 41.352 fueron stents liberadores de farmacos antiproliferativos (51,3%). Se llevaron a cabo 8.341 procedimientos de intervencionismo en el infarto agudo de miocardio, lo que supone un 13,8% mas respecto al ano 2004 y el 16,1% del total de las intervenciones coronaries percutaneas. En el intervencionismo no coronario se observo una disminucion del numero de valvuloplastias mitrales (7%) y un aumento de procedimientos de cierre percutaneo de comunicacion interauricular en pacientes adultos (40%), asi como un muy ligero incremento de los procedimientos intervencionistas en pacientes en edad pediatrica (1,7%). Finalmente, destaca el alto grado de participacion de centros en el Registro, lo que hace que los datos aqui presentados sean representativos de la actividad hemodinamica en nuestro pais.

Registro Español de Hemodinámica y Cardiología Intervencionista: XIII Informe Oficial de la Sección de Hemodinámica y Cardiología Intervencionista de la Sociedad Española de Cardiología (1990-2003)

Se presentan los resultados del Registro de Actividad de la Seccion de Hemodinamica y Cardiologia Intervencionista de la Sociedad Espanola de Cardiologia del ano 2003. Se recogen datos de 112 centros, casi la totalidad de los laboratorios del pais. De ellos, 104 realizaron su actividad sobre todo en pacientes adultos y 8 exclusivamente en pacientes pediatricos. Se realizaron 105.939 estudios diagnosticos con 90.939 coronariografias, lo que representa un aumento del 8,5% respecto al ano 2002 y una tasa de 2.171 coronariografias por millon de habitantes. Se efectuaron 40.584 procedimientos de intervencionismo coronario, con un incremento del 14,4% respecto al ano anterior y una tasa de 969 intervenciones por millon de habitantes. Se empleo stent intracoronario en el 92,5% de los procedimientos, con 47.249 unidades utilizadas (incremento del 22%), de las cuales 11.699 fueron stents liberadores de farmacos antiproliferativos (20,2%). Se llevaron a cabo 6.080 procedimientos de intervencionismo en el infarto agudo de miocardio, lo que supone un 27,5% mas respecto al ano 2002 y el 14,9% del total de las intervenciones coronarias percutaneas. En el intervencionismo no coronario destaca un aumento del numero de valvuloplastias mitrales (21,6%), un incremento de los cierres percutaneos de comunicacion interauricular en pacientes adultos (86%) y un ligero aumento de los procedimientos intervencionistas en pacientes en edad pediatrica (13,3%). Finalmente, destacamos el alto grado de participacion de centros en el registro, lo que hace que los datos aqui presentados sean representativos de la actividad hemodinamica en nuestro pais.

Registro Español de Hemodinámica y Cardiología Intervencionista. XIV Informe Oficial de la Sección de Hemodinámica y Cardiología Intervencionista de la Sociedad Española de Cardiología (1990-2004)

Se presentan los resultados del Registro de Actividad de la Seccion de Hemodinamica y Cardiologia Intervencionista de la Sociedad Espanola de Cardiologia del ano 2004. Se recogen datos de 121 centros, casi la totalidad de los laboratorios del pais. De ellos, 110 realizaron su actividad sobre todo en pacientes adultos y 11 exclusivamente en pacientes pediatricos. Se realizaron 111.451 estudios diagnosticos con 97.785 coronariografias, lo que representa un aumento del 6,6% respecto al ano 2003 y una tasa de 2.263 coronariografias por millon de habitantes. Se efectuaron 45.469 procedimientos de intervencionismo coronario, con un incremento del 12% respecto al ano anterior y una tasa de 1.052 intervenciones por millon de habitantes. Se empleo stent intracoronario en el 91,4% de los procedimientos, con 68.892 unidades utilizadas (incremento del 12%), de las cuales 25.148 fueron stents liberadores de farmacos antiproliferativos (36,5%). Se llevaron a cabo 7.326 procedimientos de intervencionismo en el infarto agudo de miocardio, lo que supone un 20,5% mas respecto al ano 2003 y el 16,1% del total de las intervenciones coronarias percutaneas. En el intervencionismo no coronario se observo una disminucion del numero de valvuloplastias mitrales (8%) y de cierres percutaneos de comunicacion interauricular en pacientes adultos (7%), y un ligero incremento de los procedimientos intervencionistas en pacientes en edad pediatrica (12%). Finalmente, destacamos el alto grado de participacion de centros en el registro, lo que hace que los datos aqui presentados sean representativos de la actividad hemodinamica en nuestro pais.

Study design for the “effect of METOprolol in CARDioproteCtioN during an acute myocardial InfarCtion” (METOCARD-CNIC): A randomized, controlled parallel-group, observer-blinded clinical trial of early pre-reperfusion metoprolol administration in ST-segment elevation myocardial infarction

BACKGROUND Infarct size predicts post-infarction mortality. Oral β-blockade within 24 hours of a ST-segment elevation acute myocardial infarction (STEMI) is a class-IA indication, however early intravenous (IV) β-blockers initiation is not encouraged. In recent magnetic resonance imaging (MRI)-based experimental studies, the β(1)-blocker metoprolol has been shown to reduce infarct size only when administered before coronary reperfusion. To date, there is not a single trial comparing the pre- vs. post-reperfusion β-blocker initiation in STEMI. OBJECTIVE The METOCARD-CNIC trial is testing whether the early initiation of IV metoprolol before primary percutaneous coronary intervention (pPCI) could reduce infarct size and improve outcomes when compared to oral post-pPCI metoprolol initiation. DESIGN The METOCARD-CNIC trial is a randomized parallel-group single-blind (to outcome evaluators) clinical effectiveness trial conducted in 5 Counties across Spain that will enroll 220 participants. Eligible are 18- to 80-year-old patients with anterior STEMI revascularized by pPCI ≤6 hours from symptom onset. Exclusion criteria are Killip-class ≥III, atrioventricular block or active treatment with β-blockers/bronchodilators. Primary end point is infarct size evaluated by MRI 5 to 7 days post-STEMI. Prespecified major secondary end points are salvage-index, left ventricular ejection fraction recovery (day 5-7 to 6 months), the composite of (death/malignant ventricular arrhythmias/reinfarction/admission due to heart failure), and myocardial perfusion. CONCLUSIONS The METOCARD-CNIC trial is testing the hypothesis that the early initiation of IV metoprolol pre-reperfusion reduces infarct size in comparison to initiation of oral metoprolol post-reperfusion. Given the implications of infarct size reduction in STEMI, if positive, this trial might evidence that a refined use of an approved inexpensive drug can improve outcomes of patients with STEMI.

Closed-chest experimental porcine model of acute myocardial infarction-reperfusion

INTRODUCTION Progress in cardiovascular regenerative medicine research requires the availability of appropriate experimental animal models that are as close to humans as feasible. Our objective was to assess the validity of a porcine endovascular model of myocardial infarction and reperfusion. METHODS Fifteen domestic pigs (Large White race) were anesthetized and pre-medicated with amiodarone. Endovascular fluoroscopy-guided coronary procedures were performed to occlude the mid-left anterior descending artery using a coronary angioplasty balloon. Occlusion was confirmed by angiography and electrocardiography. After 75 min the balloon catheter system was withdrawn and the presence of reperfusion flow was verified. The animals were sacrificed after 1 and 2 weeks of follow-up, the hearts were explanted, and the extent of myocardial infarction with respect to the left ventricle was quantified. RESULTS Overall survival rate was 67%. Five animals died prematurely: 3 showing signs of heart failure, 1 had reperfusion failure (final TIMI flow grade 1) and 1 succumbed to acute stress. The most common adverse event was ventricular fibrillation (87% of the animals) and defibrillation was effective in all affected animals. The extent of myocardial infarct in the animals followed-up for 1 and 2 weeks was similar (20.4+/-4.3% vs. 20.9+/-2.8%, respectively; p=0.8) but was significantly greater in the animals that died prematurely (29.5+/-3.6%, p=0.02). CONCLUSIONS The endovascular porcine model we have explored constitutes a feasible and reproducible alternative for the evaluation of human myocardial infarction and reperfusion.

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.