Antonio Pinero

Early Metoprolol Administration Before Coronary Reperfusion Results in Increased Myocardial Salvage Analysis of Ischemic Myocardium at Risk Using Cardiac Magnetic Resonance

Background— &bgr;-Blockers improve clinical outcome when administered early after acute myocardial infarction. However, whether &bgr;-blockers actually reduce the myocardial infarction size is still in dispute. Cardiac magnetic resonance imaging can accurately depict the left ventricular (LV) ischemic myocardium at risk (T2-weighted hyperintense region) early after myocardial infarction, as well as the extent of necrosis (delayed gadolinium enhancement). The aim of this study was to determine whether early administration of metoprolol could increase myocardial salvage, measured as the difference between the extent of myocardium at risk and myocardial necrosis. Methods and Results— Twelve Yorkshire pigs underwent a 90-minute left anterior descending coronary occlusion, followed by reperfusion. They were randomized to metoprolol (7.5 mg during myocardial infarction) or placebo. Global and regional LV function, extent of myocardium at risk, and myocardial necrosis were quantified by cardiac magnetic resonance imaging studies performed 4 and 22 days after reperfusion in 10 survivors. Despite similar extent of myocardium at risk in metoprolol- and placebo-treated pigs (30.9% of LV versus 30.6%; P=NS), metoprolol resulted in 5-fold-larger salvaged myocardium (32.4% versus 6.2% of myocardium at risk; P=0.015). The LV ejection fraction significantly improved in metoprolol-treated pigs between days 4 and 22 (37.2% versus 43.0%; P=0.037), whereas it remained unchanged in pigs treated with placebo (35.1% versus 35.0%; P=NS). The extent of myocardial salvage was related directly to LV ejection fraction improvement (P=0.031) and regional LV wall motion recovery (P=0.039) at day 22. Conclusions— Early metoprolol administration during acute coronary occlusion increases myocardial salvage. The extent of myocardial salvage, measured as the difference between myocardium at risk and myocardial necrosis, was associated with regional and global LV motion improvement.

Rapid change in plaque size, composition, and molecular footprint after recombinant apolipoprotein A-I Milano (ETC-216) administration: magnetic resonance imaging study in an experimental model of atherosclerosis

OBJECTIVES This study sought to assess the effect of short-term apolipoprotein (apo) A-I(Milano) administration on plaque size and on suspected markers of plaque vulnerability. BACKGROUND Long-term lipid-lowering interventions can regress and stabilize atherosclerotic plaques. However, the majority of recurrent events occur early after the first episode. Interventions able to acutely induce plaque regression and stabilization are lacking. Regression of human coronary lesions after 5 weeks of treatment with apoA-I(Milano) administration has been shown. However, there are no data regarding its effect on plaque vulnerability. METHODS Advanced aortic lesions were induced in New Zealand White rabbits (n = 40). Plaque size was assessed by magnetic resonance imaging (MRI) at the end of atherosclerosis induction. Animals were randomized to placebo or apoA-I(Milano) phospholipids (ETC-216), 2 infusions 4 days apart. After the last dose, another MRI study was performed and aortas were processed for cellular composition and gene protein expression of markers associated with plaque instability. RESULTS Pre-treatment MRI showed similar plaque size in both groups, whereas post-treatment MRI showed 6% smaller plaques in apoA-I(Milano)-treated animals compared with placebo (p = 0.026). The apoA-I(Milano) treatment induced a 5% plaque regression (p = 0.003 vs. pre-treatment), whereas the placebo showed no significant effect. Plaque regression by apoA-I(Milano) was associated with a reduction in plaque macrophage density and a significant down-regulation in gene and protein expression of tissue factor, monocyte chemoattractant protein-1, and cyclooxygenase-2, as well as marked decrease in gelatinolytic activity. Conversely, cyclooxygenase-1 was significantly up-regulated. CONCLUSIONS Acute plaque regression observed after short-term apoA-I(Milano) administration was associated with a significant reduction in suspected makers of plaque vulnerability in an experimental model of atherosclerosis.

Recombinant HDLMilano exerts greater anti-inflammatory and plaque stabilizing properties than HDLwild-type

OBJECTIVE The aim of this study was to compare the effects of HDL(Milano) and HDL(wild-type), on regression and stabilization of atherosclerosis. METHODS Atherosclerotic New Zealand White rabbits received 2 infusions, 4 days apart, of HDL(Milano) (75mg/kg of apoA-I(Milano)), HDL(wild-type) (75mg/kg apoA-I(wild-type)) or placebo. Pre- and post-treatment plaque volume was assessed by MRI. Markers of plaque vulnerability and inflammation were evaluated. Liver and aortic cholesterol content, aortic ABCA-1 and liver SR-BI were quantified. The effect of apoA-I Milano and wild-type proteins on MCP-1 and COX-2 expression by macrophages was evaluated in vitro. RESULTS Both forms of HDL induced aortic plaque regression (-4.1% and -2.6% vs. pre-treatment in HDL(Milano) and HDL(wild-type) respectively, p<0.001 and p=0.009). A similar reduction in cholesterol content of aorta and liver was observed with both treatments vs. placebo. The expression of aortic ABCA-1 and hepatic SR-BI was significantly higher in both treated groups vs. placebo. A significantly reduced plaque macrophage density was observed in the HDL(Milano) vs. both HDL(wild-type) and placebo groups. Plaque levels of COX-2, MCP-1, Caspase-3 antigen and MMP-2 activity were significantly reduced in the HDL(Milano) vs. both HDL(wild-type) and placebo groups. In vitro studies showed that apoA-I(Milano) protein significantly reduced expression of COX-2 and MCP-1 in oxLDL loaded macrophages vs. apoA-I(wild-type). CONCLUSIONS Despite a similar effect on acute plaque regression, the infusion of HDL(Milano) exerts superior anti-inflammatory and plaque stabilizing effects than HDL(wild-type) in the short term.

Nuevas técnicas de imagen para la cuantificación de la carga aterosclerótica global

La aterotrombosis (aterosclerosis y sus complicaciones tromboticas) es un proceso sistemico con manifestaciones locales. Una comprension basica de los procesos implicados en la genesis y progresion de esta enfermedad permite un enfoque global orientado a un diagnostico precoz en vistas a un tratamiento temprano. El conocimiento de la carga aterosclerotica global individual es de alta importancia, ya que permite un manejo mas agresivo de los factores de riesgo. El campo de la imagen no invasiva ofrece la posibilidad de cuantificar la carga aterosclerotica en regiones accesibles (carotidas, aorta). Existen datos que sugieren una correlacion entre la carga aterosclerotica presente en dichos territorios y la existente en otros territorios menos accesibles (coronarias), y, por tanto, es posible realizar una estimacion de la carga aterosclerotica global de forma no invasiva. Nuevas modalidades como la tomografia axial computarizada con multidetectores permite explorar de forma no invasiva en el territorio coronario, con resultados altamente prometedores tanto diagnosticos como de cribado en pacientes de alto riesgo. Las tecnicas de imagen molecular permiten un abordaje no invasivo no solo de la anatomia, sino de la funcionalidad de diferentes tejidos/territorios. Estas nuevas modalidades son altamente prometedoras a la hora de realizar un diagnostico precoz de regiones de alto riesgo.

Quantification of serial changes in plaque burden using multi-detector computed tomography in experimental atherosclerosis

UNLABELLED Assessment of changes in plaque volume is increasingly used as a surrogate-endpoint in clinical trials testing the efficacy of anti-atherosclerotic interventions. Multi-detector computed tomography (MDCT) can detect and quantify non-calcified atherosclerotic plaques, but its ability to monitor changes in plaque volume has not yet been tested. We sought to test the ability of MDCT to detect and quantify serial changes in atheroma burden in comparison with magnetic resonance imaging (MRI). METHODS Rabbits (n=12) with experimentally induced abdominal atherosclerosis were randomized to receive a plaque-regressing agent (recombinant apoA-I(Milano), n=8) or placebo (n=4). All animals underwent two 64-slice MDCT angiography and MRI studies (pre- and post-treatment). The primary endpoint was the change in plaque burden (defined as vessel wall volume in the 5cm distal to the left renal artery) between pre- and post-treatment MDCT in comparison with MRI. RESULTS MDCT detected a significant decrease in plaque burden caused by recombinant apoA-I(Milano) (464 [423-535] to 405 [363-435]mm(3), p=0.03) that was confirmed by MRI (324 [286-412] to 298 [282-399]mm(3), p=0.03). No significant effect was noted in the placebo group either by MDCT or MRI. There were strong correlations between both modalities for the quantification of plaque burden (r=0.750, p<0.001) and change in plaque burden (r=0.657, p=0.020). MDCT overestimated plaque burden compared to MRI. On MDCT, the mean interobserver variability for plaque burden was 2.5+/-0.4%. CONCLUSIONS In an animal model of atherosclerosis, MDCT accurately documented serial changes in aortic plaque burden, demonstrating good correlation and agreement with MRI-derived measurements and low interobserver variability.

Novel Imaging Techniques for Quantifying Overall Atherosclerotic Burden

Atherothrombosis (i.e., atherosclerosis and its thrombotic complications) is a systemic disease with local manifestations. Basic understanding of the pathological processes involved in the development and progression of the disease makes it possible to adopt a general approach to early diagnosis with a view to timely treatment. Knowledge of an individuals overall atherosclerotic burden is extremely important, as it enables risk factors to be treated more aggressively. Non-invasive imaging provides a means of quantifying atherosclerotic burden in accessible areas such as the carotid arteries and the aorta. There is some evidence that there is a correlation between atherosclerotic burden in these areas and that in other less accessible areas, such as the coronary arteries. It may be possible, therefore, to obtain an estimate of overall atherosclerotic burden using non-invasive techniques. Novel imaging modalities, such as multidetector computed axial tomography, enable the coronary artery tree to be explored non-invasively, with highly promising results for both diagnosis and screening in high-risk patients. Molecular imaging techniques enable not only the anatomy but also the function of specific tissues and anatomical territories to be studied non-invasively. These new techniques provide highly promising tools for an early diagnosis in high-risk locations.

Plasma Levels of Monocyte Chemoattractant Protein-1, n-Terminal Fragment of Brain Natriuretic Peptide and Calcidiol Are Independently Associated with the Complexity of Coronary Artery Disease.

Background and Objectives We investigated the relationship of the Syntax Score (SS) and coronary artery calcification (CAC), with plasma levels of biomarkers related to cardiovascular damage and mineral metabolism, as there is sparse information in this field. Methods We studied 270 patients with coronary disease that had an acute coronary syndrome (ACS) six months before. Calcidiol, fibroblast growth factor-23, parathormone, phosphate and monocyte chemoattractant protein-1 [MCP-1], high-sensitivity C-reactive protein, galectin-3, and N-terminal pro-brain natriuretic peptide [NT-proBNP] levels, among other biomarkers, were determined. CAC was assessed by coronary angiogram as low-grade (0–1) and high-grade (2–3) calcification, measured with a semiquantitative scale ranging from 0 (none) to 3 (severe). For the SS study patients were divided in SS<14 and SS≥14. Multivariate linear and logistic regression analyses were performed. Results MCP-1 predicted independently the SS (RC = 1.73 [95%CI = 0.08–3.39]; p = 0.040), along with NT-proBNP (RC = 0.17 [95%CI = 0.05–0.28]; p = 0.004), male sex (RC = 4.15 [95%CI = 1.47–6.83]; p = 0.003), age (RC = 0.13 [95%CI = 0.02–0.24]; p = 0.020), hypertension (RC = 3.64, [95%CI = 0.77–6.50]; p = 0.013), hyperlipidemia (RC = 2.78, [95%CI = 0.28–5.29]; p = 0.030), and statins (RC = 6.12 [95%CI = 1.28–10.96]; p = 0.013). Low calcidiol predicted high-grade calcification independently (OR = 0.57 [95% CI = 0.36–0.90]; p = 0.013) along with ST-elevation myocardial infarction (OR = 0.38 [95%CI = 0.19–0.78]; p = 0.006), diabetes (OR = 2.35 [95%CI = 1.11–4.98]; p = 0.028) and age (OR = 1.37 [95%CI = 1.18–1.59]; p<0.001). During follow-up (1.79 [0.94–2.86] years), 27 patients developed ACS, stroke, or transient ischemic attack. A combined score using SS and CAC predicted independently the development of the outcome. Conclusions MCP-1 and NT-proBNP are independent predictors of SS, while low calcidiol plasma levels are associated with CAC. More studies are needed to confirm these data.