Effects of intravenous lysine acetylsalicylate versus oral aspirin on platelet responsiveness in patients with ST-segment elevation myocardial infarction: the ECCLIPSE-STEMI trial.

Prasugrel and ticagrelor, new P2Y12-ADP receptor antagonists, are associated with greater pharmacodynamic inhibition and reduction of cardiovascular events in patients with an acute coronary syndrome. However, evidence is lacked about the effects of achieving faster and stronger cyclooxygenase inhibition with intravenous lysine acetylsalicylate (LA) compared to oral aspirin. Recently, we demonstrated in healthy volunteers that the administration of intravenous LA resulted in a significantly reduction of platelet reactivity compared to oral aspirin. Loading dose of LA achieves platelet inhibition faster, and with less variability than aspirin. However, there are no data of this issue in patients with an ST-segment elevation myocardial infarction (STEMI). This is a prospective, randomized, multicenter, open platelet function study conducted in STEMI patients. Subjects were randomly assigned to receive a loading dose (LD) of intravenous LA 450 mg plus oral ticagrelor 180 mg, or LD of aspirin 300 mg plus ticagrelor 180 mg orally. Platelet function was evaluated at baseline, 30 min, 1 h, 4 h and 24 h using multiple electrode aggregometry and vasodilator-stimulated phosphoprotein phosphorylation (VASP). The primary endpoint of the study is the inhibition of platelet aggregation (IPA) after arachidonic acid (AA) 0.5 mM at 30 min. Secondary endpoints were the IPA at 1, 4, and 24 h after AA, and non-AA pathways through the sequence (ADP and TRAP). A total of 32 STEMI patients were randomized (16 LA, 16 aspirin). The inhibition of platelet aggregation after AA 0.5 mM at 30 min was greater in subjects treated with LA compared with aspirin: 166 vs. 412 respectively (p = 0.001). This differential effect was observed at 1 h (p = 0.01), but not at 4 and 24 h. Subjects treated with LA presented less variability and faster inhibition of platelet aggregation wit AA compared with aspirin. The administration of intravenous LA resulted in a significantly reduction of platelet reactivity compared to oral aspirin on ticagrelor inhibited platelets in patients with STEMI. Loading dose of LA achieves an earlier platelet inhibition, and with less variability than aspirin.Trial Registration: Unique identifier: NCT02929888; URL: http://www.clinicaltrials.gov.

Vascular Injury After Stenting　- Insights of Systemic Mechanisms of Vascular Repair.

BACKGROUND: The role of circulating progenitor cells (CPC) in vascular repair following everolimus-eluting stent (EES) implantation is largely unknown. The aim of the study was to investigate the relationship between temporal variation in CPC levels following EES implantation and the degree of peri-procedural vascular damage, and stent healing, as measured by optical coherence tomography (OCT).Methods and Results: CPC populations (CD133+/KDR+/CD45low) included patients with stable coronary artery disease undergoing stent implantation, and were evaluated using a flow cytometry technique both at baseline and at 1 week. OCT evaluation was performed immediately post-implantation to quantify the stent-related injury and at a 9-month follow up to assess the mid-term vascular response. Twenty patients (mean age 66±9 years; 80% male) with EES-treated stenoses (n=24) were included in this study. Vascular injury score was associated with the 1-week increase of CD133+/KDR+/CD45low (ß 0.28 [95% CI 0.15; 0.41]; P<0.001) and with maximum neointimal thickness at a 9-month follow up (ß 0.008 [95% CI 0.0004; 0.002]; P=0.04). Inverse relationships between numbers of uncoated and apposed struts for the 9-month and the 1-week delta values of CD133+/KDR+/CD45low (ß -12.53 [95% CI -22.17; -2.90]; P=0.011), were also found. CONCLUSIONS: The extent of vessel wall injury influences early changes in the levels of CPC and had an effect on mid-term vascular healing after EES implantation. Early CPC mobilisation was associated with mid-term strut coverage.

Serum Metabolomic Analysis Suggests Impairment of Myocardial Energy Production in Takotsubo Syndrome.

INTRODUCTION: Takotsubo syndrome is a complex entity that, although it usually has a good prognosis, can be life threatening. While recent advances have improved the knowledge of takotsubo syndrome, many aspects of its etiology still remain uncertain. Metabolomics, a hypothesis generating approach, could provide novel pathophysiology information about this disease. METHODS AND RESULTS: Serum samples were obtained from takotsubo (n = 19) and acute myocardial infarction patients (n = 8) at the cath lab and, in the case of takotsubo, again once the patient had recovered, 3 months after the main event. 1H NMR spectra of the serum were acquired at 9.4T using a CPMG pulse sequence (32 ms effective delay). Supervised and unsupervised pattern recognition approaches where applied to the data. Pattern recognition was able to differentiate between takotsubo and acute myocardial infarction during the acute phase with 95% accuracy. Myocardial infarction patients showed an increase in lipid signals, a known risk factor for the disease while takotsubo patients showed a relative increase in acetate that could suggest a reduced turnover of the Krebs cycle. When comparing acute and recovered phases, we could detect an increase in alanine and creatine once patients recovered. CONCLUSIONS: Our results demonstrate that takotsubo syndrome is metabolically different than AMI, showing limited myocardial energy production capacity during the acute phase. We achieved high classification success against AMI; however, this study should be considered as a proof of concept regarding clinical application of metabolic profiling in takotsubo cardiomyopathy.

Platelet Apoptotic Response May Be Associated With the Capacity of Aspirin to Inhibit Platelets.

An inadequate platelet response to aspirin (ASA) has been identified in some patients under chronic ASA treatment. The aim of this study was to analyze if ASA-sensitive and ASA-resistant platelets have differences in their apoptotic capability. Clinically stable ischemic coronary patients who had been taking ASA (100 mg/d) for at least 9 months before inclusion were divided into ASA-resistant (n = 11) and ASA-sensitive (n = 13) groups as defined by the PFA-100 test. Platelets from ASA-sensitive patients showed higher expression of the proapoptotic proteins Bak and Bax than those from ASA-resistant patients, although only Bak protein remained different when the results were adjusted by age. In resting platelets, neither caspase-3 activity nor cytosolic cytochrome C levels were different between both experimental groups. Stimulation of platelets with calcium ionophore (10 nmol/L, A23187) increased caspase-3 activity (1.91-fold higher; P < 0.05) and cytosolic cytochrome C levels (1.84-fold higher; P < 0.05) to a higher degree in ASA-sensitive than in ASA-resistant platelets. In conclusion, ASA-sensitive platelets seem to be better prepared to undergo apoptosis during robust platelet activation.

Neutrophil stunning by metoprolol reduces infarct size.

The ß1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. The prevailing view has been that metoprolol acts mainly on cardiomyocytes. Here, we demonstrate that metoprolol reduces reperfusion injury by targeting the haematopoietic compartment. Metoprolol inhibits neutrophil migration in an ADRB1-dependent manner. Metoprolol acts during early phases of neutrophil recruitment by impairing structural and functional rearrangements needed for productive engagement of circulating platelets, resulting in erratic intravascular dynamics and blunted inflammation. Depletion of neutrophils, ablation of Adrb1 in haematopoietic cells, or blockade of PSGL-1, the receptor involved in neutrophil-platelet interactions, fully abrogated metoprolol's infarct-limiting effects. The association between neutrophil count and microvascular obstruction is abolished in metoprolol-treated AMI patients. Metoprolol inhibits neutrophil-platelet interactions in AMI patients by targeting neutrophils. Identification of the relevant role of ADRB1 in haematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.

Impact of Intravenous Lysine Acetylsalicylate Versus Oral Aspirin on Prasugrel-Inhibited Platelets: Results of a Prospective, Randomized, Crossover Study (the ECCLIPSE Trial).

BACKGROUND: Prasugrel and ticagrelor, new P2Y12-adenosine diphosphate receptor antagonists, are associated with greater pharmacodynamic inhibition and reduction of cardiovascular events compared with clopidogrel in patients with an acute coronary syndrome. However, evidence is lacking about the effects of achieving faster and stronger cyclooxygenase inhibition with intravenous lysine acetylsalicylate (LA) compared with oral aspirin on prasugrel-inhibited platelets. METHODS AND RESULTS: This was a prospective, randomized, single-center, open, 2-period crossover platelet function study conducted in 30 healthy volunteers. Subjects were randomly assigned to receive a loading dose of intravenous LA 450 mg plus oral prasugrel 60 mg or loading dose of aspirin 300 mg plus prasugrel 60 mg orally in a crossover fashion after a 2-week washout period between treatments. Platelet function was evaluated at baseline, 30 minutes, 1 h, 4 h, and 24 h using light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The primary end point of the study, inhibition of platelet aggregation after arachidonic acid 1.5 mmol/L at 30 minutes, was significantly higher in subjects treated with LA compared with aspirin: 85.3% versus 44.3%, respectively, P=0.003. This differential effect was observed at 1 hour (P=0.002) and 4 hours (P=0.048), but not at 24 hours. Subjects treated with LA presented less variability and faster and greater inhibition of platelet aggregation with arachidonic acid compared with aspirin. CONCLUSIONS: The administration of intravenous LA resulted in a significant reduction of platelet reactivity compared with oral aspirin on prasugrel-inhibited platelets. Loading dose of LA achieves an earlier platelet inhibition and with less variability than aspirin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02243137.

Platelet function in Takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TK) includes a transient left ventricular dysfunction without obstructive coronary disease, sometimes after stressful situations with elevated cathecolamines. Since catecholamines activate platelets we aimed to study the platelet influence in a TK setting. We included 32 patients with a TK diagnosis, 13 with an acute coronary syndrome (ACS) and 18 healthy volunteers. Once consent informed was obtained, blood samples were extracted and processed (at admission and after 3 months follow-up). Clinical, ecg, echocardiographic and angiographic features were thoroughly recorded.Previous treatment before admission was similar between groups. No differences were observed in clinical features or any of the acute markers studied regarding platelet reactivity between TK compared to ACS. After follow-up, aggregation levels and platelet reactivity showed differences, mainly due to the antithrombotic therapy prescribed at discharge, but similar to volunteers. Circulating epinephrine during the acute phase was significantly higher in TK (p < 0.001). Patients with higher levels of epinephrine had elevated platelet activation and aggregation after 3 months. No differences were observed in Takotsubo acute platelet aggregation compared to patients with ACS, in spite of higher blood levels of adrenaline. Takotsubo patients had elevated platelet aggregation and activation compared with ACS patients at 3 months follow-up because they were less frequently on chronic clopidogrel and ASA. However, they had similar platelet aggregation and activation levels to healthy volunteers despite treatment with low-dose ASA. Takotsubo patients who had higher levels of adrenaline in the acute phase displayed increased platelet reactivity during follow-up.

Selected CD133⁺ progenitor cells to promote angiogenesis in patients with refractory angina: final results of the PROGENITOR randomized trial.

RATIONALE: Refractory angina constitutes a clinical problem. OBJECTIVE: The aim of this study was to assess the safety and the feasibility of transendocardial injection of CD133(+) cells to foster angiogenesis in patients with refractory angina. METHODS AND RESULTS: In this randomized, double-blinded, multicenter controlled trial, eligible patients were treated with granulocyte colony-stimulating factor, underwent an apheresis and electromechanical mapping, and were randomized to receive treatment with CD133(+) cells or no treatment. The primary end point was the safety of transendocardial injection of CD133(+) cells, as measured by the occurrence of major adverse cardiac and cerebrovascular event at 6 months. Secondary end points analyzed the efficacy. Twenty-eight patients were included (n=19 treatment; n=9 control). At 6 months, 1 patient in each group had ventricular fibrillation and 1 patient in each group died. One patient (treatment group) had a cardiac tamponade during mapping. There were no significant differences between groups with respect to efficacy parameters; however, the comparison within groups showed a significant improvement in the number of angina episodes per month (median absolute difference, -8.5 [95% confidence interval, -15.0 to -4.0]) and in angina functional class in the treatment arm but not in the control group. At 6 months, only 1 simple-photon emission computed tomography (SPECT) parameter: summed score improved significantly in the treatment group at rest and at stress (median absolute difference, -1.0 [95% confidence interval, -1.9 to -0.1]) but not in the control arm. CONCLUSIONS: Our findings support feasibility and safety of transendocardial injection of CD133(+) cells in patients with refractory angina. The promising clinical results and favorable data observed in SPECT summed score may set up the basis to test the efficacy of cell therapy in a larger randomized trial.

Effect of an optimized treatment with insulin on platelet reactivity after discharge in patients with an acute coronary syndrome and hyperglycemia.

INTRODUCTION AND OBJECTIVES: Intensive glucose control with insulin in patients with an acute coronary syndrome reduces platelet reactivity during hospitalization, compared to conventional control. However, the effect of strict, long-term glucose control on platelet reactivity in these patients remains uncertain. METHODS: This is a prospective, randomized trial evaluating the effects of optimized glucose control (target glucose, 80-120mg/dL) with insulin, compared with conventional control (target glucose, <180 mg/dL), on platelet reactivity after hospital discharge in patients with an acute coronary syndrome and hyperglycemia. The primary endpoint was assessment of platelet aggregation after stimulation with adenosine diphosphate 20 µM at 12-month follow-up. RESULTS: One hundred four patients were randomized to optimized management (n=53) or conventional management (n=51). There were no differences between groups in baseline characteristics or platelet function. After 12 months of follow-up, blood glucose levels were significantly lower in the optimized treatment group (104 vs 119 mg/dL; P<.001). However, platelet aggregation following adenosine diphosphate 20 µM stimulation showed no differences between the groups (54.2% [14.3%] vs 55.1% [18.3%] respectively; P=.81). There were no significant differences for other platelet function tests. CONCLUSIONS: Long-term optimized glucose control with insulin in patients with an acute coronary syndrome did not result in a reduction in platelet reactivity compared to conventional control.

Efecto del tratamiento optimizado con insulina en la reactividad plaquetaria tras el alta de pacientes hiperglucémicos con síndrome coronario agudo / Effect of an optimized treatment with insulin on platelet reactivity after discharge in patients with an acute coronary syndrome and hyperglycemia

Introducción y objetivos. El control intensivo con insulina de la glucemia de pacientes con un síndrome coronario agudo reduce la reactividad plaquetaria durante la fase hospitalaria en comparación con un tratamiento convencional. Sin embargo, se desconoce el efecto en la reactividad plaquetaria con un control estricto de la glucemia a largo plazo. Métodos. Ensayo prospectivo y aleatorizado que evaluó el efecto de un tratamiento optimizado para el control de la glucemia (objetivo, 80-120 mg/dl) con insulina comparado con un tratamiento convencional (objetivo, < 180 mg/dl) en la reactividad plaquetaria al alta hospitalaria de pacientes con un síndrome coronario agudo e hiperglucemia. El objetivo primario es la valoración de la agregación plaquetaria tras estímulo con adenosina difosfato 20 mM a los 12 meses de seguimiento. Resultados. Se incluyó a 104 pacientes (53 al tratamiento optimizado y 51 al convencional). No se encontraron diferencias en las características basales de ambos grupos, incluida la función plaquetaria. A los 12 meses de seguimiento, las cifras de glucemia eran significativamente menores en el grupo de tratamiento optimizado (104 frente a 119 mg/dl; p < 0,001). Sin embargo, la agregación plaquetaria tras estímulo con adenosina difosfato 20 mM no mostró diferencias significativas entre los grupos (tratamiento optimizado frente a convencional, 54,2 ± 14,3% frente a 55,1 ± 18,3%; p = 0,81). Tampoco se objetivaron diferencias significativas con los otros tests de función plaquetaria evaluados. Conclusiones. El control optimizado de la glucemia con insulina a largo plazo en pacientes que han sufrido un síndrome coronario agudo no reduce la reactividad plaquetaria en comparación con un tratamiento convencional (AU)

Introduction and objectives. Intensive glucose control with insulin in patients with an acute coronary syndrome reduces platelet reactivity during hospitalization, compared to conventional control. However, the effect of strict, long-term glucose control on platelet reactivity in these patients remains uncertain. Methods. This is a prospective, randomized trial evaluating the effects of optimized glucose control (target glucose, 80-120 mg/dL) with insulin, compared with conventional control (target glucose, <180 mg/dL), on platelet reactivity after hospital discharge in patients with an acute coronary syndrome and hyperglycemia. The primary endpoint was assessment of platelet aggregation after stimulation with adenosine diphosphate 20 mM at 12-month follow-up. Results. One hundred four patients were randomized to optimized management (n=53) or conventional management (n=51). There were no differences between groups in baseline characteristics or platelet function. After 12 months of follow-up, blood glucose levels were significantly lower in the optimized treatment group (104 vs 119 mg/dL; P<.001). However, platelet aggregation following adenosine diphosphate 20 mM stimulation showed no differences between the groups (54.2% [14.3%] vs 55.1% [18.3%] respectively; P=.81). There were no significant differences for other platelet function tests. Conclusions. Long-term optimized glucose control with insulin in patients with an acute coronary syndrome did not result in a reduction in platelet reactivity compared to conventional control (AU)

Morphological characteristics of culprit coronary lesions according to clinical presentation: insights from a multimodality imaging approach.

The aim of this study was to prospectively evaluate the morphological characteristics of culprit coronary lesions according to clinical presentation. A combined, comprehensive, multi-imaging modality protocol was systematically used. A total of 46 consecutive patients with stable angina (n = 24) or acute coronary syndromes (n = 22) were included. Culprit lesions were prospectively studied with angiography, multislice computed tomography (MSCT), intravascular ultrasound and virtual histology. MSCT showed a lower radiographic density and a higher remodeling index in culprit lesions of patients with acute coronary syndromes. Intravascular ultrasound examination demonstrated a larger remodeling index, a lower degree of calcification and a higher prevalence of soft lesions in unstable patients. Virtual histology analysis showed a lower percentage of calcium in the area of greatest stenosis and a higher prevalence of lesions with vulnerable characteristics in unstable patients. In multivariable logistic regression analysis, remodeling index by intravascular ultrasound and radiographic density in MSCT were the only independent predictors for identifying unstable culprit lesions. Our study adds further evidence on the best morphological criteria of instability in culprit lesions. Remodeling index by IVUS and low radiographic density by MSTC were the only independent predictors of unstable lesions.

Influence of HbA1c levels on platelet function profiles associated with tight glycemic control in patients presenting with hyperglycemia and an acute coronary syndrome. A subanalysis of the CHIPS Study ("Control de HIperglucemia y Actividad Plaquetaria en Pacientes con Síndrome Coronario Agudo").

Patients with hyperglycemia, an acute coronary syndrome and poor glycemic control have increased platelet reactivity and poor prognosis. However, it is unclear the influence of a tight glycemic control on platelet reactivity in these patients. This is a subanalysis of the CHIPS study. This trial randomized patients with hyperglycemia to undergo an intensive glucose control (target blood glucose 80-120 mg/dL), or conventional glucose control (target blood glucose <180 mg/dL). We analyzed platelet function at discharge on the subgroup of patients with poor glycemic control, defined with admission levels of HbA1c higher than 6.5%. The primary endpoint was maximal platelet aggregation following stimuli with 20 µM ADP. We also measured aggregation following collagen, epinephrine, and thrombin receptor-activated peptide, as well as P2Y12 reactivity index and surface expression of glycoprotein IIb/IIIa and P-selectin. A total of 67 patients presented HbA1c ≥ 6.5% (37 intensive, 30 conventional), while 42 had HbA1c < 6.5% (20 intensive, 22 conventional). There were no differences in baseline characteristics between groups. At discharge, patients with HbA1c ≥6.5% had significantly reduced MPA with intensive glucose control compared with conventional control (46.1 ± 22.3 vs. 60.4 ± 20.0%; p = 0.004). Similar findings were shown with other measures of platelet function. However, glucose control strategy did not affect platelet function parameters in patients with HbA1c < 6.5%. Intensive glucose control in patients presenting with an acute coronary syndrome and hyperglycemia results in a reduction of platelet reactivity only in the presence of elevated HbA1c levels.

How to manage hyperglycemia in an acute coronary syndrome patient.

OPINION STATEMENT: Evidences on hyperglycemia management in patients with acute coronary syndrome (ACS) are scarce and controversial. While approaches such as infusion of glucose, insulin, and potassium (GIK therapy) have not demonstrated any improvement in outcome, glycemic control by means of either continuous insulin infusion or subcutaneous on-demand boluses may be useful only when glycaemia is successfully controlled. Nevertheless, results from several studies are controversial and there is no consensus on glycaemia target values. Concerning oral antidiabetic treatment, previous reports stated an increase in heart attacks throughout their chronic use, however no studies have addressed the effects of either starting or continuing oral antidiabetics during ACS setting. Therefore, there is not enough evidence to strongly recommend any specific therapy to manage hyperglycemia in an ACS patient other than trying to keep glycaemia within reasonable levels (usually defined by consensus), and there is evidence discouraging the use of GIK therapy since no beneficial effect has been observed.

Enfermedad coronaria aguda y crónica. ¿Cómo tratamos los diferentes subgrupos? / Acute and chronic coronary artery disease. how should we treat different subgroups?

La aparición de los nuevos antiagregantes orales que actúan bloqueando el receptor de adenosindifosfato P2Y12 en las plaquetas ha supuesto un importante avance en el manejo de los pacientes con síndrome coronario agudo. En el espectro general de los síndromes coronarios agudos, tanto el prasugrel como el ticagrelor se han demostrado más eficaces que el clopidogrel en reducir el riesgo de nuevos eventos cardiovasculares, aunque con un discreto aumento en el número de hemorragias. Por otro lado, los pacientes que sufren un síndrome coronario agudo tienen un perfil heterogéneo, y tanto los beneficios como los riesgos en la utilización de estos nuevos tratamientos no son uniformes. En este contexto, el objetivo de este artículo es revisar los resultados de los análisis de subgrupos que comparan la eficacia y la seguridad del prasugrel y el ticagrelor frente al clopidogrel con la intención de definir los perfiles clínicos con el balance riesgo-beneficio más propicio al manejo con los nuevos bloqueadores orales del receptor P2Y12 (AU)

The introduction of new oral antiplatelet drugs that act by blocking the adenosine diphosphate P2Y12 receptor in platelets represents a substantial step forward in the treatment of patients with acute coronary syndrome. Both prasugrel and ticagrelor have been shown to be more effective than clopidogrel in preventing cardiovascular events in a broad spectrum of acute coronary syndromes, although there is also a small increase in the number of bleeding events. On the other hand, patients suffering from acute coronary syndromes form a heterogeneous group, which means that the benefits and risks of these new treatments may vary. With this variability in mind, the aim of this article was to review the results of a subgroup analysis that compared the efficacy and safety of prasugrel and ticagrelor with the efficacy and safety of clopidogrel and which had as its objective the identification of patients with clinical profiles associated with a favorable risk-benefit balance on treatment with the new oral P2Y12 receptor antagonists (AU)

Síndrome de tako-tsubo e insuficiencia cardiaca: seguimiento a largo plazo / Tako-tsubo syndrome and heart failure: long-term follow-up

Introducción y objetivos. El síndrome de tako-tsubo induce un grado variable de disfunción ventricular izquierda transitoria. Nuestro objetivo es determinar su pronóstico a corto y largo plazo y valorar la incidencia de insuficiencia cardiaca en este ámbito, los factores de riesgo relacionados con su desarrollo y su influencia en la evolución posterior en nuestro medio. Métodos. Se recogieron prospectivamente las características clínicas y los eventos durante el ingreso hospitalario y durante el seguimiento de 100 pacientes con síndrome de tako-tsubo. Se llevó a cabo un análisis estratificado en relación con el desarrollo de insuficiencia cardiaca (Killip ≥ II) durante el ingreso índice. Resultados. El 89% eran mujeres (media de edad, 68 años); 70 pacientes cursaban sin insuficiencia cardiaca; 15 estaban en Killip II; 5; en Killip III, y 10, en Killip IV. Los factores de riesgo cardiovascular -diabetes incluida- eran frecuentes, pero más en el grupo con insuficiencia cardiaca. La fracción de eyección del ventrículo izquierdo era inferior en aquellos con insuficiencia cardiaca al ingreso (el 51 frente al 42%; p<0,01). No se detectaron diferencias en cuanto a los tratamientos previos al ingreso ni en los biomarcadores de necrosis. Durante una mediana de seguimiento de 1.380 días, se observaron más complicaciones intrahospitalarias y en la cohorte con insuficiencia cardiaca tanto para la variable combinada como para muerte. Conclusiones. En el síndrome de tako-tsubo, la insuficiencia cardiaca es frecuente; se observa sobre todo en pacientes con más comorbilidades y peores clases funcionales previas y se asocia a más eventos adversos, tanto durante el ingreso como en el seguimiento a largo plazo. El pronóstico a largo plazo es generalmente bueno (AU)

Introduction and objectives. Tako-tsubo syndrome produces a variable degree of transient left ventricular dysfunction. Our objective was to determine the short- and long-term prognosis of this syndrome, the incidence of and risk factors for the development of heart failure, and the influence on heart failure on the long-term outcome in our patient population. Methods. We prospectively recorded the clinical features and events during the hospital stay and follow-up of 100 patients with tako-tsubo syndrome. The risk factors for heart failure during hospital stay, considered as Killip class≥II, were assessed. Results. Most of the patients were women (89%), with a mean age of 68 years. The distribution according to Killip class was: Killip I, 70 patients; Killip II, 15; Killip III, 5; and Killip IV, 10. Cardiovascular risk factors, including diabetes, were common in the overall group, but were more so in the heart failure cohort. The left ventricular ejection fraction was lower in the heart failure group (51% vs 42%; P<.01). There were no differences in preadmission medications or biomarkers of necrosis. Over a median follow-up of 1380 days, the incidence of events reported during the hospital stay and long-term follow-up, both for death and the combined endpoints, was higher in the heart failure cohort. Conclusions. Although the prognosis in tako-tsubo syndrome is usually good, heart failure occurs quite frequently, mainly in patients with a greater number of comorbidities and poorer previous functional class. Moreover, heart failure is associated with a higher number of early and late adverse events. The overall long-term prognosis is good (AU)

Spontaneous coronary artery dissection: long-term follow-up of a large series of patients prospectively managed with a "conservative" therapeutic strategy.

OBJECTIVES: This study sought to assess the long-term clinical outcome of patients with spontaneous coronary artery dissection (SCD) managed with a conservative strategy. BACKGROUND: SCD is a rare, but challenging, clinical entity. METHODS: A prospective protocol, including a conservative management strategy, was followed. Revascularization was only considered in cases with ongoing/recurrent ischemia. Inflammatory/immunologic markers were systematically obtained. RESULTS: Forty-five consecutive patients (incidence 0.27%) were studied during a 6-year period. Of these, 27 patients (60%) had "isolated" SCD (I-SCD), and 18 had SCD associated with coronary artery disease (A-SCD). Age was 53 ± 11 years, and 26 patients were female. Most patients presented with an acute myocardial infarction. SCD had a diffuse angiographic pattern (length: 31 ± 23 mm). In 11 patients, the diagnosis was confirmed by intracoronary imaging techniques. Sixteen patients (35%) required revascularization during initial admission. One patient died after surgery, but no additional patient experienced recurrent myocardial infarction. No significant inflammatory/immunologic abnormalities were detected. At follow-up (median 730 days), only 3 patients presented with adverse events (1 died of congestive heart failure, and 2 required revascularization). No patient experienced a myocardial infarction or died suddenly. Event-free survival was similar (94% and 88%, respectively) in patients with I-SCD and A-SCD. Notably, at angiographic follow-up, spontaneous "disappearance" of the SCD image was found in 7 of 13 (54%) patients. CONCLUSIONS: In this large prospective series of consecutive patients with SCD, a "conservative" therapeutic strategy provided excellent long-term prognosis. Clinical outcome was similar in patients with I-SCD and A-SCD. The natural history of SCD includes spontaneous healing with complete resolution.

Tako-tsubo syndrome and heart failure: long-term follow-up.

INTRODUCTION AND OBJECTIVES: Tako-tsubo syndrome produces a variable degree of transient left ventricular dysfunction. Our objective was to determine the short- and long-term prognosis of this syndrome, the incidence of and risk factors for the development of heart failure, and the influence on heart failure on the long-term outcome in our patient population. METHODS: We prospectively recorded the clinical features and events during the hospital stay and follow-up of 100 patients with tako-tsubo syndrome. The risk factors for heart failure during hospital stay, considered as Killip class≥II, were assessed. RESULTS: Most of the patients were women (89%), with a mean age of 68 years. The distribution according to Killip class was: Killip I, 70 patients; Killip II, 15; Killip III, 5; and Killip IV, 10. Cardiovascular risk factors, including diabetes, were common in the overall group, but were more so in the heart failure cohort. The left ventricular ejection fraction was lower in the heart failure group (51% vs 42%; P<.01). There were no differences in preadmission medications or biomarkers of necrosis. Over a median follow-up of 1380 days, the incidence of events reported during the hospital stay and long-term follow-up, both for death and the combined endpoints, was higher in the heart failure cohort. CONCLUSIONS: Although the prognosis in tako-tsubo syndrome is usually good, heart failure occurs quite frequently, mainly in patients with a greater number of comorbidities and poorer previous functional class. Moreover, heart failure is associated with a higher number of early and late adverse events. The overall long-term prognosis is good. Full English text available from:www.revespcardiol.org.

Impact of insulin receptor substrate-1 genotypes on platelet reactivity and cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease.

OBJECTIVES: The aim of this study was to assess the association between genetic variants of the insulin receptor substrate (IRS)-1 gene, platelet function, and long-term outcomes in patients with type 2 diabetes mellitus (DM) and stable coronary artery disease while on aspirin and clopidogrel therapy. BACKGROUND: The effects of pharmacogenetic determinants on platelet function and cardiovascular outcomes in type DM patients are unknown. METHODS: The association between IRS-1 genetic variants, platelet function, and the risk of major adverse cardiac events (MACE) at 2 years was assessed in 187 patients with type 2 DM and stable coronary artery disease on maintenance aspirin and clopidogrel therapy. RESULTS: Seven tag single nucleotide polymorphisms were selected. Individuals with high platelet reactivity were more frequent among carriers of the C allele (GC and CC genotypes; approximately 20% of population) of the rs956115 marker (44.4% vs. 20.5%; odds ratio: 3.1, 95% confidence interval [CI]: 1.44 to 6.67; p = 0.006). These patients were at higher risk of MACE (28.0% vs. 10.9%; hazard ratio: 2.90, 95% CI: 1.38 to 6.11; p = 0.005). The C allele carriers of the rs956115 marker were more commonly associated with a hyperreactive platelet phenotype. This was confirmed in an external validation cohort of patients with type 2 DM but not in an external validation cohort of patients without DM. Carriers of the C allele of the rs956115 marker also had a significantly higher risk of MACE compared with noncarriers (30.6% vs. 11.4%; hazard ratio: 2.88, 95% CI: 1.35 to 6.14; p = 0.006). CONCLUSIONS: Type 2 DM patients who are carriers of the C allele of the rs956115 marker of the IRS-1 gene have a hyperreactive platelet phenotype and increased risk of MACE.

Can resistance to aspirin be reversed after an additional dose?

Aspirin resistance or aspirin non-responsiveness is a recently described phenomenon which has been consistently associated with an increased risk of cardiovascular events. This study was designed to determine the effects of an additional dose of 100 mg of aspirin on platelet function and proportion of aspirin non-responders using the platelet function analyzer-100 (PFA-100), in a well characterized population of stable coronary heart disease patients already on long-term aspirin treatment. Platelet function was assessed using PFA-100 in 141 patients (64.8 ± 10.1 years, 87.9% men) on long-term aspirin treatment (100 mg/day) before and 1 h after "in site" oral aspirin administration (100 mg). Prevalence of aspirin non-responders using PFA-100 was 50.7% (95% confidence interval 42.4-59). One hour after 100 mg of oral aspirin, reassessment of aspirin effects showed a prevalence of non-responders using PFA of 35.0% (95% CI 27.3-43.2) (P < 0.001 vs. pre-dose proportion). Using the PFA-100 system, reassessment of platelet function following oral administration of daily aspirin dosage significantly reduces the number of stable coronary disease patients considered to be non-responders to such treatment.

Effects of intensive glucose control on platelet reactivity in patients with acute coronary syndromes. Results of the CHIPS Study ("Control de Hiperglucemia y Actividad Plaquetaria en Pacientes con Sindrome Coronario Agudo").

OBJECTIVES: Hyperglycaemia has been associated with increased platelet reactivity and impaired prognosis in patients with acute coronary syndrome (ACS). Whether platelet reactivity can be reduced by lowering glucose in this setting is unknown. The aim of this study was to assess the functional impact of intensive glucose control with insulin on platelet reactivity in patients admitted with ACS and hyperglycaemia. METHODS: This is a prospective, randomised trial evaluating the effects of either intensive glucose control (target glucose 80-120 mg/dl) or conventional control (target glucose 180 mg/dl or less) with insulin on platelet reactivity in patients with ACS and hyperglycaemia. The primary endpoint was platelet aggregation following stimuli with 20 µM ADP at 24 h and at hospital discharge. Aggregation following collagen, epinephrine and thrombin receptor-activated peptide, as well as P2Y12 reactivity index and surface expression of glycoprotein IIb/IIIa and P-selectin were also measured. RESULTS: Of the 115 patients who underwent random assignment, 59 were assigned to intensive and 56 to conventional glucose control. Baseline platelet functions and inhospital management were similar in both groups. Maximal aggregation after ADP stimulation at hospital discharge was lower in the intensive group (47.9 ± 13.2% vs 59.1 ± 17.3%; p=0.002), whereas no differences were found at 24 h. Similarly all other parameters of platelet reactivity measured at hospital discharge were significantly reduced in the intensive glucose control group. CONCLUSIONS: In this randomised trial, early intensive glucose control with insulin in patients with ACS presenting with hyperglycaemia was found to decrease platelet reactivity. Clinical Trial Registration Number http://www.controlledtrials.com/ISRCTN35708451/ISRCTN35708451.