Martín J. García González

Levosimendan : molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan

The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.

Pharmacologic Treatment of Heart Failure due to Ventricular Dysfunction by Myocardial Stunning

The treatment of heart failure continues to pose a real challenge for clinicians. This condition is sometimes reversible and therapy should therefore pursue this outcome. In the context of coronary ischemic syndromes, myocardial stunning can cause heart failure and even cardiogenic shock, with important prognostic repercussions. Myocardial stunning is mainly due to calcium overload in the cytosol of myocardial cells, the loss of myofilaments and their reduced sensitivity to calcium. Enhanced immune activation with inflammatory phenomena also plays an important role in the pathophysiology of cardiac dysfunction. Increasing evidence has shown that the myocardial ATP-dependent potassium channel (KATP) plays an important role in many myocardial cell functions and that it is involved in ischemia-reperfusion injury and myocardial stunning. KATP is thus considered a therapeutic target in this setting. Currently used inotropic drugs improve contractility by increasing intracellular concentrations of free calcium, but they increase myocardial consumption of energy and even produce arrhythmia; therefore, in this clinical context, they do not seem to be ‘pathophysiologically correct’ drugs. Levosimendan, a new calcium-sensitizing agent, increases contractility by enhancing the sensitivity of myofilaments to calcium by binding to the C cardiac troponin in cardiac muscle in a calcium-dependent way. Levosimendan also exerts a coronary and systemic vasodilatory effect through its KATP channel-opening properties and may exert other cardioprotective actions through this mechanism. Levosimendan produces positive hemodynamic effects without increasing myocardial oxygen demand or causing arrhythmias. Intravenous levosimendan is generally well tolerated and has been approved by several European countries, and recently recommended in European Society of Cardiology guidelines, as inotropic therapy for the short-term treatment of acute severe decompensated heart failure in adults. Randomized, double-blind trials have shown that levosimendan is not only more clinically and hemodynamically effective but also that it significantly reduces morbidity and mortality when compared with dobutamine or placebo. Clinical trials addressing the use and efficacy of intravenous levosimendan in acute heart failure in patients with systolic dysfunction or cardiogenic shock due to myocardial stunning are scarce. Beneficial effects on myocardial contractility in patients with myocardial stunning have only been shown in small clinical trials. A positive experience with levosimendan in a small series of patients with cardiogenic shock complicating ST-elevation myocardial infarction suggests that the use of this drug in cardiogenic shock should be further evaluated.The treatment of heart failure continues to pose a real challenge for clinicians. This condition is sometimes reversible and therapy should therefore pursue this outcome. In the context of coronary ischemic syndromes, myocardial stunning can cause heart failure and even cardiogenic shock, with important prognostic repercussions. Myocardial stunning is mainly due to calcium overload in the cytosol of myocardial cells, the loss of myofilaments and their reduced sensitivity to calcium. Enhanced immune activation with inflammatory phenomena also plays an important role in the pathophysiology of cardiac dysfunction. Increasing evidence has shown that the myocardial ATP-dependent potassium channel (KATP) plays an important role in many myocardial cell functions and that it is involved in ischemia-reperfusion injury and myocardial stunning. KATP is thus considered a therapeutic target in this setting. Currently used inotropic drugs improve contractility by increasing intracellular concentrations of free calcium, but they increase myocardial consumption of energy and even produce arrhythmia; therefore, in this clinical context, they do not seem to be ‘pathophysiologically correct’ drugs. Levosimendan, a new calcium-sensitizing agent, increases contractility by enhancing the sensitivity of myofilaments to calcium by binding to the C cardiac troponin in cardiac muscle in a calcium-dependent way. Levosimendan also exerts a coronary and systemic vasodilatory effect through its KATP channel-opening properties and may exert other cardioprotective actions through this mechanism. Levosimendan produces positive hemodynamic effects without increasing myocardial oxygen demand or causing arrhythmias. Intravenous levosimendan is generally well tolerated and has been approved by several European countries, and recently recommended in European Society of Cardiology guidelines, as inotropic therapy for the short-term treatment of acute severe decompensated heart failure in adults. Randomized, double-blind trials have shown that levosimendan is not only more clinically and hemodynamically effective but also that it significantly reduces morbidity and mortality when compared with dobutamine or placebo. Clinical trials addressing the use and efficacy of intravenous levosimendan in acute heart failure in patients with systolic dysfunction or cardiogenic shock due to myocardial stunning are scarce. Beneficial effects on myocardial contractility in patients with myocardial stunning have only been shown in small clinical trials. A positive experience with levosimendan in a small series of patients with cardiogenic shock complicating ST-elevation myocardial infarction suggests that the use of this drug in cardiogenic shock should be further evaluated.

Undisclosed cocaine use and chest pain in emergency departments of Spain

AimsIllicit cocaine consumption in Spain is one of the highest in Europe. Our objective was to study the incidence of undisclosed cocaine consumption in patients attending in two Spanish Emergency Departments for chest pain.MethodsWe analysed urine samples from consenting consecutive patients attending ED for chest pain to determine the presence of cocaine, and other drugs, by semiquantative tests with fluorescence polarization immunoassay (FPIA).ResultsOf 140 cases, 15.7 presented positive test for drugs, and cocaine was present in 6.4%. All cocaine-positive patients were younger (p < 0.001); none was admitted to Hospital (p = 0.08). No significant differences in ED stay or need for hospitalization were found between cocaine-positive and negative patients.ConclusionThis finding in chest pain patients who consented to urine analysis suggests that the true incidence of cocaine use leading to such ED visits may be higher.

Influencia de la diabetes mellitus en el tratamiento y el pronóstico del síndrome coronario agudo sin elevación del segmento ST

La diabetes mellitus condiciona un peor pronostico del sindrome coronario agudo. Presentamos un estudio retrospectivo cuyo objetivo fue analizar la influencia de la presencia de diabetes en el pronostico y el tratamiento de pacientes con sindrome coronario agudo sin elevacion del segmento ST. Se compararon las caracteristicas clinicas de 273 pacientes (93 pacientes diabeticos frente a 180 no diabeticos) ingresados en nuestro centro con el diagnostico de sindrome coronario agudo sin elevacion del segmento ST. Durante la hospitalizacion analizamos en ambos grupos el tratamiento medico y la realizacion de coronariografia, intervencionismo y cirugia coronaria. Finalmente, analizamos la incidencia acumulada de insuficiencia cardiaca intrahospitalaria y la mortalidad a los 28 dias y 6 meses en ambos grupos. El analisis multifactorial demostro que la diabetes fue un predictor independiente de mortalidad durante el periodo de seguimiento. Estos hallazgos no se acompanaron en nuestro registro de un tratamiento mas intervencionista en el grupo de pacientes diabeticos.

Association Between Serum Interleukin 10 Level and Development of Heart Failure in Acute Myocardial Infarction Patients Treated by Primary Angioplasty

Introduction and objectives. Interleukin 10 (IL-10) is an anti-inflammatory cytokine that inhibits the synthesis of proinflammatory cytokines. It has been shown that IL-10 is released into the circulation during post-ischemic myocardial reperfusion. The objective of this study was to determine whether the serum IL-10 concentration in patients with acute myocardial infarction who were undergoing primary angioplasty was related to the subsequent presence or absence of heart failure. Patients and method. The study included 65 patients who underwent successful primary angioplasty. During their subsequent stay in the coronary unit, their maximum degree of heart failure was recorded. Patients were then divided into 2 groups: group A patients were in Killip class I and group B patients in Killip classes II-IV. The serum IL-10 concentration was measured during the 24 hours following admission to the coronary unit. Results. The 2 groups were similar with regard to age, sex, and coronary risk factors. The IL-10 concentration was significantly higher in the group of patients with acute myocardial infarction without heart failure than in the group with heart failure (30.4±10.8 vs 19.8±7.9 pg/mL; P<.001). Conclusions. In patients with acute myocardial infarction who had undergone successful primary angioplasty, the serum IL-10 concentration measured during the following 24 hours was significantly higher in those who did not develop heart failure. These findings suggest that this anti-inflammatory cytokine has a protective effect on the myocardium during ischemia or reperfusion, or both.

Endocarditis infecciosa sobre válvulas protésicas causada por Staphylococcus capitis: un nuevo caso

Se presenta el caso de un paciente varon, portador de protesis valvular aortica y mitral con endocarditis infecciosa por Staphylococcus capitis , bacteria recientemente descrita como agente productor de endocarditis, tanto sobre valvulas cardiacas nativas en pacientes con lesiones predisponentes como sobre valvulas protesicas. El curso evolutivo del paciente fue desfavorable, a pesar de tratamiento antibioterapico especifico, siendo necesaria la sustitucion valvular quirurgica, que consiguio la resolucion completa del cuadro clinico. Este caso pone en relevancia que, si bien es poco frecuente la presentacion de endocarditis infecciosa por Staphylococcus capitis , su patogenia es importante.

Influence of Diabetes Mellitus on the Management and Prognosis of Non-ST-Elevation Acute Coronary Syndrome

The presence of diabetes mellitus worsens prognosis in acute coronary syndromes. The aim of our study was to analyze retrospectively the influence of diabetes mellitus on the management and prognosis of patients with non-ST-segment elevation acute coronary syndrome. We compared the baseline clinical characteristics of 273 patients (93 diabetic and 180 non-diabetic) admitted consecutively to our department with the diagnosis of non-ST-segment elevation acute coronary syndrome. In both groups, we assessed the medical treatment given during hospitalization and the use of coronary angiography, percutaneous coronary intervention, and coronary artery bypass grafting. Finally, we determined the incidence of heart failure during hospitalization and mortality at 28 days and 6 months in both groups. Multifactorial analysis revealed that diabetes was an independent risk factor for mortality during the study period. Data from our registry indicate that these findings were not associated with more extensive use of interventions in diabetic patients.

Light/Dark Cycle Variations in Proinflammatory Cytokines in Acute Coronary Syndromes

We have read with great interest the recent review by Angiolillo et al1 that provided an excellent overview of inflammation in acute coronary syndromes, but we were surprised that the authors did not mention light-dark cycles of proinflammatory cytokines. The implication or association of physiological rhythms with peak activity at a certain time of day or night might be suspected, given that the onset of cardiovascular accidents follows a circadian pattern.2 Several studies suggest that increased cardiovascular mortality in winter might be related to alterations in the biological clock controlled by the suprachiasmatic nucleus. This is regulated by day-night alternations, that is, by light-dark cycles.3,4 Other functions such as cortisol secretion,5 blood pressure variations,6 and vasomotor tone9 also depend on these rhythms. Our group has shown that interleukin 6 follows a lightdark cycle in patients with acute myocardial infarction.8 These variations can be attributed to the centrally controlled release of this compound by the neuroendocrine system. Such control would be exercised through synthesis and release of melatonin by the pineal gland, which, in turn, is regulated by light-dark variations.9 Although the study of the light-dark variations in proinflammatory cytokines in itself lacks clinical relevance, these findings point the way to new lines of investigation in the field of biological rhythms in humans. More studies will be needed to help clarify the mechanisms that underlie the cyclic nature of the presentation of some acute coronary syndromes. Such knowledge will undoubtedly lead to therapeutic interventions that provide better protection at times of greatest risk.