José A. Ortiz

Control of Human Muscle-type Carnitine Palmitoyltransferase I Gene Transcription by Peroxisome Proliferator-activated Receptor

The expression of several genes involved in intra- and extracellular lipid metabolism, notably those involved in peroxisomal and mitochondrial β-oxidation, is mediated by ligand-activated receptors, collectively referred to as peroxisome proliferator-activated receptors (PPARs). To gain more insight into the control of expression of carnitine palmitoyltransferase (CPT) genes, which are regulated by fatty acids, we have examined the transcriptional regulation of the human MCPT I gene. We have cloned by polymerase chain reaction the 5′-flanking region of this gene and demonstrated its transcriptional activity by transfection experiments with the CAT gene as a reporter. We have also shown that this is a target gene for the action of PPARs, and we have localized a PPAR responsive element upstream of the first exon. These results show that PPAR regulates the entry of fatty acids into the mitochondria, which is a crucial step in their metabolism, especially in tissues like heart, skeletal muscle and brown adipose tissue in which fatty acids are a major source of energy.

Radial Artery Spasm in Transradial Cardiac Catheterization. Assessment of Factors Related to Its Occurrence, and of Its Consequences During Follow-Up

INTRODUCTION AND OBJECTIVES Radial artery spasm is the most frequent complication of transradial cardiac catheterization. It causes patient discomfort and reduces the procedures success rate. The aims of this study were to identify variables associated with this complication, such as clinical parameters, angiographic characteristics of the radial artery and factors related to the procedure, and to analyze the clinical consequences of spasm, both generally and for radial artery patency, during follow-up. PATIENTS AND METHOD The study included 637 patients who were undergoing transradial cardiac catheterization. Radial artery spasm was recorded using a scale that reflected the presence of pain and the technical difficulty of the procedure. RESULTS Radial artery spasm was reported in 127 patients (20.2%). Multivariate analysis showed that the variables associated with radial artery spasm were radial artery anatomical anomalies (odds ratio [OR]=5.1; 95% confidence interval [95% CI]: 2.1-11.4), use of >size-3 catheters (OR=3.0; 95% CI: 1.9-4.7), moderate-to-severe pain during radial artery cannulation (OR=2.6; 95% CI: 1.4-4.9), the use of phentolamine as a spasmolytic (OR=1.8; 95% CI: 1.1-2.9), and postvasodilation radial artery diameter (OR=0.98; 95% CI: 0.98-0.99). At follow-up [20 (18) days], severe pain in the forearm was more frequent in patients who presented with radial artery spasm (12.4% vs 5.3%), but there was no significant difference in the radial artery occlusion rate (4.5% vs 2.2%). CONCLUSION Radial artery spasm during transradial catheterization mainly depends on radial artery characteristics and procedural variables. At follow-up, radial artery spasm was associated with more frequent severe pain in the forearm, but the radial artery occlusion rate was not increased.

Relation of plasma brain natriuretic peptide levels on admission for ST-elevation myocardial infarction to left ventricular end-diastolic volume six months later measured by both echocardiography and cardiac magnetic resonance.

The main objective of this study was to investigate the relation between brain natriuretic peptide (BNP) levels within the first 96 hours after ST-segment elevation acute myocardial infarction (STEMI) and the development of left ventricular (LV) dilatation at 6-month follow-up. Eighty-two patients with first STEMIs, reperfused within 12 hours of symptom onset, were prospectively included. Plasma BNP was determined on admission and at 1- and 6-month follow-up. Clinically significant LV dilatation, defined as a >20% increase in LV end-diastolic volume at 6-month follow-up, was assessed using echocardiography and cardiac magnetic resonance. Thirty-two percent of patients developed clinically significant LV dilatation. BNP values on admission and at follow-up were significantly higher in patients who developed clinically significant LV dilatation at 6 months (182 +/- 117 vs 106 +/- 91 pmol/ml). After adjusting for age, infarct size, E-wave deceleration time, and the LV ejection fraction, BNP on admission was an independent predictor of LV dilatation, whether assessed by echocardiography (B = 0.075, p = 0.04) or cardiac magnetic resonance (B = 0.085, p = 0.04). In conclusion, high BNP levels on admission and at follow-up predict LV dilatation after STEMI. The early determination of plasma BNP upon admission for STEMI could be helpful in identifying patients at higher risk for LV dilatation, in whom aggressive management is warranted.

Espasmo radial en el cateterismo cardíaco transradial. Análisis de los factores asociados con su aparición y de sus consecuencias tras el procedimiento

Introduccion y objetivos El espasmo radial es la complicacion mas frecuente en el cateterismo cardiaco transradial y ocasiona un procedimiento mas doloroso para el paciente, con una menor tasa de exito. El objetivo es analizar los factores que se asocian con el espasmo radial durante el cateterismo cardiaco (variables clinicas, caracteristicas angiograficas de la arteria radial y variables del procedimiento), asi como sus consecuencias (clinicas y de permeabilidad de la arteria radial) en el seguimiento. Pacientes y metodo Se ha incluido a 637 pacientes en los que se realizo un cateterismo cardiaco por via radial. El espasmo radial se registro segun una escala que valora las molestias del paciente y las dificultades tecnicas. Resultados Se produjo espasmo radial en 127 pacientes (20,2%). El analisis multivariable mostro que las variables relacionadas con el espasmo radial fueron: una anomalia anatomica radial (odds ratio [OR] = 5,1; intervalo de confianza [IC] del 95%, 2,1-11,4), el empleo > 3 cateteres (OR = 3,0; IC del 95%, 1,9-4,7), el dolor moderado-intenso en la canulacion radial (OR = 2,6; IC del 95%, 1,4-4,9), la utilizacion de fentolamina como vasodilatador (OR = 1,8; IC del 95%, 1,1-2,9) y el diametro radial tras el empleo del vasodilatador (OR = 0,98; IC del 95%, 0,98-0,99). Durante el seguimiento (20 ± 18 dias), los pacientes con espasmo radial presentaron un mayor porcentaje de dolor moderado-intenso en el antebrazo (el 12,4 frente al 5,3%), pero sin diferencias significativas en la tasa de oclusion radial (el 4,5 frente al 2,2%). Conclusion La aparicion del espasmo radial tiene un componente multifactorial en el que predominan las caracteristicas de la arteria y las variables del procedimiento. Durante el seguimiento, el espasmo no condiciono una mayor tasa de oclusion radial, aunque si de persistencia de dolor importante en el antebrazo.

Assessment of Peripheral Endothelial-Dependent Vasodilatation Within the First Year After Heart Transplantation

BACKGROUND Peripheral endothelial dysfunction (ED) has been found in patients with severe heart failure. Whether ED improves after heart transplantation (HTx) is still a matter of controversy. METHODS Forearm endothelium-dependent vasoreactivity was assessed in 40 patients after HTx. Flow-mediated vasodilatation (FMD) was measured by high-resolution brachial artery ultrasound to assess endothelial function at 1, 6, and 12 months after HTx. Cardiac allograft vasculopathy (CAV) was assessed by coronary angiography at 1 and 12 months and by intravascular ultrasound (IVUS) at 1 year. RESULTS Mean FMD at 1 month was 1.9% +/- 2.6%, improving to 3.3% +/- 3.2% at 6 months (p < 0.005) and to 5.1% +/- 3.4% at 1 year (p < 0.0001). FMD was significantly impaired in 33 patients (82%) at 1 month, in 27 (67%) at 6 months, and in 19 (47%) at 1 year after HTx. CAV was diagnosed by IVUS in 19 patients (63%) at 1 year. Patients without peripheral ED at 1 month had lower incidence of increased intimal thickness of 0.5 mm or more at 1 year after HTx (20% vs 75%, p < 0.01). CONCLUSIONS Impairment of peripheral FMD was highly prevalent soon after HTx and was present in nearly 50% of patients at 1 year. Patients without peripheral ED at 1 month were associated with lower probability of CAV. Although more studies are needed, the evaluation of peripheral endothelial function at 1 month after HTx could be potentially useful to identify patients at lower risk of CAV.

Transcriptional Regulation by Activation and Repression Elements Located at the 5′-Noncoding Region of the Human α9 Nicotinic Receptor Subunit Gene

The α9 subunit is a component of the neuronal nicotinic acetylcholine receptor gene superfamily that is expressed in very restricted locations. The promoter of the human gene has been analyzed in the human neuroblastoma SH-SY5Y, where α9 subunit expression was detected, and in C2C12 cells that do not express α9. A proximal promoter region (from –322 to +113) showed maximal transcriptional activity in SH-SY5Y cells, whereas its activity in C1C12 cells was much lower. Two elements unusually located at the 5′-noncoding region exhibited opposite roles. A negative element located between +15 and +48 appears to be cell-specific because it was effective in C2C12 but not in SH-SY5Y cells, where it was counterbalanced by the presence of the promoter region 5′ to the initiation site. An activating element located between +66 and +79 and formed by two adjacent Sox boxes increased the activity of the α9 promoter about 4-fold and was even able to activate other promoters. This element interacts with Sox proteins, probably through a cooperative mechanism in which the two Sox boxes are necessary. We propose that the Sox complex provides an initial scaffold that facilitates the recruiting of the transcriptional machinery responsible for α9 subunit expression.

Perfil clínico, tratamiento y pronóstico de los pacientes con infarto agudo de miocardio no ingresados en una unidad coronaria: utilidad de una unidad de cuidados intermedios como lugar de ingreso inicial

Introduction and objectives. There is little information about the management and prognosis of patients with acute myocardial infarction (AMI) who are not admitted to coronary care units (CCU) because of the lack of available beds. The aim of this study was to evaluate the characteristics and prognosis of the patients who were admitted to the intermediate care unit (INTCU) of a cardiology department. Methods. We compared the clinical profile, management, and 12-month prognosis of the patients admitted to the INTCU or general ward (Ward) instead of the CCU. Results. Out of 242 patients with AMI, 62 (23%) were not admitted to the CCU due to the lack of available beds. Of these, 29 (12%) were admitted to the INTCU and 26 (11%) to the Ward after being monitored for at least 24 h in the emergency room. Patients admitted to the CCU arrived at the hospital early, were younger, less frequently female, and had a lower prevalence of diabetes. ST-segment elevation AMI was more frequent in patients admitted to the CCU than in patients admitted to the INTCU or Ward (67 vs 17 and 23%, respectively; p < 0.0001), and non-Q wave AMI was less frequent (30 vs 76 and 81%; p < 0.0001). No differences were found between groups in the number of stress tests or revascularization procedures performed after the first 24 h, the duration of the hospital stay (median 8 days), or in-hospital mortality. The 12month survival was 82, 80, and 64% in the patients admitted to the CCU, INTCU, or Ward (p < 0.05), respectively. These differences ceased to be significant after adjusting for the patients’ baseline clinical profile and treatment received at admission. Conclusion. Compared to patients with AMI admitted to the CCU, patients admitted to the INTCU or Ward after being monitored at least 24 h had non-ST elevation and non-Q wave AMI more frequently, but a less favorable risk profile for long-term mortality. The different types of

Analysis of the arrhythmogenic substrate in human heart failure

BACKGROUND The mechanism of sudden cardiac death in patients with heart failure (HF) is uncertain. Both electrical instability and structural remodelling could be factors that lead to fatal arrhythmias. We sought to analyse the expression of the sodium (SCN5A) and potassium (KCND3) channels as well as the fibrosis content in the ventricles of human HF and of non-diseased hearts under different post-mortem intervals. METHODS AND RESULTS We analysed normal human hearts as controls [n=20 for the right ventricle (RV) and n=13 for the left ventricle (LV)] and human hearts from HF patients, which were obtained at the time of cardiac transplantation, as cases (n=48 for RV and n=34 for LV). Transcription of the SCN5A (probes SCN5A E4-5, E11-12, and E28) and KCND3 channels and of COLLAGEN I and III were assayed by real-time polymerase chain reaction. In addition, paraffin sections were used to analyse the percentage of collagen deposition in both cases and controls. KCND3 mRNA expression in the LV was lower in the cases than in controls (P<.001). Higher levels of SCN5A mRNA were found in the HF samples when analysed with probe SCN5A E4-5 (P<.05). SCN5A expression was lower in the controls with longer post-mortem interval (n=4) than in the controls with a shorter post- mortem interval (n=16, P<.01). KCND3 mRNA levels were also different between the two control groups (P<.05). Collagen deposition was higher in the LV tissues of the cases when compared to controls (P<.001), and it was higher in the LV from HF patients than in the RV (P<.05). Furthermore, collagen deposition was higher in the LV samples from patients with implanted cardiac defibrillator (ICD) therapy than in the LV of patients with no ICD therapy (P<.05). CONCLUSIONS These data indicate that ionic and structural remodelling could be pathophysiological mechanisms of cardiac arrhythmias in HF patients.

Tirofiban and eptifibatide treatment of patients presenting with acute coronary syndrome with non-ST segment elevation

Objective: This retrospective study was conducted to determine the usage patterns and tolerability of tirofiban and eptifibatide during the first year of their use.Methods: We have assessed the appropriate use of these drugs according to the criteria implemented by the Clinical Institute of Cardiovascular Disease as part of a protocol for treating acute coronary syndrome with non-ST segment elevation.Results: 37 patients received tirofiban and 19 patients received eptifibatide. These patients were at high risk of poor outcomes such as myocardial infarction or death. Tirofiban and eptifibatide were used according to the indication criteria: only one case fell outside them. Dosing, time for drug initiation (from last chest pain) and time of infusion were considered appropriate. Tirofiban was involved in two cases of minor bleeding complications and eptifibatide in one case of thrombocytopenia (80,000 platelets per millimeter). These mild adverse drug reactions were reversible with the early withdrawal of the drugs.Conclusions: This study shows that tirofiban and eptifibatide have been used optimally, with a close adherence to the pre-established protocol. Both drugs have shown a good level of tolerability.