Patients With High Cardiovascular Risk as Candidates to Bempedoic Acid, After Treatment With Statins, Ezetimibe and PCSK9 Inhibitors: An Estimation and Cost-Effectiveness Analysis.

ABSTRACT: Low-density lipoprotein cholesterol (LDLc) is the lead effector of atherosclerosis and main treatment target. Bempedoic acid is a novel oral drug in the therapeutic armamentarium which is able to reduce LDLc. The objectives of this study were (1) to select the potential patients for administering bempedoic acid such as those with a very high cardiovascular risk in which objectives of LDLc were not achieved despite conventional treatment with PCSK9 inhibitors (PCSK9i) and/or statins and ezetimibe and (2) to estimate the cost-effectiveness of bempedoic acid in different scenarios. The methods used were a multicenter and retrospective study of 652 patients initiating treatment with any PCSK9 inhibitor in 17 different hospitals. Before and on-treatment LDLc cholesterol levels, medical treatments, clinical indication, and baseline characteristics were recorded. The results obtained from 443 subjects in secondary prevention were analyzed. The mean (±) LDLc level at baseline was 142.5 ± 46.4 mg/dL and 61.5 ± 40.5 mg/dL in the follow-up, with a reduction of 55.9% ( P < 0.0001); 71.6% of the patients reached the target of LDL < 55 mg/dL or >50% reduction. Of those patients treated with medium-intensity and low-intensity statins plus PCSK9 inhibitors (with or without ezetimibe), only 5.7% of them were able to reduce LDL below 55 mg/dL and the main LDLc reduction in this group was the lowest (42.9% on average). Patients with TG values >135 mg/dL represented 41.6% of the sample, of which approximately 10% of them were using fibrates. Assuming only LDLc reduction and the UK price, the incremental cost-effectiveness ratio was 88,359€; 83,117€; 82,378€; and 79,015€ for different discount rates. In conclusion, one-third of the patients could achieve the target LDL proposed in the 2019 ESC/EAS guidelines. Approximately 10% of them could also benefit from treating hypertriglyceridemia as indicated in the 2021 ESC guidelines on cardiovascular disease prevention. Patients with medium-intensity and low-intensity statins plus PCSK9i and ezetimibe would be the most benefited. Bempedoic acid could be a not cost-efficacy therapy in all the scenarios, but we need to wait for the CLEAR OUTCOMES Trial results.

Effect of PCSK9 inhibitors on remnant cholesterol and lipid residual risk: The LIPID-REAL registry.

BACKGROUND: Monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 55%, regardless of baseline treatments. Nonetheless, the effect of other lipid parameters, such as cholesterol remnants or, the so-called lipid residual risk, is unknown. METHODS: Multicenter and retrospective registry of patients treated with PCSK9 inhibitors from 14 different hospitals in Spain. Before and on-treatment lipid parameters were recorded. Residual lipid risk was estimated by (1) cholesterol remnants, (2) triglycerides/HDLc ratio (TG/HDL), (3) total cholesterol/HDLc (TC/HDL) and (4) the triglycerides-to-glucose index (TGGi). RESULTS: Six hundred fifty-two patients were analysed, mean age of 60.2 (9.63) years, 24.69% women and mean LDLc before treatment 149.24 (49.86) mg/dl. Median time to second blood determination was 187.5 days. On-treatment LDLc was 67.46 (45.78) mg/dl, which represented a 55% reduction. Significant reductions were observed for TG/HDL ratio, cholesterol remnants, TC/HDL ratio and TGGi. As consequence, 34.61% patients had LDLc <55 mg/dl and cholesterol remnants <30 mg/dl; additionally, 31.95% had cholesterol remnants <30 mg/dl but LDLc >55 mg/dl. Patients who had levels of cholesterol remnants >30 mg/dl before initiating the treatment with PCSK9 had higher reductions in cholesterol remnants, TG/HDL ratio, TC/HDL and TGGi. By contrast, no reduction differences were observed according to baseline LDLc (< or > the mean), age, gender or obesity. CONCLUSIONS: This multicenter and retrospective registry of real-world patients treated with PCSK9 inhibitors demonstrates a positive effect on cholesterol remnants and lipid residual risk beyond LDLc reductions.

Sex Differences in Low-Density Lipoprotein Cholesterol Reduction With PCSK9 Inhibitors in Real-world Patients: The LIPID-REAL Registry.

BACKGROUND: Previous evidence supports that monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 50%-65%, regardless of baseline treatments. We tested possible sex differences in a multicentre registry of real-world patients treated with PCSK9 inhibitors. METHODS: This is a multicentre and retrospective study of 652 patients initiating treatment with any PCSK9 inhibitor in 18 different hospitals. Before-treatment and on-treatment LDLc and medical treatments, clinical indication, and clinical features were recorded. RESULTS: Women represented 24.69% of the cohort. The use of statins was similar in both sexes, but women were receiving most frequently ezetimibe. Before-treatment median LDLc was 135 (interquartile range 115-166) mg, and it was higher in women. The median on-treatment LDLc was 57 (interquartile range 38-84) mg/dL, which represented a mean 54.5% reduction. On-treatment LDLc was higher in women, and the mean LDLc reduction was lower in women (47.4% vs. 56.9%; P = 0.0002) receiving evolocumab or alirocumab. The percentage of patients who achieved ≥50% LDLc reduction was higher in men (71.36% vs. 57.62%; P = 0.002). According to LDLc before-treatment quartiles, LDLc reduction was statistically lower in women in the 2 highest and a significant interaction of women and baseline LDLc >135 mg/dL was observed. Women were negatively associated with lower rates of LDLc treatment target achievement (odds ratio: 0.31). Differences were also observed in women with body mas index >25 kg/m2. Only 14 patients (2.14%) presented side effects. CONCLUSIONS: This multicentre and retrospective registry of real-world patients treated with PCSK9 inhibitors highlights significant gender differences in LDLc reduction.

Asociación de los polimorfismos rs2200733 y rs7193343 con la fibrilación auricular en población española y metanálisis de la evidencia existente / Association Between rs2200733 and rs7193343 Genetic Variants and Atrial Fibrillation in a Spanish Population, and Meta-analysis of Previous Studies

Introducción y objetivos Los objetivos del estudio son analizar en población española la asociación entre dos variantes genéticas (rs2200733 y rs7193343) y el riesgo de sufrir fibrilación auricular y realizar una revisión sistemática y un metanálisis de estas asociaciones. Métodos Estudio de casos y controles con 257 casos de fibrilación auricular y 379 controles. Los casos eran donantes del Banco Nacional de ADN; los controles participaron en un estudio transversal de base poblacional. La genotipificación se realizó mediante pruebas TaqMan. Se realizó una búsqueda bibliográfica sistemática, dos revisores independientes extrajeron la información necesaria. Se realizó un metanálisis, un análisis de heterogeneidad y de metarregresión para identificar las variables que explicaran la heterogeneidad entre estudios. Resultados En nuestra población se observa una asociación entre el rs2200733 y la presencia de fibrilación auricular (odds ratio = 1,87; intervalo de confianza del 95%, 1,30-2,70), pero no con el rs7193343 (odds ratio = 1,18; intervalo de confianza del 95%, 1,11-1,25) para el rs7193343. En la asociación entre el rs2200733 y la fibrilación auricular se observó heterogeneidad entre estudios, parcialmente relacionada con el diseño del estudio, con mayor magnitud de asociación en estudios de casos y controles (odds ratio = 1,83) que en cohortes (odds ratio = 1,41). Conclusiones: Las variantes rs2200733 y rs7193343 se asocian con mayor riesgo de fibrilación auricular. Los estudios de casos y controles tienden a sobrestimar la magnitud de la asociación entre estas variantes genéticas y la fibrilación auricular

Introduction and objectives The objectives of this study were to analyze the association between two genetic variants (rs2200733 and rs7193343) in a Spanish population and the risk of developing atrial fibrillation, and to carry out a systematic review and meta-analysis of these associations. Methods We performed a case-control study involving 257 case patients with atrial fibrillation and 379 controls. The case patients were individuals who had donated samples to the Spanish National DNA Bank; the controls were participating in a population-based cross-sectional study. Genotyping was carried out using a TaqMan assay. We conducted a systematic literature search in which 2 independent reviewers extracted the necessary information. The study involved a meta-analysis, a heterogeneity analysis, and a meta-regression analysis to identify the variables that explain the heterogeneity across studies. Results In our population, the presence of atrial fibrillation was found to be associated with rs2200733 (odds ratio = 1.87; 95% confidence interval, 1.30-2.70), but not with rs7193343 (odds ratio = 1.18; 95% confidence interval, 0.80-1.73). In the meta-analysis, we observed an association between atrial fibrillation and both variants: odds ratio = 1.71 (95% confidence interval, 1.54-1.90) for rs2200733 and odds ratio = 1.18 (95% confidence interval, 1.11-1.25) for rs7193343. We observed heterogeneity among the studies dealing with the association between rs2200733 and atrial fibrillation, partially related to the study design, and the strength of association was greater in case-control studies (odds ratio = 1.83) than in cohort studies (odds ratio = 1.41). Conclusions: Variants rs2200733 and rs7193343 are associated with a higher risk of atrial fibrillation. Case-control studies tend to overestimate the strength of association between these genetic variants and atrial fibrillation

Association between rs2200733 and rs7193343 genetic variants and atrial fibrillation in a Spanish population, and meta-analysis of previous studies.

INTRODUCTION AND OBJECTIVES: The objectives of this study were to analyze the association between two genetic variants (rs2200733 and rs7193343) in a Spanish population and the risk of developing atrial fibrillation, and to carry out a systematic review and meta-analysis of these associations. METHODS: We performed a case-control study involving 257 case patients with atrial fibrillation and 379 controls. The case patients were individuals who had donated samples to the Spanish National DNA Bank; the controls were participating in a population-based cross-sectional study. Genotyping was carried out using a TaqMan assay. We conducted a systematic literature search in which 2 independent reviewers extracted the necessary information. The study involved a meta-analysis, a heterogeneity analysis, and a meta-regression analysis to identify the variables that explain the heterogeneity across studies. RESULTS: In our population, the presence of atrial fibrillation was found to be associated with rs2200733 (odds ratio = 1.87; 95% confidence interval, 1.30-2.70), but not with rs7193343 (odds ratio = 1.18; 95% confidence interval, 0.80-1.73). In the meta-analysis, we observed an association between atrial fibrillation and both variants: odds ratio = 1.71 (95% confidence interval, 1.54-1.90) for rs2200733 and odds ratio = 1.18 (95% confidence interval, 1.11-1.25) for rs7193343. We observed heterogeneity among the studies dealing with the association between rs2200733 and atrial fibrillation, partially related to the study design, and the strength of association was greater in case-control studies (odds ratio = 1.83) than in cohort studies (odds ratio = 1.41). CONCLUSIONS: Variants rs2200733 and rs7193343 are associated with a higher risk of atrial fibrillation. Case-control studies tend to overestimate the strength of association between these genetic variants and atrial fibrillation.

Factores predictivos de reversión a ritmo sinusal precardioversión eléctrica en pacientes con fibrilación auricular persistente tratados con antiarrítmicos / Predictors of reversion to sinus rhythm previous to electrical cardioversion in patients with persistent atrial fibrillation treated with anti-arrhythmic drugs

Introducción: Algunos pacientes con fibrilación auricular persistente que se tratan con antiarrítmicos al indicarse una cardioversión eléctrica revierten a ritmo sinusal antes de la misma. El conocimiento de los factores que predicen esta situación puede ser de utilidad clínica. Metodología: Se analizaron los datos de los pacientes del Registro sobre la cardio- versión en España (REVERSE) que recibieron fármacos antiarrítmicos con capacidad cardioversora previamente a la cardioversión eléctrica. Se estudió mediante regresión logística los factores predictivos de reversión a ritmo sinusal precardioversión. Resultados: De los 752 pacientes tratados con antiarrítmicos, 160 (21%) revirtieron a ritmo sinusal antes de la cardioversión eléctrica. El fármaco más utilizado fue amiodarona (82%), que consiguió una reversión a ritmo sinusal superior al resto de los antiarrítmicos, aunque sin alcanzar diferencias significativas (amiodarona 22% frente a otros antiarrítmicos 17%; p = 0,22). La ausencia de obesidad (índic de masa corporal < 30 kg/m2) (odds ratio [OR] 1,9; p = 0,006), la duración de la fibrilación auricular < 1 año (OR 3,4; p = 0,02) y la ausencia de cardiopatía estructural (OR 1,59; p = 0.01) se identificaron como variables independientes predictoras de reversión a ritmo sinusal. Entre los pacientes tratados con amiodarona que cumplían los 3 criterios, un 31% revirtieron a ritmo sinusal. Conclusión: En pacientes con fibrilación auricular persistente tratados con antiarrítmicos se debe tener cuenta que la ausencia de obesidad, la duración de la fibrilación auricular < 1 año y la ausencia de cardiopatía estructural constituyen factores clínicos que pueden predecir la reversión a ritmo sinusal antes de la cardioversión eléctrica (AU)

Background: Some patients with persistent atrial fibrillation treated pharmacologically revert to sinus rhythm prior to electrical cardioversion. Knowledge of factors predicting this effect may be clinically useful. Methodology: Data were obtained from patients enrolled in the study REgistro sobre la cardioVERSio´n en Espan˜a (REVERSE) and treated with antiarrhythmic drugs that potentially may cause pharmacological reversal. We analized by means of logistic regression predictive factors related to reversion to sinus rhythm precardioversion. Results: Of the 752 patients treated with antiarrhythmic drugs, 160 (21%) reverted to sinus rhythm without electrical cardioversion. Amiodarone was the most widely used active compound (82%) and apparently the most effective. However, differences with other antiarrhythmic drugs were not significant (amiodarone 22% versus other antiarrhythmic drugs 17%, P = .22). Lack of obesity (body mass index < 30 kg/m2) (odds ratio [OR] = 1.9; P = .006), duration of atrial fibrillation 1 year (OR 3.4; P = .02) and the absence of structural heart disease (OR 1,59; P = .01) were identified as independent variables ith predictive value of pharmacological reversal to sinus rhythm. Among patients treated with amiodarone who met these criteria, the frequency of successful treatment increased up to 31%. Conclusion: In patients with persistent atrial fibrillation treated with anti-arrhythmic drugs, lack of obesity, duration of atrial fibrillation < 1 year and the absence of structural heart disease are predictors of reversion to sinus rhythm before electrical cardioversion (AU)

The relevance of the association between inflammation and atrial fibrillation.

BACKGROUND: The relevance of the association between inflammation and atrial fibrillation (AF) is not firmly established. The clinical importance is considerable because inflammation is usually not targeted as a treatment option, minimizing a probable benefit. MATERIALS AND METHODS: We have used a case-control study with a Mendelian randomization rationale to assess whether proposed risk factors that have a genetic component and are readily detected in circulating blood are causally related to AF. The studied variables were C-reactive protein (CRP) and a representative of the chemokine system, the monocyte chemoattractant protein-1 (CCL2). RESULTS: Plasma CRP and CCL2 concentrations were significantly higher in AF patients than in the unaffected population. However, when segregated between paroxysmal and permanent, the difference for CRP was only observed in patients with a permanent condition. Plasma CCL2 was raised in both subgroups. Confounding factors were carefully considered, and multivariable analyses revealed that circulating CCL2 was significant and CRP was negligible to explain the presence of AF. The duration of the episode also bore a significant predictive value. Odd ratios for AF as a function of genotype did not differ from 1·0 for any of the individual CRP and CCL2 polymorphisms, or any combinations. CONCLUSIONS: Elevated plasma CRP concentration per se does not increase atrial fibrillation risk. Values obtained for CCL2 suggest that inflammation is probably a consequence of AF. Our data also suggest that the effect of the duration of the episode should be further studied in the assessment of the actual role of inflammation.

[Predictors of reversion to sinus rhythm previous to electrical cardioversion in patients with persistent atrial fibrillation treated with anti-arrhythmic drugs]. / Factores predictivos de reversión a ritmo sinusal precardioversión eléctrica en pacientes con fibrilación auricular persistente tratados con antiarrítmicos.

BACKGROUND: Some patients with persistent atrial fibrillation treated pharmacologically revert to sinus rhythm prior to electrical cardioversion. Knowledge of factors predicting this effect may be clinically useful. METHODOLOGY: Data were obtained from patients enrolled in the study REgistro sobre la cardioVERSión en España (REVERSE) and treated with antiarrhythmic drugs that potentially may cause pharmacological reversal. We analized by means of logistic regression predictive factors related to reversion to sinus rhythm precardioversion. RESULTS: Of the 752 patients treated with antiarrhythmic drugs, 160 (21%) reverted to sinus rhythm without electrical cardioversion. Amiodarone was the most widely used active compound (82%) and apparently the most effective. However, differences with other antiarrhythmic drugs were not significant (amiodarone 22% versus other antiarrhythmic drugs 17%, P = .22). Lack of obesity (body mass index < 30 kg/m(2)) (odds ratio [OR] = 1.9; P = .006), duration of atrial fibrillation < 1 year (OR 3.4; P=.02) and the absence of structural heart disease (OR 1,59; P = .01) were identified as independent variables with predictive value of pharmacological reversal to sinus rhythm. Among patients treated with amiodarone who met these criteria, the frequency of successful treatment increased up to 31%. CONCLUSION: In patients with persistent atrial fibrillation treated with anti-arrhythmic drugs, lack of obesity, duration of atrial fibrillation < 1 year and the absence of structural heart disease are predictors of reversion to sinus rhythm before electrical cardioversion.

Trends in the use of electrical cardioversion for atrial fibrillation: influence of major trials and guidelines on clinical practice.

BACKGROUND: The purpose of the present study was to assess the trends in the use of ECV following published studies that had compared rhythm and rate control strategies on atrial fibrillation (AF), and the recommendations included in the current clinical practice guidelines. METHODS: The REVERCAT is a population-based assessment of the use of electrical cardioversion (ECV) in treating persistent AF in Catalonia (Spain). The initial survey was conducted in 2003 and the follow-up in 2010. RESULTS: We observed a decrease of 9% in the absolute numbers of ECV performed (436 in 2003 vs. 397 in 2010). This is equivalent to 27% when considering population increases over this period. The patients treated with ECV in 2010 were younger, had a lower prevalence of previous embolism, a higher prevalence of diabetes, and increased body weight. Underlying heart disease factors indicated, in 2010, a higher proportion of NYHA ≥ II and left ventricular ejection fraction <30%. We observed a reduction in the number of ECV performed in 16 of the 27 (67%) participating hospitals. However, there was an increase of 14% in the number of procedures performed in tertiary hospitals, and was related to the increasing use of ECV as a bridge to AF ablation. Considering the initial number of patients treated with ECV, the rate of sinus rhythm at 3 months was almost unchanged (58% in 2003 vs. 57% in 2010; p=0.9) despite the greater use of biphasic energy in 2010 and a similar prescription of anti-arrhythmic drugs. CONCLUSIONS: Although we observed a decrease in the number of ECVs performed over the 7 year period between the two studies, this technique remains a common option for treating patients with persistent AF. The change in the characteristics of candidate patients did not translate into better outcomes.

Insuficiencia cardíaca. Perspectiva desde atención primaria / Heart failure: a view from primary care

Objetivo: Conocer la situación de la insuficiencia cardíaca (IC) en atención primaria (AP). Diseño: Estudio transversal multicéntrico. Emplazamiento: Cuatro centros de salud y el hospital de referencia de un área urbana de Barcelona. Participantes: De una población de 35.212 habitantes mayores de 45 años, se incluyeron todos los pacientes (333) diagnosticados de IC en AP en 2006.MedicionesMediante cuestionario estandarizado se recogieron datos demográficos, clínicos y tratamiento. Resultados: Un 61,4% eran mujeres, la edad media en varones fue de 74,5 (desviación estándar [DE]: 10) y en mujeres de 79 (DE: 9,8) (p<0,0001), el 46% tenía una evolución de la enfermedad menor de 5 años. La comorbilidad en el momento del diagnóstico y al inicio del estudio fue hipertensión (65,4–73%), diabetes (33,6–40%), dislipidemia (40–53%), enfermedad coronaria (30–27%), valvulopatías (23,7–27%) y enfermedad pulmonar obstructiva crónica (20–26%). Resultados: Un 64% tenía registrado el grado funcional New York Heart Association (el 48% de clase II; el 30%, III; el 6,6%, IV). El 36% de los varones y el 20,5% de las mujeres tenían controlada la presión arterial (p=0,002). En un 75,4% constaba registro de electrocardiograma, un 57% de radiografía de tórax, un 58% en varones y un 46% en mujeres (p=0,02) de ecocardiograma. Los fármacos más prescritos fueron diuréticos (85,3%), inhibidores de la enzima de conversión de la angiotensina (43%), antagonistas de los receptores de la angiotensina (33%) y bloqueadores beta (27%). Conclusiones: Los pacientes atendidos son fundamentalmente mujeres de avanzada edad y elevada comorbilidad. Debe preocuparnos en AP el poco registro de exploraciones complementarias básicas y la poca utilización de BB (AU)

Objective: Our aim was to find out the situation of heart failure (HF) in primary care. Design: Cross-sectional multicentre study.Setting Four primary health care centres and a hospital in an urban area of Barcelona. Participants: From a registered population of 35,212 inhabitants older than 45 years, we studied all patients (333) diagnosed with HF in 2006 in primary care. Measurements: A standardised questionnaire was used to record demographic, clinical and treatment data. Results: There were 61.4% females. Mean age was 74.5 (standard deviation [SD]: 10) for men and 79 (SD: 9.8) for women. A total of 46% of patients had HF for <5 years. The comorbidity diagnosis and at the beginning of the study were: hypertension 65.4% and 73%, diabetes 33.6% and 40%, dyslipaemia 40% and 53%, coronary disease 30% and 27%, and valvular disease 23.7% and 27%, respectively. Results: A total of 64% of patients had registered New York Heart Association functional class (48% class II, 30% III and 6.6% IV). Blood pressure was controlled in 36% men and 20.5% women (P=0.002); 75.4% had an electrocardiogram, 57% X-ray; 58% of men and 46% of women (P=0.02) had echocardiography. The most prescribed drugs were diuretics 85.3%, the least, beta blockers 27%.ConclusionsPatients with HF in primary care are elderly females with a lot of comorbidities. We must be concerned by the suboptimal use of basic investigations (electrocardiogram and X-ray) and beta blocker treatments (AU)

[Heart failure: a view from primary care]. / Insuficiencia cardíaca. Perspectiva desde atención primaria.

OBJECTIVE: Our aim was to find out the situation of heart failure (HF) in primary care. DESIGN: Cross-sectional multicentre study. SETTING: Four primary health care centres and a hospital in an urban area of Barcelona. PARTICIPANTS: From a registered population of 35,212 inhabitants older than 45 years, we studied all patients (333) diagnosed with HF in 2006 in primary care. MEASUREMENTS: A standardised questionnaire was used to record demographic, clinical and treatment data. RESULTS: There were 61.4% females. Mean age was 74.5 (standard deviation [SD]: 10) for men and 79 (SD: 9.8) for women. A total of 46% of patients had HF for <5 years. The comorbidity diagnosis and at the beginning of the study were: hypertension 65.4% and 73%, diabetes 33.6% and 40%, dyslipaemia 40% and 53%, coronary disease 30% and 27%, and valvular disease 23.7% and 27%, respectively. A total of 64% of patients had registered New York Heart Association functional class (48% class II, 30% III and 6.6% IV). Blood pressure was controlled in 36% men and 20.5% women (P=0.002); 75.4% had an electrocardiogram, 57% X-ray; 58% of men and 46% of women (P=0.02) had echocardiography. The most prescribed drugs were diuretics 85.3%, the least, beta blockers 27%. CONCLUSIONS: Patients with HF in primary care are elderly females with a lot of comorbidities. We must be concerned by the suboptimal use of basic investigations (electrocardiogram and X-ray) and beta blocker treatments.

Disfunción ventricular transitoria o síndrome de Tako-Tsubo / Transient ventricular dysfunction or Tako-Tsubo syndrome

El síndrome de disfunción ventricular transitoria (SDAT) o Tako-Tsubo es una entidad que se presenta en mujeres de mediana edad, sin riesgo cardiovascular elevado, que se caracteriza por un cuadro clínico indicativo de síndrome coronario agudo de causa desconocida desencadenado por una situación de estrés súbito. Se presenta un caso clínico de este síndrome. Mujer de 46 años de edad, atendida de urgencias en su centro de salud por un cuadro de dolor torácico precordial, con cambios electrocardiográficos de lesión subepicárdica encara anterior. En el hospital de referencia, se detectó elevación de los marcadores de daño miocárdico. El cateterismo no mostró lesiones angiográficamente significativas. En la ventriculografía se observó aquinesia apical confracción de eyección disminuida. El resultado de las exploraciones complementarias orientó al diagnóstico de SDAT. El SDAT es una entidad a tener en cuenta en pacientes sin riesgo cardiovascular elevado, dada la diferente implicación pronóstica y de tratamiento (AU)

Transient ventricular dysfunction (TVD) or Tako-Tsubo syndrome is a disorder that occurs in middle aged women with an increased cardiovascular risk. It is characterised by a clinical picture suggestive of acute coronary syndrome of unknown cause, triggered by an acute stress situation. A clinical case of this syndrome is presented. A 46 year old female patient was seen as an emergency in her health centre die to a clinical picture of precordial chest pain with electrocardiography changes of an anterior subepicardiallesion. Increases in the myocardial damage markers were detected in the reference hospital. The angiographic catheter showed significant lesions. Ventriculography showed evidence of apical a kinesia with a decrease dejection fraction. The results of the complementary examinations led to the diagnosis of a transient ventricular dysfunction syndrome TVDS). TVDS is a condition to take into account inpatients who do not have a high cardiovascular risk given the prognostic and treatment implications (AU)

[Natural history of and risk factors for idiopathic atrial fibrillation recurrence (FAP Registry)]. / Historia natural y factores de riesgo de recurrencia de la fibrilación auricular primaria (Registro FAP).

INTRODUCTION AND OBJECTIVES: The natural history of idiopathic atrial fibrillation is not well understood. The aim of this study was to investigate the frequency of and risk factors for disease recurrence. METHODS: The study involved 115 patients with a first episode of paroxysmal atrial fibrillation of unknown origin who were included the FAP registry, which contains data from 11 district hospitals in Catalonia, Spain. All patients underwent comprehensive clinical, laboratory, electro-cardiographic and echocardiographic investigations at baseline and were followed up periodically every 6 months to identify the occurrence of new symptomatic episodes and their complications. RESULTS: During a mean follow-up period of 912 (445) days, 32 (27.8%) patients experienced recurrence of atrial fibrillation. Those who experienced recurrence had a significantly higher left ventricular ejection fraction (P=.023) and smaller end-systolic volume (P<.001), and they were more likely to consume alcohol regularly (P=.013). Cox regression analysis confirmed that these variables had independent prognostic value. In contrast, the occurrence of syncope during the initial episode was associated with a lower likelihood of recurrence (P=.017). CONCLUSIONS: The risk of recurrence of idiopathic atrial fibrillation was high, and was enhanced by moderate alcohol consumption and increased left ventricular activity, probably of sympathetic origin. This trend was less marked in paroxysmal atrial fibrillation of vagal origin.

Historia natural y factores de riesgo de recurrencia de la fibrilación auricular primaria (Registro FAP) / Natural history of and risk factors for idiopathic atrial fibrillation recurrence (FAP Registry)

Introducción y objetivos. La historia natural de la fibrilación auricular (FA) primaria o idiopática tiene aspectos poco conocidos. El objeto del estudio fue describir la frecuencia y los factores determinantes de las recurrencias. Métodos. Se estudió a 115 pacientes atendidos en su primera crisis de FA paroxística sin causa conocida incluidos en el «registro FAP», en el que participan 11 centros comarcales de Cataluña. Se les practicó un estudio clínico, analítico, electrocardiográfico y ecocardiográfico exhaustivo y fueron seguidos periódicamente cada 6 meses para detectar la aparición de nuevas crisis sintomáticas y sus complicaciones. Resultados. Durante el seguimiento de 912 ± 445 días de promedio, 32 (27,8%) pacientes presentaron una recidiva de la fibrilación auricular. Los pacientes con recurrencias tenían una fracción de eyección más elevada (p = 0,023), un menor volumen telesistólico (p < 0,001) y eran con mayor frecuencia consumidores habituales de alcohol (p = 0,013). El análisis de regresión de Cox confirmó el valor predictivo independiente de estas variables. En cambio, la presencia de lipotimias en el episodio agudo se asoció con una menor tendencia a recidivar (p = 0,017). Conclusiones. La fibrilación auricular idiopática mostró una notable tendencia a las recidivas, favorecida por el consumo moderado de alcohol y el aumento de la actividad ventricular, probablemente de origen simpático. La tendencia fue menor en la fibrilación paroxística de origen vagal

Introduction and objectives. The natural history of idiopathic atrial fibrillation is not well understood. The aim of this study was to investigate the frequency of and risk factors for disease recurrence. Methods. The study involved 115 patients with a first episode of paroxysmal atrial fibrillation of unknown origin who were included the FAP registry, which contains data from 11 district hospitals in Catalonia, Spain. All patients underwent comprehensive clinical, laboratory, electro-cardiographic and echocardiographic investigations at baseline and were followed up periodically every 6 months to identify the occurrence of new symptomatic episodes and their complications. Results. During a mean follow-up period of 912 (445) days, 32 (27.8%) patients experienced recurrence of atrial fibrillation. Those who experienced recurrence had a significantly higher left ventricular ejection fraction (P=.023) and smaller end-systolic volume (P<.001), and they were more likely to consume alcohol regularly (P=.013). Cox regression analysis confirmed that these variables had independent prognostic value. In contrast, the occurrence of syncope during the initial episode was associated with a lower likelihood of recurrence (P=.017). Conclusions. The risk of recurrence of idiopathic atrial fibrillation was high, and was enhanced by moderate alcohol consumption and increased left ventricular activity, probably of sympathetic origin. This trend was less marked in paroxysmal atrial fibrillation of vagal origin

Azathioprine acts upon rat hepatocyte mitochondria and stress-activated protein kinases leading to necrosis: protective role of N-acetyl-L-cysteine.

Azathioprine is an immunosuppressant drug widely used. Our purpose was to 1) determine whether its associated hepatotoxicity could be attributable to the induction of a necrotic or apoptotic effect in hepatocytes, and 2) elucidate the mechanism involved. To evaluate cellular responses to azathioprine, we used primary culture of isolated rat hepatocytes. Cell metabolic activity, reduced glutathione, cell proliferation, and lactate dehydrogenase release were assessed. Mitochondria were isolated from rat livers, and swelling and oxygen consumption were measured. Mitogen-activated protein kinase pathways and proteins implicated in cell death were analyzed. Azathioprine decreased the viability of hepatocytes and induced the following events: intracellular reduced glutathione (GSH) depletion, metabolic activity reduction, and lactate dehydrogenase release. However, the cell death was not accompanied by DNA laddering, procaspase-3 cleavage, and cytochrome c release. The negative effects of azathioprine on the viability of hepatocytes were prevented by cotreatment with N-acetyl-L-cysteine. In contrast, 6-mercaptopurine showed no effects on GSH content and metabolic activity. Azathioprine effect on hepatocytes was associated with swelling and increased oxygen consumption of intact isolated rat liver mitochondria. Both effects were cyclosporine A-sensitive, suggesting an involvement of the mitochondrial permeability transition pore in the response to azathioprine. In addition, the drug's effects on hepatocyte viability were partially abrogated by c-Jun N-terminal kinase and p38 kinase inhibitors. In conclusion, our findings suggest that azathioprine effects correlate to mitochondrial dysfunction and activation of stress-activated protein kinase pathways leading to necrotic cell death. These negative effects of the drug could be prevented by coincubation with N-acetyl-L-cysteine.

Insulin receptor substrate-4 signaling in quiescent rat hepatocytes and in regenerating rat liver.

This study was designed to characterize insulin receptor substrate-4 (IRS-4) in isolated rat hepatocytes and to examine its role in liver regeneration. Subcellular fractionation revealed that 85% of IRS-4 is located at isolated hepatocyte plasma membranes. The distribution of IRS-4 among intracellular compartments remained unchanged in insulin-stimulated cells. Two bands corresponding to 145 and 138 kd were observed in immunoblotting experiments. Immunoprecipitation of hepatocyte lysates with a highly specific antibody against IRS-4 led to an insulin and insulin-like growth factor 1 (IGF-1)-dependent increase in phosphotyrosine residues of the 145-kd band. IRS-4 was found to be associated with Src homology 2 (SH2) domain-containing proteins (phosphatidylinositol 3-kinase [PI 3-kinase] and Src homology phosphatase [SHP-2]) and with protein kinase C zeta (PKC zeta). Insulin and IGF-1 elicited a rapid and dose-dependent binding of these 3 proteins to IRS-4. These data suggest that IRS-4 is insulin-/IGF-1-activated by phosphorylation and not by translocation, inducing the recruitment of SH2 domain-containing proteins and PKC zeta to the membrane. To evaluate the possible role of IRS-4 in liver regeneration, we also examined this system after partial hepatectomy (PH). One day after PH, IRS-1 expression increased, consistent with a stimulatory role in the regenerative process, whereas it decreased 7 days after liver resection. This drastic IRS-1 depletion occurred at the expense of increased IRS-2 and IRS-4 expression 7 days after PH. In addition, at this period of time after surgery, the in vivo insulin stimulation of remnant rat livers showed an increase in IRS-4/PI 3-kinase association. Given that 1 and 7 days after PH isolated hepatocytes responded similarly to insulin in terms of induced cell proliferation, a compensatory role is proposed for IRS-2/4 induction. In conclusion, IRS-4 is activated by insulin and IGF-1-like IRS-1 in rat hepatocytes, and the induced expression of IRS-4 is a compensatory mechanism that plays a role in conditions of liver regeneration.

Pretreatment with FK506 up-regulates insulin receptors in regenerating rat liver.

This report examines the effect of FK506 pretreatment on liver insulin receptor expression in partially (70%) hepatectomized rats. FK506 pretreatment led to an increased insulin receptor number 24 hours after hepatectomy, detected by means of insulin binding and cross-linking procedures. This increase was related to enhanced insulin receptor expression determined by in vitro mRNA translation and Western blot techniques. We also tested the functionality of the expressed insulin receptors by [(3)H] thymidine incorporation into DNA in insulin-stimulated hepatocytes. The results show that FK506 pretreatment elicits an increase in the amount of insulin receptor alpha-subunits as measured by Western blot. Maximum alpha-subunit expression recorded 24 hours after surgery was preceded by increased insulin receptor mRNA levels, which were detected 6 hours after hepatectomy. Moreover, in FK506-pretreated rat hepatocytes, obtained from remnant livers 24 hours after partial hepatectomy (PH), the increase in insulin receptor number was associated with improved sensitivity to the hormone. However, in both experimental groups (FK506-pretreated and nonpretreated rats), the sensitivity of hepatocytes toward epidermal growth factor (EGF) showed no significant change, which suggests a specific effect of FK506 on insulin receptor expression. In conclusion, our findings suggest that FK506 pretreatment induces insulin receptor expression in regenerating rat liver and promotes liver regeneration in hepatectomized rats.