La administración de N-acetilcisteína atenúa el remodelado post infarto de miocardio / Administration of N-acetylcysteine Attenuates Post-Myocardial Infarction Remodeling

RESUMEN Introducción: La cardiopatía isquémica es la principal causa de muerte en la República Argentina. La forma de presentación que prevalece es el infarto de miocardio (IM), caracterizado por insuficiente perfusión sanguínea, muerte celular y pérdida de masa contráctil. La evolución del remodelado ventricular provoca dilatación ventricular, deterioro hemodinámico, insuficiencia cardíaca y disminución de la sobrevida. Durante este proceso existe un estrés oxidativo miocárdico que podría ser atenuado mediante la administración de N-acetil cisteína (NAC), a través de un aumento de los niveles de glutatión. Objetivos: Evaluar el efecto de la NAC sobre el remodelado post IM. Material y métodos: Se estudiaron durante 28 días conejos neozelandeses en tres grupos experimentales: Control, IM e IM+NAC. Bajo anestesia general se realizó una toracotomía izquierda y, en los grupos con IM, ligadura de una rama de la coronaria izquierda. Al finalizar el período de seguimiento posterior al infarto, se realizaron estudios ecocardiográficos, hemodinámicos y morfológicos del ventrículo izquierdo (VI). Resultados: En los grupos IM e IM+NAC los infartos estaban ubicados en la pared libre del VI y tuvieron tamaños similares. La administración de NAC evitó el adelgazamiento de la zona no infartada y disminuyó la dilatación provocada por el infarto. También pudo observarse que preservó las funciones sistólica y diastólica del VI, con atenuación del deterioro que las mismas sufrieron como consecuencia del infarto. Conclusión: Estos resultados sugieren que la administración de NAC es una terapéutica promisoria para mitigar los efectos desfavorables del remodelado post IM.

ABSTRACT Background: Ischemic heart disease is the main cause of death in Argentina. The prevailing form of presentation is myocardial infarction (MI), characterized by insufficient blood perfusion, cell death and loss of contractile mass. The evolution of ventricular remodeling causes ventricular dilation, hemodynamic impairment, heart failure, and decreased survival. The oxidative stress occurring during this process could be attenuated by the administration of N-acetyl cysteine (NAC) through increased glutathione levels. Objectives: The aim of this study was to evaluate the effect of NAC administration on post-MI remodeling. Methods: New Zealand rabbits were divided into three experimental groups: Control, MI and MI+NAC. A left thoracotomy was performed under general anesthesia, and in the MI groups a branch of the left coronary artery was ligated. Echocardiographic, hemodynamic and morphological studies of the left ventricle were performed at the end of the 28-day post infarction follow-up period. Results: In the MI and MI+NAC groups, the infarcts were located in the left ventricular free wall and had similar sizes. The administration of NAC prevented non-infarcted area thinning and decreased the dilation caused by the infarction. It also preserved left ventricular systolic and diastolic functions, attenuating the impairment that they suffered as a consequence of the infarction. Conclusion: These results suggest that NAC administration is a promising therapy to mitigate the unfavorable effects of post-MI remodeling.

Remote ischemic preconditioning prevents sarcolemmal-associated proteolysis by MMP-2 inhibition.

The death of myocytes occurs through different pathways, but the rupture of the plasma membrane is the key point in the transition from reversible to irreversible injury. In the myocytes, three major groups of structural proteins that link the extracellular and intracellular milieus and confer structural stability to the cell membrane: the dystrophin-associated protein complex, the vinculin-integrin link, and the spectrin-based submembranous cytoskeleton. The objective was to determine if remote ischemic preconditioning (rIPC) preserves membrane-associated cytoskeletal proteins (dystrophin and ß-dystroglycan) through the inhibition of metalloproteinase type 2 (MMP-2) activity. A second objective was to describe some of the intracellular signals of the rIPC, that modify mitochondrial function at the early reperfusion. Isolated rat hearts were subjected to 30 min of global ischemia and 120 min of reperfusion (I/R). rIPC was performed by 3 cycles of ischemia/reperfusion in the lower limb (rIPC). rIPC significantly decreased the infarct size, induced Akt/GSK-3 ß phosphorylation and inhibition of the MPTP opening. rIPC improved mitochondrial function, increasing membrane potential, ATP production and respiratory control. I/R increased ONOO- production, which activates MMP-2. This enzyme degrades ß-dystroglycan and dystrophin and collaborates to sarcolemmal disruption. rIPC attenuates the breakdown of ß-dystroglycan and dystrophin through the inhibition of MMP-2 activity. Furthermore, we confirm that rIPC activates different intracellular pathway that involves the an Akt/Gsk3ß and MPTP pore with preservation of mitochondrial function.

Validation of a form for assessing the professional performance of residents in cardiology by nurses.

BACKGROUND: There is a strong need for transformation in our assessment systems from one that evaluates performance based on levels of training to another that focuses on professional competence to meet the expected requirements for the practice of the profession. The aim of this study is to validate for the first time a Spanish version of a new tool for assessing the professional performance of residents by nurses newly developed in the Ottawa Hospital (O-RON). MATERIALS AND METHODS: After the author's written authorization, the original O-RON form was translated and cross-culturally adapted. Then we conducted a prospective observational study in two cardiology centers in the city of Buenos Aires. The validity of the tools was evaluated by the ability of the instrument to discriminate the level of experience of the residents according to their post-graduate year level. Data is expressed as percentages and frequencies of the qualifications obtained in the different questions. The chi-square test was used to assess the significance of the differences obtained. A generalizability test was used to evaluate reliability. Feasibility was defined as a minimum of 4 assessments per resident per evaluation round. Satisfaction of evaluators was assessed using a survey with a 10-point scale designed by the authors. RESULTS: A total of 838 evaluations were performed. Regarding validity, the 15-item form could significantly discriminate the experience of the residents according to their postgraduate year level (P < 0,005). Thirty evaluations per resident are required to obtain reliable results. The tool is feasible to implement and an average of 4.55 assessment per resident per evaluation round were achieved throughout the entire experience. This value remained stable during the 8 rounds (1st: 4.65; 2nd: 4.34; 3rd: 4.47; 4th: 6.17; 5th: 4.56; 6th: 4.08; 7th: 4.36; 8th: 3.91). The levels of satisfaction among the evaluators were acceptable. CONCLUSION: The Spanish version of the O-RON form can provide residents with a valuable source of feedback from the eyes of nurses on important aspects of their professional training. This tool, positively assessed by the raters, significantly discriminates residents' experience. Its implementation is feasible in our environment, and it is user-friendly, though it requires a considerable number of assessments to achieve high reliability.

Asociación entre niveles de empatía en médicos y satisfacción del paciente / Association between empathy levels in physicians and patient satisfaction

Resumen Introducción: Una buena relación médico-paciente es crucial para la práctica médica. Un elemento fundamen tal de la misma es la empatía del médico tratante, y esta puede ser cuantificada mediante una escala validada llamada Escala de Empatía de Jefferson. Métodos: En este estudio buscamos correlacionar los valores de empatía de los médicos del servicio con los resultados de las encuestas de satisfacción del pa ciente ambulatorio, medido mediante una herramienta llamada HCAPS. Resultados: Encontramos que los pacientes percibían un mayor trato respetuoso y que se les explicaba mejor sus opciones de tratamiento por parte de los médicos con mayores niveles de empatía. No hubo diferencias en los niveles de empatía de los médicos según su edad, sexo, o tiempo desde la obtención del título de especialista. Discusión: Los resultados validan a la empatía como una habilidad clave dentro de la relación médico-paciente.

Abstract Introduction: A good doctor-patient relationship is crucial to medical practice. A fundamental element of it is the empathy of the treating physician, and it can be quantified by means of a validated scale called the Jefferson Empathy Scale. Methods: In this study we sought to correlate the empathy values of our physicians with the results of outpatient satisfaction surveys, measured using a tool called HCAPS. Results: We found that patients perceived greater respectful treatment and had their treatment options better explained to them by physicians with higher lev els of empathy. There were no differences in physicians' empathy levels according to their age, gender, or time since qualifying as a specialist. Discussion: These results validate empathy as a key skill in the doctor-patient relationship.

[Association between empathy levels in physicians and patient satisfaction]. / Asociación entre niveles de empatía en médicos y satisfacción del paciente.

INTRODUCTION: A good doctor-patient relationship is crucial to medical practice. A fundamental element of it is the empathy of the treating physician, and it can be quantified by means of a validated scale called the Jefferson Empathy Scale. METHODS: In this study we sought to correlate the empathy values of our physicians with the results of outpatient satisfaction surveys, measured using a tool called HCAPS. RESULTS: We found that patients perceived greater respectful treatment and had their treatment options better explained to them by physicians with higher levels of empathy. There were no differences in physicians' empathy levels according to their age, gender, or time since qualifying as a specialist. DISCUSSION: These results validate empathy as a key skill in the doctor-patient relationship.

Introducción: Una buena relación médico-paciente es crucial para la práctica médica. Un elemento fundamental de la misma es la empatía del médico tratante, y esta puede ser cuantificada mediante una escala validada llamada Escala de Empatía de Jefferson. Métodos: En este estudio buscamos correlacionar los valores de empatía de los médicos del servicio con los resultados de las encuestas de satisfacción del paciente ambulatorio, medido mediante una herramienta llamada HCAPS. Resultados: Encontramos que los pacientes percibían un mayor trato respetuoso y que se les explicaba mejor sus opciones de tratamiento por parte de los médicos con mayores niveles de empatía. No hubo diferencias en los niveles de empatía de los médicos según su edad, sexo, o tiempo desde la obtención del título de especialista. Discusión: Los resultados validan a la empatía como una habilidad clave dentro de la relación médico-paciente.

Macrophages Mediate Healing Properties of Fenofibrate in Experimental Chagasic Cardiomyopathy.

Chronic cardiomyopathy is one of the most relevant outcomes of Chagas disease associated with parasite persistence and exacerbated inflammatory response. Fenofibrate, a third generation fibric acid derivative and peroxisome proliferator-activated receptor-α ligand, is involved in the regulation of inflammatory response. However, the participation of macrophages in this scenario has not been elucidated. Here we show, for the first time, that macrophages play a fundamental role in the fenofibrate-mediated modulation of heart pro-inflammatory response and fibrosis caused by the infection with Trypanosoma cruzi. Furthermore, macrophages are required for fenofibrate to improve the loss of ventricular function and this restoration correlates with an anti-inflammatory microenvironment. Understanding the contributions of macrophages to the healing properties of fenofibrate reinforces its potential use as a therapeutic drug, with the aim of helping to solve a public health problem, such as chronic Chagas disease.

Infarto de miocardio en un modelo murino de hiperactividad simpática cardíaca / Myocardial Infarction in a Murine Model of Cardiac Sympathetic Hyperactivity

RESUMEN Introducción: La disautonomía es uno de los mecanismos fisiopatológicos principales que marcan el pronóstico de la cardiopatía isquémica y la insuficiencia cardíaca. La búsqueda de nuevas oportunidades de tratamiento requiere un conocimiento más profundo de los efectos cardíacos de la activación simpática crónica. Objetivos: Estudiar el tamaño del infarto y la función ventricular izquierda en un modelo de ratones transgénicos con sobreexpresión de la proteína Gs-α cardíaca en el contexto de la isquemia/reperfusión miocárdica y el infarto crónico. Material y métodos: Ratones transgénicos (TG) con sobreexpresión cardíaca de la subunidad alfa de la proteína Gs y sus respectivos controles wild-type (WT) fueron sometidos a isquemia miocárdica regional de 30 minutos con 2 horas de reperfusión (IR) o un infarto sin reperfusión (I) de 28 días de evolución. Se cuantificó el tamaño del infarto (TI) con cloruro de 2,3,5-trifeniltetrazolio y se evaluó la función ventricular izquierda mediante ecocardiografía y estudio hemodinámico. Cada grupo experimental estuvo acompañado por un grupo control (WT / TG Sham-2hrs y WT / TG Sham-28d). Resultados: No hubo diferencias significativas en el TI luego de la IR entre los ratones TG y WT (57,3 ± 3,5% vs 59,2±2,5%, respectivamente, p = NS). La frecuencia cardíaca en los ratones TG fue mayor durante el desarrollo de todo el protocolo. Con la infarto se observó un descenso de la fracción de eyección (WT: Sham-28d: 82 ± 2,4% vs I-28d: 44 ± 4% y TG: Sham-28d 89 ± 2% vs I-28d 42 ± 3%; p <0,05) conjuntamente con una disminución de la fracción de acortamiento (FA), y los cambios del área fraccional (CAF) del ventrículo izquierdo (VI) en comparación con los valores basales y sus respectivos grupos controles. Sin embargo, no se observaron diferencias entre los grupos WT y TG. Conclusión: la sobreexpresión de la proteína Gs-α cardíaca no aumenta el tamaño del infarto ni modifica la función ventricular izquierda en la isquemia/reperfusión aguda y en el infarto crónico en comparación con sus respectivos controles

ABSTRACT Background: Dysautonomia is one of the main pathophysiological mechanisms that define the prognosis of ischemic heart disease and heart failure. The search for new treatment opportunities requires a deeper understanding of the cardiac effects of chronic sympathetic activation. Objective: The aim of this study was to analyze left ventricular infarct size and ventricular function in a transgenic mouse model with overexpression of the cardiac Gs-α protein, in the context of myocardial ischemia/reperfusion and chronic infarction. Methods: Transgenic mice (TG) overexpressing cardiac Gs-α and its wild-type variant (WT) were subjected to 30-minute regional myocardial ischemia followed by 2-hour reperfusion (IR) or non- reperfusion (I) with a 28-day follow-up period. Infarct size (IS) was quantified using 2,3,5-triphenyltetrazolium chloride and left ventricular function was evaluated by echocardiography and LV catheterization. Each experimental group was accompanied by a control group (WT/TG Sham-2hrs and WT/TG Sham-28d). Results: There were no significant differences in IS after IR between TG and WT mice (57.3 ± 3.5% vs. 59.2 ± 2.5%, respectively, p = NS). The heart rate in TG mice was higher throughout the experiment. With ischemia, a in ejection fraction (WT: Sham-28d: 82 ± 2.4% vs. I-28d: 44 ± 4% and TG: Sham-28d 89 ± 2% vs. I-28d 42 ± 3%; p <0.05) was observed together with a decrease in shortening fraction and left ventricular fractional area changes compared with baseline values and their respective control (Sham) groups. However, no differences were observed between the WT and TG groups. Conclusions: Cardiac Gs-α protein overexpression does not increase infarct size or modify left ventricular function in acute ischemia / reperfusion and chronic infarction compared with their respective controls.

Myocardial remote ischemic preconditioning: from cell biology to clinical application.

Remote ischemic preconditioning (rIPC) is a cardioprotective phenomenon where brief periods of ischemia followed by reperfusion of one organ/tissue can confer subsequent protection against ischemia/reperfusion injury in other organs, such as the heart. It involves activation of humoral, neural or systemic communication pathways inducing different intracellular signals in the heart. The main purpose of this review is to summarize the possible mechanisms involved in the rIPC cardioprotection, and to describe recent clinical trials to establish the efficacy of these strategies in cardioprotection from lethal ischemia/reperfusion injury. In this sense, certain factors weaken the subcellular mechanisms of rIPC in patients, such as age, comorbidities, medication, and anesthetic protocol, which could explain the heterogeneity of results in some clinical trials. For these reasons, further studies, carefully designed, are necessary to develop a clearer understanding of the pathways and mechanism of early and late rIPC. An understanding of the pathways is important for translation to patients.

Cardiac Natriuretic Peptide Profiles in Chronic Hypertension by Single or Sequentially Combined Renovascular and DOCA-Salt Treatments.

The involvement of natriuretic peptides was studied during the hypertrophic remodeling transition mediated by sequential exposure to chronic hemodynamic overload. We induced hypertension in rats by pressure (renovascular) or volume overload (DOCA-salt) during 6 and 12 weeks of treatment. We also studied the consecutive combination of both models in inverse sequences: RV 6 weeks/DS 6 weeks and DS 6 weeks/RV 6 weeks. All treated groups developed hypertension. Cardiac hypertrophy and left ventricular ANP gene expression were more pronounced in single DS than in single RV groups. BNP gene expression was positively correlated with left ventricular hypertrophy only in RV groups, while ANP gene expression was positively correlated with left ventricular hypertrophy only in DS groups. Combined models exhibited intermediate values between those of single groups at 6 and 12 weeks. The latter stimulus associated to the second applied overload is less effective than the former to trigger cardiac hypertrophy and to increase ANP and BNP gene expression. In addition, we suggest a correlation of ANP synthesis with volume overload and of BNP synthesis with pressure overload-induced hypertrophy after a prolonged treatment. Volume and pressure overload may be two mechanisms, among others, involved in the differential regulation of ANP and BNP gene expression in hypertrophied left ventricles. Plasma ANP levels reflect a response to plasma volume increase and volume overload, while circulating BNP levels seem to be regulated by cardiac BNP synthesis and ventricular hypertrophy.

IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease.

IL-10 is an anti-inflammatory cytokine that plays a significant role in the modulation of the immune response in many pathological conditions, including infectious diseases. Infection with Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas disease, results in an ongoing inflammatory response that may cause heart dysfunction, ultimately leading to heart failure. Given its infectious and inflammatory nature, in this work we analyzed whether the lack of IL-10 hinders the anti-inflammatory effects of fenofibrate, a PPARα ligand, in a murine model of Chagas heart disease (CHD) using IL-10 knockout (IL-10 KO) mice. Our results show fenofibrate was able to restore the abnormal cardiac function displayed by T. cruzi-infected mice lacking IL-10. Treatment with fenofibrate reduced creatine kinase (CK) levels in sera of IL-10 KO mice infected with T. cruzi. Moreover, although fenofibrate could not modulate the inflammatory infiltrates developing in the heart, it was able to reduce the increased collagen deposition in infected IL-10 KO mice. Regarding pro-inflammatory mediators, the most significant finding was the increase in serum IL-17. These were reduced in IL-10 KO mice upon fenofibrate treatment. In agreement with this, the expression of RORγt was reduced. Infection of IL-10 KO mice increased the expression of YmI, FIZZ and Mannose Receptor (tissue healing markers) that remained unchanged upon treatment with fenofibrate. In conclusion, our work emphasizes the role of anti-inflammatory mechanisms to ameliorate heart function in CHD and shows, for the first time, that fenofibrate attains this through IL-10-dependent and -independent mechanisms.

Reliability and acceptability of the multiple mini-interview for selection of residents in cardiology.

INTRODUCTION: The multiple mini-interview (MMI) model can be useful to evaluate non-cognitive domains and guide the selection process in medical residency programs. The aim of this study was to evaluate the reliability and acceptability of the MMI model for the selection of residents in a cardiology residency program. METHODS: We conducted an observational and prospective study. It was performed in a tertiary-care center specialized in cardiology and included candidates for the cardiology residency program in March 2018. Ten stations were developed to evaluate different non-cognitive domains. Reliability was evaluated by the generalizability G coefficient. Candidates and interviewers were surveyed to evaluate the acceptability of the MMI model. RESULTS: Nine faculty members were trained and 22 candidates were evaluated. The G study showed a relative G coefficient between 0.56 and 0.73, according to the design. 91% of the candidates stated that they preferred MMI over other types of interviews as a selection method for admission to the residency program, and all the interviewers considered they had enough time to evaluate the candidates and their strengths as future residents. CONCLUSION: The MMI is a reliable model to evaluate candidates for a residency program in cardiology with high acceptability among residents and observers.

Validation of a Spanish version of a 360° feedback tool for residents' performance: A pilot study.

Background: The 360° feedback tool emerges as one of the most effective techniques for the assessment of humanistic qualities and communication skills of medical trainees, providing effective feedback. A valid Spanish version of this tool has not yet been published. The aim of this study was to evaluate the validity, reliability and feasibility rates of the Mini-peer Assessment Tool (Mini-PAT), a 360° feedback instrument, translated into Spanish applied on a cardiology residency program. Methods: : We translated the Mini-PAT questionnaire into Spanish. The validation sample included all residents in our cardiology program (n = 19). Each resident was evaluated by 8 raters chosen by themselves, through a 4-point Likert scale. Validity was evaluated with factor analysis and reliability by analyzing internal consistency using the Cronbach's alpha coefficient. Feasibility was defined by a minimum of 80% of the raters responding the questionnaire. Results: The factor analysis clearly identified five item groupings, similar to the theoretical attributes predefined in the original questionnaire, providing evidence of the validity of the Spanish version. The Cronbach's alpha coefficient was 0.92, indicating high internal consistency of the items included. All the evaluators proposed completed the electronic form (152 surveys) demonstrating feasibility to implement. Discussion: This study provides evidence of reliability and validity of the Spanish version of the 360° feedback tool Mini-PAT performed in a cardiology residency program to assess global performance and humanistic qualities.

Thioredoxin-1 is required for the cardioprotecive effect of sildenafil against ischaemia/reperfusion injury and mitochondrial dysfunction in mice.

Sildenafil is a phosphodiesterase type 5 inhibitor which confers cardioprotection against myocardial ischaemia/reperfusion (I/R) injury. The aim of this study was to determine if Trx1 participates in cardioprotection exerted by sildenafil in an acute model of I/R, and to evaluate mitochondrial bioenergetics and cellular redox status. Langendorff-perfused hearts from wild type (WT) mice and a dominant negative (DN-Trx1) mutant of Trx1 were assigned to placebo or sildenafil (0.7 mg/kg i.p.) and subjected to 30 min of ischaemia followed by 120 min of reperfusion. WT + S showed a significant reduction of infarct size (51.2 ± 3.0% vs. 30 ± 3.0%, p < .001), an effect not observed in DN-Trx. After I/R, sildenafil preserved state 3 oxygen consumption from WT, but had a milder effect in DN-Trx1 only partially protecting state 3 values. Treatment restored respiratory control (RC) after I/R, which resulted 8% (WT) and 24% (DN-Trx1) lower than in basal conditions. After I/R, a significant increase in H2O2 production was observed both for WT and DN-Trx (WT: 1.17 ± 0.13 nmol/mg protein and DN-Trx: 1.38 ± 0.12 nmol/min mg protein). With sildenafil, values were 21% lower only in WT I/R. Treatment decreased GSSG levels both in WT and DN-Trx1. In addition, GSSG/GSH2 ratio was partially restored by sildenafil. Also, an increase in p-eNOS/eNOS even before the myocardial ischaemia was observed with sildenafil, both in WT (14%, p > .05) and in DN-Trx (35%, p < .05). Active Trx1 is required for the onset of the cardioprotective effects of sildenafil on I/R injury, together with the preservation of cellular redox balance and mitochondrial function.