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.

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.

A Step Further-The Role of Trigeminocardiac Reflex in Therapeutic Implications: Hypothesis, Evidence, and Experimental Models.

The trigeminocardiac reflex (TCR) is a well-recognized brainstem reflex that represents a unique interaction between the brain and the heart through the Vth and Xth cranial nerves and brainstem nuclei. The TCR has mainly been reported as an intraoperative phenomenon causing cardiovascular changes during skull-base surgeries. However, it is now appreciated that the TCR is implicated during non-neurosurgical procedures and in nonsurgical conditions, and its complex reflex pathways have been explored as potential therapeutic options in various neurological and cardiovascular diseases. This narrative review presents an in-depth overview of hypothetical and experimental models of the TCR phenomenon in relation to the Vth and Xth cranial nerves. In addition, primitive interactions between these 2 cranial nerves and their significance are highlighted. Finally, therapeutic models of the complex interactions of the TCR and areas for further research will be considered.

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.

Effects of third-generation ß-blockers, atenolol or amlodipine on blood pressure variability and target organ damage in spontaneously hypertensive rats.

BACKGROUND: ß-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection. METHOD: Considering the differences in the pharmacological properties of ß-blockers, the present work compared the effects of third-generation ß-blockers - carvedilol and nebivolol - with a first-line agent - amlodipine - on hemodynamic parameters, including short-term blood pressure variability (BPV), and their ability to prevent target organ damage in spontaneously hypertensive rats (SHR). SHR rats were orally treated with carvedilol, nebivolol, atenolol, amlodipine or vehicle for 8 weeks. Wistar Kyoto rats treated with vehicle were used as normotensive group. Echocardiographic evaluation, BP, and short-term BPV measurements were performed. Left ventricle and thoracic aorta were removed for histological evaluations and to assess the expression of transforming growth factor ß (TGF-ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). RESULTS: Carvedilol, nebivolol or amlodipine induced a greater reduction of carotid BP, short-term BPV and echocardiography parameters than atenolol in SHR rats. Carvedilol, nebivolol and amlodipine were more effective than atenolol in the prevention of cardiac hypertrophy, and cardiac and aortic collagen deposit. Carvedilol and nebivolol, but not atenolol, reduced the expressions of fibrotic and inflammatory biomarkers - TGF-ß, TNF-α and IL-6 - in SHR rats to a similar extent to that of amlodipine. CONCLUSION: Chronic treatment with carvedilol or nebivolol attenuates carotid BP and short-term BPV, and reduces target organ damage in SHR to a greater extent than atenolol. Our findings suggest that the lower cardiovascular protection of nonvasodilating ß-blockers, as atenolol, in hypertension must not be translated to third-generation ß-blockers.

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.

Mitochondrial bioenergetics links inflammation and cardiac contractility in endotoxemia.

There is current awareness about the central role of mitochondrial dysfunction in the development of cardiac dysfunction in systemic inflammatory syndromes, especially in sepsis and endotoxemia. The aim of this work was to elucidate the mechanism that governs the link between the severity of the systemic inflammatory insult and mitochondrial function, analysing the consequences on heart function, particularly in cardiac contractile state. Female Sprague-Dawley rats were subjected to low-grade endotoxemia (i.p. injection LPS 0.5 mg kg-1 body weight) and severe endotoxemia (i.p. injection LPS 8 mg kg-1 body weight) for 6 h. Blood NO, as well as cardiac TNF-α and IL-1ß mRNA, were found increased as the severity of the endotoxemia increases. Cardiac relaxation was altered only in severe endotoxemia, although contractile and lusitropic reserves were found impaired in both treatments in response to work-overload. Cardiac ultrastructure showed disorientation of myofibrillar structure in both endotoxemia degrees, but mitochondrial swelling and cristae disruption were only observed in severe endotoxemia. Mitochondrial ATP production, O2 consumption and mitochondrial inner membrane potential decreases were related to blood NO levels and mitochondrial protein nitration, leading to diminished ATP availability and impairment of contractile state. Co-treatment with the NOS inhibitor L-NAME or the administration of the NO scavenger c-PTIO leads to the observation that mitochondrial bioenergetics status depends on the degree of the inflammatory insult mainly determined by blood NO levels. Unravelling the mechanisms involved in the onset of sepsis and endotoxemia improves the interpretation of the pathology, and provides new horizons for novel therapeutic targets.

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.

Dyslipidemia in Ischemia/Reperfusion Injury.

Ischemic heart disease is the main cause of morbidity and mortality in the developed world. Although reperfusion therapies are currently the best treatment for this entity, the restoration of blood flow leads, under certain circumstances, to a form of myocardial damage called reperfusion injury. Several studies have shown that age, sex, smoking, diabetes and dyslipidemia are risk factors for cardiovascular diseases. Among these risk factors, dyslipidemias are present in 40% of patients with ischemic heart disease and represent the clinical factor with the greatest impact on the prognosis of patients with cardiovascular diseases. It is known that during reperfusion the increase of the oxidative stress is perhaps one of the most important mechanisms implicated in cell damage. That is why several researchers have studied protective mechanisms against reperfusion injury, such as the ischemic pre- and post- conditioning, making emphasis mainly on the reduction of oxidative stress. However, few of these efforts have been successfully translated into the clinical setting. The controversial results in regards to the relation between cardioprotective mechanisms and dyslipidemia/hypercholesterolemia are mainly due to the difference among quality, composition and the time of administration of hypercholesterolemic diets, as well as the difference in the species used in each of the studies. Therefore, in order to compare results, it is crucial that all variables that could modify the obtained results are taken into consideration.

Adenosine A1 receptors and mitochondria: targets of remote ischemic preconditioning.

Adenosine is involved in classic preconditioning in most species and acts especially through adenosine A1 and A3 receptors. The aim of the present study was to evaluate whether remote ischemic preconditioning (rIPC) activates adenosine A1 receptors and improves mitochondrial function, thereby reducing myocardial infarct size. Isolated rat hearts were subjected to 30 min of global ischemia and 60 min of reperfusion [ischemia-reperfusion (I/R)]. In a second group, before isolation of the heart, a rIPC protocol (3 cycles of hindlimb I/R) was performed. Infarct size was measured with tetrazolium staining, and Akt/endothelial nitric oxide (NO) synthase (eNOS) expression/phosphorylation and mitochondrial function were evaluated after ischemia at 10 and 60 min of reperfusion. As expected, rIPC significantly decreased infarct size. This beneficial effect was abolished only when 8-cyclopentyl-1,3-dipropylxanthine (adenosine A1 receptor blocker) and NG-nitro-l-arginine methyl ester (NO synthesis inhibitor) were administered during the reperfusion phase. At the early reperfusion phase, rIPC induced significant Akt and eNOS phosphorylation, which was abolished by the perfusion with an adenosine A1 receptor blocker. I/R led to impaired mitochondrial function, which was attenuated by rIPC and mediated by adenosine A1 receptors. In conclusion, we demonstrated that rIPC limits myocardial infarct by activation of adenosine A1 receptors at early reperfusion in the isolated rat heart. Interestingly, rIPC appears to reduce myocardial infarct size by the Akt/eNOS pathway and improves mitochondrial function during myocardial reperfusion. NEW & NOTEWORTHY Adenosine is involved in classic preconditioning and acts especially through adenosine A1 and A3 receptors. However, its role in the mechanism of remote ischemic preconditioning is controversial. In this study, we demonstrated that remote ischemic preconditioning activates adenosine A1 receptors during early reperfusion, inducing Akt/endothelial nitric oxide synthase phosphorylation and improving mitochondrial function, thereby reducing myocardial infarct size.