Cardiac chymase: pathophysiological role and therapeutic potential of chymase inhibitors

On release from cardiac mast cells, alpha-chymase converts angiotensin I (Ang I) to Ang II. In addition to Ang II formation, alpha-chymase is capable of activating TGF-beta 1 and IL-1 beta, forming endothelins consisting of 31 amino acids, degrading endothelin-1, altering lipid metabolism, and degrading the extracellular matrix. Under physiological conditions the role of chymase in the mast cells of the heart is uncertain. In pathological situations, chymase may be secreted and have important effects on the heart. Thus, in animal models of cardiomyopathy, pressure overload, and myocardial infarction, there are increases in both chymase mRNA levels and chymase activity in the heart. In human diseased heart homogenates, alterations in chymase activity have also been reported. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of cardiac disease. The selective chymase inhibitors developed to date include TY-51076, SUN-C8257, BCEAB, NK320, and TEI-E548. These have yet to be tested in humans, but promising results have been obtained in animal models of myocardial infarction, cardiomyopathy, and tachycardia-induced heart failure. It seems likely that orally active inhibitors of chymase could have a place in the treatment of cardiac diseases where injury-induced mast cell degranulation contributes to the pathology.

Hydrodynamic evaluation of kangaroo aortic valve matrices for tissue valve engineering

We evaluated the hydrodynamic performance of kangaroo aortic valve matrices (KMs) (19, 21, and 23 mm), as potential scaffolds in tissue valve engineering using a pulsatile left heart model at low and high cardiac outputs (COs) and heart rates (HRs) of 60 and 90 beats/min. Data were measured in two samples of each type, pooled in two CO levels (2.1 +/- 0.7 and 4.2 +/- 0.6 L/min; mean +/- standard errors on the mean), and analyzed using analysis of variance with CO level, HR, and valve type as fixed factors and compared to similar porcine matrices (PMs). Transvalvular pressure gradient (Delta P) was a function of HR (P < 0.001) and CO (P < 0.001) but not of valve type (P = 0.39). Delta P was consistently lower in KMs but not significantly different from PMs. The effective orifice area and performance index of kangaroo matrices was statistically larger for all sizes at both COs and HRs.

Diastolic dysfunction is a manifestation of ventricular-vascular interaction in patients with type 2 diabetes mellitus

Vascular disease is accelerated in patients with Type 2 diabetes mellitus (T2DM). Since the systemic vasculature plays a pivotal role in myocardial loading, this study aimed to determine the effect of arterial characteristics on left ventricular (LV) morphology and function in patients with T2DM. Conventional echocardiography and tissue Doppler imaging were performed in 172 T2DM patients (95 men; aged 55±11y) with preserved ejection fraction (62±5%). Patients were stratified into groups based on LV geometric pattern (normal [n = 79], concentric remodeling [n = 33], concentric hypertrophy [n = 29], eccentric hypertrophy [n = 31]). Total arterial compliance (TAC) was recorded by simultaneous radial tonometry and aortic outflow pulsed wave Doppler. Arterial (brachial and carotid) structure and function were determined by standard ultrasound methods. There were no significant differences between the LV geometric groups in demographic or clinical parameters. The concentric hypertrophy group had significantly increased carotid artery diameter (6.0±0.7mm versus 6.5±0.7mm; p < 0.05) and stiffness (1912±1203 dynes/cm2mm versus 2976±2695 dynes/cm2mm×10−6; p < 0.05) compared to those with normal geometry. However, TAC did not differ between groups. LV diastolic function, as determined by the ratio of diastolic mitral inflow velocity to mitral annulus tissue velocity (E/E_), was significantly associated with carotid artery relative wall thickness and intima media thickness (p < 0.05). Moreover, E/E_ was independently predicted by carotid artery relative wall thickness (β = 22.9; p = 0.007). We conclude that structural characteristics of the carotid artery are associated with abnormal LV structure and function in patients with T2DM. The LV functional irregularities may be a downstream consequence of amplified pressure wave reflections effecting sub-optimal ventricular-vascular interaction.

Melanocytes in the developing and adult atrioventricular valves of the murine heart

The Neural Crest (NC) is a multipotential group of cells that arises from the dorsal aspect of the neural tube early in development. It is well established that a group of NC cells named Cardiac Neural Crest (CNC) migrates to the heart and plays a critical role in the remodeling of the aortic arch arteries and septation of the outflow tract. In this study, using the mouse mutant Pax3sp/sp that has CNC deficits I have identified a putative novel role for the CNC in regulating apoptosis in the atrioventricular (AV) endocardial cushion. The AV endocardial cushion undergoes remodeling to give rise to the cardiac AV valves. Using a transgenic mouse that carries the LacZ reporter gene under the control of the Dopachrome tautomerase promoter (Dct-LacZ), I found that another NC derived population, melanocyte precursors, also contribute to the AV endocardial cushion and developing AV valves. The analysis of Dct-LacZ embryos at different stages showed that NC cells already committed to the melanocytic fate migrate to the heart along the same initial pathway taken by those that will populate the skin. Hypopigmented mice carrying mutations in the Kit and Endothelin receptor b genes, that are critical for the proper development of skin melanocytes, do not have cardiac melanocytes indicating that cardiac and skin melanocyte precursors share the same initial signaling requirements. The analysis of murine adult hearts showed that melanocytes are mostly found in the atrial sides of the tricuspid and mitral valve leaflets. The distribution of melanocytes in the AV valves corresponds exactly to areas of high Versican B expression, a proteoglycan essential for the process of AV valve remodeling. To evaluate a potential role for melanocytes in the AV valves, a nanoindentation analysis of the tricuspid valves of wild type, hypopigmented and hyperpigmented mice was performed. The storage modulus, a measure of stiffness, for the leaflets obtained from hyperpigmented mice was considerably higher (10.5GPa) than that for the leaflets from wild type (7.5GPa) and hypopigmented animals (between 3.5 and 5.5 GPa) suggesting that melanocytes may contribute to the mechanical properties of the AV valves.

Noradrenergic modulatoins of odor learning and odor representation in the rat

How experience alters neuronal ensemble dynamics and how locus coeruleus-mediated norepinephrine release facilitates memory formation in the brain are the topics of this thesis. Here we employed a visualization technique, cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH), to assess activation patterns of neuronal ensembles in the olfactory bulb (OB) and anterior piriform cortex (aPC) to repeated odor inputs. Two associative learning models were used, early odor preference learning in rat pups and adult rat go-no-go odor discrimination learning. With catFISH of an immediate early gene, Arc, we showed that odor representation in the OB and aPC was sparse (~5-10%) and widely distributed. Odor associative learning enhanced the stability of the rewarded odor representation in the OB and aPC. The stable component, indexed by the overlap between the two ensembles activated by the rewarded odor at two time points, increased from ~25% to ~50% (p = 0.004-1.43E⁻4; Chapter 3 and 4). Adult odor discrimination learning promoted pattern separation between rewarded and unrewarded odor representations in the aPC. The overlap between rewarded and unrewarded odor representations reduced from ~25% to ~14% (p = 2.28E⁻⁵). However, learning an odor mixture as a rewarded odor increased the overlap of the component odor representations in the aPC from ~23% to ~44% (p = 0.010; Chapter 4). Blocking both α- and β-adrenoreceptors in the aPC prevented highly similar odor discrimination learning in adult rats, and reduced OB mitral and granule ensemble stability to the rewarded odor. Similar treatment in the OB only slowed odor discrimination learning. However, OB adrenoceptor blockade disrupted pattern separation and ensemble stability in the aPC when the rats demonstrated deficiency in discrimination (Chapter 5). In another project, the role of α₂-adrenoreceptors in the OB during early odor preference learning was studied. OB α2-adrenoceptor activation was necessary for odor learning in rat pups. α₂-adrenoceptor activation was additive with β-adrenoceptor mediated signalling to promote learning (Chapter 2). Together, these experiments suggest that odor representations are highly adaptive at the early stages of odor processing. The OB and aPC work in concert to support odor learning and top-down adrenergic input exerts a powerful modulation on both learning and odor representation.

Situación del riesgo de embolia y de hemorragia según las escalas CHADS₂, CHA₂DS₂-VASc y HAS-BLED en pacientes con diagnóstico de fibrilación auricular crónica, en un centro de salud de Madrid

La fibrilación auricular (FA) es la arritmia sostenida más frecuente en la práctica clínica, consistente en la desorganización total de la actividad eléctrica de la aurícula y ausencia de contracción auricular ordenada. Las últimas guías americanas AHA/ACC/HRS del 2014 definen “fibrilación auricular no valvular” (FANV) como aquella que aparece en ausencia de estenosis mitral reumática, prótesis valvular cardíaca o reparación valvular mitral, que en la FA en la que basamos este trabajo. La prevalencia estimada de fibrilación auricular en el mundo desarrollado es de un 1,5-2%, cuya incidencia aumenta escalonadamente en función de las décadas de la vida, siendo la edad media presentación entre los 75 y los 85 años. En España se estima que la FA afecta a un 8,5% de la población mayor de 60 años, es decir que existen más de 1 millón de personas con FA, de los cuales más de 90.000 se encuentran sin diagnosticar. La FA puede aparecer como consecuencia de una cardiopatía estructural, aunque otras enfermedades extracardíacas también se asocian a la FA, por mecanismos hemodinámicos, como la embolia pulmonar, EPOC, SAOS, o bien por la modulación del SNA, como en el caso del hipertiroidismo. La importancia de la FA radica en su creciente prevalencia, así como por la importante carga de morbilidad y mortalidad que genera. La FA está asociada a una tasa aumentada de muerte, ACV y otros episodios tromboembólicos, insuficiencia cardiaca y hospitalizaciones, pérdida de calidad de vida, deterioro cognitivo, capacidad reducida para el ejercicio y disfunción ventricular izquierda. El riesgo de muerte es el doble que el de la población sin dicha patología. Y el riesgo de ictus es de 3-5 veces mayor...

School and Community Screening Shows Malawi, Africa, to Have a High Prevalence of Latent Rheumatic Heart Disease

Rheumatic heart disease (RHD) is the largest cardiac cause of morbidity and mortality in the world's youth. Early detection of RHD through echocardiographic screening in asymptomatic children may identify an early stage of disease, when secondary prophylaxis has the greatest chance of stopping disease progression. Latent RHD signifies echocardiographic evidence of RHD with no known history of acute rheumatic fever and no clinical symptoms.

OBJECTIVE: Determine the prevalence of latent RHD among children ages 5-16 in Lilongwe, Malawi.

DESIGN: This is a cross-sectional study in which children ages 5 through 16 were screened for RHD using echocardiography.

SETTING: Screening was conducted in 3 schools and surrounding communities in the Lilongwe district of Malawi between February and April 2014.

OUTCOME MEASURES: Children were diagnosed as having no, borderline, or definite RHD as defined by World Heart Federation criteria. The primary reader completed offline reads of all studies. A second reader reviewed all of the studies diagnosed as RHD, plus a selection of normal studies. A third reader served as tiebreaker for discordant diagnoses. The distribution of results was compared between gender, location, and age categories using Fisher's exact test.

RESULTS: The prevalence of latent RHD was 3.4% (95% CI = 2.45, 4.31), with 0.7% definite RHD and 2.7% borderline RHD. There was no significant differences in prevalence between gender (P = .44), site (P = .6), urban vs. peri-urban (P = .75), or age (P = .79). Of those with definite RHD, all were diagnosed because of pathologic mitral regurgitation (MR) and 2 morphologic features of the mitral valve. Of those with borderline RHD, most met the criteria by having pathological MR (92.3%).

CONCLUSION: Malawi has a high rate of latent RHD, which is consistent with other results from sub-Saharan Africa. This study strongly supports the need for a RHD prevention and control program in Malawi.

Oclusão percutânea do apêndice auricular esquerdo e estrutura auricular: efeito na função mecânica e endócrina auricular

Mestrado em Tecnologia de Diagnóstico e Intervenção Cardiovascular - Área de especialização: Intervenção Cardiovascular.

Agrandissement des feuillets mitraux en insuffisance aortique : un mécanisme actif pouvant prévenir l’insuffisance mitrale dans le ventricule dilaté

L’insuffisance mitrale (IM) fonctionnelle est une complication fréquente des cardiopathies, causée par la dilatation du ventricule gauche (VG) qui empêche la valve de se fermer. L’insuffisance aortique (IA) est une condition associée à des valves mitrales (VM) inhabituellement grandes, et relativement peu d’IM malgré des VG très dilatés. Cet élargissement de la VM a le potentiel de prévenir l’IM dans les VG dilatés. Les mécanismes sont cependant peu compris : il n’est pas clair s’il s’agit d’une croissance active ou d’un étirement passif des feuillets. Également, le timing de l’adaptation valvulaire n’est pas connu. Notre hypothèse est que l’agrandissement de la valve mitrale en IA est un phénomène actif avec réactivation des mécanismes de croissance embryonnaire. Cent-onze rats ont été divisés en deux groupes : IA (perforation aortique) et contrôle. Les animaux ont été sacrifiés à 48 h, 1 semaine et 3 mois après la création du modèle. Des échocardiographies ont évalué la sévérité de l’IA, la présence d’IM et les dimensions du VG. Les valves ont été prélevées pour analyses microscopiques et moléculaires. La création de l’insuffisance aortique a entrainé une dilatation et une hypertrophie du VG. Malgré cette dilatation rapide du VG, aucun animal n’a développé de l’IM fonctionnelle. À l’échographie, le feuillet antérieur mitral était significativement plus long dans les groupes IA. Par microscopie, les feuillets étaient plus épais dés la première semaine. L’IA était associée à une surexpression de collagène α-SMA (un marqueur de myofibroblastes), TGF-β1 et MMP-2 dans le tissu valvulaire dès la première semaine. Les valves exposées à l’IA étaient également positives pour ces différents facteurs dés les premiers jours. L’agrandissement de la VM est un phénomène actif qui survient rapidement après la création de l’IA, en parallèle de la dilatation du VG. La stimulation de cette croissance dans d’autres pathologies pourrait contribuer à prévenir l’IM fonctionnelle.

Two cases of right atrial myxoma in redo patients. A mere coincidence?

We describe two cases of right atrial myxoma in redo patients who had previously undergone to coronary artery by-pass grafting (CABGs) and mitral valve replacement respectively. Both of patients experienced effort dyspnea and were assessed by trans-thoracic echocardiography, revealing the right atrial masses. They were operated on for myxoma resection and postoperative course was uneventful. Our report deals with the interesting topic of the location of benign masses that are usually more common in the left atrium. Should we hypothesize that the right atrial manipulation during the previous surgery induces the onset of the right atrial mass? It is an interesting matter to debate.

Behind Recurrent Thromboembolic Events

We describe the case of a 68-year-old man, who presented with an ischemic stroke due to cardiac embolization related to mitral valve endocarditis. Blood cultures were always negative and post-operative valve histology did not show microorganisms. The patient also presented further recurrent peripheral embolic events. These clinical aspects were the first sign of a pancreas adenocarcinoma, which was only diagnosed in the clinical autopsy. In conclusion, these clinical findings of recurrent thromboembolic events with no microorganisms isolated suggests the diagnostic of a marantic endocarditis.

Importância do eletrocardiograma de doze derivações na localização da via acessória no padrão de Wolff-Parkinson-White

A ablação por cateter de radiofrequência tornou-se o tratamento de escolha para os pacientes com síndrome de Wolff-Parkinson-White, sintomáticos. A localização da via acessória a partir da morfologia do QRS no eletrocardiograma basal, torna-se útil para o planeamento do procedimento de ablação, por permitir um conjunto de informações que ajudam na escolha da melhor abordagem terapêutica, em particular no que respeita ao intervalo para a ablação, a necessidade de punção transeptal e o risco de bloqueio aurículo-ventricular, se a via acessória estiver próxima do nódulo aurículo-ventricular ou do feixe de His. Estão descritos vários algoritmos para prever a localização da via acessória a partir da análise da morfologia do QRS basal. Os seus autores relatam elevados índices de acerto, todavia, estudos subsequentes obtiveram resultados distintos, com índices de acerto menores. O presente estudo tem como objetivo principal a avaliação da capacidade diagnóstica do eletrocardiograma de doze derivações na localização da via acessória no padrão de Wolff- Parkinson-White. Os dados clínicos necessários a este estudo foram recolhidos no Serviço de Cardiologia do Centro Hospitalar S. João – EPE, através da consulta dos exames eletrocardiograma e estudo eletrofisiológico, nos indivíduos com diagnóstico prévio de síndrome de Wolff-Parkinson- White. Numa amostra formada por 111 indivíduos de ambos os géneros e com idade média de 36,54 (± 15,27) anos (idade mínima de 7 anos e idade máxima de 75 anos), procedeu-se à comparação da localização da via acessória no estudo eletrofisiológico, com a obtida pela aplicação dos algoritmos de Arruda et al., Boersma et al., Chiang et al., Ávila et al., Fitzpatrick et al., Iturralde et al. e Xie et al. (harmonizadas para todos os algoritmos, as localizações possíveis das vias acessórias). Em volta do anel mitral, encontravam-se distribuídas 59 vias acessórias (53,15%), sendo 52 as vias acessorias distribuídas em torno do anel tricúspide (46,85%). Nesta distribuição não se observaram diferenças estatisticamente significativas de acordo com o género. O acerto global em todos os algoritmos variou entre 27,00% a 47,00%, aumentando para 40,00% a 76,00%, incluindo as localizações adjacentes. A concordância entre os investigadores variou entre 40,00% a 80,00%, observando-se que em relação ao valor médio de concordância, os algoritmos com menores localizações possíveis para as vias acessórias, obtiveram melhor resultado (64,00%). O acerto para as vias acessórias septais (51 no total) variou entre 2,00% a 52,20% (aumentando para 5,90% a 90,20%, incluindo as localizações adjacentes). As vias acessórias direitas, 13 no total, obtiveram acerto entre 7,70% a 69,20% (aumentando para 42,90% a 100%, incluindo as vias acessórias adjacentes). Por último, as vias acessórios esquerdas, 47 no total, obtiveram acerto entre 21,70% a 54,50% (aumentando para 50,00% a 87,00%, incluindo as vias acessórias adjacentes). Para esta distribuição das vias acessórias (localização septal, direita e esquerda), não se observaram diferenças estatisticamente significativas, de acordo com o género. Os resultados obtidos revelam que todos os algoritmos obtiveram valores de acerto inferiores aos enunciados pelos seus autores, permitindo concluir que embora o eletrocardiograma constitua um método muito importante no diagnóstico da pré-excitação ventricular do tipo Wolff-Parkinson-White, este não é sensível, nem específico para a deteção da localização da via acessória.

La ateromatosis aórtica aumenta el riesgo de ataque cerebrovascular isquémico

Antecedentes: el ataque cerebrovascular isquémico (ACVi) es causa de mortalidad y discapacidad importante en adultos, siendo la cardioembolia, sobre todo por fibrilación auricular (FA), una etiología importante. Se conocen otras etiologías, cardíacas y no cardíacas, que no siempre pueden definirse, refiriéndose como probables o posibles de cardioaortoembolia. El rol de alguna de ellas, como la ateromatosis aórtica (AA), continúa siendo discutido. Objetivo: analizar fuentes posibles de cardioaortoembolia en pacientes con ACVi reciente. Material y método: estudio caso-control. Se analizaron 100 sujetos con ACVi de menos de 30 días de evolución estudiados prospectivamente con ecocardiograma transesofágico (ETE), entre febrero de 2012 y marzo de 2014. Se apareó cada caso según edad, sexo, presencia de flutter/FA y ausencia de prótesis valvular cardíaca, con un control que se buscó retrospectiva y aleatoriamente entre sujetos con ETE estudiados entre 2010 y 2015 sin ACVi. Se compararon variables binarias mediante test de McNemar y las cuantitativas por test de t pareado; se realizó regresión logística múltiple para ACVi con variables clínicas y hallazgos de ETE y p < 0,1 en el análisis univariado. Se consideró significativo p < 0,05. Variables cuantitativas se expresan en media y desvío estándar (DE) y nominales en valor absoluto y porcentaje, índice de probabilidad (OR) en su valor e intervalo de confianza (IC) 95%. Resultados: se formaron finalmente 76 pares caso-control. Edad casos: 64,3±1,4 y control 64,9±1,3 años (p=0,19); 39 mujeres (51,3%) y 15 sujetos (19,7%) con flutter/FA en cada grupo (p=1). No hubo diferencias significativas según factores de riesgo cardiovascular (FRCV) globales (p=0,06) ni alcoholismo (p=0,80); se encontraron diferencias significativas en la prevalencia de dislipemia (p=0,03) e hipertensión arterial (HTA) (p <0,05). Las indicaciones principales del ETE en los controles fueron: previo a cardioversión eléctrica de FA, sospecha de endocarditis, y valoración de valvulopatía mitral. La ateromatosis aórtica proximal y compleja (AAPC) (p=0,002, OR 5,5, IC95% 1,9-15,9) y la AA en forma global (p=0,001, OR 4,1, IC95% 1,8-9,3), además de la dislipemia (p=0,02, OR 2,8 IC95% 1,2-6,4), se asociaron significativamente con la presencia de ACVi en el análisis multivariado. Conclusión: la AA aumenta significativamente las chances de ACVi y las quintuplica cuando es proximal y compleja. La dislipemia se asoció a ACVi.

Oral Anticoagulation in the Elderly: New Oral Anticoagulants-Innovative Solution for an Old Problem?

Direct oral anticoagulants emerge as the most innovative and promising drug toward preventing and treating cardiovascular disease, raising great interest among the scientific community. Numerous studies and meta-analysis generated much data clarifying clinicians' doubts; however, uncertainties remain regarding their use in particular groups such as patients with prosthetic valves, in valvular atrial fibrillation (defined as atrial fibrillation related to mitral rheumatic heart disease or prosthetic heart valves), among the elderly, in paraneoplastic thromboembolism, in pulmonary embolism with hemodynamic compromise, and scarcity of specific antidotes. This review article intends to condense the vast scientific production addressing new oral anticoagulants by focusing on their advantages and disadvantages when used on the elderly.

Disfunción diastólica en pacientes con hipertensión arterial grado I - II Hospital José Carrasco Arteaga, Cuenca 2006

Estudio descriptivo realizado con el objetivo de determinar la prevalencia de disfunción diastólica en pacientes con hipertensión arterial grado I-III, en edades de 30-60 años; a través de ecocardiograma doppler pulsado de flujo transvalvular mitral, hospital José Carrasco Arteaga, Cuenca 2006. Los pacientes fueron 76 seleccioados por asignación secuencial. Resultados: la edad media de los pacientes fue de 51 +- 6 años; 61,3corresponde al sexo femenino; con un índice de masa corporal de 26 kg (talla)2; el 60con hipertensión grado I y 40grado II; 72,5presentó hipertrofia ventricular izquierda; la alteración diastólica fue de 86,3(grado I 85,4y grado II 87,5), con predominio de patrón de relajación retardada (58,8). Conclusiones: el 86,3de pacientes con hipertensión arterial presentan disfución diastólica; con mínima diferencia entre hipertensión grado I y II (85,4y 87,5); concluyendo que a mayor grado de hipertensión arterial menor porcentaje de patrón normal de función diastólica, al igual que a mayor tiempo de hipertensión arterial (mayor de 10 años) mayor grado de disfunción diastólica. El patrón de disfunción diastólica predominante en hipertensión arterial grado I y II fue el de relajación retardada; incluso independientemente del peso