Gender differences in right ventricular function in patients with non-ischaemic cardiomyopathy

The aim of this study is to evaluate sex-related differences in right ventricular (RV) function, assessed with cardiac magnetic resonance imaging, in patients with stable non-ischaemic dilated cardiomyopathy. Mean age was 60.9 ± 12.2 years. Men presented higher levels of haemoglobin and white blood cell counts than women, and performed better in cardiopulmonary stress testing. A total of 24 patients (12 women) presented severe left ventricular (LV) systolic dysfunction, 32 (13 female) moderate and 15 (8 women) mild LV systolic dysfunction. In the group with severe LV systolic dysfunction, average right ventricular ejection fraction (RVEF) was normal in women (52 ± 4 %), whereas it was reduced in men (39 ± 3 %) p = 0.035. Only one woman (8 %) had severe RV systolic dysfunction (RVEF < 35 %) compared with 6 men (50 %) p < 0.001. In patients with moderate and mild LV dysfunction , the mean RVEF was normal in both men and women. In the 14 healthy volunteers, the lowest value of RVEF was 48 % and mean RVEF was normal in women (56 ± 2 %) and in men (51 ±  1 %), p = 0.08. In patients with dilated cardiomyopathy, RV systolic dysfunction is found mainly in male patients with severe LV systolic dysfunction.

Passive control of a bi-ventricular assist device : an experimental and numerical investigation

For the last two decades heart disease has been the highest single cause of death for the human population. With an alarming number of patients requiring heart transplant, and donations not able to satisfy the demand, treatment looks to mechanical alternatives. Rotary Ventricular Assist Devices, VADs, are miniature pumps which can be implanted alongside the heart to assist its pumping function. These constant flow devices are smaller, more efficient and promise a longer operational life than more traditional pulsatile VADs. The development of rotary VADs has focused on single pumps assisting the left ventricle only to supply blood for the body. In many patients however, failure of both ventricles demands that an additional pulsatile device be used to support the failing right ventricle. This condition renders them hospital bound while they wait for an unlikely heart donation. Reported attempts to use two rotary pumps to support both ventricles concurrently have warned of inherent haemodynamic instability. Poor balancing of the pumps’ flow rates quickly leads to vascular congestion increasing the risk of oedema and ventricular ‘suckdown’ occluding the inlet to the pump. This thesis introduces a novel Bi-Ventricular Assist Device (BiVAD) configuration where the pump outputs are passively balanced by vascular pressure. The BiVAD consists of two rotary pumps straddling the mechanical passive controller. Fluctuations in vascular pressure induce small deflections within both pumps adjusting their outputs allowing them to maintain arterial pressure. To optimise the passive controller’s interaction with the circulation, the controller’s dynamic response is optimised with a spring, mass, damper arrangement. This two part study presents a comprehensive assessment of the prototype’s ‘viability’ as a support device. Its ‘viability’ was considered based on its sensitivity to pathogenic haemodynamics and the ability of the passive response to maintain healthy circulation. The first part of the study is an experimental investigation where a prototype device was designed and built, and then tested in a pulsatile mock circulation loop. The BiVAD was subjected to a range of haemodynamic imbalances as well as a dynamic analysis to assess the functionality of the mechanical damper. The second part introduces the development of a numerical program to simulate human circulation supported by the passively controlled BiVAD. Both investigations showed that the prototype was able to mimic the native baroreceptor response. Simulating hypertension, poor flow balancing and subsequent ventricular failure during BiVAD support allowed the passive controller’s response to be assessed. Triggered by the resulting pressure imbalance, the controller responded by passively adjusting the VAD outputs in order to maintain healthy arterial pressures. This baroreceptor-like response demonstrated the inherent stability of the auto regulating BiVAD prototype. Simulating pulmonary hypertension in the more observable numerical model, however, revealed a serious issue with the passive response. The subsequent decrease in venous return into the left heart went unnoticed by the passive controller. Meanwhile the coupled nature of the passive response not only decreased RVAD output to reduce pulmonary arterial pressure, but it also increased LVAD output. Consequently, the LVAD increased fluid evacuation from the left ventricle, LV, and so actually accelerated the onset of LV collapse. It was concluded that despite the inherently stable baroreceptor-like response of the passive controller, its lack of sensitivity to venous return made it unviable in its present configuration. The study revealed a number of other important findings. Perhaps the most significant was that the reduced pulse experienced during constant flow support unbalanced the ratio of effective resistances of both vascular circuits. Even during steady rotary support therefore, the resulting ventricle volume imbalance increased the likelihood of suckdown. Additionally, mechanical damping of the passive controller’s response successfully filtered out pressure fluctuations from residual ventricular function. Finally, the importance of recognising inertial contributions to blood flow in the atria and ventricles in a numerical simulation were highlighted. This thesis documents the first attempt to create a fully auto regulated rotary cardiac assist device. Initial results encourage development of an inlet configuration sensitive to low flow such as collapsible inlet cannulae. Combining this with the existing baroreceptor-like response of the passive controller will render a highly stable passively controlled BiVAD configuration. The prototype controller’s passive interaction with the vasculature is a significant step towards a highly stable new generation of artificial heart.

In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function.

BACKGROUND: The clinical syndrome of heart failure (HF) is characterized by an impaired cardiac beta-adrenergic receptor (betaAR) system, which is critical in the regulation of myocardial function. Expression of the betaAR kinase (betaARK1), which phosphorylates and uncouples betaARs, is elevated in human HF; this likely contributes to the abnormal betaAR responsiveness that occurs with beta-agonist administration. We previously showed that transgenic mice with increased myocardial betaARK1 expression had impaired cardiac function in vivo and that inhibiting endogenous betaARK1 activity in the heart led to enhanced myocardial function. METHODS AND RESULTS: We created hybrid transgenic mice with cardiac-specific concomitant overexpression of both betaARK1 and an inhibitor of betaARK1 activity to study the feasibility and functional consequences of the inhibition of elevated betaARK1 activity similar to that present in human HF. Transgenic mice with myocardial overexpression of betaARK1 (3 to 5-fold) have a blunted in vivo contractile response to isoproterenol when compared with non-transgenic control mice. In the hybrid transgenic mice, although myocardial betaARK1 levels remained elevated due to transgene expression, in vitro betaARK1 activity returned to control levels and the percentage of betaARs in the high-affinity state increased to normal wild-type levels. Furthermore, the in vivo left ventricular contractile response to betaAR stimulation was restored to normal in the hybrid double-transgenic mice. CONCLUSIONS: Novel hybrid transgenic mice can be created with concomitant cardiac-specific overexpression of 2 independent transgenes with opposing actions. Elevated myocardial betaARK1 in transgenic mouse hearts (to levels seen in human HF) can be inhibited in vivo by a peptide that can prevent agonist-stimulated desensitization of cardiac betaARs. This may represent a novel strategy to improve myocardial function in the setting of compromised heart function.

Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-adrenergic receptor in the heart : prospects for molecular ventricular assistance.

BACKGROUND: Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of beta(2)-adrenergic receptors (beta(2)ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human beta(2)AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. METHODS AND RESULTS: Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-betaGal) or the beta(2)AR (Adeno-beta(2)AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-beta(2)AR resulted in approximately 10-fold overexpression in a chamber-specific manner. Delivery of Adeno-betaGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of beta(2)ARs in the LV improved global LV contractility, as measured by dP/dt(max), at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. CONCLUSIONS: Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the beta(2)AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.

Ebstein's anomaly: one and a half ventricular repair.

Patients with Ebstein's anomaly can present after childhood or adolescence with cyanosis, arrhythmias, severe right ventricular dysfunction and frequently with left ventricular dysfunction secondary to the prolonged cyanosis and to the right ventricular interference. At this point conventional repair is accompanied by elevated mortality and morbidity and poor functional results. We report our experience with three patients (8, 16 and 35 years of age) with Ebstein's anomaly, very dilated right atrium, severe tricuspid valve regurgitation (4/4), bi-directional shunt through an atrial septal defect and reduced left ventricular function (mean ejection fraction = 58%, mean shortening fraction = 25%). All underwent one and a half ventricular repair consisting of closure of the atrial septal defect, tricuspid repair with reduction of the atrialised portion of the right ventricle and end-to-side anastomosis of the superior vena cava to the right pulmonary artery. All patients survived, with a mean follow-up of 33 months. In all there was complete regression of the cyanosis and of the signs of heart failure. Postoperative echocardiography showed reduced degree of tricuspid regurgitation (2/4) and improvement of the left ventricular function (mean ejection fraction = 77%, mean shortening fraction = 40%). In patients with Ebstein's anomaly referred late for surgery with severely compromised right ventricular function or even with reduced biventricular function, the presence of a relatively hypoplastic and/or malfunctioning right ventricular chamber inadequate to sustain the entire systemic venous return but capable of managing part of the systemic venous return, permits a one and a half ventricular repair with good functional results.

Morbimortalidad, función ventricular e incidencia del rechazo celular en el trasplante cardíaco en la Clínica Abood Shaio

INTRODUCCION: El trasplante cardiaco es una terapia efectiva para los pacientes con falla cardiaca terminal . Al momento no hay registros Colombianos actualizados y publicados de la morbimortalidad del trasplante cardiaco en relación a los episodios de rechazo celular. MATERIALES Y METODOS: Estudio descriptivo retrospectivo de mayores de 18 años trasplantados en la Clínica Shaio. Se realizaron cálculos de frecuencia, promedios y curvas de Kaplan Meier. RESULTADOS: La edad promedio fue 46,7 años +/- 13.La indicaciones fueron miocardiopatía dilatada 45%, coronaria 30%, miocarditis 9%, Chagas 9%, valvular 7%. El rechazo celular en los tres primeros años: 57%, 54% y 41% que se reduce 25% entre los tres y cinco años. Las causas de muerte fueron falla del trasplante 46%, infecciones y falla cardiaca 23%, rechazo 8%.El primer año la mortalidad fue 65%, principalmente falla del injerto. La mortalidad a 30 días 29,5%, y supervivencia del 90% al año, 64% a 5 años, 48% a 10 años y 15% a 13 años. La supervivencia media fue 8 años. La vasculopatía fue 33%. La función ventricular 53,5% +/- 12,6 el primer año; 58,4 +/- 5,4% al tercer año; 51,7 +/- 11,9 % al quinto año 46% +/- 15,8 al decimo año. DISCUSION: Se observo mayor frecuencia de rechazo celular, ocasionando mas falla cardiaca y muerte.

Evaluación de la mecánica ventricular izquierda mediante speckle tracking en pacientes sanos en la Clínica Shaio

Introducción: La ecocardiografía es actualmente la técnica de imagen diagnóstica más utilizada para la evaluación de la anatomía y la función cardiovascular. En la actualidad se está utilizando la ecocardiografía por speckle tracking la cual permite una evaluación mas objetiva y confiable de la función ventricular, sin embargo se requieren valores de referencia que hagan que los valores obtenidos sean válidos y útiles para determinar en forma mas oportuna conductas previas al deterioro de su función. Objetivo general: Determinar los valores de referencia para mecánica ventricular izquierda mediante ecocardiografía bidimensional por speckle tracking con equipo Toshiba Artida con transductor multifrecuencia de 3 megahertzios en pacientes sin patología cardiaca conocida en la Fundación Clínica Shaio en el año 2014. Metodología: Análisis de una cohorte prospectiva de todos los pacientes que ingresaron a la Fundación Clínica Shaio para evaluación ecocardiográfica sin patología cardiaca conocida entre los meses Agosto y Diciembre del 2014. Resultados: Se presenta este estudio de la evaluación de la mecánica ventricular izquierda en adultos sanos, los resultados son similares a los obtenidos en estudios de referencia, sin embargo se consideran de gran importancia ya que de acuerdo a la guía actual de evaluación de la mecánica ventricular por strain rate es importante que cada equipo se encuentre estandarizado con el fin de tener resultados válidos de acuerdo a las diferentes patologías en las que se puede aplicar y a nuestra población.

Predictores de cambio en la función ventricular izquierda posterior a implante valvular aórtico transcateter comparado con reemplazo valvular aórtico quirúrgico en el hospital universitario fundación Cardioinfantil instituto de cardiología – Bogotá

Objetivos: Identificar predictores de recuperación de la función ventricular izquierda y comparar los hallazgos ecocardiográficos en pacientes con estenosis aórtica crítica sometidos a reemplazo quirúrgico de la válvula aórtica (RVA) o implantación de válvula aórtica transcatéter (TAVI). Métodos: Cuarenta y cuatro pacientes tratados con RVA se compararon con 34 pacientes con TAVI, los datos ecocardiográficos fueron retrospectivamente obtenidos antes de la intervención y previo al alta. Resultados: Se analizaron retrospectivamente pacientes tratados en la FCI - IC desde 2009 - 2015 (n = 78 pacientes, con una media de edad 70,29 ± 11,63, EuroSCORE logístico 3,75 (3-8,55) en RVA y 20,4 (15 , 47-23,32) en TAVI. Ambos grupos mostraron una disminución en los gradientes de la válvula aórtica, más en pacientes de TAVI, con un gradiente transaórtico pico (24,5 vs 18,5, p = 0,001) y medio (14 vs 10, p = 0,002) En comparación con RVA, TAVI presentó un mayor número de pacientes con insuficiencia aórtica paravalvular (47,1% frente a 2,3% p = 0.000). En total, el 61,5% presentó mejoría precoz de la función ventricular, el predictor en severo compromiso de la función del ventrículo izquierdo fue un alto índice de masa ventricular izquierda. Conclusiones: La implantación transcatéter de válvula aórtica es una alternativa al reemplazo quirúrgico de la válvula aórtica en pacientes con estenosis aórtica y alto riesgo quirúrgico. La recuperación postoperatoria precoz de la función ventricular izquierda en pacientes con severo compromiso de la función ventricular estuvo asociada a alto índice de masa ventricular izquierda.

Systemic delivery of adult stem cells improves cardiac function in spontaneously hypertensive rats

Heart regeneration after myocardial infarction (MI) can occur after cell therapy, but the mechanisms, cell types and delivery methods responsible for this improvement are still under investigation. In the present study, we evaluated the impact of systemic delivery of bone marrow cells (BMC) and cultivated mesenchymal stem cells (MSC) on cardiac morphology, function and mortality in spontaneously hypertensive rats (SHR) submitted to coronary occlusion. Female syngeneic adult SHR, submitted or not (control group; C) to MI, were treated with intravenous injection of MSC (MI + MSC) or BMC (MI + BM) from male rats and evaluated after 1, 15 and 30 days by echocardiography. Systolic blood pressure (SBP), functional capacity, histology, mortality rate and polymerase chain reaction for the Y chromosome were also analysed. Myocardial infarction induced a decrease in SBP and BMC, but not MSC, prevented this decrease. An improvement in functional capacity and ejection fraction (38 +/- 4, 39 +/- 3 and 58 +/- 2% for MI, MI + MSC and MI + BM, respectively; P < 0.05), as well as a reduction of the left ventricle infarcted area, were observed in rats from the MI + BM group compared with the other three groups. Treated animals had a significantly reduced lesion tissue score. The mortality rate in the C, MI + BM, MI + MSC and MI groups was 0, 0, 16.7 and 44.4%, respectively (P < 0.05 for the MI + MSC and MI groups compared with the C and MI + BM groups). The results of the present study suggest that systemic administration of BMC can improve left ventricular function, functional capacity and, consequently, reduce mortality in an animal model of MI associated with hypertension. We speculate that the cells transiently home to the myocardium, releasing paracrine factors that recruit host cells to repair the lesion.

Endurance training modulates lymphocyte function in rats with post-MI CHF

Purpose: Exercise training restores innate immune system cell function in post-myocardial infarction (post-MI) rats. However, studies of the involvement of lymphocyte (Ly) in the setting of the congestive heart failure (CHF) are few. To address this issue, we investigated the function of Ly obtained from cervical lymph nodes from post-MI CHF rats submitted to treadmill running training. Methods: Twenty-five male Wistar rats were randomly assigned to the following groups: rats submitted to ligation of the left coronary artery, which were sedentary (MI-S, N= 7, only limited activity) or trained (MI-T, N= 6, on a treadmill (0% grade at 13-20 m.m(-1)) for 60 min.d(-1), 5 d.wk(-1), for 8-10 wk); or sham-operated rats, which were sedentary (sham-S, N = 6) or trained (sham-T, N = 6). The incorporation of [2-C-14]-thymidine by Ly cultivated in the presence of concanavalin A (Con A) and lipopolysaccharide (LPS), cytokine production by Ly cultivated in the presence of phytohemagglutinin (PHA), and plasma concentration of glutamine were assessed in all groups, 48 h after the last exercise session. Results: Proliferative capacity was increased, following incubation with Con-A in the MI groups, when compared with the sham counterparts. When incubated in the presence of PHA, MI-S produced more IL-4 (96%) than sham-S (P < 0.001). The training protocol induced a 2.2-fold increase in the production of interleukin-2 (P < 0.001) of the cells obtained from the cervical lymph nodes of MI-T, compared with MI-S. Conclusion: The moderate endurance training protocol caused an increase in IL-2 production, and a trend toward the reversion of the Th-1/Th-2 imbalance associated with IL-4 production increased in the post-MI CHF animal model.

Associação de variáveis histopatológicas de biópsias endomiocárdicas pré e pós cirúrgicas com os resultados clínicos de pacientes com disfunção ventricular esquerda grave submetidos à revascularização do miocárdio

Introdução: A cirurgia de revascularização do miocárdio em pacientes com disfunção ventricular esquerda grave, criteriosamente selecionados, pode levar a um incremento na fração de ejeção e/ou melhora da classe functional da New York Heart Association (NYHA) de insuficiência cardíaca. Neste estudo, buscamos variáveis histopatológicas que pudessem estar associadas com a melhora da fração de ejeção ventricular esquerda e/ou melhora na classe funcional de insuficiência cardíaca seis meses após a cirurgia. Métodos: Vinte e quatro pacientes com indicação de cirurgia de revascularização do miocárdio, fração de ejeção ventricular esquerda < 35%, classe funcional de insuficiência cardíaca variando de NYHA II a IV e idade média de 59±9 anos, foram selecionados. Foram realizadas biópsias endomiocárdicas no transoperatório e repetidas seis meses depois através de punção venosa. Extensão de fibrose (% da área do miocárdio do espécime avaliado), miocitólise (número de células encontradas com miocitólise por campo) e hipertrofia da fibra miocárdica (medida através do menor diâmetro celular) foram quantificados utilizando um sistema analizador de imagem (Leica - Image Analysis System). As medidas de fração de ejeção, por ventriculografia radioisotópica, e avaliação da classe funcional de insuficiência cardíaca (NYHA), também foram repetidas após seis meses. Resultados: Dos 24 pacientes inicialmente selecionados, sete foram a óbito antes dos seis meses e um recusou-se a repetir a segunda biópsia. Houve uma melhora significativa na classe funcional NYHA de insuficiência cardíaca nos sobreviventes seis meses após a cirurgia (2,8±0,7 vs. 1,7±0,6; p<0,001), enquanto que a fração de ejeção ventricular esquerda não se alterou (25±6% vs. 26±10%; p = NS). O grau de hipertrofia da fibra muscular permaneceu estável entre o pré e o pós operatório (21 ± 4 vs.22 ± 4μm), porém a extensão de fibrose (8±8 vs. 21±15% de área) e a quantidade de células apresentando miocitólise (9±11 vs. 21±15%/células) aumentaram. significativamente. Uma composição de escore histológico, combinando as três variáveis histopatológicas, indicando um menor grau de remodelamento no pré operatório, identificou um subgrupo de pacientes que apresentaram um incremento na fração de ejeção ventricular esquerda após a cirurgia de revascularização do miocárdio. Conclusão: Em pacientes portadores de cardiopatia isquêmica e grave disfunção ventricular esquerda, a cirurgia de revascularização do miocárdio foi associada com um incremento na função ventricular em um subgrupo de pacientes que apresentavam, no pré operatório, um menor grau de remodelamento ventricular adverso, estimado pela composição de um escore histológico. Apesar da melhora na classe funcional de insuficiência cardíaca na maioria dos pacientes, e incremento na fração de ejeção ventricular esquerda em um subgrupo, alterações histológicas favoráveis, indicativos de reversão do remodelamento ventricular esquerdo, não devem ser esperados após a revascularização, ao menos num período de seis meses após a cirurgia.

Tobacco smoke-induced left ventricular remodelling is not associated with metalloproteinase-2 or -9 activation

Aim: To investigate the role of MMP-2 and MMP-9 in cardiac remodelling induced by tobacco smoke exposure in rats.Methods: Rats were allocated into two groups: C (n = 9): control animals; ETS (n = 9): exposed to tobacco smoke. After 4months, the animals underwent echocardiography, morphometric study and determination of MMP-2 and MMP-9 activity.Results: ETS rats had larger diastolic (C= 15.6 +/- 1.2 mm/kg, ETS = 18.0 +/- 0.9 mm/kg; p < 0.001) and systolic (C= 7.3 +/- 1.2 mm/kg, ETS = 9.2 0.9 mm/kg; p = 0.001) ventricular diameters adjusted for body weight. Fractional shortening (C= 53 +/- 4.8%, ETS = 48 +/- 3.3%; p = 0.031) and ejection fraction (C= 0. 89 +/- 0.03 5 ETS = 0. 86 +/- 0.02; p = 0.03 0) were smaller in the ETS group. Myocyte cross-sectional area (C= 245 8 mu m(2), ETS=253 8 mu m(2); p = 0.028) was higher in ETS rats. There were no differences in MNtP-2 (C=50 +/- 14%; ETS 43 +/- 11%, p 0.22 +/- 8) or MMP-9 (C=0.36 +/- 0.3%; ETS=0.62 +/- 0.3%, p=0.630) activity between the groups.Conclusion: MMP-2 and MMP-9 did not participate in the remodelling process induced by tobacco smoke exposure. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.