Protective effects of bone marrow mononuclear cell therapy on lung and heart in an elastase-induced emphysema model

We hypothesized that bone marrow-derived mononuclear cell (BMDMC) therapy protects the lung and consequently the heart in experimental elastase-induced emphysema. Twenty-four female C57BL/6 mice were intratracheally instilled with saline (C group) or porcine pancreatic elastase (E group) once a week during 4 weeks. C and E groups were randomized into subgroups receiving saline (SAL) or male BMDMCs (2 x 10(6), CELL) intravenously 3 h after the first saline or elastase instillation. Compared to E-SAL group, E-CELL mice showed, at 5 weeks: lower mean linear intercept, neutrophil infiltration, elastolysis, collagen fiber deposition in alveolar septa and pulmonary vessel wall, lung cell apoptosis, right ventricle wall thickness and area, higher endothelial growth factor and insulin-like growth factor mRNA expressions in lung tissue, and reduced platelet-derived growth factor, transforming growth factor-beta, and caspase-3 expressions. In conclusion, BMDMC therapy was effective at modulating the inflammatory and remodeling processes in the present model of elastase-induced emphysema. (c) 2012 Elsevier B.V. All rights reserved.

Morfologia e topografia do fígado e pâncreas de emas Rhea americana

As emas são aves ratitas nativas do continente sul americano, são consideradas aves primitivas do ponto de vista filogenético que constituem um grupo altamente especializado. Este estudo buscou caracterizar macro e microscopicamente o fígado e pâncreas de emas. O material foi coletado no Centro de Multiplicação de Animais Silvestres (CEMAS), na cidade de Mossoró-RN, Brasil, (Registro IBAMA n° 14.78912). Utilizaram-se 20 animais jovens com idade entre dois e seis meses independente do sexo. Em emas, o fígado se relacionava cranialmente com o ápice do coração, dorsalmente com os pulmões, esôfago e o proventrículo gástrico, caudalmente, com o ventrículo gástrico, o baço, o duodeno e parte do jejuno. Apresentava coloração vermelha escura e possuía apenas dois lobos, sendo o direito ligeiramente menor que o esquerdo. Histologicamente, era revestido por uma cápsula de tecido conjuntivo delgada e cada lóbulo hepático pôde ser identificado pela presença evidente de veias centrais, com muitos sinusoides comunicando-se com elas. O pâncreas, ventralmente, apresentava-se como uma fita fina, formado por um lobo dorsal e um lobo ventral. Longitudinalmente o pâncreas em emas localiza-se no mesentério dorsal desde o fígado até a flexura cranial do duodeno, mantendo-se preso às alças duodenais por ligamentos. Histologicamente, era composto por uma cápsula delgada de tecido conjuntivo denso, com discretos lóbulos separados por tecido conjuntivo capsular, compostos por estruturas tubuloalveolares e ductos. O fígado e pâncreas de emas apresentam padrão morfológico similar ao descrito para aves domésticas.

Survival Analysis of Patients with Heart Failure: Implications of Time-Varying Regression Effects in Modeling Mortality

Background: Several models have been designed to predict survival of patients with heart failure. These, while available and widely used for both stratifying and deciding upon different treatment options on the individual level, have several limitations. Specifically, some clinical variables that may influence prognosis may have an influence that change over time. Statistical models that include such characteristic may help in evaluating prognosis. The aim of the present study was to analyze and quantify the impact of modeling heart failure survival allowing for covariates with time-varying effects known to be independent predictors of overall mortality in this clinical setting. Methodology: Survival data from an inception cohort of five hundred patients diagnosed with heart failure functional class III and IV between 2002 and 2004 and followed-up to 2006 were analyzed by using the proportional hazards Cox model and variations of the Cox's model and also of the Aalen's additive model. Principal Findings: One-hundred and eighty eight (188) patients died during follow-up. For patients under study, age, serum sodium, hemoglobin, serum creatinine, and left ventricular ejection fraction were significantly associated with mortality. Evidence of time-varying effect was suggested for the last three. Both high hemoglobin and high LV ejection fraction were associated with a reduced risk of dying with a stronger initial effect. High creatinine, associated with an increased risk of dying, also presented an initial stronger effect. The impact of age and sodium were constant over time. Conclusions: The current study points to the importance of evaluating covariates with time-varying effects in heart failure models. The analysis performed suggests that variations of Cox and Aalen models constitute a valuable tool for identifying these variables. The implementation of covariates with time-varying effects into heart failure prognostication models may reduce bias and increase the specificity of such models.

Long-Term Follow-Up of Implantable Cardioverter-Defibrillator for Secondary Prevention in Chagas' Heart Disease

Assessing the efficacy of implantable cardioverter-defibrillators (ICD) in patients with Chagas' heart disease (ChHD) and identifying the clinical predictors of mortality and ICD shock during long-term follow-up. ChHD is associated with ventricular tachyarrhythmias and an increased risk of sudden cardiac death. Although ChHD is a common form of cardiomyopathy in Latin American ICD users, little is known about its efficacy in the treatment of this population. The study cohort included 116 consecutive patients with ChHD and an ICD implanted for secondary prevention. Of the 116 patients, 83 (72%) were men; the mean age was 54 +/- 10.7 years. Several clinical variables were tested in a multivariate Cox model for predicting long-term mortality. The average follow-up was 45 +/- 32 months. New York Heart Association class I-II developed in 83% of patients. The mean left ventricular ejection fraction was 42 +/- 16% at implantation. Of the 116 patients, 58 (50%) had appropriate shocks and 13 (11%) had inappropriate therapy. A total of 31 patients died (7.1% annual mortality rate). New York Heart Association class III (hazard ratio [HR] 3.09, 95% confidence interval 1.37 to 6.96, p = 0.0064) was a predictor of a worse prognosis. The left ventricular ejection fraction (HR 0.972, 95% confidence interval 0.94 to 0.99, p = 0.0442) and low cumulative right ventricular pacing (HR 0.23, 95% confidence interval 0.11 to 0.49, p = 0.0001) were predictors of better survival. The left ventricular diastolic diameter was an independent predictor of appropriate shock (I-ER 1.032, 95% confidence interval 1.004 to 1.060, p = 0.025). In conclusion, in a long-term follow-up, ICD efficacy for secondary sudden cardiac death prevention in patients with ChHD was marked by a favorable annual rate of all-cause mortality (7.1%); 50% of the cohort received appropriate shock therapy. New York Heart Association class III and left ventricular ejection fraction were independent predictors of worse prognosis, and low cumulative right ventricular pacing defined better survival. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1040-1045)

Higher incidence of death in multi-vessel coronary artery disease patients associated with polymorphisms in chromosome 9p21

Background: We investigated whether 9p21 polymorphisms are associated with cardiovascular events in a group of 611 patients enrolled in the Medical, Angioplasty or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease (CAD) and preserved left ventricular function. Methods: The participants of the MASS II were genotyped for 9p21 polymorphisms (rs10757274, rs2383206, rs10757278 and rs1333049). Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, death from cardiac causes and myocardial infarction using a Cox proportional hazards survival model. Results: We observed significant differences between patients within each polymorphism genotype group for baseline characteristics. The frequency of diabetes was lower in patients carrying GG genotype for rs10757274, rs2383206 and rs10757278 (29.4%, 32.8%, 32.0%) compared to patients carrying AA or AG genotypes (49.1% and 39.2%, p = 0.01; 52.4% and 40.1%, p = 0.01; 47.8% and 37.9%, p = 0.04; respectively). Significant differences in genotype frequencies between double and triple vessel disease patients were observed for the rs10757274, rs10757278 and rs1333049. Finally, there was a higher incidence of overall mortality in patients with the GG genotype for rs2383206 compared to patients with AA and AG genotypes (19.5%, 11.9%, 11.0%, respectively; p = 0.04). Moreover, the rs2383206 was still significantly associated with a 1.75-fold increased risk of overall mortality (p = 0.02) even after adjustment of a Cox multivariate model for age, previous myocardial infarction, diabetes, smoking and type of coronary anatomy. Conclusions: Our data are in accordance to previous evidence that chromosome 9p21 genetic variation may constitute a genetic modulator in the cardiovascular system in different scenarios. In patients with established CAD, we observed an association between the rs2383206 and higher incidence of overall mortality and death from cardiac causes in patients with multi-vessel CAD.

Sidestream cigarette smoke effects on cardiovascular responses in conscious rats: involvement of oxidative stress in the fourth cerebral ventricle

Background: Cigarette exposure increases brain oxidative stress. The literature showed that increased brain oxidative stress affects cardiovascular regulation. However, no previous study investigated the involvement of brain oxidative stress in animals exposed to cigarette and its relationship with cardiovascular regulation. We aimed to evaluate the effects of central catalase inhibition on baroreflex and cardiovascular responses in rats exposed to sidestream cigarette smoke (SSCS). Methods: We evaluated males Wistar rats (320-370 g), which were implanted with a stainless steel guide cannula into the fourth cerebral ventricle (4th V). Femoral artery and vein were cannulated for mean arterial pressure (MAP) and heart rate (HR) measurement and drug infusion, respectively. Rats were exposed to SSCS during three weeks, 180 minutes, 5 days/week (CO: 100-300 ppm). Baroreflex was tested with a pressor dose of phenylephrine (PHE, 8 mu g/kg, bolus) to induce bradycardic reflex and a depressor dose of sodium nitroprusside (SNP, 50 mu g/kg, bolus) to induce tachycardic reflex. Cardiovascular responses were evaluated before, 5, 15, 30 and 60 minutes after 3-amino-1,2,4-triazole (ATZ, catalase inhibitor, 0.001 g/100 mu L) injection into the 4th V. Results: Central catalase inhibition increased basal HR in the control group during the first 5 minutes. SSCS exposure increased basal HR and attenuated bradycardic peak during the first 15 minutes. Conclusion: We suggest that SSCS exposure affects cardiovascular regulation through its influence on catalase activity.

Comparative analysis between ventricular and sinoatrial node vascularization in cats

Biasi C., Borelli V., Benedicto H.G., Pereira M.R., Favaron P.O. & Bombonato P.P. 2012. [Comparative analysis between ventricular and sinoatrial node vascularization in cats.] Analise comparativa entre a vascularizacao ventricular e do no sinoatrial em gatos. Pesquisa Veterinaria Brasileira 31(1): 78-82. Setor de Anatomia dos Animais Domesticos e Silvestres, Faculdade de Medicina Veterinaria e Zootecnia, Universidade de Sao Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, Cidade Universitaria, Sao Paulo, SP 05508-000, Brazil. E-mail: caiobiasi@usp.br The possible existence of interdependence in the blood nutrition of both atrial and ventricular territories has been a subject of concern to cardiologists, mainly related to vascularization of the sinoatrial node and its dependence on just one coronary artery or both, and its relation with the predominance of these vessels in the ventricular vascularization. Therefore, this research aimed evaluated the relation of blood irrigation of the sinoatrial node in relation to the coronary artery predominance in the ventricle vascularization. In doing so, we analyzed 30 hearts of cats without pedigree, males and females, adults of several ages. They were not carrying any heart problems. The hearts were injected by the thoracic aorta with Neoprene Latex 450, stained with red pigment, and then they were dissected. It was found that when there was a prevalence of ventricular vascularization of the left type (63.34%) the sinoatrial node irrigation was predominantly in the dependency of the Ramus proximalis atrii dextri (78.9%) or with less frequency by Ramus proximalis atrii sinister (21.1%). In the ventricular vascularization of the balanced type (33.34%), the pacemaker irrigation was in dependence more often of Ramus proximalis atrii dextri (80%) or with less frequency the nutrition of the sinoatrial node occurred by Ramus proximalis atril sinister (20%). In a single-case, we observed the ventricular vascularization of the right type (3.34%), the pacemaker nutrition was in an exclusive dependence of the Ramus intermedius atril dextri. These results suggest in this species there is no relationship between both the sinoatrial node irrigation and the type of ventricular vascularization, regardless of gender.

Hollow-fiber liquid-phase microextraction and gas chromatography-mass spectrometry of barbiturates in whole blood samples

Here, we present a method for measuring barbiturates (butalbital, secobarbital, pentobarbital, and phenobarbital) in whole blood samples. To accomplish these measurements, analytes were extracted by means of hollow-fiber liquid-phase microextraction in the three-phase mode. Hollow-fiber pores were filled with decanol, and a solution of sodium hydroxide (pH 13) was introduced into the lumen of the fiber (acceptor phase). The fiber was submersed in the acidified blood sample, and the system was subjected to an ultrasonic bath. After a 5 min extraction, the acceptor phase was withdrawn from the fiber and dried under a nitrogen stream. The residue was reconstituted with ethyl acetate and trimethylanilinium hydroxide. An aliquot of 1.0 mu L of this solution was injected into the gas chromatograph/mass spectrometer, with the derivatization reaction occurring in the hot injector port (flash methylation). The method proved to be simple and rapid, and only a small amount of organic solvent (decanol) was needed for extraction. The detection limit was 0.5 mu g/mL for all the analyzed barbiturates. The calibration curves were linear over the specified range (1.0 to 10.0 mu g/mL). This method was successfully applied to postmortem samples (heart blood and femoral blood) collected from three deceased persons previously exposed to barbiturates.

Clinical Usefulness of Coronary Angiography in Patients with Left Ventricular Dysfunction

Background: Performing a coronary angiography in patients with heart failure of unknown etiology is often justified by the diagnostic assessment of ischemic heart disease. However, the clinical benefit of this strategy is not known. Objective: To evaluate the prevalence of ischemic heart disease by angiographic criteria in patients with heart failure and reduced ejection fraction of unknown etiology, as well as its impact on therapy decisions. Methods: Consecutive outpatients with heart failure and systolic dysfunction, who had an indication for coronary angiography to clarify the etiology of heart disease were assessed from 1 January 2009 to December 31, 2010. Patients diagnosed with coronary artery disease, positive serology for Chagas disease, congenital heart disease, valve disease or patients undergoing cardiac transplantation were excluded from the analysis. The sample was divided into two groups according to the indication for catheterization. Group-1: Symptomatic due to angina or heart failure. Group-2: Presence of >= 2 risk factors for coronary artery disease Results: One hundred and seven patients were included in the analysis, with 51 (47.7%) patients in Group 1 and 56 (52.3%) in Group 2. The prevalence of ischemic heart disease was 9.3% (10 patients), and all belonged to Group 1 (p = 0.0001). During follow-up, only 4 (3.7%) were referred for CABG; 3 (2.8%) patients had procedure-related complications. Conclusion: In our study, coronary angiography in patients with heart failure and systolic dysfunction of unknown etiology, although supported by current guidelines, did not show benefits when performed only due to the presence of risk factors for coronary artery disease. (Arq Bras Cardiol 2012;98(5):437-441)

Body packing by rectal insertion of cocaine packets: a case report

Background: Body packing is used for international drug transport, immediate drug concealment during a police searching or introducing drugs inside prisons. Despite the high level of specialization of dealers who have started to manufacture more complex packs, up to 5% of patients could develop intoxication due to pack rupture. Bowel obstruction is another acute complication. Case presentation: A 27-year-old black male patient was sent to the hospital by court order for clinical evaluation and toxicological examination. The patient was conscious, oriented, had good color, normal arterial pressure and heart rate, and no signs of acute intoxication. Abdominal examination revealed discrete pain upon deep palpation and a small mass in the left iliac fossa. A plain abdominal radiograph revealed several oval structures located in the rectum and sigmoid. Fasting and a 50 g dose of activated charcoal every six hours were prescribed. After three days, the patient spontaneously evacuated 28 cocaine packs. Conclusion: Adequate clinical management and prompt identification of potential complications are of fundamental importance in dealing with body packing.

Parameters and algorithms to evaluate cardiac mechanics by conductance catheter

This work is structured as follows: In Section 1 we discuss the clinical problem of heart failure. In particular, we present the phenomenon known as ventricular mechanical dyssynchrony: its impact on cardiac function, the therapy for its treatment and the methods for its quantification. Specifically, we describe the conductance catheter and its use for the measurement of dyssynchrony. At the end of the Section 1, we propose a new set of indexes to quantify the dyssynchrony that are studied and validated thereafter. In Section 2 we describe the studies carried out in this work: we report the experimental protocols, we present and discuss the results obtained. Finally, we report the overall conclusions drawn from this work and we try to envisage future works and possible clinical applications of our results. Ancillary studies that were carried out during this work mainly to investigate several aspects of cardiac resynchronization therapy (CRT) are mentioned in Appendix. -------- Ventricular mechanical dyssynchrony plays a regulating role already in normal physiology but is especially important in pathological conditions, such as hypertrophy, ischemia, infarction, or heart failure (Chapter 1,2.). Several prospective randomized controlled trials supported the clinical efficacy and safety of cardiac resynchronization therapy (CRT) in patients with moderate or severe heart failure and ventricular dyssynchrony. CRT resynchronizes ventricular contraction by simultaneous pacing of both left and right ventricle (biventricular pacing) (Chapter 1.). Currently, the conductance catheter method has been used extensively to assess global systolic and diastolic ventricular function and, more recently, the ability of this instrument to pick-up multiple segmental volume signals has been used to quantify mechanical ventricular dyssynchrony. Specifically, novel indexes based on volume signals acquired with the conductance catheter were introduced to quantify dyssynchrony (Chapter 3,4.). Present work was aimed to describe the characteristics of the conductancevolume signals, to investigate the performance of the indexes of ventricular dyssynchrony described in literature and to introduce and validate improved dyssynchrony indexes. Morevoer, using the conductance catheter method and the new indexes, the clinical problem of the ventricular pacing site optimization was addressed and the measurement protocol to adopt for hemodynamic tests on cardiac pacing was investigated. In accordance to the aims of the work, in addition to the classical time-domain parameters, a new set of indexes has been extracted, based on coherent averaging procedure and on spectral and cross-spectral analysis (Chapter 4.). Our analyses were carried out on patients with indications for electrophysiologic study or device implantation (Chapter 5.). For the first time, besides patients with heart failure, indexes of mechanical dyssynchrony based on conductance catheter were extracted and studied in a population of patients with preserved ventricular function, providing information on the normal range of such a kind of values. By performing a frequency domain analysis and by applying an optimized coherent averaging procedure (Chapter 6.a.), we were able to describe some characteristics of the conductance-volume signals (Chapter 6.b.). We unmasked the presence of considerable beat-to-beat variations in dyssynchrony that seemed more frequent in patients with ventricular dysfunction and to play a role in discriminating patients. These non-recurrent mechanical ventricular non-uniformities are probably the expression of the substantial beat-to-beat hemodynamic variations, often associated with heart failure and due to cardiopulmonary interaction and conduction disturbances. We investigated how the coherent averaging procedure may affect or refine the conductance based indexes; in addition, we proposed and tested a new set of indexes which quantify the non-periodic components of the volume signals. Using the new set of indexes we studied the acute effects of the CRT and the right ventricular pacing, in patients with heart failure and patients with preserved ventricular function. In the overall population we observed a correlation between the hemodynamic changes induced by the pacing and the indexes of dyssynchrony, and this may have practical implications for hemodynamic-guided device implantation. The optimal ventricular pacing site for patients with conventional indications for pacing remains controversial. The majority of them do not meet current clinical indications for CRT pacing. Thus, we carried out an analysis to compare the impact of several ventricular pacing sites on global and regional ventricular function and dyssynchrony (Chapter 6.c.). We observed that right ventricular pacing worsens cardiac function in patients with and without ventricular dysfunction unless the pacing site is optimized. CRT preserves left ventricular function in patients with normal ejection fraction and improves function in patients with poor ejection fraction despite no clinical indication for CRT. Moreover, the analysis of the results obtained using new indexes of regional dyssynchrony, suggests that pacing site may influence overall global ventricular function depending on its relative effects on regional function and synchrony. Another clinical problem that has been investigated in this work is the optimal right ventricular lead location for CRT (Chapter 6.d.). Similarly to the previous analysis, using novel parameters describing local synchrony and efficiency, we tested the hypothesis and we demonstrated that biventricular pacing with alternative right ventricular pacing sites produces acute improvement of ventricular systolic function and improves mechanical synchrony when compared to standard right ventricular pacing. Although no specific right ventricular location was shown to be superior during CRT, the right ventricular pacing site that produced the optimal acute hemodynamic response varied between patients. Acute hemodynamic effects of cardiac pacing are conventionally evaluated after stabilization episodes. The applied duration of stabilization periods in most cardiac pacing studies varied considerably. With an ad hoc protocol (Chapter 6.e.) and indexes of mechanical dyssynchrony derived by conductance catheter we demonstrated that the usage of stabilization periods during evaluation of cardiac pacing may mask early changes in systolic and diastolic intra-ventricular dyssynchrony. In fact, at the onset of ventricular pacing, the main dyssynchrony and ventricular performance changes occur within a 10s time span, initiated by the changes in ventricular mechanical dyssynchrony induced by aberrant conduction and followed by a partial or even complete recovery. It was already demonstrated in normal animals that ventricular mechanical dyssynchrony may act as a physiologic modulator of cardiac performance together with heart rate, contractile state, preload and afterload. The present observation, which shows the compensatory mechanism of mechanical dyssynchrony, suggests that ventricular dyssynchrony may be regarded as an intrinsic cardiac property, with baseline dyssynchrony at increased level in heart failure patients. To make available an independent system for cardiac output estimation, in order to confirm the results obtained with conductance volume method, we developed and validated a novel technique to apply the Modelflow method (a method that derives an aortic flow waveform from arterial pressure by simulation of a non-linear three-element aortic input impedance model, Wesseling et al. 1993) to the left ventricular pressure signal, instead of the arterial pressure used in the classical approach (Chapter 7.). The results confirmed that in patients without valve abnormalities, undergoing conductance catheter evaluations, the continuous monitoring of cardiac output using the intra-ventricular pressure signal is reliable. Thus, cardiac output can be monitored quantitatively and continuously with a simple and low-cost method. During this work, additional studies were carried out to investigate several areas of uncertainty of CRT. The results of these studies are briefly presented in Appendix: the long-term survival in patients treated with CRT in clinical practice, the effects of CRT in patients with mild symptoms of heart failure and in very old patients, the limited thoracotomy as a second choice alternative to transvenous implant for CRT delivery, the evolution and prognostic significance of diastolic filling pattern in CRT, the selection of candidates to CRT with echocardiographic criteria and the prediction of response to the therapy.

Electrolyte disorders in the human ventricle. A simulation study.

Ventricular cells are immersed in a bath of electrolytes and these ions are essential for a healthy heart and a regular rhythm. Maintaining physiological concentration of them is fundamental for reducing arrhythmias and risk of sudden cardiac death, especially in haemodialysis patients and in the heart diseases treatments. Models of electrically activity of the heart based on mathematical formulation are a part of the efforts to improve the understanding and prediction of heart behaviour. Modern models incorporate the extensive and ever increasing amounts of experimental data in incorporating biophysically detailed mechanisms to allow the detailed study of molecular and subcellular mechanisms of heart disease. The goal of this project was to simulate the effects of changes in potassium and calcium concentrations in the extracellular space between experimental data and and a description incorpored into two modern biophysically detailed models (Grandi et al. Model; O’Hara Rudy Model). Moreover the task was to analyze the changes in the ventricular electrical activity, in particular by studying the modifications on the simulated electrocardiographic signal. We used the cellular information obtained by the heart models in order to build a 1D tissue description. The fibre is composed by 165 cells, it is divided in four groups to differentiate the cell types that compound human ventricular tissue. The main results are the following: Grandi et al. (GBP) model is not even able to reproduce the correct action potential profile in hyperkalemia. Data from hospitalized patients indicates that the action potential duration (APD) should be shorter than physiological state but in this model we have the opposite. From the potassium point of view the results obtained by using O’Hara model (ORD) are in agreement with experimental data for the single cell action potential in hypokalemia and hyperkalemia, most of the currents follow the data from literature. In the 1D simulations we were able to reproduce ECGs signal in most the potassium concentrations we selected for this study and we collected data that can help physician in understanding what happens in ventricular cells during electrolyte disorder. However the model fails in the conduction of the stimulus under hyperkalemic conditions. The model emphasized the ECG modifications when the K+ is slightly more than physiological value. In the calcium setting using the ORD model we found an APD shortening in hypocalcaemia and an APD lengthening in hypercalcaemia, i.e. the opposite to experimental observation. This wrong behaviour is kept in one dimensional simulations bringing a longer QT interval in the ECG under higher [Ca2+]o conditions and vice versa. In conclusion it has highlighted that the actual ventricular models present in literature, even if they are useful in the original form, they need an improvement in the sensitivity of these two important electrolytes. We suggest an use of the GBP model with modifications introduced by Carro et al. who understood that the failure of this model is related to the Shannon et al. model (a rabbit model) from which the GBP model was built. The ORD model should be modified in the Ca2+ - dependent IcaL and in the influence of the Iks in the action potential for letting it him produce a correct action potential under different calcium concentrations. In the 1D tissue maybe a heterogeneity setting of intra and extracellular conductances for the different cell types should improve a reproduction of the ECG signal.

Utilzzo dei parametri ecocardiografici tradizionali ed a Doppler tissutale nella valutazione della disfunzione atrio-ventricolare in cani affetti da malattia mitralica cronica

In questo lavoro ci siamo posti come obiettivo lo studio della disfunzione atrio-ventricolare mediante tecniche ecocardiografiche avanzate (come il Tissue Doppler Imaging - TDI) in cani affetti da malattia mitralica cronica (MVD). Una prima parte è volta alla valutazione della funzionalità diastolica del ventricolo destro. Ci siamo proposti di analizzare la funzione del ventricolo destro in cani affetti da malattia del cuore sinistro per comprendere se quest’ultima possa condizionare direttamente la performance del settore cardiaco controlaterale. I risultati più importanti che abbiamo riscontrato sono: l’assenza di differenze significative nella disfunzione sisto-diastolica del ventricolo destro in cani con MVD a diverso stadio; la diretta correlazione tra le variabili TDI di funzionalità del ventricolo destro con il grado di disfunzione del ventricolo sinistro, come indicatori di interdipendenza ventricolare; ed infine il riscontro di una maggior tendenza ad alterazioni diastoliche del ventricolo sinistro in cani con ipertensione polmonare. A quest’ultimo proposito, per quanto riguarda le variabili TDI, il rapporto E/e’ dell’anulus mitralico laterale e settale è risultato avere una differenza significativa tra i cani con ipertensione polmonare e quelli privi di ipertensione polmonare (P<0,01). Nel secondo studio abbiamo applicato il TDI per l’analisi della funzione sisto-diastolica dell’atrio sinistro. Il lavoro è stato articolato in una parte di validazione della metodica su cani normali ed una su animali affetti da MDV. I risultati ottenuti mostrano che la valutazione ecocardiografica delle proprietà di deformazione dell’atrio sinistro basata sul TDI è attuabile e riproducibile nel cane. Abbiamo fornito dei valori di normalità per questa specie e confrontato questi dati con quelli ricavati in cani portatori di MVD. Le differenza tra le varie classi di malattia, nei diversi gradi di dilatazione atriale, sono risultate limitate, ma abbiamo individuato delle correlazioni tra i parametri TDI ed alcune variabili di funzionalità atriale.

Valutazione delle funzioni cardio-respiratorie ed epatiche in pazienti con cuore univentricolare trattati con intervento di connessione cavo-polmonare totale

L'intervento di connessione cavo-polmonare totale (TCPC) nei pazienti portatori di cuore univentricolare, a causa della particolare condizione emodinamica, determina un risentimento a carico di numerosi parenchimi. Scopo della ricerca è di valutare l'entità di questo danno ad un follow-up medio-lungo. Sono stati arruolati 115 pazienti, sottoposti ad intervento presso i centri di Cardiochirurgia Pediatrica di Bologna (52 pz) e Torino (63 pz). Il follow-up medio è stato di 125±2 mesi. I pazienti sono stati sottoposti ad indagine emodinamica (88 pz), test cardiopolmonare (75 pz) e Fibroscan ed ecografia epatica (47 pz). La pressione polmonare media è stata di 11.5±2.6mmHg, ed in 12 pazienti i valori di pressione polmonare erano superiori a 15mmHg. La pressione atriale media era di 6.7±2.3mmHg ed il calcolo delle resistenze vascolari polmonari indicizzate (RVP) era in media di 2±0.99 UW/m2. In 29 pazienti le RVP erano superiori a 2 UW/m2. La VO2 max in media era pari a 28±31 ml/Kg/min, 58±15 % del valore teorico. La frequenza cardiaca massima all'apice dello sforzo era di 151±22 bpm, pari al 74±17% del valore teorico. Il Fibroscan ha fornito un valore medio di 17.01 kPa (8-34.3kPa). Cinque pazienti erano in classe F2, 9 pazienti in classe F3 e 33 pazienti risultavano in classe F4. Nei pazienti con follow-up maggiore di 10 anni il valore di stiffness epatica (19.6±5.2kPa) è risultato significativamente maggiore a quello dei pazienti con follow-up minore di 10 anni (15.1±5.8kPa, p<0.01). La frequenza cardiaca massima raggiunta durante lo sforzo del test cardiopolmonare è risultata significativamente correlata alla morfologia del ventricolo unico, risultando del 67.8±14.4% del valore teorico nei pazienti portatori di ventricolo destro contro il 79.6±8.7% dei portatori di ventricolo sinistro (p=0.006). L'intervento di TCPC determina un risentimento a carico di numerosi parenchimi proporzionale alla lunghezza del follow-up, e necessita pertanto un costante monitoraggio clinico-strumentale multidisciplinare.

The medical management after surgery for advanced heart failure

The aim of the Research of this Ph D Project is to improve the medical management after surgery for advanced heart failure, both after left ventricular assist devices (LVAD) implantation, and after heart transplantation in the long-term. Regarding heart transplantation (HTx), the Research Project is focused on diagnostics, classification, prevention and treatment of cardiac allograft vasculopathy (CAV), and on treatment of post-HTx cancers; the results are presented in the first part of this Thesis. In particular, the main aspect investigated are the prognostic role of information derived from coronary angiography, coronary tomography and intravascular ultrasound, and the different sensitivity of these techniques in predicting outcomes and in diagnosing CAV. Moreover, the role of mTOR inhibitors on CAV prevention or treatment is investigated, both alone and in combination with different anti-CMV prevention strategies, as well as the impact of mTOR inhibitors on clinical outcomes in the long term. Regarding LVAD, the main focus is on the role of transthoracic echocardiography in the management of patients with a continuous-flow, centrifugal, intrapericardial pump (HVAD, Heartware); this section is reported in the second part of this Thesis. The main aspects investigated are the use of echocardiography in patients with HVAD device and its interaction with the information derived from pump curves' analysis in predicting aortic valve opening status, a surrogate of the condition of support provided by the LVAD.