The world health organization has identified cardiovascular disease as the leading cause of non-accidental deaths in the world. The heart is identified as diseased when it is not operating at peak efficiency. Early diagnosis of heart disease can impact treatment and improve a patient's outcome. An early sign of a diseased heart is a reduction in its pumping ability, which can be measured by performing functional evaluations. These are typically focused on the ability of the ventricles to pump blood to the lungs (right ventricle) or to the rest of the body (left ventricle). Non-invasive imaging modalities such as cardiac magnetic resonance have allowed the use of quantitative methods for ventricular functional evaluation. The evaluation still requires the tracing of the ventricles in the end-diastolic and end-systolic phases. Even though manual tracing is still considered the gold standard, it is prone to intra- and inter-observer variability and is time consuming. Therefore, substantial research work has been focused on the development of semi- and fully automated ventricle segmentation algorithms. In 2009 a medical imaging conference issued a challenge for short-axis left ventricle segmentation. A semi-automated technique using polar dynamic programming generated results that were within human variability. This is because a path in a polar coordinate system yields a circular object in the Cartesian grid and the left ventricle can be approximated as a circular object. In 2012 there was a right ventricle segmentation challenge, but no polar dynamic programming algorithms were proposed. One reason may be that polar dynamic programming can only segment circular shapes. To use polar dynamic programming for the segmentation of the right ventricle we first expanded the capability of the technique to segment non-circular shapes. We apply this new polar dynamic programming in a framework that uses user-selected landmarks to segment the right ventricle in the four chamber view. We also explore the use of four chamber right ventricular segmentation to segment short-axis views of the right ventricle.

Right ventricular dysfunction is the most frequent cause of death in patients with pulmonary arterial hypertension. Although abnormal energy substrate use has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in failing right ventricular tissue remain incomplete. In the present dissertation we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy. Two different rat models of RV hypertrophy were studied. The model of right ventricular failure (SU5416/hypoxia) exhibited a significantly decreased gene expression of peroxisome proliferator-activated receptor- coactivator-1α, peroxisome proliferator- activated receptor-α and estrogen-related receptor-α. The expression of multiple peroxisome proliferator-activated receptor- coactivator-1α target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor- coactivator-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of transcription factor A, mitochondrial, and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that, in right ventricular failure tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from right ventricular failure tissue had a significantly reduced ADP- stimulated (state 3) rate for complex I. Conversely, functional right ventricular hypertrophy in the pulmonary artery banding model showed normal expression of peroxisome proliferator-activated receptor- coactivator-1α, whereas the expression of fatty acid oxidation genes was either preserved or unregulated. Moreover, pulmonary artery banding-right ventricular tissue exhibited preserved transcription factor A mitochondrial expression and mitochondrial respiration despite elevated right ventricular pressure-overload. We conclude that right ventricular dysfunction, but not functional right ventricular hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.

Introduction. Computational modelling has been used widely in biological and clinical applications, but relatively less in surgical design and optimization. Magnetic resonance image (MRI)-based right ventricle (RV) models were introduced for patients with repaired Tetralogy of Fallot (rTOF) to assess ventricle cardiac function, and to identify morphological and mechanical parameters which can be used to predict and optimize post-surgery cardiac outcome. Tetralogy of Fallot is a common congenital heart defect which includes a ventricular septal defect and severe right ventricular outflow obstruction, account for the majority of cases with late onset RV failure. The current surgical approach for the patients with repaired ToF including pulmonary valve replacement/insertion (PVR) has yielded mixed results. It is of great interest to identify parameters which may be used to predict surgical cardiac function outcome after PVR. Data, Model, and Methods. Cardiac Magnetic Resonance (CMR) data from 20 healthy volunteers (11 males, mean year : 22.8) and 56 TOF patients (37 males, mean year : 25.3) were provided by Children's Hospital - Boston, Harvard Medical School from our NIH-funded project (R01 HL089269). RV wall thickness (WT), circumferential and longitudinal curvature (C-cur and L-cur), surface area (SA) and surface to volume ratio (SVR) were obtained based on CMR data for morphological analysis. 6 healthy volunteers and 16 TOF patients were chosen to construct 3D computational models for mechanical analysis. The 3D CMR-based RV/LV/Patch combination models included a) isotropic and anisotropic material properties, b) myocardial fiber orientation, c) active contraction with two zero-load geometries, and d) fluid-structure interactions. The models were used to obtain the assessment for RV mechanical conditions, which might be helpful for PVR surgical outcome prediction. All the computational models were built and solved in a commercial finite element software ADINA. Statistical methods including Linear Mixed- effort Method and Logistical regression were used in the morphological and mechanical analysis to find out potential indicators for predicting PVR outcome from the morphological and mechanical parameters. Results. In morphological analysis, statistically significant differences were found in RV SA and SVR between better-outcome patient group (BPG) and worse-outcome patient group (WPG). At begin of ejection, mean RV SA of BPG was 13.6% lower than that from WPG (241.1 cm2 v.s. 279.0 cm2, p =0.0161). Mean RV SVR of BPG was 13.1% lower than that from WPG (1.26 cm2/ml v.s. 1.45 cm2/ml, p =0.0271). Similar results were also found in RV SA and SVR at begin of filling. Furthermore, RV EF change from pre- to post-PVR were found negatively correlated with RV SA and SVR. In mechanical analysis, 22 structure-only models with one zero-load geometry (1G) were constructed to obtain stress/strain distributions. Stress-P1 from BPG was found to be closer to that from HG, compared to Stress- P1 of WPG. At the beginning of ejection, mean Stress-P1 of BPG was only 6.8% higher than that from healthy group (p =0.6889), while average Stress-P1 of WPG was 84.1% higher than that of healthy group (p =0.0418). Similar results were also found at begin of filling. The results suggested that comparing patients' RV stress values with healthy RV stress values may help identify patients with possible better outcome. The models with two zero-load geometries (2G models) and FSI models were also constructed. Their numerical results indicated that 2G models can provide end-ejection and end-filling results which were not available in 1G models, and FSI models can provide flow velocity, pressure and shear stress information which lacked in structure-only models (1G and 2G models). Conclusion. In vivo image-based 3D patient- specific computational models could lead to considerable potential gain not only in surgical design and outcome prediction, but also in understanding the mechanisms of RV failure for patients with repaired TOF.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

The population of adolescent and adults with congenital heart disease (CHD) has grown rapidly. Right ventricular (RV) dysfunction remains an important issue of concern in the long-term follow up of these patients. While circulating biomarkers have shown promise in the assessment and monitoring of adult patients with left heart diseases, little is known of the role of biomarkers in reflecting RV performance in CHD patients. Emerging circulating biomarkers that reflect underlying pathophysiologic processes have gained increasing attention. These include inflammatory cytokines namely tumour necrosis factor (TNF)-α, a biomarker of apoptosis annexin A5 (AnxA5), carboxy-terminal propeptide of type I procollagen (PICP) and amino-terminal propeptide of type III procollagen (PIIINP) that reflects collagen synthesis and turnover, low circulating levels of cardiac troponin T as detected by highly sensitive assay (hs-cTnT) that may reflect subclinical myocardial injury, and microRNAs found to be involved in cardiac remodeling. The studies in this thesis aimed to test the hypothesis that circulating biomarkers may be altered in patients with volume-overloaded right ventricles after repair of tetralogy (TOF) and pressure-overloaded right ventricles after atrial switch operation for complete transposition of the great arteries (TGA), and are related to indices of RV function. In patients after TOF repair, increased circulating PICP and PIIINP levels were associated with worse subpulmonary RV and left ventricular (LV) function. In particular, these propeptides correlated positively with LV mechanical dyssynchrony, implicating a possible role of increased collagen synthesis in its pathogenesis. Increased plasma levels of hs-cTnT were further found in 30% of female, but not male patients. Female patients with elevated hs-cTnT levels compared to those without had greater RV volumes and LV mechanical dyssynchrony. Independent correlates of hs-cTnT in patients as determined from multivariate analysis were sex and RV ejection fraction. MicroRNA profiling following validation confirmed alteration of circulating levels of miR-99b and miR-766 in repaired TOF patients, a pattern distinct from that reported for left heart diseases. The miRNA expression was, however, not related to the cardiac functional indices. Patients after atrial repair for TGA had significantly higher circulating AnxA5 and TNF-αlevels, but similar PICP, PIIINP levels, compared with controls. Elevated AnxA5 level was associated with impaired systemic RV myocardial deformation, increased subpulmonary ventricular eccentricity, and increased TNF-αlevel. Elevation of hs-cTnT is found in 39% of the patients. The positive correlation between hs-cTnT level and systemic RV volume may suggest a role of hs-cTnT in reflecting RV remodeling. Circulating microRNA expression profiling and further validation identified 11 upregulated microRNAs (miR-16, miR-106a, miR-144*, miR-18a, miR-25, miR-451, miR-486-3p, miR-486-5p, miR-505*, let-7e and miR-93). Among them, miR-18a and miR-486-5p correlated negatively with systemic ventricular myocardial acceleration during isovolumic contraction, a relatively-load independent measure of systemic RV contractility. To conclude, these biomarkers reflect in varying extent the structural, functional, biological alteration of the subpulmonary and systemic right ventricles of the CHD patients late after surgical repair. These data may provide new perspectives in the understanding of progressive RV dysfunction in the adult CHD population and hopefully shed more lights on novel therapeutic interventions. / published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Το πεδίο έρευνας της παρούσας διδακτορικής διατριβής είναι η υπολογιστική καρδιολογία και συγκεκριμένα η μέτρηση όγκου δεξιάς κοιλίας με χρήση υπερήχων σε καθετήρα πνευμονικής αρτηρίας (ΚΠΑ) για την αποτελεσματικότερη διαχείριση των βαριά πασχόντων ασθενών. Μέχρι τώρα ο ΚΠΑ μετράει μόνο τις πιέσεις ενδοκοιλοτικά. Τα αποτελέσματα από τη χρήση του δεν είναι επαρκώς ενθαρρυντικά. Έχει βρεθεί ότι για την καλύτερη αντιμετώπιση των βαριά πασχόντων στην μονάδα εντατικής θεραπείας (ΜΕΘ), ή στην μονάδα εμφραγμάτων, ή ακόμα και κατά την προετοιμασία ή τη διάρκεια μιας σοβαρής χειρουργικής επέμβασης, σημαντική παράμετρος πέρα από την πίεση είναι ο τελοσυστολικός και ο τελοδιαστολικός όγκος της δεξιάς κοιλίας. Αυτές οι παράμετροι συνδυαζόμενες με τις πιέσεις, προσφέρουν σαφώς καλύτερη εκτίμηση και αποτελεσματικότερη αιμοδυναμική διαχείριση των βαριά πασχόντων ασθενών με απώτερο στόχο την ελάττωση της νοσηρότητας και θνησιμότητας. Γι’ αυτό το λόγο μοντελοποιήθηκε σύστημα μέτρησης όγκου δεξιάς κοιλίας από εικόνες MRI (μαγνητικού συντονισμού) με προσομοίωση υπερήχων. Επίσης το γεγονός ότι δεν υπάρχει μέθοδος υπολογισμού όγκου ενδοκοιλιακά που να συνδυάζεται με τον δεξιό καθετηριασμό, καθιστά την παρούσα διατριβή ως καινοτόμα αφ’ ενός στον υπολογισμό του όγκου της δεξιάς κοιλίας και αφ’ ετέρου στην διαχείριση της αιμοδυναμικής κατάστασης των βαριά πασχόντων. / The research field of this PhD thesis is the computational cardiology and more specifically the right ventricle’s volume measurement using ultrasound technology on the pulmonary artery catheter (PAC) for the effective management of critically ill patients. Hitherto, right cardiac catheterization with a pulmonary artery catheter provides only intracavity pressure measurements. Several studies showed that the use of PAC in critically illness does not make any effect in patient management. It was found that for the reliable management of critical ill patients in intensive care unit (ICU), or in infarctions unit, or even during serious surgery, pressures, is the right ventricle end-diastolic and end-systolic volume. The combination of those parameters with pressures, provides obviously better estimation and effective hemodynamic management of critically ill patients seeking in mortality and morbidity reduction. For that reason, a right ventricle’s volume measurement system was modeled from cardiac MRIs with ultrasound simulation. The fact that there is not any intraventricular volume calculation method combined with right catheterization, makes this PhD thesis innovative as the right ventricle’s volume and the hemodynamic management of critically ill patients regards.

Made available in DSpace on 2014-06-11T19:32:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-26Bitstream added on 2014-06-13T21:03:38Z : No. of bitstreams: 1 coleta_kd_dr_botfm.pdf: 391595 bytes, checksum: dde69b55ebd37c6d547a6c2e6321775d (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Pacientes com doença pulmonar obstrutiva crônica (DPOC) apresentam risco elevado para eventos cardiovasculares. Entretanto, existem poucos estudos sobre a função do ventrículo esquerdo (VE) nesses pacientes e os resultados são controversos. Os objetivos deste estudo foram: analisar a estrutura e função do ventrículo direito (VD) e câmaras cardíacas esquerdas, por meio de Dopplerecocardiografia, em pacientes com DPOC e avaliar a associação entre as variáveis ecocardiográficas e as variáveis clínicas relevantes. Foram avaliados 45 pacientes com DPOC (idade: 65,8 ± 10,6 anos, 64% homens): 17 pacientes com DPOC leve a moderada (grau I e II) provenientes do Serviço de Pneumologia da Faculdade de Medicina de Botucatu (FMB) e 28 pacientes com DPOC muito grave (grau IV) acompanhados no Ambulatório de Oxigenoterapia da FMB. Os critérios de inclusão foram: diagnóstico de DPOC, estabilidade clínica e, para os pacientes com DPOC IV, uso de oxigênio domiciliar por período mínimo de três meses. Para o grupo controle foram selecionados 15 indivíduos saudáveis (idade: 64,3 ± 10,1, 47% homens). Os critérios de exclusão foram: imagem ecocardiográfica inadequada, hipertensão arterial sistêmica, diabetes mellitus, doença coronariana, valvopatias, arritmias, patologias respiratórias associadas ou outras patologias cardíacas. Espirometria pré e pós-broncodilatador e oximetria de pulso foram realizadas por todos os sujeitos da pesquisa e gasometria arterial somente para os pacientes com DPOC... / Chronic obstructive pulmonary disease (COPD) is a strong risk factor for cardiovascular events. However, the status of left ventricle (LV) has been less studied and the results are controversial. The objectives were: to analyse the right ventricle (RV) and the left heart chambers structure and function in COPD patients by echocardiogram, and to analyse the association between echocardiographic variables and the relevant clinical variables. Forty-five COPD patients (age: 65,8 ± 10.6 years; 64% male) were evaluated: 17 mild to moderate COPD patients (grade I and II) and 28 very severe COPD patients (grade IV). The inclusion criteria were: COPD diagnosis, clinical stability and home oxygen therapy for at least three months (very severe COPD). The control group consisted of 15 healthy subjects (age: 64.3 ± 10.1 years; 47% male). Exclusion criteria were: poor quality echocardiographic image, history of systemic hypertension, diabetes mellitus, coronary artery disease, valvular heart disease, arrhythmias, associated lung diseases or other heart diseases. Pre and post-bronchodilator spirometry and pulse oximetry were performed in all subjects and arterial gasometry was performed in COPD patients only... (Complete abstract click electronic access below)

Resumo: Pacientes com doença pulmonar obstrutiva crônica (DPOC) apresentam risco elevado para eventos cardiovasculares. Entretanto, existem poucos estudos sobre a função do ventrículo esquerdo (VE) nesses pacientes e os resultados são controversos. Os objetivos deste estudo foram: analisar a estrutura e função do ventrículo direito (VD) e câmaras cardíacas esquerdas, por meio de Dopplerecocardiografia, em pacientes com DPOC e avaliar a associação entre as variáveis ecocardiográficas e as variáveis clínicas relevantes. Foram avaliados 45 pacientes com DPOC (idade: 65,8 ± 10,6 anos, 64% homens): 17 pacientes com DPOC leve a moderada (grau I e II) provenientes do Serviço de Pneumologia da Faculdade de Medicina de Botucatu (FMB) e 28 pacientes com DPOC muito grave (grau IV) acompanhados no Ambulatório de Oxigenoterapia da FMB. Os critérios de inclusão foram: diagnóstico de DPOC, estabilidade clínica e, para os pacientes com DPOC IV, uso de oxigênio domiciliar por período mínimo de três meses. Para o grupo controle foram selecionados 15 indivíduos saudáveis (idade: 64,3 ± 10,1, 47% homens). Os critérios de exclusão foram: imagem ecocardiográfica inadequada, hipertensão arterial sistêmica, diabetes mellitus, doença coronariana, valvopatias, arritmias, patologias respiratórias associadas ou outras patologias cardíacas. Espirometria pré e pós-broncodilatador e oximetria de pulso foram realizadas por todos os sujeitos da pesquisa e gasometria arterial somente para os pacientes com DPOC... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Chronic obstructive pulmonary disease (COPD) is a strong risk factor for cardiovascular events. However, the status of left ventricle (LV) has been less studied and the results are controversial. The objectives were: to analyse the right ventricle (RV) and the left heart chambers structure and function in COPD patients by echocardiogram, and to analyse the association between echocardiographic variables and the relevant clinical variables. Forty-five COPD patients (age: 65,8 ± 10.6 years; 64% male) were evaluated: 17 mild to moderate COPD patients (grade I and II) and 28 very severe COPD patients (grade IV). The inclusion criteria were: COPD diagnosis, clinical stability and home oxygen therapy for at least three months (very severe COPD). The control group consisted of 15 healthy subjects (age: 64.3 ± 10.1 years; 47% male). Exclusion criteria were: poor quality echocardiographic image, history of systemic hypertension, diabetes mellitus, coronary artery disease, valvular heart disease, arrhythmias, associated lung diseases or other heart diseases. Pre and post-bronchodilator spirometry and pulse oximetry were performed in all subjects and arterial gasometry was performed in COPD patients only... (Complete abstract click electronic access below) / Orientador: Irma de Godoy / Coorientador: Katashi Okoshi / Banca: Beatriz Matsubara / Banca: Leonardo Zornoff / Banca: Maria Inês Zanetti Feltrim / Banca: Oliver Augusto do Nascimento / Doutor

Transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging are two commonly used imaging modalities for evaluating the size and function of the heart. There are advantages and disadvantages associated with both modalities when examining the right ventricle (RV). The RV is positioned partly behind the sternum and lung, sometimes causing shadows in the TTE images. This along with the complex shape of the RV makes volume calculations challenging by 2D TTE. CMR is considered to be the reference method for volume calculations of the ventricles. The valve separating the RV from the right atrium is however often oblique compared to the valve separating the left ventricle from the left atrium. This complicates RV volume calculations using conventional CMR short-axis stack images. The aim of this thesis was to find ways to improve the RV stroke volume and ejection fraction calculations using TTE and CMR. A method, transferring the position of the tricuspid plane from RV long-axis images to short-axis images, was developed to improve the separation of the right atrium from the RV when calculating RV stroke volumes by CMR. The method provided calculations of RV stroke volumes with good agreement to reference volumes. Further, the movements contributing to the RV stroke volume was studied aiming to find new ways of calculating RV stroke volumes and ejection fraction by TTE. A model for RV stroke volume and ejection fraction calculations was evaluated showing underestimation of stroke volumes by TTE compared to CMR, which probably depend on differences in distance measurements using the two modalities. The model provided, however, promising results for ejection fraction calculations which was validated in a study of 37 participants that covered a wide range of EF.

Background-Pulmonary artery hypertension (PAH) is characterized by progressive vascular changes causing increased pulmonary resistance and eventual right heart failure (HF). It has been suggested that altered myocardial substrate utilization may be associated with right HF, however these changes have not yet been well characterized. The aim of this study was to evaluate in vivo right ventricular (RV) function and RV glucose and fatty acid metabolism in an experimental model of PAH using non-invasive positron emission tomography (PET) imaging and to investigate the effect of a novel endothelin receptor antagonist, Macitentan, on the development of PAH and RV energetics. Methods and Results-Severe PAH was induced in a total of 11 male Sprague-Dawley rats using a single injection of Sugen5416 followed by chronic hypoxia. The rats were then randomized to treatment or no treatment with Macitentan (30 mg/kg daily) Five and eight weeks post injection, substrate utilization was serially assessed with 2-[18F]fluoro-2-deoxyglucose (FDG) and 4-[18F]fluoro-6-thia-heptadecanoate (FTHA) PET scans for glucose and fatty acid metabolism respectively, and reported as a standardized uptake value (SUV). This data was correlated with in vivo functional measurements with echocardiography and multi gated acquisition scans. The Sugen-hypoxia (SuHx) model resulted in an increase in RV FDG uptake over 8 weeks (SUV control: 1.56 ± 0.38, week 5 SuHx: 4.06 ± 1.90, week 8 SuHx: 4.00 ± 1.60, p<0.005 between control and week 5 SuHx). RV FTHA data showed a trend towards increased uptake with onset of PAH at week 5 SuHx (SUV control: 1.50 ± 0.40, week 5 SuHx: 3.06 ± 1.10, p>0.05). Macitentan significantly decreased RV FDG uptake (SUV week 8 SuHx: 4.00 ± 1.60, week 8 SuHx +ERA: 2.54 ± 0.90, p<0.05). This was associated with improved RV ejection fraction (PAH week 8 untreated: 53.15 ± 9.9% vs PAH week 8 treated: 73.22 ± 4.8%, p<0.01) and improved pulmonary artery pressures measured by pulmonary artery acceleration time (PAH week 8 untreated: 17.32 ± 2.30 ms vs. PAH week 8 treated: 24.38 ± 3.90 ms, p<0.001). There was a strong correlation between increased pulmonary artery pressures and increased RV FDG uptake (r=0.87, p=0.001) as well as a significant inverse relationship between improved RV ejection fraction and decreased RV FDG uptake (r=-0.72, p=0.01). Conclusion-PAH is associated with metabolic changes in the RV, characterized by increased glucose uptake and a trend towards increased RV fatty acid uptake with onset of PAH. Macitentan attenuated RV FDG uptake and significantly increased RV function as well as hemodynamics compared to untreated group.