Heart failure and left ventricular dysfunction are major causes of morbidity and mortality. In this thesis, metabolic, hormonal, genetic and prognostic aspects of echocardiographically determined left ventricular function were investigated in a fairly large longitudinal population-based study of men. The participants were examined both at age 50 and 70 years and were followed for mortality using the national cause-of-death registry. Several factors associated with the insulin resistance syndrome predicted left ventricular systolic dysfunction independent of myocardial infarction, hypertension, diabetes and the use of cardiovascular medication after twenty years follow-up. Plasma levels of N-terminal atrial natriuretic peptide (N-ANP) were significantly increased in men with left ventricular dysfunction in comparison to healthy men. However, the diagnostic accuracy was poor due to the extensive overlapping between the groups. Relations between a haplotype of the novel hUNC-93B1 gene and the E/A-ratio were found and validated in separate samples of the cohort. Myocardial performance index (a Doppler derived index of combined left ventricular systolic and diastolic function) and left ventricular ejection fraction were found to be predictors for cardiovascular mortality independent of traditional cardiovascular risk factors in a longitudinal analysis with a mean follow-up of seven years. In conclusion, this thesis showed that left ventricular function is influenced by metabolic, hormonal and genetic factors and that echocardiographic measurements of left ventricular function, such as the myocardial performance index, are strong independent risk factors for cardiovascular mortality in elderly men.

Background: It is well known that performance of the right ventricle (RV) determines exercise capacity and may confer prognostic information in different cardiopulmonary diseases. To allow optimal patient management, ideal methods to assess right heart function are therefore important. Echocardiography is an attractive investigation for that purpose, although limited by the anatomical and functional complexities of the RV. The aim of the present thesis was to present applicable methods useful in clinical practice by traditional 2D/Doppler echocardiography and Doppler tissue imaging (DTI) in the assessment of global and regional RV function in both health and disease. Methods: The studies were performed on 4 different groups; (1) 255 healthy subjects (125 females), (2) 92 consecutive patients with different cardiac diseases (36 females), (3) 26 patients with systemic sclerosis, (SSc) (21 females) and (4) 26 consecutive patients with heart failure (8 females) undergoing cardiac catheterisation. Results: RV outflow tract fractional shortening (RVOT fs), which is a new method in the assessment of RV function, correlated significantly with RV systolic long axis motion (r= 0.66, p< 0.001), pulmonary artery acceleration time (r= 0.80, p< 0.001) and RV-right atrial peak systolic pressure drop gradient (r= -0.53, p< 0.001). Furthermore, RVOT fs was reduced in patients with pulmonary hypertension whereas RV systolic long axis motion was not in difference. This finding was confirmed after comparing RV function with invasive pressures. In healthy subjects, while the systolic myocardial velocities were preserved over age, the peak isovolumic contraction velocity (IVCv) was weakly increased with advanced age (r= 0.34, p< 0.01). Furthermore, both global and regional E/A ratios were reduced (r= -0.57, r= -0.67, p< 0.001 for both) with age whereas no alteration was found in the myocardial isovolumic relaxation time (IVRt). In patients with systemic sclerosis (SSc) both global (64± 23 vs. 39± 12 ms, p< 0.001) as well as regional (83± 40 vs. 46± 24 ms, p< 0.001) IVRt were prolonged. After evaluating echocardiographic parameters with invasive pressures we found a significant correlation between DTI derived IVRt and pulmonary artery systolic pressures (r= 0.83, p< 0.01) while the IVCv was related to the state of contractility (r= 0.77, p< 0.001). Furthermore, an IVCv below 6 cm/s was shown to be an accurate marker of increased right atrial pressure (>6 mm Hg). In conclusion, RVOT fs can be used as a complementary measurement of RV systolic function, being more sensitive to elevated pulmonary artery systolic pressures than the systolic longitudinal RV motion. Right heart function, mainly the diastolic function, is relatively weakly influenced by age compared to the left heart function. In patients with SSc, we found diastolic disturbances, including a prolonged IVRt and proposed the findings to be early markers related to intermittent pulmonary hypertension. This observation was strengthened after evaluating IVRt against invasive pulmonary artery systolic pressures. IVCv can be used to determine the state of RV contractility and also be used to identify patients with elevated filling pressures. The presented methods can be used to detect early signs of RV dysfunction which might prohibit right heart failure. All presented methods are non-invasive, reproducible, easy obtainable, and thus useful in clinical practice.

Left ventricular (LV) volumes and ejection fraction (EF) are important predictors of cardiac morbidity and mortality. LV volumes provide valuable prognostic information which isparticularly useful in the selection of therapy or determination of the optimal time for surgery. Two-dimensional (2D) echocardiography is the most widely used non-invasive method forassessment of cardiac function, 2D echocardiography has however several limitations inmeasuring LV volumes and EF since the formulas for quantifications are based on geometricalassumptions. Three-dimensional (3D) echocardiography has been available for almost twodecades, although the use of this modality has not gained wide spread acceptance. 3D echocardiography can overcome the above mentioned limitation in LV volume and EF evaluation since it is not based on geometrical assumption. 3D echocardiography has been shownin several studies to be more accurate and reproducible with low inter- and intraobservervariability in comparison to 2D echocardiography regarding the measurements of LV volumesand EF. The overall aim of the thesis was to evaluate the feasibility and accuracy of 3D echocardiography based-methods in the clinical context. In Study I the feasibility of 3D echocardiography was investigated for determination of LV volumes and EF using parasternal, apical and subcostal approaches. The study demonstrated that the apical 3D echocardiography view offers superior visualization. Study II tested the possibility of creating flow-volume loops to differentiate patients with valvular abnormalities from normal subjects. There were significant differences in the pattern from flow-volume loops clearly separating the groups. In Study III the visual estimation, “eyeballing” of EF was evaluated with two- and tri-plane echocardiography in comparison to quantitative 3D echocardiography. The study confirmed that an experienced echocardiographer can, with a high level of agreement estimate EF both with two- and tri-plane echocardiography. Study IV exposed the high accuracy of stroke volume and cardiac output determination using a3D biplane technique by planimetrically tracing the left ventricular outflow tract and indicating that an assumption of circular left ventricular outflow tract is not reliable. In Study V, two 3D echocardiography modalities, single-beat and four-beat ECG-gated 3D echocardiography were evaluated in patients having sinus rhythm and atrial fibrillation. Thesingle-beat technique showed significantly lower inter-and intraobserver variability in LV volumes and EF measurements in patients having atrial fibrillation in comparison to four-beat ECG-gated acquisition due to absence of stitching artifact. All studies demonstrated good results suggesting 3D echocardiography to be a feasible andaccurate method in daily clinical settings. / degree of Medical DoctorQC 20100629

Echocardiography is a well established technique when evaluating the size and function of the heart. One of the most common ways to measure the size of the right ventricle (RV) is to measure the RV outflow tract 1(RVOT1). Several ways to measure RVOT1 are described in the literature.These ways were compared with echocardiography on 27 healthy subjects.The result showed significant differences in RVOT1, depending on the way it was measured, concluding that the same site, method and body positionshould be used when comparing RVOT1 in the same subject over time.One parameter to evaluate the RV diastolic function (RVDF) is to measure the RV isovolumetric relaxation time (RV-IVRT), a sensitive marker ofRV dysfunction. There are different ways to measure this. In this thesis two ways of measuring RV-IVRT and their time intervals were compared in 20 patients examined with echocardiography. There was a significant difference between the two methods indicating that they are not measuring the same interval.Another way to assess the RVDF is to measure the maximal early diastolicvelocity (MDV) in the long-axis direction. MDV can be measured bydifferent methods, hence 29 patients were examined and MDV was measured according to two methods. There was a good correlation but a poor agreement between the two methods meaning that reference values cannot be used interchangeably.Takotsubo cardiomyopathy is characterized by apical wall motion abnormalities without coronary stenosis. The pathology of this condition remains unclear. To evaluate biventricular changes in systolic long-axisfunction and diastolic parameters in the acute phase and after recovery, 13 patients were included and examined with echocardiography at admission and after recovery. The results showed significant biventricular improvementof systolic long-axis function while most diastolic parameters remainedunchanged.

Contexte : Les maladies valvulaires dégénératives (MVD) représentent la pathologie cardiaque acquise la plus fréquente chez le chien. Malgré une recherche active, à l’heure actuelle aucun traitement étudié ne s’est avéré efficace dans le traitement du stade asymptomatique de la condition. Le pimobendane est un nouvel agent inodilatateur, qui s’est montré prometteur dans le traitement des stades avancés des MVD, mais peu est connu sur ses effets hémodynamiques et son impact sur le volume de régurgitation dans les MVD naturelles asymptomatiques. Hypothèses : L’introduction du pimobendane réduit la fraction de régurgitation (FR) chez les chiens atteints de MVD asymptomatiques. Sujets étudiés : Vingt-quatre chiens de compagnie, appartenant à la clientèle du Centre Hospitalier Universitaire Vétérinaire (CHUV) de l’université de Montréal et affectés par une MVD de classe ISACHC 1b. Méthode: Étude prospective, contrôlée et conduite à l’aveugle. Les chiens ont été assignés à un groupe traitement (n=19) recevant du pimobendane (0,2-0,3 mg/Kg q12h) ou à un groupe contrôle (n=5). Les évaluations échocardiographiques ont été effectuées sur une période de 6 mois. Résultats : L’introduction du pimobendane n’a pas été associée à une diminution de la FR chez les chiens affectés par une MVD asymptomatique de classe ISACHC 1b au cours de l’étude (p=0,85). Une augmentation significative de la fraction d’éjection (80,8 +/- 1,42 vs. 69,0 +/- 2,76, p=0,0064) ainsi qu’une baisse du diamètre ventriculaire gauche télé systolique (p=0.011) ont été observées chez le groupe pimobendane au jour 30. Toutefois, cet effet sur la fonction systolique n’a pas persisté au cours des 6 mois d’évaluation. / Background: Mitral Valve disease (MVD) is the most common acquired cardiac affectation of the dog, and is therefore associated with an undeniable clinical and economical importance for veterinarians and pet owners. Despite active research, at this time no known treatment has been proven to delay the onset of congestive heart failure. Pimobendan is a novel inodilator that has shown promising results in the treatment of advanced MVD, but little is known about its hemodynamic effects, especially regarding the mitral regurgitant volume in naturally occurring asymptomatic MVD. Hypothesis: Administration of pimobendan decreases the regurgitant fraction (RF) of dogs with asymptomatic MVD. Animals: Twenty-four client-owned dogs affected by ISACHC class Ib MVD. Methods: Prospective, blinded, controlled clinical trial. Dogs were assigned to a pimobendan (0.2-0.3 mg/Kg q12h) treatment group (n=19) or a control group (n=5). Echocardiographic evaluations were performed over a 6 month study period. Results: Administration of pimobendan to treatment did not decrease the RF of dogs affected by asymptomatic class 1b MVD over the study period (p=0.85). There was a significant increase in the ejection fraction of the pimobendan treated dogs at day (80.8 +/- 1.42 vs. 69.0 +/- 2.76, p=0.0064), and a decrease in systolic left ventricular diameter (p=0.011). However, this improvement in systolic function was not sustained over the 6 month trial period.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Lors de la systole, le ventricule gauche (VG) se déforme suite à la contraction des cardiomyocytes. De part l’orientation en spirale des fibres myocardiques, ces déformations incluent un mouvement de torsion, la base et l’apex du VG tournant dans des sens opposés. L’emmagasinement d’énergie élastique par ce mécanisme et surtout sa restitution très précoce en début de diastole jouent un rôle clé dans le remplissage ventriculaire gauche. Les objectifs de ce travail ont été d’étudier les adaptations mécaniques ventriculaires gauche en se focalisant sur le rôle de la torsion 1) lors d’un exercice d’intensité croissante chez le sujet sédentaire jeune, 2) suite à l’entrainement aérobie au repos et lors d’un exercice d’intensité croissante et, 3) concomitantes aux dysfonctions cardiaques observées après un exercice épuisant de longue durée. Pour cela, nous avons effectué des échocardiographies au repos et/ou lors d’épreuves d’effort d’intensité croissante en incluant l’utilisation d’un nouvel outil échocardiographique basé sur le "speckle tracking" (STE). Nos résultats soulignent le rôle clé de la torsion dans le couplage systole – diastole à l’effort. De plus, nos résultats montrent une modification des adaptations mécaniques ventriculaires gauche à l’effort en parallèle à l’amélioration de la fonction diastolique chez les sportifs entrainés en endurance aérobie. Enfin, la dysfonction ventriculaire gauche transitoire observée après un exercice épuisant de longue durée est caractérisée par une diminution et un décalage dans le temps de la torsion, limitant probablement la diminution précoce des pressions intraventriculaires gauche et donc le remplissage. L’ensemble de ces résultats mettent en évidence, d’une part, l’intérêt de l’évaluation par STE de la mécanique ventriculaire gauche au repos et à l’effort, et d’autre part le rôle clé du mécanisme de torsion – détorsion dans l’explication de fonctions diastoliques améliorées ou altérées / During systole, contraction of cardiomyocytes induces left ventricular (LV) strains. Moreover, the helical orientation of myofibers induces LV torsion consequently to LV basal and apical rotations. LV torsion stores energy in elastic component that is released very early in diastole and constitutes a key factor of LV filling. The aims of this thesis were to characterize LV mechanicals adaptations focussing on the role of LV torsion 1) during a progressive exercise test in healthy sedentary subjects, 2) induced by aerobic training at rest and during a progressive exercise test and, 3) concomitant with cardiac dysfunctions after prolonged and strenuous exercise. We used a novel echocardiographic tool, based on Speckle Tracking (STE), in order to evaluate LV function at rest and/or during a progressive exercise test. Our results underlined the key role of LV torsion in systolic – diastolic coupling during exercise. Moreover, our results showed an alteration of LV mechanical adaptation paralleling the enhancement of diastolic function during effort in aerobic trained subjects. At last, transient LV dysfunction after prolonged and strenuous exercise was associated with decreased and delayed LV torsion, probably limiting the early drop of LV intraventricular pressures and thus LV filling. All together, these results underlined the usefulness to evaluate LV mechanics at rest and during effort by STE, and point out the key role of twisting – untwisting mechanism in improved or depressed LV diastolic function

This thesis addresses the task of developing automatic algorithms for analysing the two-dimensional ultrasound video footage obtained from fetal heart screening scans. These scans are typically performed in the second trimester of pregnancy to check for congenital heart anomalies and require significant training and anatomical knowledge to perform. The aim is to develop a tool that runs at high frame rates with no user initialisation and infers the visibility, position, orientation, view classification, and cardiac phase of the heart, and additionally the locations of cardiac structures of interest (such as valves and vessels) in a manner that is robust to the various sources of variation that occur in real-world ultrasound scanning. This is the first work to attempt such a detailed automated analysis of these videos. The problem is posed as a Bayesian filtering problem, which provides a principled framework for aggregating uncertain measurements across a number of frames whilst exploiting the constraints imposed by anatomical feasibility. The resulting inference problem is solved approximately with a particle filter, whose state space is partitioned to reduce the problems associated with filtering in high-dimensional spaces. Rotation-invariant features are captured from the videos in an efficient way in order to tackle the problem of unknown orientation. These are used within random forest learning models, including a novel formulation to predict circular-valued variables. The algorithm is validated on an annotated clinical dataset, and the results are compared to estimates of inter- and intra-observer variation, which are significant in both cases due to the inherent ambiguity in the imagery. The results suggest that the algorithm's output approaches these benchmarks in several respects, and fall slightly behind in others. The work presented here is an important first step towards developing automated clinical tools for the detection of congenital heart disease.

Introdução: Os efeitos agudos da ventilação não invasiva (VNI), comparando os modos continuous positive airway pressure (CPAP) versus bilevel positive airway pressure (BiPAP) devem ser melhor verificados em pacientes insuficiência cardíaca (IC) crônica. Objetivo: avaliar os efeitos agudos da VNI em pacientes com IC na resposta hemodinâmica da função cardíaca por ecocardiografia com Doppler Tissular e na avaliação da capacidade funcional através do teste de caminhada de 6 minutos (TC6min), utilizando modo CPAP versus BiPAP. Métodos vinte e seis pacientes portadores de insuficiência cardíaca selecionados de ambulatórios de cardiologia de hospitais-escola de Porto Alegre. Os pacientes foram randomizados para receber VNI pelos modos CPAP ou BiPAP durante 60 minutos. Foram realizados TC6min e ecocardiograma antes e após o uso da VNI. No modo CPAP foi utilizada pressão de 8 cmH2O, e no BiPAP foram 8 cmH2O de pressão inspiratória e 4 cmH2O de pressão expiratória. Resultados: o tempo de relaxamento isovolumétrico (TRIV) diminuiu após uso do CPAP (pré = 104,7±18,9 mseg versus pós = 60,48±19,2 mseg; p<0,05) e a fração de encurtamento (FS) diminuiu em ambos os modos (pré = 25,9±1,4% versus pós = 23,15±1,02%, P < 0,05). Entre os pacientes com fração de ejeção do ventrículo esquerdo (FEVE) >= 50%, houve aumento do diâmetro sistólico final do VE (DSFVE) (pré = 37,27±2,84mm versus pós = 41,8±2,77mm; p<0,05) e diminuição da FEVE (pré = 61,9±2,6% versus pós = 53,32±2,9%). A capacidade funcional não foi alterada com o uso da VMNI. Conclusão: O CPAP alterou significativamente o TRIV. A FEVE preservada influenciou os resultados da função contrátil do VE. A VNI não provocou alterações significativas sobre a capacidade funcional. / Introdução: The noninvasive ventilation (NIV) acute effects da ventilação não invasiva by comparing continuous positive airway pressure (CPAP) versus bilevel positive airway pressure (BiPAP) should be more investigated in patients with chronic heart failure (CHF). Objective: evaluate the acute effects of NIV in patients with heart failure (HF) in the hemodynamic response of the cardiac function through echocardiography with Tissue Doppler and in the assessment of functional capability through the 6-minute walk test (6MWT), using CPAP vs. BiPAP modes. Methods: twenty-six patients with HF recruited from outpatient clinics of Cardiology schoolhospitals in Porto Alegre. The patients were randomized to receive NIV through CPAP or BiPAP modes for 60 minutes. The 6MWT and echocardiogram were performed before and after the use of NIV. In CPAP mode, 8 cmH2O pressure was applied and in BiPAP mode 8 cmH2O inspiratory pressure and 4 cmH2O expiratory pressure were applied. Results: The isovolumic relaxation time (IVRT) was reduced after the use of CPAP (before = 104.7±18.9 msec. vs. after = 60.48±19.2 msec.; p<0.05) and the shortening fraction was reduced in both modes (before = 25.9±1.4% vs. after = 23.15±1.02%, p<0.05). Patients with left ventricle ejection factor (LVEF)>= 50% presented increased left ventricle end systolic diameter (LVESD) (before = 37.27±2.84mm vs. after = 41.8±2.77mm; p<0.05) and reduced LVEF (before = 61.9±2.6% vs. after = 53.32±2.9%). The functional capability was not altered with the use of NIV. Conclusion: The CPAP significantly altered the IVRT. The preserved LVEF affected the results of LV contractile function. The NIV did not cause any significant alteration to the functional capability.