Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant cardiovascular complications, including stroke, myocardial infarction, heart failure, and premature death. The presence of subtle left ventricular (LV) dysfunction is increasingly recognised in patients with AF, raising questions regarding the underlying pathophysiology and potential treatment strategies. I used advanced and multiparametric cardiac magnetic resonance (CMR) methods to investigate potential mechanisms that could contribute to LV dysfunction in patients with AF, controlled ventricular rate and no significant cardiovascular comorbidities (i.e., with so-called 'lone' AF). Patients were evaluated before and after catheter ablation, allowing examination of the effect of restoration of sinus rhythm and reduction in AF burden on LV structure, function, energetics, tissue characteristics, and perfusion. I demonstrated for the first time that patents with lone AF before ablation have significantly impaired ventricular energetics and a subtle reduction in LV systolic function compared to control subjects in sinus rhythm. Furthermore, there was only modest improvement (but not normalisation) in LV function following successful ablation, and myocardial energetics remained impaired despite a significant and sustained reduction in AF burden. These findings imply that lone AF may actually be the consequence (rather than the cause) of an underlying cardiomyopathy. Next, to interrogate advanced ventricular tissue characteristics (such as diffuse myocardial fibrosis) in patients with tachyarrhythmia, I developed a novel CMR method involving a systolic readout T1-mapping sequence. Methodological work in volunteers and patients with tachyarrhythmia demonstrated that this method reports clinically equivalent T1 values to the conventional diastolic readout in healthy volunteers, and was feasible in tachyarrhythmia, producing excellent quality T1 maps. When applied to the investigation of patients with AF, I demonstrated that subtle LV dysfunction in lone AF occurs in the absence of CMR evidence of diffuse myocardial fibrosis, suggesting that LV dysfunction may be reversible with appropriate and targeted therapeutic strategies initiated prior to the development of structural LV remodelling. Finally, I used quantitative perfusion imaging to determine absolute myocardial blood flow and coronary reserve in patients with AF, and determine whether microvascular coronary dysfunction could underlie impaired LV function and energetics in patients with AF. I found that myocardial perfusion is significantly reduced in patients with AF in the absence of significant epicardial coronary artery disease, both at baseline and under conditions of vasodilator stress. Lower baseline blood flow was related to reduced LV performance, and there was no significant change in perfusion after successful AF ablation. These novel findings indicate that coronary microvascular dysfunction may be an important pathophysiological mechanism in lone AF, and at least partially responsible for LV dysfunction. Overall, the findings reported in this thesis have potentially far-reaching implications for the management of patients with AF. They suggest that approaches that predominantly target rhythm control (including anti-arrhythmic medications and ablation) are insufficient to normalise the systemic and cardiometabolic phenotype in patients with AF. Further studies are needed to investigate whether novel approaches that target microvascular and energetic dysfunction in patients with AF can contribute to durable restoration of sinus rhythm and improve clinical outcomes.

Haemodialysis (HD) patients have a high mortality risk and most have echocardiographic evidence of abnormal cardiac structure or function. Markers, such as left ventricular hypertrophy (LVH), show association with adverse outcome in the general population and can aid in clinical decision making. The aim of this research was to explore the prognostic utility of established and novel two-dimensional (2DE) and three-dimensional transthoracic echocardiographic (RT3DE) techniques in HD patients. Adult maintenance HD patients from a single tertiary nephrology centre including satellite dialysis units were enrolled. Exclusion criteria were if patients were clinically unstable, unable to consent, or if required ambulance transportation for echocardiography visits. Consented patients underwent 2DE with speckle tracking (STE), RT3DE and VicorderTm measurements of pulse wave velocity (PWV) on a non-dialysis day, after the short inter-dialytic break. Clinical phenotype data, 3-month averaged blood results and dialysis prescriptions were obtained from the hospital electronic patient records. All patients screened were followed-up until death, renal transplantation, moving out of the region, or 16th November 2015. Regression analysis was used to assess the cross-sectional relationship between echocardiographic parameters. Relationship of echocardiographic parameters with outcome was assessed by Cox regression analysis. The first study explored whether patients recruited had similar characteristics and survival compared with patients who declined consent or who were excluded from the study. Patients who declined consent had an adjusted hazard ratio (HR) for all-cause mortality compared with recruited patients of 1.70, 95% confidence interval (CI) 1.10-2.52, and excluded patients had an adjusted HR of 1.30, 95% CI 0.75-2.25. Recruited patients may be a 'fitter' population and this needs to be considered when interpreting results. The second study reports that when global longitudinal strain (GLS) is combined in a multivariable model with PWV; PWV is superior to GLS in its association with mortality (adjusted HR 1.23, 95% CI 1.03-1.47 versus HR 1.00, 95% CI 0.86-1.17). When this analysis was repeated in a sub-group of patients with LVH, neither GLS nor PWV were associated with mortality, whilst both were prognostically significant in a preserved LVEF sub-group (PWV: HR 1.23, 95% CI 1.04-1.4 and GLS: HR 1.16, 95% CI 1.01-1.33). Therefore GLS has different prognostic implications in different patient sub-groups. The third study explored whether tissue motion mitral annular displacement (TMAD) measured by STE may be a more useful alternative to GLS as it measures strain but is quicker and less user-dependent. TMAD was closely correlated to GLS (r=-0.614, p<0.001), but had no prognostic power for mortality (adjusted HR 1.04,95% CI 0.91-1.19). The correlation between 2DE and RT3DE determined LV mass and volume measurements and the prognostic significance of RT3DE measurements were assessed. Although there was good correlation between 2DE and RT3DE LV volume measurements, 2DE overestimated LV mass compared to RT3DE. RT3DE measures gave no added prognostic value, and there were added difficulties in obtaining adequate images for RT3DE (35% of patients who had adequate 2D images). Furthermore, although RT3DE determined LV mechanical dyssynchrony index was prolonged in HD patients compared with published general population controls, it failed to show any prognostic significance (HR 2.16, 95% CI 0.96-4.89) for mortality, but was associated with hospitalisation for heart failure (HR 1.03, 95% CI 1.00-1.06). These results indicate that novel measurements of sub-clinical cardiac dysfunction have the potential to aid prognostication in this high risk population. Follow-up studies exploring the longitudinal change in these parameters is ongoing.

Objective: Aortic stenosis (AS) patients with eccentric hypertrophy (Ecc-LVH) have increased left ventricular (LV) size and possibly reduced ejection fraction (EF). However, previous studies suggest worse outcomes with concentric remodeling and hypertrophy. We hypothesized that Ecc-LVH pattern in AS patients will also be associated with greater heart failure (HF) and all-cause mortality (ACM). Methods: We queried the electronic medical record from a community-based university practice for all AS patients. We included patients with >60 days follow-up and interpretable Doppler echocardiograms. We recorded demographics, Doppler-echo parameters, laboratories, HF readmission and ACM with follow-up to 2083 days. There were 329 patients divided into 4 groups based on the presence of LV hypertrophy (LVH) and relative wall thickness (RWT) by echocardiography. Ecc-LVH had RWT<0.43 and LVH. Results: Patients with severe AS were older, had greater coronary disease prevalence, lower hemoglobin, greater LV mass index, more abnormal diastolic function, greater HF and ACM. Multivariate Cox proportional analysis revealed that valvulo-arterial impedance (p=0.017) and Ecc-LVH (p=0.033) were HF predictors. Brain natriuretic peptide>100 pg/ml (p<0.001) and Ecc-LVH (p=0.019) were ACM predictors. ACM was increased in Ecc-LVH patients with both moderate (HR=3.67-8.18 vs other geometries, p=0.007-0.0007) and severe AS (HR=3.94-9.48 vs normal and concentric remodeling, p=0.0002). In patients with HF, Ecc-LVH was associated with greater HF in moderate AS vs normal geometry (HR=3.28, p=0.0135) and concentric remodeling (HR=2.66, p=0.0472). Conclusions: Patients with AS and Ecc-LVH have greater ACM than other LV geometries with both moderate and severe AS and greater HF in moderate AS.

Aims: The peak transmitral velocity/peak mitral annular velocity (E/e′) ratio has been used as a left ventricular (LV) filling pressure (LVFP) correlate. However, the E/e′ and its changes with haemodynamic alterations have not always correlated with changes in LVFP's. We hypothesized that indexing E/e′ to a measure of LV filling volume may enhance the correlation with LVFP and LVFP changes. Methods and results: We summarized previously obtained haemodynamic and Doppler echo data in 137 dogs with coronary microsphere embolization induced-chronic LV dysfunction prior to and following haemodynamic induced alterations in LVFP's. E/e′ values were obtained as E∗tau where tau is the inverse logarithmic LV pressure decay. E∗tau was indexed to LV filling volume by dividing by the diastolic time velocity integral (DVI) and correlated with LV mean diastolic pressure (LVmDP). Similarly, the relationship of E/e′ and E/e′/DVI to LV pre A wave pressure was evaluated in 84 patients by invasive haemodynamics and Doppler echo. Combining data from all interventions, LVmDP correlated with E∗tau (r = 0.408) but more strongly with E∗tau/DVI (r = 0.667, z = 3.03, P = 0.0008). The change in LVmDP correlated with the change in E∗tau/DVI (r = 0.742) more strongly than E∗Tau (r = 0.187, Z = 4.01, P < 0.0001). In the patient cohort, E/e′ was modestly correlated with LV pre A wave pressure (r = 0.301) but more strongly correlated with E/e′/DVI (r = 0.636, z = 2.36, P = 0.0161). Conclusion: Indexing E to both LV relaxation and filling volume results in a more robust relation with LVFP's and with LVFP changes.

La surcharge ventriculaire droite (VD), volumétrique ou barométrique, est devenue depuis quelques années un problème de santé publique chez les patients atteints de cardiopathie congénitale.Grâce aux progrès de la prise en charge de ces patients, cette population est grandissante avec des complications spécifiques. La défaillance ventriculaire gauche (VG) est une des complications les plus graves des pathologies de surcharge du VD.L’objectif de ce travail est de déterminer s’il existe des signes d’atteinte précoce du VG chez ces patients grâce à l’étude de 2 modèles chirurgicaux de surcharge du VD (volumétrique : tétralogie de Fallot TOF et barométrique : HYPPE), et si la cardiométrie peut être un outil de dépistage.La première partie de ce travail a consisté en la validation de la technique de cardiométrie électrique chez l’homme pour mesurer le débit cardiaque mais aussi évaluer la volémie.La deuxième partie a consisté en l’analyse du VG des maladies de surcharge du VD : les résultats mettent en évidence, principalement dans le modèle HYPPE plutôt que dans le modèle TOF, une fibrose, des anomalies des tubules T, des anomalies du couplage excitation-contraction associées à une altération de la contraction et de la relaxation sarcomèrique. Même si ces premiers résultats chez le gros animal sont prometteurs, ils nécessitent d’être confirmés par l’inclusion de plus de sujets.En conclusion, la cardiométrie a montré son excellente corrélation au cathéter de conductance pour évaluer la contractilité du VG en situation de stress de façon non invasive, confirmant l’utilité de cet appareil dans le diagnostic et suivi hémodynamique de nos patients. / Right heart overload is become since few years a real public health problem in congenital heart disease. Grow up with congenital heart disease patients have become a large population and suffer from many specific complications, like left ventricular failure. Right heart overload come mainly from two ways, volume or pressure that we reproduce thanks to two porcine models: tetralogy of Fallot (TOF) for volume and pulmonary hypertension (HYPPE). We try to determine on these models if there is early left heart failure and if electrical cardiometry can detect it.First part of this work is a validation of electrical cardiometry as cardiac output evaluation and fluid management reliable tool in healthy newborns and congenital heart disease patients.Second part is a left ventricle analysis of these models: we highlighted early left ventricle lesions of fibrosis, t-tubules disorganization, excitation-contraction coupling abnormalities associated with alteration of sarcomere relaxation and contraction. Even if first results are promising on large animals, we need to include more subjects to confirm these data.In conclusion, we highlighted than electrical cardiometry had an excellent and strong correlation with conductance catheter to evaluate LV contractility by noninvasive way. These results confirm this device usefulness in diagnosis and screening of our patients.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21652号 / 医博第4458号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川村 孝, 教授 福原 俊一, 教授 佐藤 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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