Hokkaido University (北海道大学) / 博士 / 医学

<p>Knowledge of the leftventricular (LV) pressure-volume relation, along withparameters derived from this relation, have led to newpossibilities for the characterisation of cardiac pumpfunction, in both experimental studies and clinicalsettings.</p><p>The pressure-volume diagram is apowerful tool for visualising LV performance, but in order tobe clinically useful it is necessary to make plots continuouslyand on-line. The conductance catheter technique offers thispossibility. The conductance catheter system has experiencedgrowing interest among cardiologists, physiologists, surgeons,and anaesthesiologists around the world as a powerful newresearch tool, but the invasiveness of this technique has beena limiting factor for most clinical applications. The catheterneeds to be thinner and softer in order to make this techniquemore suitable for human use.</p><p>This thesis reports of a newthin and soft conductance catheter for continuously and on-linemeasurements of LV pressure and volume.</p><p>One way to reduce both cathetersize and stiffness is to decrease the number of electrodes onthe catheter. Theoretical calculations shown in this thesisproves that it is possible to obtain the same performance witha single segment catheter as with a five-segment catheter. Thethin catheter has been tested and compared to a commercialfive-segment conductance catheter in animal studies.</p><p>We conclude that the thin singlesegment conductance catheter can measure left ventricularvolume and pessure. The regression coefficient between the twomethods is good independent of loading condition and duringbaseline conditions the catheters produce very similar volumecurves. During preload reduction the estimated volume reductionis different in the two systems.</p><p>Our thin catheter does notdisturb the heart's normal electrophysiology, neither by thecatheter current nor by any mechanical stimuli. The resultsdemonstrates that our thin, soft, single segment conductancecatheter has performance characteristics which warrant furtherdevelopment, with the goal to make the method available forhuman use.</p>

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.

Knowledge of the leftventricular (LV) pressure-volume relation, along withparameters derived from this relation, have led to newpossibilities for the characterisation of cardiac pumpfunction, in both experimental studies and clinicalsettings. The pressure-volume diagram is apowerful tool for visualising LV performance, but in order tobe clinically useful it is necessary to make plots continuouslyand on-line. The conductance catheter technique offers thispossibility. The conductance catheter system has experiencedgrowing interest among cardiologists, physiologists, surgeons,and anaesthesiologists around the world as a powerful newresearch tool, but the invasiveness of this technique has beena limiting factor for most clinical applications. The catheterneeds to be thinner and softer in order to make this techniquemore suitable for human use. This thesis reports of a newthin and soft conductance catheter for continuously and on-linemeasurements of LV pressure and volume. One way to reduce both cathetersize and stiffness is to decrease the number of electrodes onthe catheter. Theoretical calculations shown in this thesisproves that it is possible to obtain the same performance witha single segment catheter as with a five-segment catheter. Thethin catheter has been tested and compared to a commercialfive-segment conductance catheter in animal studies. We conclude that the thin singlesegment conductance catheter can measure left ventricularvolume and pessure. The regression coefficient between the twomethods is good independent of loading condition and duringbaseline conditions the catheters produce very similar volumecurves. During preload reduction the estimated volume reductionis different in the two systems. Our thin catheter does notdisturb the heart's normal electrophysiology, neither by thecatheter current nor by any mechanical stimuli. The resultsdemonstrates that our thin, soft, single segment conductancecatheter has performance characteristics which warrant furtherdevelopment, with the goal to make the method available forhuman use. / NR 20140805

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.

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

In this study, the relationship between maximal aerobic capacity (VO₂max) and left ventricular function was examined in two distinct age groups. A young group (20 - 30 years of age) and an elderly group (over 60 years of age) were compared. Left ventricular function was examined over wide variations in preload accomplished by 5º head-down tilt (TILT) for ninety minutes and lower body negative pressure (LBNP) to -40 mm Hg. with two-dimensional echocardiography. A greater response to an increase in preload (TILT) was related to high VO₂max levels in the young subjects but not in the elderly groups of subjects, suggesting that lower VO₂max levels of the elderly population affected the mechanism of response to the increased levels of preload. Additionally, in the elderly, greater reductions in ventricular volume reflected increased peripheral pooling due to decreased venous tone and/or increased venous compliance during LBNP and were related to increased VO₂max. In the young, VO₂max does not appear to affect the response to reduced preload.

Chronic aortic regurgitation (AR) of varying degree affects 13% of men and 8.5% of women. In persons with severe AR, the expected length of life and its quality are influenced. Some individuals remain asymptomatic for a long period, due to effective compensatory mechanisms, but dysfunction of the left ventricle (LV) usually begins before symptoms appear and can be irreversible by then. This thesis addresses questions of LV function and optimal time for operation of patients suffering from chronic AR. Moreover, detailed echocardiographic studies of the anatomy of the normal aortic valve have been performed to obtain a better understanding of the in vivo anatomic relations within the aortic root. Patients with chronic AR, without concomitant cardiac disease, were studied both retrospectively (n=88) and prospectively (n=29) and the aortic valves of persons (n=32) free from cardiac disease were investigated. For the retrospectively studied patients, survival was 82% at 10 years which is an improvement compared with previously published results. The majority of the patients, however, had LV dysfunction preoperatively. By studying patients prospectively by echocardiography, radionuclide ventriculography (MUGA) and cardiopulmonary exercise testing (CPET) our aim was to evaluate the predictive value of measurements of LV function at rest and during exercise for postoperative outcome. LV diameters were markedly elevated prior to and diminished significantly after surgery. Patients with an abnormal exercise ejection fraction (EF) response by MUGA preoperatively, presented the same reaction postoperatively. This could not be predicted by LV function determination at rest, or by NYHA functional class. In spite of median NYHA class II, these patients had a low work capacity on CPET, which was neither improved 6 months postoperatively nor correlated to echocardiographic LV dimensions. Thus, both MUGA and CPET may be useful complements for timing of surgery in patients with chronic AR. Assuming that patients would benefit from preservation of their native valves the normal aortic valve was studied to gain detailed information about the echocardiographic anatomy and relations within the normal aortic root. This extended examination of the aortic root may facilitate a better planning of aortic valve‐preserving interventions in the future.

Master of Science / Department of Kinesiology / Brad J. Behnke / Prostate cancer is the most common type of non-skin cancer found in men and preliminary evidence suggests prostate cancer has atrophic effects on cardiac and left ventricle (LV) mass which are associated with reduced endurance exercise capacity in rats. Using a pre-clinical orthotopic model of prostate cancer, echocardiography was utilized to test the hypothesis that exercise training will mitigate prostate cancer induced-cardiac and skeletal muscle atrophy and improve LV function versus sedentary tumor-bearing counterparts. Methods: Dunning R-3327 AT-1 prostate cancer cells were injected orthotopically in male Copenhagen rats aged (n=39; ~5 mo. old). Animals were randomized into four groups, exercise-trained tumor-bearing (EXTB) or control (EXCON) and sedentary tumor-bearing (SEDTB), or control (SEDCON). Exercise training was performed via a rodent treadmill set at 15m/min with a 15° incline for 60 min/day for ~30 days. Animals underwent echocardiographic evaluation using the parasternal short axis view to examine ventricle dimensions pre-cancer or exercise (PRE) and 15 (Post 1) and 30 (Post 2) days post cancer cell injection and/or exercise training with tissues collected immediately after Post 2. Results: Cardiac and LV mass of SEDTB animals were significantly lower than all groups (p<0.05). Tumor mass was significantly negatively correlated with LV mass in EXTB (-0.75, p<0.02) and SEDTB animals (-0.72, p<0.02). EXCON group had significantly higher stroke volume Post 2 assessment compared to both sedentary groups (p<0.05), but not EXTB animals. Conclusion: The current investigation demonstrates prostate cancer independent of anti-cancer treatment significantly reduces cardiac mass, and LV mass as well as locomotor muscle masses. However, moderate intensity exercise training can mitigate cardiac and skeletal muscle atrophy with prostate cancer.

Idrottshjärta är ett kardiovaskulärt tillstånd som uppträder under längre perioder av intensiv träning som orsakar strukturella, funktionella och elektriska förändringar hos hjärtat och är en fysiologisk anpassning som svar på ett ökat hemodynamiskt behov under fysisk ansträngning. De fysiologiska anpassningarna har dock blivit ett diagnostiskt dilemma att urskilja från de patologiska förändringarna såsom hypertrofisk kardiomyopati. Det finns därför ett behov av standardisering av kardiovaskulär screening hos idrottare för att upptäcka underliggande eller dolda kardiomyopatier som kan leda till allvarliga konsekvenser under fysisk ansträngning. Studiens ändamål var att undersöka den systoliska och diastoliska vänsterkammarfunktionen under ansträngning hos idrottare och öka förståelsen om vad som händer med de olika variablerna under arbete. Nio friska idrottare genomförde stressekokardiografi där cardiac index, ejektionsfraktion, fyllnadstryck, mitralisklaffplanets longitudinella rörelse (MAPSE), mitralisinflöde, vävnadsdoppler (e´ och s´) och veninflöde undersöktes före, under och efter ett ansträngningstest på ergometercykel. Variablerna under och efter cykeltestet jämfördes sedan med värdena i vila. Resultaten visade en signifikant ökning av cardiac index, MAPSE och vävnadsdoppler under ansträngning. Sammanfattningsvis visade studien att flera av variablerna förbättrades under ansträngning och en del av de visade sig vara relativt okänsliga för störningar och artefakter vilket kan vara användbart för framtida studie protokoll som avser utföra en hjärtstudie under arbete. / Athlete’s heart is a cardiovascular condition that occurs during extended periods of intense exercise that causes structural, functional and electrical changes of the heart and is a physiological adaptation in response to increased hemodynamic needs during physical exertion. However, the physiological adaptations have become a diagnostic dilemma to distinguish from the pathological changes such as hypertrophic cardiomyopathy. Therefore, there is a need for standardization of cardiovascular screening in athletes to detect underlying or hidden cardiomyopathies that can lead to severe consequences during physical exercise. The aim of the present study was to investigate the systolic and diastolic left ventricular function during exercise in athletes and to increase the understanding of what happens to the various variables during exertion. Nine healthy athletes conducted stress echocardiography where cardiac index, ejection fraction, filling pressure, mitral annular plane systolic excursion (MAPSE), mitral inflow, tissue Doppler imaging (e 'and s') and pulmonary venous inflow were examined before, during and after a cycle ergometer test. The variables during and after the cycle test were then compared to baseline. The results showed a significant increase in cardiac index, MAPSE, and tissue Doppler imaging during exertion. In conclusion, the study showed that several of the variables improved during exertion and some of them proved to be quite insensitive to disturbances and artifacts, which may be useful in future study protocols that consider carrying out a cardiac study during work.