Einleitung Erkrankungen des Bewegungsapparates haben bei Milchkühen eine hohe wirtschaftliche Bedeutung sowie enorme Auswirkungen auf das Tierwohl. Etwa 90 % der Lahmheiten beim Rind werden durch Klauenerkrankungen hervorgerufen. Die Ursachen dieser Klauenerkrankungen sind multifaktoriell und umfassen tier- und umweltassoziierte Faktoren. Die Pododermatitis aseptica diffusa ist eine der wichtigsten Ursachen für die Entstehung von umschriebenen Klauenlederhautentzündungen. In ihrer Pathogenese spielen Veränderungen der Zehendurchblutung eine zentrale Rolle. Die Pulsed-Wave (PW)-Dopplersonographie ist eine nicht invasive Technik zur Beurteilung des Blutflusses an Gefäßen und zur Untersuchung der Durchblutung von Organen. Jedoch liegen keine PW-Dopplersonographischen Untersuchungen an der Zehe des Rindes in der Literatur vor. Ziele der Untersuchungen Ziel der Untersuchungen war es, die Zehendurchblutung bei Rindern, die an einer Pododermatitis circumscripta solearis oder parietalis litten, im Milchviehbetrieb zu erfassen. Dazu wurde in einem ersten Schritt die Methodik der PW-Dopplersonographie an der Zehe der Hintergliedmaßen von gesunden Kühen etabliert. In einem zweiten Schritt wurden Blutflussmerkmale an den Hintergliedmaßen lahmer Kühe, die an einer Pododermatitis circumscripta solearis oder parietalis litten, erfasst, um Auswirkungen der Entzündung sowie weiterer als relevant erscheinender Einflussfaktoren für die Zehendurchblutung zu untersuchen. Material und Methoden In der Publikation 1 wurden 22 gesunde Deutsch Holstein Kühe einbezogen. Die Versuchstiere wurden im Betrieb einer klinischen Untersuchung inklusive einer Lahmheitsbeurteilung sowie einer Klauenpflege aller Gliedmaßen unterzogen. Am zweiten Versuchstag wurde eine sonographische Untersuchung beider Hintergliedmaßen am stehenden Tier durchgeführt. Zur sonographischen Untersuchung wurde das MyLab One (Esaote Deutschland GmbH) mit einem Linearschallkopf (10 MHz) ohne Vorlaufstrecke verwendet. Mittels Brightness(B)-Mode wurden Weichteilgewebe, synoviale Einrichtungen und Blutgefäße distal des Tarsus untersucht. In der Arteria (A.) interdigitalis wurde der Blutfluss mittels PW-Dopplersonographie beurteilt. Die Auswertung der Daten erfolgte mit dem Programm MyLap Desk auf einem Laptop. In die Publikation 2 wurden 33 lahme und 11 gesunde Deutsch Holstein Kühe einbezogen. Die lahmen Kühe litten an einer superfiziellen bis profunden Pododermatitis an der Außenklaue einer Hintergliedmaße. Die klinische und sonographische Untersuchung erfolgte wie in der Publikation 1 beschrieben. Für die statistische Bearbeitung der Daten wurde die procedure mixed (SAS, Version 9.4) verwendet. Ergebnisse In den Publikationen 1 und 2 konnte an 112 von 132 Hintergliedmaßen bei 66 Kühen ein auswertbares PW-Doppler-Signal gemessen werden. Bei 17 der 20 nicht auswertbaren Hintergliedmaßen lag nur eine mäßige B-Mode-Bildqualität vor. Die lahmen Kühe trippelten bei der sonographischen Untersuchung mehr als die gesunden Kühe. Blutflusskurventypen mit einem niedrigen peripheren Gefäßwiderstand liegen vor allem an den Hintergliedmaßen lahmer Kühe und Kurventypen mit einem hohen Widerstand am häufigsten bei gesunden Kühen vor. Lahme Kühe haben im Vergleich zu nicht-lahmen Kühen einen erhöhten Gefäßdurchmesser (D) und eine gesteigerte Blutflussrate (BF) sowie enddiastolische Blutflussgeschwindigkeit. Es bestehen keine Unterschiede zwischen der betroffenen Gliedmaße und der Gegengliedmaße lahmer Kühe. Ein numerisch höherer D, eine höhere BF sowie maximale systolische und maximale mittlere Blutflussgeschwindigkeit liegen bei Kühen mit einer mittelgradigen Lahmheit vor. Schlussfolgerungen Die PW-Dopplersonographie in Kombination mit dem in der Studie verwendeten Untersuchungsgang ist für die Messung des Blutflusses in der A. interdigitalis an den Hintergliedmaßen des Rindes sehr gut geeignet. Sowohl die bei den Kühen gefundenen Blutflusskurvenprofile als auch die quantitativen Blutflussmerkmale sind mit Werten von Pferden vergleichbar. Es liegt eine gesteigerte Durchblutung an den betroffenen Zehen und denen der Gegengliedmaße von lahmen Kühen im Vergleich zu gesunden Kühen vor. Nicht nur das Vorliegen einer umschriebenen Klauenlederhautentzündung, sondern auch ihr zeitlicher Verlauf, die Auswirkungen einer aktivierten Entzündungskaskade, das Vorliegen einer chronischen Klauenrehe und vor allem die Gewichtsbelastung und die Gewichtsverschiebung zwischen den Hintergliedmaßen müssen in die Beurteilung des digitalen Blutflusses einbezogen werden. Die erstmalig an der Rinderzehe ermittelten Blutflussdaten stellen eine gute Grundlage für weitere Forschungen auf dem Gebiet der Klauenrehe-Pathogenese dar.:Inhaltsverzeichnis 1 Einleitung 1 2 Literaturübersicht 3 2.1 Pododermatitis aseptica diffusa beim Rind 3 2.1.1 Definition 3 2.1.2 Symptomatik 3 2.1.2.1 Klinisches Stadium 3 2.1.2.1.1 Akute Form 3 2.1.2.1.2 Subakute Form 4 2.1.2.1.3 Chronische Form 4 2.1.2.2 Subklinisches Stadium 5 2.1.3 Ätiologie 5 2.1.3.1 Fütterung 5 2.1.3.1.1 Zusammenhang zwischen Fütterung und Dysfunktion des Blutgefäßsystems der Zehe 5 2.1.3.1.2 Kohlenhydrate 7 2.1.3.1.3 Proteine und Aminosäuren 9 2.1.3.1.4 Lipide 10 2.1.3.1.5 Spurenelemente 10 2.1.3.1.5.1 Kupfer 10 2.1.3.1.5.2 Zink 10 2.1.3.1.5.3 Mangan 11 2.1.3.1.5.4 Selen 11 2.1.3.1.6 Vitamine 11 2.1.3.1.6.1 Biotin 11 2.1.3.1.6.2 Vitamine A, D, E 12 2.1.3.1.7 Toxine 12 2.1.3.1.8 Bewertung der Versorgung mit Mineralstoffen, Spurenelementen und Vitaminen für die Klauengesundheit 12 2.1.3.2 Mechanische Faktoren 13 2.1.3.2.1 Digitales Fettpolster 13 2.1.3.2.2 Hypertrophie der Außenklaue an den Hintergliedmaßen 14 2.1.3.2.3 Dünne Sohlen 14 2.1.3.3 Hormonelle Veränderungen während der Transitphase 15 2.1.3.4 Haltung 17 2.1.4 Pathogenese 18 2.1.5 Reheassoziierte Klauenlederhautentzündungen 19 2.2 Anatomie des Blutgefäßsystems beim Rind 20 2.2.1 Arterien der Hintergliedmaße 20 2.2.1.1 Arterien am Ober- und Unterschenkel 20 2.2.1.2 Arterien an Mittelfuß und Zehen 21 2.2.1.2.1 Plantares System 21 2.2.1.2.2 Dorsales System 21 2.2.2 Venen der Hintergliedmaße 21 2.2.2.1 Venen am Ober- und Unterschenkel 21 2.2.2.2 Venen an Mittelfuß und Zehen 22 2.2.2.2.1 Plantares System 22 2.2.2.2.2 Dorsales System 22 2.2.3 Blutgefäßsystem der Klauen 23 2.2.3.1 Arterien 23 2.2.3.2 Venen 23 2.2.3.3 Arterio-venöse Anastomosen 24 2.3 Bildgebende Verfahren zur Darstellung des Gefäßsystems 24 2.3.1 Allgemein 24 2.3.2 Brightness Mode Sonographie 25 2.3.2.1 Prinzip 25 2.3.2.2 Allgemeine Anwendung an der Gliedmaße 25 2.3.2.3 Spezielle Anwendung zur Untersuchung des Blutgefäßsystems an der Gliedmaße distal des Tarsus 26 2.3.3 Pulsed-Wave-Dopplersonographie 27 2.3.3.1 Prinzip 27 2.3.3.2 Merkmale 29 2.3.3.3 Allgemeine Anwendung 30 2.3.3.4 Anwendung an der Gliedmaße 30 2.3.4 Weitere bildgebende Verfahren 33 2.3.4.1 Angiographie 33 2.3.4.1.1 Prinzip 33 2.3.4.1.2 Anwendung an der Gliedmaße 34 2.3.4.2 Szintigraphie 34 2.4 Zusammenfassende Schlussfolgerungen aus dem Literaturstudium 35 3 Publikation 1 37 4 Publikation 2 47 5 Diskussion 59 5.1 Auswahl des Messpunktes und Messbarkeit des Blutflusses 59 5.2 Verhalten 60 5.3 Gliedmaßenstellung 60 5.4 Qualitative Blutflussmerkmale 61 5.5 Quantitative Blutflussmerkmale 62 6 Zusammenfassung 66 7 Summary 68 8 Literaturverzeichnis 70 9 Danksagung 96 / Introduction Diseases of the locomotor system in dairy cattle have a huge economic and welfare importance. Nearly 90 % of lameness in cattle is caused by claw disease. The reasons are multifactorial and include animal as well as environmental factors. Claw horn disruption is the main cause for the development of claw horn lesions. Changes in the blood circulation of the toes play an essential role in their pathogenesis. Pulsed-Wave (PW)-Doppler ultrasonography is a non-invasive technique to evaluate the flow in blood vessels and to examine the blood circulation of an organ. However, there have not been any PW-Doppler ultrasonographical investigations for the bovine limb in the literature yet. Aims The objective of this investigation is to measure the blood flow of the toes in dairy cattle suffering from sole ulcer or white line disease in dairy farms. In a first step the PW-Doppler ultrasonography was established at the toe of hindlimbs in healthy dairy cattle. In a second step blood flow variables in the hindlimbs of lame cows affected by a sole ulcer or white line disease were recorded to evaluate the consequence of inflammation as well as to examine further factors seem to influence the blood flow of the toes. Material and Methods Twenty-two German Holstein cows were included in the first publication. The cows were examined clinically in the farm including an evaluation of the lameness score as well as a claw trimming of all limbs. One day after an ultrasonography was performed in standing position in both hind limbs. For the examination a MyLabOne (Esaote Deutschland GmbH) with a linear transducer without a standoff pad was used. Soft tissue, synovial structures and blood vessels distal of the tarsal region were examined by using a Brightness (B)-mode ultrasonography. In the interdigital arteria the blood flow was measured by PW-Doppler ultrasonography. The analysis of the data was carried out by the program MyLabDesk on a laptop. The second publication included 33 lame and 11 healthy German Holstein cows. The lame cows suffered from a superficial too profound sole ulcer or white line disease at the outer claw of one hind limb. The clinical and ultrasonographical examination took place analogically to the first publication. For the statistical analyses the MIXED procedure (SAS, version 9.4) was used. Results Combining both publications in 112 of 132 hindlimbs a usable PW-Doppler signal was generated. Seventeen of the 20 not usable signals the B-mode quality was moderate. During the ultrasonography lame cows pattered their limbs more often than healthy cows. Blood flow profiles with a low peripheral resistance are more common in the hindlimbs of lame cows and profiles with a high peripheral resistance are most frequent in healthy cows. Lame cows have a higher vessel diameter (D), blood flow rate (BF) and end-diastolic blood flow velocity compared to healthy cows. There was no difference in the affected compared to the opposite limbs of lame cows. A numerical higher D, BF as well as maximum systolic and maximum time-averaged mean blood flow velocity occurred in moderate lame cows compared to mild lame cows. Conclusions The PW-Doppler ultrasonography is well suited for the evaluation of the blood flow in the bovine interdigital artery at the hindlimbs. The observed blood flow profiles as well as quantitative blood flow parameters are comparable to data in horses. There is an increased blood circulation in the affected and the opposite limb of lame cows compared to healthy cows. Not only the existence of the claw horn lesions but also their chronological progress, the influence of the inflammatory cascade, the availability of chronic claw horn disruption and especially weight bearing and weight shifting between hindlimbs have to be considered in the assessment of the blood flow of toes. The for the first-time generated blood flow parameters provide a good basis for further investigations in the topic of claw horn disruption pathogenesis.:Inhaltsverzeichnis 1 Einleitung 1 2 Literaturübersicht 3 2.1 Pododermatitis aseptica diffusa beim Rind 3 2.1.1 Definition 3 2.1.2 Symptomatik 3 2.1.2.1 Klinisches Stadium 3 2.1.2.1.1 Akute Form 3 2.1.2.1.2 Subakute Form 4 2.1.2.1.3 Chronische Form 4 2.1.2.2 Subklinisches Stadium 5 2.1.3 Ätiologie 5 2.1.3.1 Fütterung 5 2.1.3.1.1 Zusammenhang zwischen Fütterung und Dysfunktion des Blutgefäßsystems der Zehe 5 2.1.3.1.2 Kohlenhydrate 7 2.1.3.1.3 Proteine und Aminosäuren 9 2.1.3.1.4 Lipide 10 2.1.3.1.5 Spurenelemente 10 2.1.3.1.5.1 Kupfer 10 2.1.3.1.5.2 Zink 10 2.1.3.1.5.3 Mangan 11 2.1.3.1.5.4 Selen 11 2.1.3.1.6 Vitamine 11 2.1.3.1.6.1 Biotin 11 2.1.3.1.6.2 Vitamine A, D, E 12 2.1.3.1.7 Toxine 12 2.1.3.1.8 Bewertung der Versorgung mit Mineralstoffen, Spurenelementen und Vitaminen für die Klauengesundheit 12 2.1.3.2 Mechanische Faktoren 13 2.1.3.2.1 Digitales Fettpolster 13 2.1.3.2.2 Hypertrophie der Außenklaue an den Hintergliedmaßen 14 2.1.3.2.3 Dünne Sohlen 14 2.1.3.3 Hormonelle Veränderungen während der Transitphase 15 2.1.3.4 Haltung 17 2.1.4 Pathogenese 18 2.1.5 Reheassoziierte Klauenlederhautentzündungen 19 2.2 Anatomie des Blutgefäßsystems beim Rind 20 2.2.1 Arterien der Hintergliedmaße 20 2.2.1.1 Arterien am Ober- und Unterschenkel 20 2.2.1.2 Arterien an Mittelfuß und Zehen 21 2.2.1.2.1 Plantares System 21 2.2.1.2.2 Dorsales System 21 2.2.2 Venen der Hintergliedmaße 21 2.2.2.1 Venen am Ober- und Unterschenkel 21 2.2.2.2 Venen an Mittelfuß und Zehen 22 2.2.2.2.1 Plantares System 22 2.2.2.2.2 Dorsales System 22 2.2.3 Blutgefäßsystem der Klauen 23 2.2.3.1 Arterien 23 2.2.3.2 Venen 23 2.2.3.3 Arterio-venöse Anastomosen 24 2.3 Bildgebende Verfahren zur Darstellung des Gefäßsystems 24 2.3.1 Allgemein 24 2.3.2 Brightness Mode Sonographie 25 2.3.2.1 Prinzip 25 2.3.2.2 Allgemeine Anwendung an der Gliedmaße 25 2.3.2.3 Spezielle Anwendung zur Untersuchung des Blutgefäßsystems an der Gliedmaße distal des Tarsus 26 2.3.3 Pulsed-Wave-Dopplersonographie 27 2.3.3.1 Prinzip 27 2.3.3.2 Merkmale 29 2.3.3.3 Allgemeine Anwendung 30 2.3.3.4 Anwendung an der Gliedmaße 30 2.3.4 Weitere bildgebende Verfahren 33 2.3.4.1 Angiographie 33 2.3.4.1.1 Prinzip 33 2.3.4.1.2 Anwendung an der Gliedmaße 34 2.3.4.2 Szintigraphie 34 2.4 Zusammenfassende Schlussfolgerungen aus dem Literaturstudium 35 3 Publikation 1 37 4 Publikation 2 47 5 Diskussion 59 5.1 Auswahl des Messpunktes und Messbarkeit des Blutflusses 59 5.2 Verhalten 60 5.3 Gliedmaßenstellung 60 5.4 Qualitative Blutflussmerkmale 61 5.5 Quantitative Blutflussmerkmale 62 6 Zusammenfassung 66 7 Summary 68 8 Literaturverzeichnis 70 9 Danksagung 96

O objetivo do presente estudo foi avaliar os fluxos das valvas aórtica (AO) e pulmonar (Pul) por meio de análise qualitativa (presença de regurgitações valvares e características do espectro avaliado) e quantitativa, com obtenção de parâmetros ecocardiográficos como velocidades máxima (V. Max.) e média (V. Me.), integral de velocidade (VTI), tempo de aceleração (TA) e ejeção (TE), volume sistólico (VS) e débito cardíaco (DC). Foram utilizados 30 cães, que após considerados clinicamente sadios por meio de exames físico, laboratoriais, eletrocardiográfico, ecocardiográfico (modos uni e bidimensional), radiográfico de tórax e mensuração da pressão arterial sistêmica, obtiveram-se os seguintes resultados para os referidos parâmetros: V.max. AO= 1,215 + 19,38 m/s; V. Me. AO= 0,722 + 0,08206 m/s; VTI AO= 0,141 + 0,02426m; TA AO= 38,80 + 11,29 ms; TE AO= 197,9 + 24,77 ms; VS AO= 29,63 + 14,59 mL; DC AO= 2,940 + 1,260 L/ min.; V. Max. Pul= 0,9457 + 0,1792 m/s; V. Me. Pul= 0,632 + 0,09960 m/s; VTI Pul= 0,1267 + 0,02324 m; TA Pul= 70,97 + 18,87 ms; TE Pul= 203,7 + 28,98 ms; VS Pul= 28,52 + 17,96 mL; DC Pul= 3,056 + 1,546 L/ min.. Em apenas três animais observou-se regurgitação pulmonar. Alguns parâmetros tiveram correlação negativa com a variável freqüência cardíaca (VTI AO, TE AO, VTI Pul, TA Pul, TE Pul, VS Pul), outros correlação positiva com a variável peso (VTI AO, TA AO, TE AO, VS AO, DC AO, VTI Pul, TE Pul, VS Pul, DC Pul), não sendo encontrada influência da variável sexo na maioria dos parâmetros avaliados. Na comparação entre os dois fluxos, observaram-se V. Max. AO e V. Me. AO maiores que V. Max. Pul. e V. Me. Pul., respectivamente, VTI AO maior que VTI Pul, e TA AO menor que TA Pul. Observada ainda uma correlação positiva e significativa entre VS AO e VS Pul e entre DC AO e DC Pul. / The purpose of this study was the evaluation of aortic (AO) and pulmonary (Pul) valves flow for the qualitative (valvar insufficiency presence, characteristic of flow profile) and quantitative analysis, obtaining this way chocardiographic parameters as: peak (PV) and mean (MV) velocities, velocity-time integral (VTI), acceleration (AT) and ejection (ET) time, stroke volume (SV) and cardiac output (CO). Thirty dogs were studied, and to be considered normal, physical, laboratory, electrocardiographic, echocardiographic (uni and bidimensional mode) exams, torax radiographs, and measurement of the blood pressure were accomplished, and the following echocardiographic parameters were obtained: AO PV= 1,215 19,38 m/s; AO MV= 0,722 + 0,08206 m/s; AO VTI= 0,141 + 0,02426m; AO AT= 38,80 + 11,29 ms; AO ET= 197,9 + 24,77 ms; AO SV= 29,63 + 14,59 mL; AO CO= 2,940 + 1,260 L/ min.; Pul PV= 0,9457 + 0,1792 m/s; Pul MV= 0,632 + 0,09960 m/s; Pul VTI= 0,1267 + 0,02324 m; Pul AT= 70,97 + 18,87 ms; Pul ET= 203,7 + 28,98 ms; Pul SV= 28,52 + 17,96 mL; Pul CO= 3,056 + 1,546 L/ min. The variable heart rate had negative correlation with AO VTI, AO ET, Pul VTI, Pul AT, Pul ET, Pul SV, and the variable weight had positive correlation with AO VTI, AO AT, AO ET, AO SV, AO CO, Pul VTI, Pul ET, Pul SV, Pul CO, differently from the variable sex, that had no influence on the evaluated parameters. The comparation of aortic and pulmonary valves flow demonstrated AO PV and AO MV higher than Pul PV and Pul MV, respectively, AO VTI higher than Pul VTI, and Pul AT higher than AO AT. The statistical evaluation also showed a strong and positive correlation between AO SV and Pul SV and between AO CO and Pul CO.

O objetivo do presente estudo foi avaliar os fluxos das valvas aórtica (AO) e pulmonar (Pul) por meio de análise qualitativa (presença de regurgitações valvares e características do espectro avaliado) e quantitativa, com obtenção de parâmetros ecocardiográficos como velocidades máxima (V. Max.) e média (V. Me.), integral de velocidade (VTI), tempo de aceleração (TA) e ejeção (TE), volume sistólico (VS) e débito cardíaco (DC). Foram utilizados 30 cães, que após considerados clinicamente sadios por meio de exames físico, laboratoriais, eletrocardiográfico, ecocardiográfico (modos uni e bidimensional), radiográfico de tórax e mensuração da pressão arterial sistêmica, obtiveram-se os seguintes resultados para os referidos parâmetros: V.max. AO= 1,215 + 19,38 m/s; V. Me. AO= 0,722 + 0,08206 m/s; VTI AO= 0,141 + 0,02426m; TA AO= 38,80 + 11,29 ms; TE AO= 197,9 + 24,77 ms; VS AO= 29,63 + 14,59 mL; DC AO= 2,940 + 1,260 L/ min.; V. Max. Pul= 0,9457 + 0,1792 m/s; V. Me. Pul= 0,632 + 0,09960 m/s; VTI Pul= 0,1267 + 0,02324 m; TA Pul= 70,97 + 18,87 ms; TE Pul= 203,7 + 28,98 ms; VS Pul= 28,52 + 17,96 mL; DC Pul= 3,056 + 1,546 L/ min.. Em apenas três animais observou-se regurgitação pulmonar. Alguns parâmetros tiveram correlação negativa com a variável freqüência cardíaca (VTI AO, TE AO, VTI Pul, TA Pul, TE Pul, VS Pul), outros correlação positiva com a variável peso (VTI AO, TA AO, TE AO, VS AO, DC AO, VTI Pul, TE Pul, VS Pul, DC Pul), não sendo encontrada influência da variável sexo na maioria dos parâmetros avaliados. Na comparação entre os dois fluxos, observaram-se V. Max. AO e V. Me. AO maiores que V. Max. Pul. e V. Me. Pul., respectivamente, VTI AO maior que VTI Pul, e TA AO menor que TA Pul. Observada ainda uma correlação positiva e significativa entre VS AO e VS Pul e entre DC AO e DC Pul. / The purpose of this study was the evaluation of aortic (AO) and pulmonary (Pul) valves flow for the qualitative (valvar insufficiency presence, characteristic of flow profile) and quantitative analysis, obtaining this way chocardiographic parameters as: peak (PV) and mean (MV) velocities, velocity-time integral (VTI), acceleration (AT) and ejection (ET) time, stroke volume (SV) and cardiac output (CO). Thirty dogs were studied, and to be considered normal, physical, laboratory, electrocardiographic, echocardiographic (uni and bidimensional mode) exams, torax radiographs, and measurement of the blood pressure were accomplished, and the following echocardiographic parameters were obtained: AO PV= 1,215 19,38 m/s; AO MV= 0,722 + 0,08206 m/s; AO VTI= 0,141 + 0,02426m; AO AT= 38,80 + 11,29 ms; AO ET= 197,9 + 24,77 ms; AO SV= 29,63 + 14,59 mL; AO CO= 2,940 + 1,260 L/ min.; Pul PV= 0,9457 + 0,1792 m/s; Pul MV= 0,632 + 0,09960 m/s; Pul VTI= 0,1267 + 0,02324 m; Pul AT= 70,97 + 18,87 ms; Pul ET= 203,7 + 28,98 ms; Pul SV= 28,52 + 17,96 mL; Pul CO= 3,056 + 1,546 L/ min. The variable heart rate had negative correlation with AO VTI, AO ET, Pul VTI, Pul AT, Pul ET, Pul SV, and the variable weight had positive correlation with AO VTI, AO AT, AO ET, AO SV, AO CO, Pul VTI, Pul ET, Pul SV, Pul CO, differently from the variable sex, that had no influence on the evaluated parameters. The comparation of aortic and pulmonary valves flow demonstrated AO PV and AO MV higher than Pul PV and Pul MV, respectively, AO VTI higher than Pul VTI, and Pul AT higher than AO AT. The statistical evaluation also showed a strong and positive correlation between AO SV and Pul SV and between AO CO and Pul CO.

I. Extensive experimental and clinical data suggest that certain electrical and structural changes develop in the atria of patients with atrial fibrillation (AF). These alterations are commonly referred as atrial remodeling and are considered to play a crucial role in the self-perpetuation of this arrhythmia. a. A hallmark of LA structural remodeling is the LA dilatation which is a predictor for progression to chronic AF and therapeutic failure as well. However, AF is associated not only with LA enlargement but also with asymmetrical changes in the left atrial geometry. b. Furthermore, the electrical remodeling is characterized by slower and asynchronous inter- and intra-atrial conduction that also contributes to the maintenance of AF. Some studies suggested a role of the conduction block in the Bachmann’s bundle, connecting the right and left atrium, in the AF pathophysiology and LA remodeling. II. Echocardiography and especially the tissue Doppler method can provide additional insight into the nature of the LA remodeling, because it allows the characterization of the intrinsic LA velocities. a. Using pulsed-wave tissue Doppler (PW-TDI) is possible to measure the interval from the onset of the surface P wave to the A´ velocity at the lateral mitral annulus as a representation of the total interatrial conduction time (TACT). In number of studies, it was demonstrated that prolonged TACT was associated with new-onset AF, AF after open heart surgery, and AF recurrences after electrical cardioversion and catheter ablation. b. An important limitation of the previous studies is that TACT has never been validated by direct measurements of the true electrical conduction in the LA. Moreover, it was assumed that the activation of the lateral MA must be the latest LA activation site. III. In this study, we sought to evaluate the feasibility of the PW-TDI as a simple and quick method to evaluate the LA asynchrony. For the purpose, we measured the time intervals from the onset of P-wave to the A´ (P-A´) in PW-TDI at 4 different left atrial sites next to mitral annulus (septal, lateral, anterior and inferior) in patients referred for electrophysiological study and catheter ablation because of atrial fibrillation or other arrhythmias. a. The differences between the longest and shortest P-A´ (DLS-PA´), as well as the standard deviation (SD-4PA´) of all 4 values were calculated as indexes for LA asynchrony. Importantly, LA asynchrony in patients with AF was compared with a matched control group of patients without history of AF. b. Moreover, the TACT was validated by comparing it with the actual electrical activation of the left atrium measured directly in the coronary sinus. For this purpose, the intervals between the onset of the P-wave and the local LA activation at the distal electrode pair of a catheter inserted in the coronary sinus were measured. c. Having in mind the ovoid LA shape and asymmetrical changes in LA geometry observed in patients with AF, we hypothesized that the lateral mitral annulus may not always be the latest activation spot. Therefore, we sought to determine the latest LA activation site exhibiting the longest P-A´ interval, as well as to describe the sequence of LA activation in AF patients and non-AF controls. IV. One hundred and thirty patients with AF (AF group) and 70 patients without a history of AF (non-AF control group) were examined prospectively using PW-TDI. a. Both groups were matched for the baseline characteristics, including LA diameter. The P-A´ interval measured with PW-TDI at the lateral LA showed a strong, positive, linear correlation with the P-A activation at the distal poles of the CS catheter at the lateral MA: Pearson r=0.708; P=0.0001. b. Asynchrony in the AF group was more pronounced in comparison to the non-AF control group. Patients in the AF group had longer DLS-PA´ as compared to controls: 37±16 msec. vs. 28±13 msec.; P=0.0001, as well as bigger SD-4PA´: 17±7 msec. vs. 13±5 msec.; P=0.0001. c. Furthermore, distinct patterns of LA activation were observed. Most AF patients (86.5%) showed an upward LA activation with inferior LA breakthrough, whereas the non-AF controls exhibited mostly a downward LA activation (65.5%), spreading from LA roof downwards. d. ROC analysis revealed that P-A´ at anterior LA successfully discriminated patients with AF from the non-AF controls (AUC 0.85, P<0.0001). A cut off value for P-A´ anterior > 55 msec. discriminated between AF patients and controls with 85% sensitivity; 81% specificity; positive predictive value of 0.898, and negative predictive value of 0.707. V. In conclusion, PW-TDI can be reliably used to assess the LA asynchrony. Patients with atrial fibrillation showed greater LA asynchrony in PW-TDI independently from the LA dimensions. For the first time, we described that LA activation showed 3 distinct patterns with the upward LA activation being the most frequently observed in patients with AF. Patients with AF demonstrated a prolonged P-A´ activation time at the anterior left atrium. P-A´ at anterior LA > 55 msec. discriminates between patients with AF and non-AF controls with high sensitivity and specificity. This method can be useful to identity patients at risk for occurrence of new-onset atrial fibrillation, as well as to assess the severity of the LA remodeling in order to improve the selection of patients for catheter ablation.:Table of Contents 1 Background 5 1.1 Mechanisms of initiation and perpetuation of atrial fibrillation 5 1.2 Left atrial remodeling in atrial fibrillation 7 1.3 Echocardiographic assessment of left atrial remodeling 8 1.4 Pathophysiology of interatrial conduction in atrial fibrillation 10 2 Objectives and methods 11 2.1 Study objectives 11 2.2 Methods 11 2.2.1 Echocardiography 13 2.2.2 Electrophysiological study 15 2.2.3 Statistical methods 16 3 Publication 17 4 Discussion 26 5 Limitations 30 6 Conclusion 31 7 Synopsis 32 8 References 36 9 Selbstständigkeitserklärung 47 10 Curriculum vitae and list of publications 48 11 Danksagung /Acknowledgments 56