FUNDAMENTOS: O polimorfismo e a atividade da enzima conversora da angiotensina (ECA) contribuem, de forma significante, na expressão fenotípica e no prognóstico de pacientes com cardiomiopatia. OBJETIVOS: Determinar o polimorfismo da ECA, realizar a sua dosagem sérica e correlacioná-los com o grau de hipertrofia miocárdica e o índice de massa do ventrículo esquerdo em pacientes com cardiomiopatia hipertrófica (CMH) nas formas familiar e não familiar. CASUÍSTICA E MÉTODO: Foram estudados 136 pacientes consecutivos com CMH (69 da forma familiar e 67 da forma não familiar) com média de idade de 40,53±17,45 anos, sendo 76 do sexo masculino. Os indivíduos foram submetidos ao ecocardiograma para obtenção das medidas do septo interventricular, parede posterior e massa do ventrículo esquerdo e coleta de sangue para determinação do polimorfismo e dosagem sérica da atividade da ECA. RESULTADOS: Quanto ao genótipo do polimorfismo do gene da ECA, encontramos DD 47(35%), ID 71(52%) e II 18 (13%), sendo que do genótipo DD 34% na forma familiar e 36% na forma não familiar. A média da atividade da ECA foi de 56.414±19.236 para os pacientes com CMH na forma familiar e de 55.085±22.634 para a forma não familiar (p = 0,714). A média do índice de massa do ventrículo esquerdo na forma familiar foi 154±63 g/m2 e na forma não familiar foi 174±57 g/m2 (p = 0,008). A média do septo interventricular nas formas familiar e não familiar foi, respectivamente, 19±5 mm e 21±5 mm (p = 0,020). A média da parede posterior do ventrículo esquerdo nas formas familiar e não familiar foi, respectivamente, 10±2 mm e 12±3 mm (p = 0,0001). Não observamos correlação entre o polimorfismo e o grau de hipertrofia miocárdica (p = 0,651). Houve correlação positiva entre a atividade da ECA e o índice de massa do ventrículo esquerdo (p = 0,038). Os pacientes com a forma familiar, pela curva de regressão logística, possuíam o risco de apresentar índice de massa maior ou igual 190 g/m2, somente com o dobro do valor da atividade da ECA, quando comparados aos pacientes com a forma não familiar (p = 0,022). CONCLUSÕES: Não houve diferença estatisticamente significante entre o genótipo do polimorfismo e da atividade da ECA nos pacientes com CMH nas formas familiar e não familiar. Não houve correlação entre o polimorfismo da ECA e o grau de hipertrofia miocárdica. Houve correlação positiva entre a atividade da ECA e o índice de massa do ventrículo esquerdo. / BACKGROUND: The polymorphism and the activity of the angiotensin converting enzyme (ACE) contributes of significant form in the phenotypic expression and the prognostic of patients with cardiomyopathy. OBJECTIVES: To determine the ACE polymorphism and ACE plasma levels in patients with hypertrophic cardiomyopathy (HCM) in the familial and nonfamilial forms and to correlate it with the degree of myocardium hypertrophy and with the left ventricular mass index. PATIENTS AND METHODS: 136 consecutive patients with HCM (69 of familial and 67 of nonfamilial forms) were studied. The mean age was 40.53±17.45 years, 76 were male. The individuals were submitted to the Echo-Doppler for the measurement of interventricular septum, wall thickness and the left ventricular mass index. The blood samples were taken for extraction of the DNA for the polymerase reaction and measurement of ACE plasma levels. RESULTS: Regarding the genotype of the ACE gene polymorphism, we found DD 47 (35%), ID 71 (52%) and II 18 (13%), being that of genotype DD 34% in the familial and 36% in the nonfamilial forms. The mean of the activity of the ACE was 56.414±19.236 for the patients with HCM in the familial form and 55.085±22.634 in the non familial form (p = 0.714). The mean of the left ventricular mass index in the familial form was 154±63 g/m2 and in the nonfamilial form was 174±57 g/m2 (p = 0.0080). The mean of interventricular septum in the familial and nonfamilial forms was 19±5 mm and 21±5 mm (p = 0.0200), respectively. The mean of the wall thickness in the familial and nonfamilial forms was 10±2 mm and 12±3 mm (p = 0.0001), respectively. We did not observe correlation between the polymorphism and the degree of myocardium hypertrophy (p = 0.651). A positive correlation between the activity of the ACE and the left ventricular mass index (p = 0.038) was observed. In patients with the familial form, using a logistic regression curve, they had the risk to present the left ventricular mass index >= 190 g/m2, only with the double of the value of the activity of the ACE, when compared with the patients in the nonfamilial form (p = 0.022). CONCLUSIONS: There was no difference between the patients with HCM in the familial and nonfamilial forms regarding genotype of the polymorphism and activity of the ACE. There was no correlation between the polymorphism of the ACE with the degree of myocardium hypertrophy. Positive correlation with the activity of the ACE and the left ventricular mass index was observed.

Die chirurgische Mitralklappenrekonstruktion (MKR) ist der konservativen Therapie bei signifikanter Mitralklappeninsuffizienz (MI) überlegen. Bisher fehlen sensitive präoperative Parameter zur Detektion latenter linksventrikulärer Funktionsstörungen. Aufgrund der pathophysiologisch bedingten Nachlastreduktion und Vorlaststeigerung bei MI bergen die konventionell verwendeten Ejektionsindices, Ejektionsfraktion (EF) und Fractional Area Change (FAC), die Gefahr der Überschätzung der effektiven Pumpfunktion des linken Ventrikels (LV). Der dopplersonographisch erhobene Tei Index gilt als ein Marker globaler myokardialer Funktion. Ziel der vorliegenden Studie war es, mit dem Tei Index (bzw. dem Myokardialen Performance Index, MPI) einen sensitiveren präoperativen Parameter zur Prädiktion der postoperativen linksventrikulären Funktion zu finden. Hierzu wurden im Rahmen einer prospektiven klinischen Studie 130 Patienten mit signifikanter MI am Herzzentrum Leipzig entsprechend den ASE/SCA Leitlinien vor und nach kardiopulmonaler Bypass-Operation mittels transösophagealer echokardiographischer (TEE) Bildgebung untersucht. Die Quantifizierung der MI erfolgte durch Messung der Vena contracta (VC). Die FAC wurde in der transgastrischen midpapillären kurzen Achse und die EF im midösophagealen Zwei- sowie Vier-Kammer-Blick erfasst. Die Zeitintervalle zur Berechnung des Tei Index wurden im tiefen transgastrischen und midösophagealen Vier-Kammer-Blick erfasst. Eine statistische Korrelation zwischen präoperativen Tei Index und postoperativer EF und FAC konnte zur Validierung unserer Hypothese nicht detektiert werden. Folgend kann der Tei Index nicht als Prädiktor der effektiven linksventrikulären Funktion vor MKR gewertet werden.

Patienten mit Herzinsuffizienz im Endstadium erhalten zunehmend linksventrikuläre Unterstützungssysteme (LVAD) als Dauertherapiemittel oder zur Überbrückung bis zu einer möglichen Herztransplantation. Diese Patientenklientel ist grundsätzlich durch die Driveline, als potenzielle Eintrittsstelle für Mikroorganismen, einem Infektionsrisiko ausgesetzt. Die Mundhöhle beinhaltet diverse Bakterien, die sich auch systemisch verbreiten können und so eine mögliche Quelle für Driveline-Infektionen darstellen. Es ist jedoch unklar, ob bei LVAD-Patienten Erkrankungen der Mundhöhle durch Bakteriämien zu systemischen Komplikationen und Driveline-Infektionen führen können. Aktuell fehlt es an Studien zum Mundgesundheitszustand bei diesen Patienten und über einen möglichen Zusammenhang von oralen Erkrankungen und Driveline-Infektionen. Ziel dieser Studie war daher die Beurteilung des Mundgesundheitsverhaltens, des Mundgesundheitszustands sowie der mundgesundheitsbezogenen Lebensqualität von LVAD-Patienten. Bei den in dieser Studie untersuchten LVAD-Patienten traten vermehrt schwere Parodontitiden auf. Da Parodontitis das Risiko und das Ausmaß einer systemischen Bakteriämie erhöht und möglicherweise zu kardiovaskulären Komplikationen führen könnte, kann dieser Zustand als potenziell problematisch betrachtet werden. Die aktuelle Studie konnte jedoch keinen Zusammenhang zwischen Driveline-Infektionen und dem vorliegenden zahnärztlichen Behandlungsbedarf bestätigen, sodass der Einfluss der Mundgesundheit auf systemische, krankheits- und gerätebezogene Parameter unklar bleibt. Insgesamt scheint die Erarbeitung eines interdisziplinären zahnärztlichen Versorgungskonzeptes nötig, um die unzureichende Mundgesundheitssituation von LVAD-Patienten zu verbessern.:1 Einführung 1.1 Herzinsuffizienz 1.1.1 Definition und Klassifikation 1.1.2 Ätiologie und Epidemiologie 1.1.3 Therapie 1.2 Ventrikuläre Unterstützungssysteme 1.2.1 Einteilung, Funktionsprinzipien und Aufbau 1.2.2 Indikation und Therapiekonzepte 1.2.3 Komplikationen und Überlebensraten 1.3 Mundgesundheit bei Herzinsuffizienzpatienten 1.3.1 Mundgesundheit 1.3.2 Karies 1.3.3 Parodontitis 1.3.4 Bedeutung der Mundgesundheit bei Herzinsuffizienzpatienten und zahnärztliche Therapiekonzepte 1.4 Zielsetzung und Fragestellung 2 Publikationsmanuskript 3 Zusammenfassung der Arbeit 4 Ausblick 5 Literaturverzeichnis 6 Wissenschaftliche Präsentationen 7 Darstellung des eigenen Beitrages 8 Erklärung über die eigenständige Abfassung der Arbeit 9 Danksagung

Background: The use of percutaneous left ventricular assist devices in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) is evolving. The aim of the study was to assess the long-term outcome of patients with AMICS depending on early initiation of Impella CP® support prior to a percutaneous coronary intervention (PCI). Methods: We retrospectively reviewed all patients who underwent PCI and Impella CP® support between 2014 and 2016 for AMICS at our institution. We compared survival to discharge between those with support initiation before (pre-PCI) and after (post-PCI) PCI. Results: A total of 73 consecutive patients (69±12 years old, 27.4% female) were supported with Impella CP® and underwent PCI for AMICS (34 pre-PCI vs. 39 post-PCI). All patients were admitted with cardiogenic shock, and 58.9% sustained cardiac arrest. Survival at discharge was 35.6%. Compared with the post-PCI group, patients in the pre-PCI group had more lesions treated (p=0.03), a higher device weaning rate (p=0.005) and higher survival to discharge as well as to 30 and 90 days after device implantation, respectively (50.0% vs. 23.1%, 48.5% vs. 23.1%, 46.9 vs. 20.5%, p < 0.05). Kaplan–Meier analysis showed a higher survival at one year (31.3% vs. 17.6%, log-rank p-value=0.03) in the pre-PCI group. Impella support initiation before PCI was an independent predictor of survival up to 180 days after device implantation. Conclusions: In this small, single-centre, non-randomized study Impella CP® initiation prior to PCI was associated with higher survival rates at discharge and up to one year in AMICS patients presenting with high risk for in-hospital mortality.

In adult heart, pressure overload leads to cardiac hypertrophy. Higher propensity of hypertrophied myocardium to life-threatening arrhythmia is attributed to structural, mechanical and electrical remodeling. Pro-arrhythmogenic remodeling comprise several factors depending on an experimental model and a stage of heart failure. This thesis aims to characterize the impact of these factors in our unique model of pressure overloaded neonatal rat heart. The constriction of abdominal aorta was performed at postnatal day 2 in male Wistar rats. Decreased body weight, significant since week 6, was observed during development of cardiomegaly. At 12 weeks, the heart to body weight ratio was increased by 45 % and by 109 % in group with compensated (AC I) and decompensated (AC II) heart failure, respectively. At this age, the ECG was recorded and histological and immunohistochemical measurements were performed to analyze the pro-arrhythmogenic remodeling of working myocardium and cardiac conduction system. The markers of pro-arrhytmogenic remodeling such as significant prolongation of QT and QTc intervals were observed in the ECG recordings of AC II animals. However, spontaneously occurring arrhythmias was not detected. Further analysis of working myocardium showed decrease in Cx43 expression and its...

Phenylethanolamine-N-methyltransferase (Pnmt) catalyzes the conversion of noradrenaline to adrenaline and is the last enzyme in the catecholamine biosynthetic pathway. Pnmt serves as a marker for adrenergic cells, and lineage-tracing experiments have identified the embryonic heart and hindbrain region as the first sites of Pnmt expression in the mouse. Pnmt expression in the heart occurs before the adrenal glands have formed and prior to sympathetic innervation, suggesting that the heart is the first site of catecholamine production in the mouse. The function of these Pnmt+ cells in heart development remains unclear. In the present study, we test the hypothesis that (i) a genetic ablation technique utilizing a suicide reporter gene selectively destroys Pnmt cells in the mouse, and (ii) Pnmt cells are required for normal cardiovascular and neurological function. To genetically ablate adrenergic cells, we mated Pnmt-Cre mice, in which Cre-recombinase is under the transcriptional regulation of the Pnmt promoter, and a Cre -activated diphtheria toxin A (DTA) mouse strain (ROSA26-eGFP-DTA), thereby causing activation of the toxic allele (DTA) in Pnmt-expressing (adrenergic) cells resulting in selective "suicide" of these cells in approximately half of the offspring. The other half serve as controls because they do not have the ROSA26-eGFP-DTA construct. In the Pnmt+/Cre; R26+/DTA offspring, we achieve a dramatic reduction in Pnmt transcript and Pnmt immunoreactive area in the adrenal glands. Furthermore, we show that loss of Pnmt cells results in severe left ventricular dysfunction that progressively worsens with age. These mice exhibit severely reduced cardiac output and ejection fraction due to decreased LV contractility and bradycardia at rest. Surprisingly, these mice appear to have a normal stress response, as heart rate and ejection fraction increased to a similar extent compared to controls. In addition to baseline cardiac dysfunction, these mice fail to gain body weight in a normal manner and display gross neurological dysfunction, including muscular weakness, abnormal gaiting, and altered tail suspension reflex, an indicator of neurological function. This work demonstrates that selective Pnmt cell destruction leads to severe left ventricular dysfunction, lack of weight gain, and neurological dysfunction. This novel mouse is expected to shed insight into the role of Pnmt cells in the heart, and suggests a role for Pnmt cells in neurological regulation of feeding behavior, metabolism, and motor control.

No description available.

Cardiovascular diseases are among the leading causes of deaths worldwide, but the fluid mechanics of many of these conditions and the devices used to treat them are only partially understood. This goal of this dissertation was to develop new experimental techniques that would enable translational research into two of these conditions. The first set of experiments examined <i>in-vitro</i> the changes in Wall Shear Stress (WSS) and Oscillatory Shear Index (OSI) caused by the implantation of coronary stents into the arteries of the heart using Particle Image Velocimetry. These experiments featured one-to-one scaling, commercial stents, and realistic flow and pressure waveforms, and are believed to be the most physiologically accurate stent experiments to date. This work revealed distinct differences in WSS and OSI between the different stent designs tested, and showed that changes in implantation configuration also affected these hemodynamic parameters. Also, the production of vortices near the stent struts during flow reversal was noted, and an inverse correlation between WSS and OSI was described. The second set of experiments investigated Left Ventricular Diastolic Dysfunction (LVDD) using phase contrast magnetic resonance imaging (pcMRI). Using this technique, ten patients with and without LVDD were scanned and a 2D portrait of blood flow through their heart was obtained. To augment this data, pressure fields were calculated from the velocity data using an omni-directional pressure integration scheme coupled with a proper-orthogonal decomposition-based smoothing. This technique was selected from a variety of methods from the literature based on an extensive error analysis and comparison. With this coupled information, it was observed that healthy patients exhibited different flow patterns than diseased patients, and had stronger pressure differences during early filling. In particular, the ratio of early filling pressure to late filling pressure was a statistically significant predictor of diastolic dysfunction. Based on these observations, a novel hypothesis was presented that related the motion of the heart walls to the observed flow patterns and pressure gradients, which may explain the differences observed clinically between healthy and diseased patients. / Ph. D.

(1) Background: Hemodynamic assessment of prosthetic heart valves using conventional 2D transthoracic Echocardiography-Doppler (2D-TTE) has limitations. Of those, left ventricular outflow tract (LVOT) area measurement is one of the major limitations of the continuity equation, which assumes a circular LVOT. (2) Methods: This study comprised 258 patients with severe aortic stenosis (AS), who were treated with the ACURATE neo2. The LVOT area and its dependent Dopplerderived parameters, including effective orifice area (EOA) and stroke volume (SV), in addition to their indexed values, were calculated from post-TAVI 2D-TTE. In addition, the 3D-LVOT area from pre-procedural MDCT scans was obtained and used to calculate corrected Doppler-derived parameters. The incidence rates of prosthesis patient mismatch (PPM) were compared between the 2D-TTE and MDCT-based methods (3) Results: The main results show that the 2D-TTE measured LVOT is significantly smaller than 3D-MDCT (350.4 62.04 mm2 vs. 405.22 81.32 mm2) (95% Credible interval (CrI) of differences: 55.15, 36.09), which resulted in smaller EOA (2.25 0.59 vs. 2.58 0.63 cm2) (Beta = 0.642 (95%CrI of differences: 0.85, 0.43), and lower SV (73.88 21.41 vs. 84.47 22.66 mL), (Beta = 7.29 (95% CrI: 14.45, 0.14)), respectively. PPM incidence appears more frequent with 2D-TTE- than 3D-MDCT-corrected measurements (based on the EOAi) 8.52% vs. 2.32%, respectively. In addition, significant differences regarding the EOA among the three valve sizes (S, M and L) were seen only with the MDCT, but not on 2D-TTE. (4) Conclusions: The corrected continuity equation by combining the 3D-LVOT area from MDCT with the TTE Doppler parameters might provide a more accurate assessment of hemodynamic parameters and PPM diagnosis in patients treated with TAVI. The ACURATE neo2 THV has a large EOA and low incidence of PPM using the 3D-corrected LVOT area than on 2D-TTE. These findings need further confirmation on long-term follow-up and in other studies.

Ziel: Die Ergebnisse nach aortokoronarer Bypassoperation (CABG) unterscheiden sich bei Patienten mit schlechter linksventrikulärer Pumpfunktion deutlich von denen bei Patienten ohne Einschränkungen derselben. Das Ziel dieser Studie war die Untersuchung des Einflusses einer reduzierten linksventrikulären Ejektionsfraktion (LVEF), eines vergrößerten linksventrikulären enddiastolischen Volumenindexes (LVEDVI) und eines erhöhten linksventrikulären enddiastolischen Druckes (LVEDP) auf das postoperative "outcome". Material und Methodik: Im Rahmen dieser retrospektiven Studie wurden 148 Patienten mit einer koronaren Herzkrankheit (KHK) und eingeschränkter Ejektionsfraktion (EF / Aim: Results of coronary artery bypass grafting (CABG) in patients with poor left ventricular ejection fraction (LVEF) differ from those in patients with normal LVEF. The aim of the study was a investigation into the influence of reduced LVEF, augmented left ventricular enddiastolic volume index (LVEDVI) and elevated left ventricular enddiastolic pressure (LVEDP) on the outcome of CABG. Methods: 148 Patients with LVEF < 50% underwent CABG. Exercise tolerance and LVEF were determined pre- and postoperatively. Three subgroups were built to distinguish the influence of reduced LVEF on postoperative outcome. Group I: LVEF < 30%, group II: 30% < LVEF < 40%, group III: 40% < LVEF < 50%. Results: Exercise tolerance rised from a preoperatively mean of 70 Watt to 97 Watt postoperatively. Mean NYHA class was 2,7 pre- and 1,7 postoperatively. There were no significant differences in the results of the three subgroups. Perioperative mortality in group I was 6,3%. Actuarial 1 and 2 years survival in this group is at 81 and 70% respectively. These results differ clearly from those of group II and III. Perioperativ mortality was 2,2% in group II and 1,4% in group III. Actuarial 1 and 2 years survival is at 93 and 84% in group II and at 95 and 83% in group III. There was no difference in postoperative outcome of patients with LVEDP > 12mmHg in comparison to patients with LVEDP < 12mmHg. Patients with LVEDVI > 100 ml/m2 had a sifnificant higher peri- and postoperative mortality than patients with LVEDVI < 100 ml/m2. Mean LVEDVI of those patients, whose LVEF increased postoperatively, was 84 ml/m2. Patients with no change in LVEF had a mean LVEDVI of 122 ml/m2. Conclusion: CABG in patients with reduced LVEF improves exercise tolerance and quality of life. Poor LVEF (< 30%) and augmented LVEDVI are predicting higher peri- and postopertive mortality. Postoperative increase of LVEF is unlikely in patients with enlarged left ventricels.