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Background: Acute coronary syndrome is known for its effect on cardiac function and can lead to impaired segmental and even global myocardial function. Evidence exists that myocardial revascularisation whether pharmacological, interventional or surgical results in improvement of systolic and diastolic left ventricular (LV) function, particularly that of the long axis which represents the sub-endocardial function, known as the most sensitive layer to ischaemia. Objective: We sought to gain more insight into the early effect of pharmacological and interventional myocardial revascularisation on various aspects of cardiac function including endocrine, electrical, segmental, twist, right ventricular (RV) and left atrial (LA) function. In particular, we aimed to assess the response of ventricular electromechanical function to thrombolysis and its relationship with peptides levels. We also investigated the behaviour of RV function in the setting of LV inferior myocardial infarction (IMI) during the acute insult and early recovery. In addition, we aimed to assess in detail LA electrical and mechanical function in such patients. Finally, we studied the early effect of surgical revascularisation on the LV mechanics using the recent novel of speckle tracking echocardiography technology to assess rotation, twist and torsion and the strain deformation parameters as a tool of identifying global ventricular function. Methods: We used conventionally Doppler echocardiographic transthoracic techniques including M-mode, 2-Dimentional, myocardial tissue Doppler, and speckle tracking techniques. Commercially available SPSS as a software was used for statistical analysis. Results: 1-The elevated peptide levels at 7 days post-myocardial infarction correlated with the reduced mechanical activity of the adjacent non-infarcted segment thus making natriuretic peptides related to failure of compensatory hyperdynamic activity of the non-infarcted area rather than the injured myocardial segments. 2-RV segmental and global functions were impaired in acute IMI, and recovered in 87% of patients following thrombolysis. In the absence of clear evidence for RV infarction the disturbances in the remaining 13% may represent stunned myocardium with its known delayed recovery. 3-LA electromechanical function was impaired in acute inferior STEMI and improved after thrombolysis. The partial functional recovery suggests either reversible ischaemic pathology or a response to a non-compliant LV segment. The residual LA electromechanical and pump dysfunction suggest intrinsic pathology, likely to be ischaemic in origin. 4-LV function was maintained in a group of patients with multivessel coronary artery disease who underwent coronary artery bypass graft (CABG) surgery. Surgical myocardial revascularisation did not result in any early detectable change in the three functional components of the myocardium, including twist and torsion, as opposite to conventional percutaneous coronary intervention (PCI). Conclusion: The studied different materials in this thesis provide significant knowledge on various aspects of acute ischaemic cardiac pathology and early effect of revascularisation. The use of non-invasive imaging, particularly echocardiography with its different modalities, in studying such patients should offer immediate thorough bed-side assessment and assist in offering optimum management.

Atrial natriuretic factor (ANF) is a cardiac hormone that helps maintain cardiovascular homeostasis. ANF secretion is linked to the constitutive, regulated and constitutive-like pathways. Presence of a monensin-sensitive pool that may follow constitutive-like secretion has previously been identified in an isolated atrial perfusion study. The intracellular ANF storage pools linked to each secretory pathway have not been identified. In this study, ANF storage and secretion was characterized in HL-1 atrial cardiomyocytes through the use of pharmacological agents, density gradient and RP- HPLC analysis. Treatment of HL-1 cells with monensin followed by cell fractionation was unsuccessful in identifying the monensin-sensitive pool. RP-HPLC analysis identified presence of low molecular weight ANF in low density gradient fractions that were defined by the presence of organelle markers of Golgi, early endosome, clathrin and corin. Since the monensin-sensitive pool was thought to be of a constitutive-like nature, targeting this pathway with pharmacological inhibitors of clathrin coat vesicle (CCV) formation and endosomal trafficking failed to prevent stimuli-independent secretion. Based on an inability to prevent ANF secretion by targeting the constitutive-like pathway and the presence of low molecular weight ANF in low density gradient fractions, stimuli- independent ANF secretion seems to be through a constitutive pathway.

Atrial natriuretic factor (ANF) is a cardiac hormone that helps maintain cardiovascular homeostasis. ANF secretion is linked to the constitutive, regulated and constitutive-like pathways. Presence of a monensin-sensitive pool that may follow constitutive-like secretion has previously been identified in an isolated atrial perfusion study. The intracellular ANF storage pools linked to each secretory pathway have not been identified. In this study, ANF storage and secretion was characterized in HL-1 atrial cardiomyocytes through the use of pharmacological agents, density gradient and RP- HPLC analysis. Treatment of HL-1 cells with monensin followed by cell fractionation was unsuccessful in identifying the monensin-sensitive pool. RP-HPLC analysis identified presence of low molecular weight ANF in low density gradient fractions that were defined by the presence of organelle markers of Golgi, early endosome, clathrin and corin. Since the monensin-sensitive pool was thought to be of a constitutive-like nature, targeting this pathway with pharmacological inhibitors of clathrin coat vesicle (CCV) formation and endosomal trafficking failed to prevent stimuli-independent secretion. Based on an inability to prevent ANF secretion by targeting the constitutive-like pathway and the presence of low molecular weight ANF in low density gradient fractions, stimuli- independent ANF secretion seems to be through a constitutive pathway.

Atrial fibrillation (AF) confers an independent increased risk of stroke and death. The stroke risk is very heterogeneous and current risk stratification models based on clinical variables, such as the CHADS2 and CHA2DS2VASc score, only offer a modest discriminating value. The aims of this thesis were to study cardiac biomarkers, cardiac troponin and natriuretic peptides e.g. N-terminal prohormone-B-type natriuretic peptide (NT-proBNP), and describe levels in AF patients, investigate the association with stroke or systemic embolism, cardiovascular event, major bleeding and mortality, and to assess how levels of cardiac biomarkers change over time. Cardiac troponin was analyzed with contemporary assays and high sensitivity assays. The study populations consisted of patients with atrial fibrillation and one risk factor for stroke included in the RE-LY (n=6189) and the ARISTOTLE (n=14892) biomarker substudies. Median follow-up time was 2.2 years and 1.9 years, respectively. In a subset of participants (n=2514) data from repeated measurements was available at three months. Cardiac troponin was detectable in 57.0% with the contemporary assay and 99.4% with the high sensitivity assay. NT-proBNP was elevated in approximately three quarters of the participants. In Cox models adjusted for established risk factors the cardiac biomarkers levels was independently associated with stroke or systemic embolism, cardiovascular events, and mortality. Only cardiac troponin was associated with major bleeding. In ROC analyses the prediction of stroke or systemic embolism, cardiovascular events, and mortality increased significantly by addition of cardiac troponin or NT-proBNP to the models. Persistent detectable cardiac troponin (contemporary assay) and elevated NT-proBNP levels were found in a large number of participants. Persistent detectable or elevated levels conferred significantly higher risk for stroke or systemic embolism, cardiovascular events, and mortality. By using both cardiac biomarkers simultaneously the risk stratification improved even further for all outcomes. In conclusion the analyses for the first time display that elevation of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke, cardiovascular events and mortality. Persistent elevation of troponin and NT-proBNP indicate a worse prognosis than transient elevations or no elevations of either marker. The cardiac biomarkers added substantial improvements to existing risk stratification models.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on Feb. 2, 2010). Includes bibliographical references.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Aquaporin proteins significantly increase water permeability across tissues and cell membranes. Ocular tissues, including the trabecular meshwork (TM) and retinal pigment epithelium (RPE), are especially reliant on aquaporin mediated water movement for ocular homeostasis. Even though bulk fluid movement is paracellular through the TM and transcellular through the RPE, both express aquaporin-1 (AQP1). The role and regulation of AQP1 as it relates to homeostasis in different ocular tissues is not well understood. I hypothesized that ocular tissues respond to external mechanical and molecular cues by altering AQP1 expression and function in order to regulate ocular fluid movement and maintain homeostasis.To test how AQP1 function is altered in response to external cues in order to maintain tissue-specific homeostasis, I addressed the following two aims. The first aim was directed at determining how mechanical strain, an external stimulus that routinely affects TM function, influences AQP1 expression and TM homeostasis. Primary cultures of human TM were subjected to static and cyclic stretch and then analyzed for changes in AQP1 expression by western blot and cell damage by activity of lactate dehydrogense (LDH) in conditioned media. The results show AQP1 expression and LDH release significantly increased with static stretch. Analysis of LDH release with respect to AQP1 expression revealed an inverse linear relationship (r² = 0.7780).The second aim was directed at characterizing signaling mechanisms responsible for regulating fluid transport in RPE, previously shown to be dependent upon AQP1. I treated primary cultures of human RPE with either atrial natriuretic peptide (ANP) or 8-bromo-cyclic guanosine monophosphate (8-Br-cGMP) in the presence or absence of Anantin (ANP-receptor inhibitor) or H-8 (Protein Kinase G inhibitor). The results show that ANP and 8-Br-cGMP significantly increased apical to basal net fluid movement (p < 0.05, n = 3). Inhibition of these effects was successful with Anantin treatment but not with application of H-8.The data presented demonstrate a novel role of protection for AQP1 in TM, and also expand upon cGMP dependent regulation of RPE fluid transport. The combined studies indicate tissue specific AQP1 regulation may offer new avenues to target water movement in treatment of ocular pathologies.

Bei Patienten mit akut dekompensierter Herzinsuffizienz beziehungsweise kardiogenem Schock ist die Kurz- und die Langzeitprognose stark reduziert. Ziel dieser prospektiv klinischen Studie war die Feststellung des Maximums des NTproBNP-Wertes in der Akutphase innerhalb der ersten zwölf Stunden nach Krankenhausaufnahme sowie die Untersuchung der NTproBNP-Spiegel als Prädiktor der 18-Monatsmortalität in dieser Patientengruppe. Es wurden insgesamt 148 Patienten in zwei Studienabschnitten eingeschlossen, wobei die Kurz- und Langzeitverläufe aller Patienten zu den Zeitpunkten 0, 12, 24 und 48 Stunden, 7 und 14 Tagen sowie 1, 3 und 18 Monaten untersucht wurden. Bei 32 Patienten wurden zusätzlich regelmäßige zweistündliche Untersuchungen der NTproBNP-Werte innerhalb der ersten zwölf Stunden (2, 4, 6, 8 und 10 Stunden nach Aufnahme) durchgeführt. Für Patienten mit akut dekompensierter Herzinsuffizienz bzw. kardiogenem Schock ohne akuten Myokardinfarkt fanden sich innerhalb der ersten zwölf Stunden keine siginifikant erhöhten NTproBNP-Plasmaspiegel im Vergleich zum Aufnahmewert, eine statistische Signifikanz bezüglich der 18-Monatsmortalität fand sich in dieser Gruppe innerhalb der ersten 48 Stunden nur zum Zeitpunkt 12 Stunden nach Aufnahme. In der Gruppe der Patienten mit dekompensierter Herzinsuffizienz bzw. kardiogenem Schock im Rahmen eines akuten Myokardinfarktes dagegen fanden sich statistisch signifikant steigende NTproBNP-Werte zu allen Zeitpunkten innerhalb der ersten zwölf Stunden im Vergleich zum Aufnahmewert, wobei nach zwölf Stunden der Maximalwert erreicht wurde. Weiterhin zeigten in dieser Gruppe die NTproBNP-Werte eine statistische Signifikanz in Hinsicht auf die 18-Monatsmortalität zu fast allen Zeitpunkten außer 4 Stunden nach Aufnahme. Zusammenfassend kann somit mit Bestimmung der NTproBNP-Werte 12 Stunden nach Krankenhausaufnahme unabhängig von der Genese der akuten kardialen Dekompensation eine Kurz- und Langzeitprognoseabschätzung erfolgen.

Atrial natriuretic factor (ANF) is a cardiac hormone that helps maintain cardiovascular homeostasis. ANF secretion is linked to the constitutive, regulated and constitutive-like pathways. Presence of a monensin-sensitive pool that may follow constitutive-like secretion has previously been identified in an isolated atrial perfusion study. The intracellular ANF storage pools linked to each secretory pathway have not been identified. In this study, ANF storage and secretion was characterized in HL-1 atrial cardiomyocytes through the use of pharmacological agents, density gradient and RP- HPLC analysis. Treatment of HL-1 cells with monensin followed by cell fractionation was unsuccessful in identifying the monensin-sensitive pool. RP-HPLC analysis identified presence of low molecular weight ANF in low density gradient fractions that were defined by the presence of organelle markers of Golgi, early endosome, clathrin and corin. Since the monensin-sensitive pool was thought to be of a constitutive-like nature, targeting this pathway with pharmacological inhibitors of clathrin coat vesicle (CCV) formation and endosomal trafficking failed to prevent stimuli-independent secretion. Based on an inability to prevent ANF secretion by targeting the constitutive-like pathway and the presence of low molecular weight ANF in low density gradient fractions, stimuli- independent ANF secretion seems to be through a constitutive pathway.