Furthermore, ACS patients with a high N-terminal pro-B-type natriuretic peptide (NT-proBNP) and a high ROCK activity on admission had a five-fold risk to experience a cardiovascular event, when compared to those with low NT-proBNP and low ROCK activity. In addition, patients with high NT-proBNP and high ROCK activity were also more likely to die or experience a cardiovascular event at two years when comparing to those with high NT-proBNP and low ROCK activity. / In both ACS and CHF study cohorts, all the clinical parameters were recorded and analyzed. / In the first part of this thesis, 176 ACS patients and 51 control subjects were studied. All The patients were enrolled between December 2007 and May 2009 and followed up till 15th March 2010 (mean: 15.4+/-7.6 months, from 0.5 month to 27.5 months). The main outcome measures were all cause mortality, readmission with ACS or congestive heart failure (CHF) at 2 years from presentation. Altogether, there were 23 deaths (13.1%),33 readmissions with ACS (18.8%) and 13 admissions with CHF (7.4%) within 2 years. / Recent studies have shown that ROCK may playa pivotal role in cardiovascular diseases such as vasospastic angina, ischemic stroke, heart failure and metabolic syndrome via its involvement in regulation of vascular tone, endothelial dysfunction, inflammation, and remodeling. Indeed, inhibition of ROCK by statins or other selective inhibitors leads to upregulation and activation of endothelial nitric oxide synthase (eNOS) and reduction of vascular inflammation and atherosclerosis. In this thesis, we hypothesized that ROCK activity is increased in a selected population of patients with acute coronary syndrome (ACS) and congestive heart failure (CHF) and that ROCK activity is able to predict long-term clinical outcomes in these two populations. / Rho/rho-kinase (ROCK) is a serine-threonine protein kinase, which is one of the first immediate downstream targets of RhoA and expressed ubiquitously. ROCK is involved in many cellular functions, such as, cell growth, migration, apoptosis via actin cytoskeleton organization, and gene expression. They regulate cell contraction through serine-threonine phosphorylation of adducin, ezrin-radixin-moesin proteins, LIM kinase, myosin light chain phosphatase, and Sodium-Hydrogen ion (Na/H) exchanger. / The main findings are: ROCK activity was increased in ST elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable angina (UA) groups when comparing with disease controls and healthy controls. On multivariate analysis, heart failure symptom on presentation, LDL-C level, and number of diseased coronary vessels were independent predictors of ROCK activity in ACS patients. / The ROCK activity in CHF patients was significantly higher than that of the disease control and normal control groups. New York Heart Association (NYHA) class, low left ventricular ejection fraction (LVEF) and high creatinine were independent predictors of the baseline ROCK activity in CHF. In terms of long-term heart failure mortality, ROCK activity was not an independent predictor. However, combining ROCK activity and NT-proBNP provided an incremental value in predicting long-term heart failure mortality over NT-proBNP alone. / Thus, increased ROCK activity is likely involved in cardiovascular diseases and further studies would be helpful to elucidate the potential role of ROCK activity inhibition in cardiovascular diseases. / We also recruited a group of 178 patients with CHF. All the patients were enrolled between December 2007 and January 2009 and followed up until 1st February 2010 (mean: 14.4+/-7.2 months, from 0.5 month to 26 months) or until the occurrence of cardiac death. Forty-five patients died (25.3%) within 2 years follow up. / Dong, Ming. / Adviser: Cheuk Man Yu. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 140-164). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

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Cardiovascular pathology is seen in both animals and humans after domoic acid intoxication. Whether this damage is direct (i.e., cardiotoxic) or indirect (i.e., CNS/autonomic seizures) is not known. We have previously shown that acute in vitro domoic acid (0.05-0.25[mu]M; 10 min) treatment of isolated cardiac mitochondria compromises mitochondrial FADH and NAD⁺-linked respiratory control and mitochondrial energetics. Domoic acid was shown to traverse and bind the cellular membrane of H9c2 cardiac myoblasts. However it did not compromise cellular viability as assessed using cell quantification or lactate dehydrogenase leakage assays. Exposure of intact H9c2 cells to domoic acid only resulted in complex II-III activity impairment and assessment of reactive oxygen species (superoxide and hydrogen peroxide) production in both isolated cardiac mitochondria and H9c2 cardiomyocytes failed to show any significant differences following exposure to domoic acid. Acute ex vivo domoic acid treatment of an isolated myocardium in Langendorff perfusion mode failed to result in cardiac haemodynamic dysfunction, however there appeared to be small but significant decrease in mitochondrial oxygen utilization. The absence of any substantial damage to intact cardiomyocytes and isolated myocardium suggested that domoic acid does not have a direct toxicological effect on cardiac energetics. We therefore investigated the possibility that cardiovascular pathology is an indirect consequence of autonomic seizure activity. Domoic acid was administered intraperitoneally or intrahippocampally and the development of cardiac pathologies was assessed and compared. Sprague-Dawley rats receiving either i.p. or i.h. domoic acid were assessed behaviourally and shown to reach similar levels in their cumulative seizure scores. Assessment of the cardiac haemodynamics (LVDP, dP/dt, heart rate and coronary flow) revealed a significant time-dependent decrease in function at 1, 3, 7 & 14-days post-i.p. and 7 & 14-days post-i.h. domoic acid administration. Measurement of ventricular mitochondrial oxygen utilization revealed a similar time-dependent decrease in respiratory control, which appeared to be associated with increased proton leakage, shown by an increase in state-4 respiration rate (P<0.01). Assessment of the mitochondrial electron transport chain (complexes I-V) and the mitochondrial marker of integrity, citrate synthase, showed marked time-dependent impairment in both models of domoic acid -induced seizures. Oxidative stress did play a small role in the myocardial damage as indicated by the small decrease in aconitase activity (P<0.05). Plasma IL-1α, IL-1β and TNF-α levels were significantly increased from 3-days post seizures. Haematoxylin & Eosin staining of ventricular sections revealed the formation of contraction bands, inflammation and oedema, confirming a structural pathology. Cardiac damage did not differ between i.p. and i.h. animals, suggesting cardiac damage following domoic acid results from CNS autonomic seizures and resultant sympathetic storm. This thesis has demonstrated, for the first time, that the cardiac pathology seen following domoic acid exposure is most likely to be a result of CNS activation and resultant seizure episodes, and is not a consequence of the direct interaction between domoic acid and the myocardium. We have also demonstrated for the first time, that seizure episodes result in chronic cardiac dysfunction and a structural pathology which is similar, but not identical to that seen following isoprotenerol administration in vivo.

Passive and active heat loading causes cardiovascular strain, which can have diverse and substantial effects. Thus, cardiovascular function is integral to work and heat stress tolerance, but recent hyperthermia and exercise literature has not emphasised this relationship, instead focusing on the roles of upper �critical� core temperature or rate of heat storage as primary mechanisms of fatigue. Therefore, the aim of this thesis was to examine some potential causes and effects of cardiovascular strain under heat stress, including potential strategies for attenuating that strain. Body precooling before exercise increases heat storage capacity; the primary mechanism by which attenuations in thermal and cardiovascular strain, and improved work capacity is thought to occur. However, no precooling study has utilised realistic airflow in the laboratory, possibly inflating its purported benefits. Therefore, Study One examined the cardiovascular, thermal, psychophysical and ergogenic effects of precooling with and without airflow in the heat (30�C, 50% rh). Ten males completed four trials in balanced order, comprising 60- min immersion in thermoneutral (35�C) or cool (24�C) water before cycling at 95% ventilatory threshold with airflow (~4.8 m�s⁻�) or no airflow, until exhaustion. Heart rate and mean core, body, and skin temperatures were attenuated for 15 min into cycling after precooling. Endurance time was extended by 30 � 23 min with airflow, and 16 � 15 min with precooling relative to control (28 � 12 min) but not further extended with strategies combined (29 � 21 min). Precooling removed 784 � 223 kJ�m⁻� (calorimetrically); less than the effect of airflow alone (1323 � 1128 kJ�m⁻�). Competition for blood between tissues is pronounced during exercise in the heat: skin and gut have marked increases and decreases, respectively. Gut ischemia affects epithelial tight junction integrity, allowing lippopolysaccharide ingress and immune responses. Bovine colostrum may attenuate gut permeability. Study Two (double-blind, placebo controlled) investigated the effects of aerobic fitness (7 highly fit, 8 moderately fit) and bovine colostrum on physiological and perceived strain, and performance during mixed-mode exercise; cycle 15 min at 50% maximal heart rate range (HRR), run 30 min at 80% HRR then 30 min self-selected paced before another 15 min cycle at the same work-rate. Airflow was graded to running speed. During the last cycle, blood pressure, stroke volume and total peripheral resistance were lower, heart rate and skin blood flow increased, and skin temperature was unchanged compared to the first cycle. Indices of fever response (IL-1β, TNF-α) were not evident during exercise, nor were those of blood-brain barrier permeability (S100β) or cognitive impairment (Stroop test). Neither bovine colostrum, nor higher fitness modified these measures. Moving to upright posture is orthostatically stressful and can initially decrease cerebral perfusion. Compression garments are used to assist venous return; while their effectiveness is unknown, they could reduce heat or orthostatic-induced hypoperfusion. Study Three investigated the cardiovascular and cerebrovascular responses to orthostatic stress with and without passive heating (+0.5�C). Fifteen participants completed two trials (compression v placebo garments) in balanced order. Cerebral autoregulation was assessed via 3-min stand, and via thigh cuff inflation. All participants experienced initial orthostatic hypotension upon standing in one or more trials, with 4/15 individuals experiencing presyncopal symptoms, aborting the standing protocol. In those who "fainted", reductions in blood pressure and partial pressure of end-tidal CO₂ reduced middle cerebral artery velocity. Neither training status nor compression trousers modified the responses. Collectively, cardiovascular strain to heat stress is attenuated when realistic airflow is provided. Increased cardiovascular strain does not inevitably result in clinical outcomes to heat stress. Higher fitness does not necessarily attenuate cardiovascular responses or higher tolerance to heat stress.

Atherosclerotic plaque disruption leading to thrombosis has traditionally been studied as a rupture of a thin fibrous cap over a lipid-laden necrotic core. However, two noteworthy categories of plaques that do not rupture have presented themselves: 1) in mice, plaque rupture is rare if not absent, and 2) in humans, some plaques erode and form a thrombus without rupturing. Current understanding of the biomechanical differences between plaques that rupture and those that do not is incomplete. In this research, we used patient-specific computational biomechanics tools to study differences among these groups. Lesion-specific solid mechanical modeling of murine plaques revealed that the relative distribution of stresses differs considerably between mice and man. In human vulnerable plaques, peak stresses are on the thin fibrous cap over a necrotic core, but in mice the highest stresses are in the media and adventitia, away from the plaque. Whereas atherosclerotic human arteries usually experience neointima formation around the entire circumference of the vessel, mouse plaques tend to be punctate and adjacent lesion-free regions. The difference in mechanical environment suggests that plaque rupture, if possible in mice, is likely not driven by mechanics in the same manner as humans. Similar mechanical modeling of human ruptured and eroded plaques and comparison to histological staining revealed that ruptured plaques exhibit increased levels of inflammatory markers in response to strain in ruptured plaques, but no such response was observed in plaque erosion. This suggests that treatment of inflammation, a current paradigm for care of atherosclerotic patients, may not be an effective approach to mediate plaque erosion. Computational fluid dynamics modeling of patients with plaque erosion revealed no relation between wall shear stress magnitude or direction, further suggesting that the mechanism of plaque erosion differs considerably from that of plaque rupture. Together, these findings suggest that biomechanics can help explain why not all plaques rupture and that different clinical approaches are necessary to address different phenotypes of lesions.