A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine. Johannesburg, October 2017. / Background: Positron Emission Tomography (PET) is an imaging modality that guides the revascularization management of patients with left ventricular systolic dysfunction secondary to coronary artery disease. Segments of the myocardium demonstrating reduced perfusion and increased or preserved 18FFluorodeoxyglucose (18F-FDG) uptake are considered to be viable and thus suitable for revascularization. The aim of our study was to determine the prevalence of myocardial viability as determined by FDG-PET in our local cohort and to compare our prevalence of myocardial viability to data published elsewhere. Methods: We retrospectively reviewed 240 consecutive 99mTc-sestamibi myocardial perfusion Gated Single Photon Emission Tomography (SPECT) and 18FFDG PET reports of patients referred for evaluation of myocardial viability between January 2009 and June 2015. Results: 236 patients met the inclusion criteria. There were 194 (82.2%) males. The mean age was 59.1 (SD 11.0) years. A total of 4012 segments of the left ventricle were analyzed on the gated SPECT and reduced perfusion was noted in 1862 (46.4%) segments. Perfusion-metabolism mismatch (viable myocardium) was observed in 586 (31.5%) out of 1862 perfusion defects. The prevalence of myocardial viability in the study population was 61.4%. On the multivariate logistic regression model, aspirin intake [OR:0.37; CI:0.16-0.83; p=0.016] and hypertension [OR:0.26; CI:0.12-0.58; p=0.001] were associated with the presence of viable myocardium. Smoking was associated with the likelihood of having non-viable myocardium [OR:2.31; CI:1.01-5.29; p=0.048] Conclusion: The prevalence of myocardial viability as detected by 18F FDG PET in our local cohort is similar to prevalence rates reported in the developed world. / LG2018

Blunt carotid artery injury (BCAI), resulting primarily from automobile accidents, is a major contributor to the high mortality and morbidity rates associated with carotid artery dissection. More work is needed to characterize carotid artery injury mechanisms, quantify stages of damage, and elucidate failure modalities as a result of this type of injury. The present study examines the structure and mechanics of the carotid artery in the circumferential and axial directions by employing uniaxial tensile testing, high speed videography, interruption testing, scanning electron microscopy (SEM), histological analysis, real-time environmental SEM assessment, and atomic force microscopy (AFM). Results are as follows: (i) the carotid artery exhibits anisotropic, viscoelastic behavior; (ii) intimal failure precedes ultimate tissue failure, and the layers in order of increasing strength are intima, adventitia, and media; (iii) tissue damage accumulates as strain level increases, and failure occurs as a result of void nucleation, void growth, and void coalescence.

No description available.

No description available.

A newly discovered activity in human serum protects porcine aortic endothelial cells in culture from injury by very low density lipoproteins (VLDL). This factor, toxicity-preventing activity (TxPA), was measured in 29 relatively young men (43 ± 8 years) who had undergone coronary angiography. The level of TxPA was found to be significantly reduced (P < 0.001) in men who demonstrated more than 15% narrowing of their coronary arteries. Men (n = 18) who had 15% or less narrowing were found to have 104 ± 48 units of TxPA while men (n = 11) with coronary artery disease had 48 ± 24 units of TxPA. A value derived from the product of TxPA and the high density lipoprotein cholesterol (HDL-C) level divided by the non-HDL-C (total cholesterol-HDL-C) accurately separated 97% of the men into 2 groups. TxPA thus appears to be a new protective factor in coronary artery disease, which, when combined with total cholesterol and high density lipoprotein cholesterol values, provides an accurate classification of established coronary artery disease in these subjects.

Right-heart catheterization is the most accurate method for estimating pulmonary artery pressure (PAP). Because it is an invasive procedure it is expensive, exposes patients to the risk of infection, and is not suited for long-term monitoring situations. Medical researchers have shown that PAP influences the characteristics of heart sounds. This suggests that heart sound analysis is a potential noninvasive solution to the PAP estimation problem. This thesis describes the development of a prototype system, called PAPEr, which estimates PAP noninvasively using heart sound analysis. PAPEr uses patient data with machine learning algorithms to build models of how PAP affects heart sounds. Data from 20 patients was used to build the models and data from another 31 patients was used as a validation set. PAPEr diagnosed these 31 patients for pulmonary hypertension with an accuracy of 77 percent.

Fragmented QRS (fQRS) is a marker of conduction block due to myocardial scar that presents in electrocardiography (ECG) as an additional one or more R wave (R') or notching in the S wave nadir in contiguous leads. However, fQRS description on premature ventricular contractions (PVCs) has not been previously described. We describe a case of a 67-year-old male with a past medical history of prediabetes, hypertension and coronary artery disease who presented after an ophthalmic procedure with asymptomatic PVCs and episodes of bigeminy. Initial ECG showed an isolated fQRS in V2. However, during PVCs significant extrasystoles fragmentation was seen in other coronary territories. Upon reviewing his most recent cardiac catheterization, it showed a 40% ostial and 70% distal left anterior descending stenosis with a mid-segment patent stent, 95% first diagonal stenosis and totally occluded proximal right coronary artery. Identification of diffuse fQRS known to be associated with myocardial scar, sustained arrhythmic events and sudden cardiac death, particularly when seen in the inferior leads, became extremely relevant in our patient. We noted that ejection fraction reduction from 52% to 34% on his last coronary intervention was crucial to decide if an implantable cardioverter-defibrillator would be needed. PVC fragmentation might be a new ECG marker that could uncover both scar and arrhythmia potential in patients at risk of adverse cardiac events.

Background and objectives: Coronary artery disease (CAD) is the leading cause of death among women both nationally and internationally. Despite increased knowledge regarding CAD in women, early diagnosis remains a difficult clinical task. A correlation between peripheral arterial disease (PAD) and CAD has been noted in previous research; however, these studies were either retrospective or did not focus on women. This research investigates the correlation of ankle brachial index (ABI), measurements used to diagnose PAD, and presence of CAD in women, in an effort to determine the predictive value of ABI specifically in women. Subjects and methods: A prospective correlation design was used to study women (n = 30) who were undergoing a diagnostic cardiac catheterization. Ankle brachial index readings were obtained prior to the catheterization procedure. Catheterization findings were grouped according to absence of CAD or presence of 1-vessel or multivessel CAD and coupled with each woman's ABI and recorded cardiovascular risk factors. Results: Peripheral arterial disease (based on ABI of <0.90 mm Hg) was found in 13.3% of the women. A significant correlation was found between ABI of less than 0.90 mm Hg and increasing age (t = -2.30, P =.029). Coronary artery disease was found in 82.1% of the women; more than half (57.1%) had multivessel disease. Absence of CAD was noted in 17.9%. Women with CAD were older than women without CAD (F = 3.86, P =.035). No significant differences were found between presence or absence of PAD based on ABI and diagnosis of no coronary disease or 1-vessel or multivessel coronary disease. Conclusions: This study failed to show the expected correlation between ABI of less than 0.90 mm Hg and CAD, but did show a significant correlation of age with presence of both PAD and CAD. Further research that focuses specifically on women is needed and should include a larger sample, additional unique cardiovascular risk factors, and innovative diagnostic tests to determine presence of CAD in women early in the disease process.

Preeclampsia is an important disease during pregnancy and causes significant maternal and fetal mortality and morbidity. Despite intense research efforts, the etiology and pathogenesis of the disease remain largely unknown. Since placentas from preeclamptic patients are smaller than normal, and cytokine growth factors are suggested to be important in placental growth, the effects of macrophage-colony stimulating factor (M-CSF) on human trophoblast cells were examined. While term trophoblast cells did not respond to M-CSF, those from early trimester and choriocarcinoma cells showed enhanced growth after treatment. In addition, the serum level of M-CSF in hypertensive pregnant women at the second trimester were significantly lower than those of normal pregnant women. These data suggest possible roles of M-CSF in preeclampsia. When M-CSF was administered to pregnant rats on days 8-11, rats had smaller placentas at day 12 and increased fetal resorption rate at day 20. The effects of interleukin-12 (IL-12) was also examined on days 8-11. While placental development was normal at both days 12 and 20, fetuses were significantly smaller at day 20. To remedy the difficulties and dangers associated with obtaining human placentas, I characterized endovascular trophoblast cell behavior in pregnant rats. In normal pregnancy, rat trophoblast cells simulated all features of human endovascular trophoblast behavior including selective invasion into the spiral arteries, retrograde migration, embedding, and secretion of PAS-positive materials as well as IIphysiological changes," In pregnancy terminated with a certain type of spontaneous fetal resorption, defective endovascular trophoblast cell behavior was observed, which was similar to that reported in preeclamptic pregnancy. Finally, the roles of cytoskeleton on trophoblast cell locomotion were investigated in vivo with a cytoskeleton-disrupting agent, cytochalasin B. This treatment impaired trophoblast cell invasion at day 12 and induced smaller fetuses at day 20, suggesting the importance of cytoskeleton in trophoblast movement. In conclusion, the results suggest the importance of the use of appropriate specimens and endpoints in the study of pregnancy, and rats may serve as a suitable animal model for the study of endovascular trophoblast cell behavior with clinical relevance to preeclampsia. / Ph. D.

The underlying pathological process of coronary artery disease (CAD) is the development of coronary artery atherosclerotic occlusions and associated myocardial infarction. Both increased chronic inflammation and plasma low-density lipoprotein (LDL) cholesterol levels promote atherosclerosis. Inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) is widely known for its role in enhancing LDL receptor (LDLR)-mediated cholesterol lowering when the LDLR-apolipoprotein E (APOE) axis is intact and protecting against atherosclerosis progression by reducing plasma cholesterol levels. In this thesis, we sought to test the effects of PCSK9 inhibition mediated cholesterol lowering on pre-existing CAD as well as the plasma cholesterol independent effects of PCSK9 inhibition on CAD by utilizing different mouse models. One year old scavenger receptor class B type I (Sr-b1) knockout (KO) mice which have an intact LDLR-APOE axis, develop coronary artery atherosclerosis and myocardial fibrosis induced by a high fat, high cholesterol and cholate containing (HFCC) diet. Weekly anti-PCSK9 antibody treatment initiated one week before switching to an HFCC diet increased hepatic LDLR protein levels, and reduced plasma cholesterol levels and the progression of atherosclerosis in both the aortic sinus and coronary arteries in one year old Sr-b1 KO mice (maintained on an HFCC diet for 7 weeks). Weekly anti-PCSK9 antibody treatment initiated 7 weeks after switching to an HFCC diet also increased hepatic LDLR protein levels and reduced plasma cholesterol levels in one year old Sr-b1 KO mice (maintained on an HFCC diet for 12 weeks). More importantly, anti-PCSK9 antibody treatment during the last 5 weeks of the 12-week HFCC diet feeding period also slowed down the growth of pre-existing atherosclerosis in both the aortic sinus and coronary arteries and reduced myocardial fibrosis and damage. Mice deficient in both Sr-b1 and ApoE (Sr-b1/ApoE double KO (dKO) mice) spontaneously and rapidly develop features reminiscent of human CAD. Whole body Pcsk9 genetic KO in both female and male Sr-b1/ApoE dKO mice did not affect plasma cholesterol levels despite increased hepatic LDLR protein levels, presumably due to the lack of APOE. However, genetic Pcsk9 inactivation significantly attenuated atherosclerosis in both the aortic sinus and coronary arteries, myocardial fibrosis and damage, left ventricle (LV) dysfunction and cardiac enlargement in both female and male Sr-b1/ApoE dKO mice. Restoring circulating PCSK9 by a recombinant adeno associated virus 8 (AAV8)-mediated hepatic expression of a Pcsk9 cDNA in Pcsk9/Sr-b1/ApoE triple KO mice reversed the plasma cholesterol independent protective effects of genetic PCSK9 KO on aortic sinus and coronary artery atherosclerosis and myocardial fibrosis and damage in both females and males. Treatment of Sr-b1/ApoE dKO mice with an anti-PCSK9 antibody which disrupts the interaction between the LDLR and PCSK9 protected against aortic sinus and coronary artery atherosclerosis in males but not in females and did not protect either males or females against myocardial fibrosis and damage, LV dysfunction or cardiac enlargement. My thesis demonstrates that anti-PCSK9 antibody mediated plasma cholesterol lowering delays the continued development of pre-existing CAD. My thesis also demonstrates that liver-derived, circulating PCSK9 promotes CAD in a plasma cholesterol independent manner in Sr-b1/ApoE dKO mice and these effects appear to be largely independent of the PCSK9-LDLR interaction, particularly in females. / Thesis / Doctor of Philosophy (PhD)