published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Purpose: The aim was to determine the echocardiographic features of patients with infective endocarditis, and to compare the findings in HIV positive versus HIV negative patients. Methods: This was a prospective study, conducted over three years using the modified Duke criteria in diagnoses. A control group of age-matched patients with clinical and echocardiographic evidence of valvular regurgitation, who did not satisfy the criteria and who underwent surgery was used in comparison. Results: During this period 91 patients were screened for infective endocarditis. 77 satisfied the criteria for a definite diagnosis of IE. Blood cultures were positive in 46% cases. The commonest organism was S. aureus. Most patients had advanced valve disruption with heart failure and a high peri-operative mortality. The clinical features in the two groups of patients was similar. The incidence of echocardiographic complications was 50.6% in the whole group. Except for leaflet aneurysms in four HIV positive cases, complications were not more frequent in this group. Conclusion: There was a high rate of culture negative cases in this study, probably related to prior antibiotic usage; in this setting the modified Duke criteria have diagnostic limitations. There was no difference in the clinical presentation of infective endocarditis between HIV positive and HIV negative patients. Leaflet aneurysms were more common in the HIV positive patients. / Thesis (M.Med.)-University of KwaZulu-Natal, 2008.

Background: In breast cancer patients, the administration of Trastuzumab and Doxorubicin is associated with an increased risk of cardiotoxicity. The aim of the study was to determine if the antioxidant probucol would be useful in attenuating this drug induced cardiotoxicity. Methods: In an acute murine model of chemotherapy induced cardiomyopathy, wild-type C57Bl/6 mice received one of the following regimens: (1) control; (2) doxorubicin; (3) trastuzumab; (4) dox+trastuzumab; (5) probucol; (6) probucol +dox; (7) probucol+trastuzumab; (8) probucol+dox+trastuzumab. Serial murine echocardiography with tissue Doppler imaging was performed daily. Histological and biochemical studies were conducted at day 10 of the experiment. Results: Mice treated with prophylactic probucol demonstrated minimal cardiotoxicity compared with those treated with doxorubicin+trastuzumab. Survival rate was only 27% at day 3 of the experiment in the doxorubicin+trastuzumab group compared to 82% of mice receiving probucol+ doxorubicin+trastuzumab. Survival, apoptosis and histological remodeling were preserved in mice prophylactically treated with probucol following the administration of trastuzumab+doxorubicin. Conclusion: The synergistic cardiotoxicity of trastuzumab plus doxorubicin is attenuated by the antioxidant probucol.

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Das Ziel der vorliegenden Studie war die Analyse der Detektierbarkeit von Stenosen und Lumenverschlüssen im proximalen Bereich der rechten Koronararterie mit konventioneller 2D- und 3D- Echokardiographie von transthorakal. Zusätzlich wurden die Befunde der 3D-Echoloops mit den Untersuchungsergebnissen der Koronarangiographie verglichen. Methodisch wurden daher bei Patienten mit bestehender Indikation zur Koronarangiographie vorhergehende zweidimensionale parasternale Lang- (n=91) und Kurzachsenaufnahmen (n=76), sowie parasternale dreidimensionale (n=91) echokardiographische Aufnahmen des Ostiums und der proximalen Region der rechten Herzkranzarterie durchgeführt. Durch zusätzliche Schnittebenen der proximalen Abschnitte der rechten Koronararterie sollte die konventionelle zweidimensionale Echokardiographie für eine Stenosendetektion ergänzt werden. Diese ermöglichten eine genaue Darstellung der rechtskoronaren Morphologie im proximalen Gefäßbereich. Maximal konnten die proximalen 35mm der rechten Koronararterie untersucht werden. Die Ergebnisse der einzelnen verschiedenen echokardiographischen Dokumentationen wurden miteinander und mit denen der Koronarangiographie verglichen. Insgesamt zeigten sich keine signifikanten Unterschiede zwischen den Ergebnissen der 2D Echokardiographie und der Koronarangiographie. Die Diameter der Streckenmessungen an der rechten Koronararterie in der 3D-Echokardiographie und der Koronarangiographie sind hingegen in ihren Mittelwerten signifikant verschieden. Dies ist durch häufigere Sekantenanschnitte der Gefäße mittels Echokardiographie bedingt. Die höchste Sensitivität konnte mittels 3D-Echokardiographie (98%) nachgewiesen werden, wohingegen die zweidimensionale Technik bessere Spezifitäten (91% in 2D-Langachsen- und 92% in 2D-Kurzachsen-Aufnahmen) aufweist. Diese Ergebnisse zeigen den Nutzen der Echokardiographie im klinischen Alltag zur intravasalen Stenosendetektion der rechten Koronararterie.

The metabolic syndrome (MS), consequent upon the pandemic of obesity and diabetes, is associated with an increased risk for cardiovascular (CV) disease. Development of sub-clinical cardiac structural and functional changes associated with CV disease risk factors may be detected on echocardiography. The extent to which these structural changes and CV risk factors are dependent on genetic factors is not clearly established. This project was designed to investigate the relationship between CV disease risk factors, cardiac structural and functional changes and underlying genetic abnormalities. Specifically, the risk factor profile and the presence of the MS were determined. This was then correlated with the echocardiographic findings and gene polymorphisms. Method: A randomly selected cohort of 1428 subjects from the Phoenix community was studied. Demographic data was collected using the WHO STEPS instrument. Blood samples for biochemistry and genetic analysis, together with anthropometric measurements, were collected. Blood pressure and echocardiography was performed on all subjects. The metabolic syndrome was classified according to the National Cholesterol Education Panel (NECP) Adult Treatment Panel III (ATP III) and International Diabetes Federation (IDF) criteria. The Lipoprotein Lipase and Human Paraoxonase-1 genes were genotyped on a Light Cycler 480 Real-Time PCR instrument, using allele-specific probes and sequencing. Results: There was a high prevalence of CV risk factors in this sample; particularly increased waist circumference (79%), obesity (64%) insulin resistance (58%) and hypertension (50%) across the age groups. This translated into a high prevalence of MS (38% using NCEP ATPIII and 46% using IDF criteria). There were significant echocardiographic differences between subjects with and without MS for chamber dimensions (p<0.001), left ventricular wall thickness (p<0.001) and mass (p<0.001), diastolic indices (E-wave {p<0.001}, trans-mitral ratio {p=0.017}) and sub-epicardial adipose tissue (SEAT) thickness (p<0.001). Stepwise multivariate analysis identified age (95% CI 0.975; 0.998), gender (95%CI 0.48; 0.9) and hypertension (95% CI 0.53; 0.99) as independent risk factors for diastolic abnormalities. Logistic regression identified age as the most significant contributor to diastolic abnormalities (OR=1.02; 95%CI 1.009; 1.03; Wald=13.4), followed by the waist circumference (OR=1.025; 95%CI 1.014; 1.037) and BMI (OR=1.075; 95% CI 1.035; 1.117). Genetic analysis showed significant associations between the heterozygous variant of Q192R genotype (PON-1 gene) and elevated HDL levels and also between this variant and obese women (p= <0.05). Conclusion: The high prevalence of CV risk factors and MS in this community has reached epidemic proportions. Although the MS was associated with significant remodelling of cardiac structure, alteration of diastolic indices and increased sub-epicardial adipose tissue thickness, BMI and waist circumference were stronger promoters of altered cardiac physiology. This augurs poorly for this population group unless intervention is introduced to address the markedly high prevalence of these culprit drivers. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2013.

Background: In breast cancer patients, the administration of Trastuzumab and Doxorubicin is associated with an increased risk of cardiotoxicity. The aim of the study was to determine if the antioxidant probucol would be useful in attenuating this drug induced cardiotoxicity. Methods: In an acute murine model of chemotherapy induced cardiomyopathy, wild-type C57Bl/6 mice received one of the following regimens: (1) control; (2) doxorubicin; (3) trastuzumab; (4) dox+trastuzumab; (5) probucol; (6) probucol +dox; (7) probucol+trastuzumab; (8) probucol+dox+trastuzumab. Serial murine echocardiography with tissue Doppler imaging was performed daily. Histological and biochemical studies were conducted at day 10 of the experiment. Results: Mice treated with prophylactic probucol demonstrated minimal cardiotoxicity compared with those treated with doxorubicin+trastuzumab. Survival rate was only 27% at day 3 of the experiment in the doxorubicin+trastuzumab group compared to 82% of mice receiving probucol+ doxorubicin+trastuzumab. Survival, apoptosis and histological remodeling were preserved in mice prophylactically treated with probucol following the administration of trastuzumab+doxorubicin. Conclusion: The synergistic cardiotoxicity of trastuzumab plus doxorubicin is attenuated by the antioxidant probucol.

Background: The molecular and cellular mechanisms corresponding to the compensatory and maladaptive hypertrophy and remodeling of the left ventricle with chronic doxorubicin (DOX) treatment are currently unclear. Non-invasive methods of determining these changes are still deficient. To investigate these changes, 8 groups of rats in 4 different studies including a control saline group of the same age, gender and strain were evaluated for cardiac morphology and function including: (1) DOX dose response using a cumulative dose of 7.5mg/kg, and 15mg/kg in 8-10 week old female Sprague-Dawley (SD) rats, (2) strain differences were investigated in response to a cumulative dose of 15mg/kg in 8-10 week old female Fisher (F344) rats compared to the SD rats treated with same dose, (3) the role of gender and aging were studied in response to DOX at a cumulative dose of 3mg/kg in male and female neonates, and (4) combined losartan and a cumulative dose of 15mg/kg of DOX in 8-10 week old female SD rats compared to controls of saline and 15mg/kg treated SD rats. Method: Onset of cardiac toxicity was assessed by echocardiography and the rat model of heart failure was developed when the fractional shortening declined ≤ 40%. The mean arterial pressure and single-photon-emission computer tomography scanning and Tc-99m-HYNIC-Annexin V were performed at week 10 to analyze blood pressure and quantify apoptosis, respectively. All rats were euthanized at week 10 except for the neonates and two of the 7.5mg/kg-treated SD rats that were left alive for study of long -term cardiac side effects. The heart and kidney tissues were harvested for protein isolation and histopathological studies. Blood samples were collected for hematological and lipid profile analysis in all the rats. Results: A dose- and time-dependent increase in LVmass coincided with a parallel increase in MAP, kidney damage, expression of myocardial erbB2, heat shock protein 90 Akt, mTOR, GSK-3β, TGF-β, pSMAD2, and cardiomyocyte apoptosis in SD rats treated with 7.5mg/kg and 15mg/kg of DOX at week 10. The 7.5 kg/kg treatment showed adaptive hypertrophy whereas the 15mg/kg treatment group showed maladaptive hypertrophy. However decompensation was apparent by week 14 in other rats treated with 7.5mg/kg. LVmass, FS, MAP, kidney damage, red blood cells and blood lipid levels were not significantly altered in the F344 rats compared to the 15 mg/kg-treated SD rats. Losartan supplementation reduced the left ventricular hypertrophy, improved myocardial contractility, and reduced TGF-β expression compared to the DOX-treated SD rats. The 3mg/kg of DOX in neonates induced cardiac toxicity and deaths in about 60% of males 50 weeks after treatment; the females instead developed mammary tumors. Conclusion: The results of this study suggest that age, gender, and strain differences are risks factors for doxorubicin-induced harmful reno-cardiovascular toxicity. The inhibition of TGF-β expression by losartan can be used in prevention of chronic doxorubicin-induced cardiac toxicity without interfering with its anti-tumor activities.

Thesis (M.S.)--Oregon State University, 2008. / Printout. Includes bibliographical references (leaves 114-119). Also available on the World Wide Web.