M.Sc. (Med.), Faculty of Health Sciences, University of the Witwatersrand, 2011 / The cause of cardiac pathology in a significant number of patients with heart failure is
unclear. Although chronic inflammatory changes may contribute toward progressive heart
failure, whether low-grade chronic systemic inflammation, produced by infective processes or
obesity accounts in-part for the development of cardiac dysfunction and heart failure requires
further study. In this regard, although lipopolysaccharide (LPS) administration, an inflammatory
mediator derived from the walls of gram negative organisms has been shown to produce an
increased cardiomyocyte apoptosis, the lowest dose of LPS previously employed is
commensurate with doses that produce vascular shock. Hence this does not reflect the impact
of inflammatory changes produced by low-grade systemic infections. Moreover, although
inflammatory substances have been shown to be released from adipose tissue and obesity is a
cause of cardiac dysfunction and heart failure, it is uncertain to what extent inflammatory
changes mediate obesity-induced myocardial dysfunction. To clarify the role of LPS and
obesity-induced inflammation as potential causes of cardiac damage and dysfunction, in the
present dissertation I therefore evaluated the influence of pyrogenic, but non-septic doses of
LPS on cardiomyocyte apoptosis and cardiac systolic function in rats and the contribution of
inflammation as indexed by circulating high sensitivity C-reactive protein concentrations (hs-
CRP) to the relationship between obesity and myocardial systolic function in humans.
In normal rats, core body temperature (surgically implanted [in the peritoneal cavity],
temperature-sensitive radiotransmitters), cardiomyocyte apoptosis (Terminal Deoxynucleotidyl
Transferase Mediated dUTP Nick End Labeling [TUNEL]) staining) and left ventricular (LV)
systolic function (two-dimensional directed M-mode echocardiography) were evaluated following
two doses of LPS (250 μg/kg), derived from Eschericia coli, delivered 24 hours apart. Cardiac
assessments were performed 6 hours after the second LPS dose to ensure that cardiac
measurements were obtained at the time of a febrile response, whilst the first LPS dose was
employed to ensure that a sufficiently long period had occurred for apoptotic cell death to be
iii
detected using a TUNEL system. In this study LPS was able to induce a febrile response
(p<0.05, n=26, compared to normal circadian rhythm), yet failed to produce an increased
cardiomyocyte apoptosis or decreased LV systolic chamber (LV endocardial fractional
shortening-FSend) or myocardial (LV midwall fractional shortening-FSmid) function.
In 292 randomly selected participants from an urban, developing community not
receiving antihypertensive therapy, I also assessed the independent relationship between
indices of obesity or hs-CRP and LV FSend and FSmid. In this study indices of adiposity
including waist circumference (partial r=0.35, p<0.0001) were independently related to log hs-
CRP. Furthermore, waist circumference was independently and inversely associated with
FSmid (standardized β-coefficient= -0.19±0.07, p<0.01), but not with FSend. Although log hs-
CRP was associated with FSmid on bivariate analysis, no independent relationship between
these variables was noted (p=0.21). Furthermore, with the inclusion of both waist circumference
and log hs-CRP in the same regression model, waist circumference remained independently
associated with FSmid (standardized β-coefficient= -0.18±0.08, p<0.05).
In conclusion, the results of the present dissertation do not support a role for pyrogenic,
but non-septic doses of LPS in mediating cardiomyocyte apoptosis or dysfunction or a role for
low grade inflammation, as indexed by hs-CRP concentrations in mediating obesity-induced
myocardial systolic dysfunction.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/11683 |
| Date | 13 July 2012 |
| Creators | Van Rensburg, Nicol Janse |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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