Cardiac effects of infective and obesity-induced inflammation

Van Rensburg, Nicol Janse
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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.
M.Sc. (Med.), Faculty of Health Sciences, University of the Witwatersrand, 2011