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Title: Plasma cytokines and markers of remodeling in myocardial injury and repair
Author: Chaggar, Parminder
ISNI:       0000 0004 7226 2835
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2018
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Introduction: The heart failure (HF) phenotype is associated with multiple pathological changes at the cellular/biochemical level but this is not always a permanent state, despite sometimes extremely severe clinical and echocardiographic features. However, the underlying molecular and inflammatory processes are incompletely understood and often, contradictory effects are reported. This study examines a wide array of plasma pro-inflammatory markers and remodeling proteins in experimentally induced HF and recovery. Methods: Plasma IFNÎ3, CXCL-9, IP-10, IL-21, IL-17A, TNFα, decorin, sFRP-3 and VEGF-A patterns were assessed in a series of ovine models; 8 sheep that underwent tachypaced-induced HF and recovery with cessation of pacing (Recovery group); 7 sheep that underwent tachypaced-induced asymptomatic LV dysfunction and subsequent treatment with tadalafil to prevent clinical deterioration in the context of continued tachypacing (Tadalafil sheep); and 5 sheep that underwent acute myocardial ischaemia-reperfusion injury (MI group). Baseline inflammatory profiles and remodeling proteins were validated in a separate cohort of 10 healthy sheep that underwent a comprehensive frailty assessment. Results: There was a borderline inverse association between IFNÎ3 with clinical HF in the Recovery group but no correlation with LV function. High baseline levels of pro-inflammatory cytokines did not impact on susceptibility to, severity of, or recovery from HF in sheep exposed to tachycardic pacing. Furthermore, plasma decorin increases significantly with tachypaced-HF and remains elevated despite improved LV function or tadalafil treatment. Conclusion: The present study has examined a broad inflammatory profile in HF and recovery, including those mediated via TH1 (IFNÎ3, CXCL-9 and IP-10), TH2 (IL-21), TH17 (IL-17A) and monocyte (TNFα) cell lineages. The findings demonstrate that systemic inflammation has no impact on susceptibility to, severity of, or recovery from HF in sheep exposed to tachycardic pacing. The findings of this study may draw into question whether the immune system plays a pivotal role in HF disease progression and severity although further research is required before definitive conclusions can be secured. Furthermore, this study demonstrates plasma decorin increases significantly with the development of HF. This may represent a physiological response to attenuate the effects of adverse remodeling in HF. This is the first study to demonstrate temporal changes in plasma decorin during both myocardial injury and recovery in a large mammal. Decorin may serve as a biomarker of myocardial injury and could be a target for therapeutic manipulation. These findings require validation in a larger series.
Supervisor: Shaw, Steven ; Trafford, Andrew ; Fildes, James Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available