| Summary: | Heart failure (HF) is highly prevalent and associated with high mortality in chronic kidney disease (CKD). Although the cardiac structural alterations in CKD had been well studied, the pathophysiology of cardiac dysfunction in CKD, especially in the early asymptomatic stage, is not well understood. Identification of early cardiac dysfunction and an understanding of the pathophysiology of such dysfunction are vital in preventing the emergence and progression of HF in CKD. The hypothesis underlying this thesis is that CPOmax (peak cardiac power output) and cardiac functional reserve are impaired in asymptomatic CKD patients even in the absence of any known cardiac diseases or diabetes. Asymptomatic CKD patients without primary cardiac diseases or diabetes mellitus were tested. CPOmax, a direct indicator of cardiac performance, was measured non-invasively using specialised cardiopulmonary exercise test. In addition, the reversibility of subclinical cardiac dysfunction after kidney transplantation was evaluated. Furthermore, to obtain mechanistic insights, the relationship between subclinical cardiac dysfunction and serum uraemic toxin concentrations, and the direct effect of a prototype uraemic toxin on the mechanical properties of isolated rodent cardiomyocytes were also evaluated. Compared to healthy controls, the CKD patients showed a graded reduction in CPOmax across different stages of CKD. The impairment was found to be reversible with kidney transplantation. The impairment correlated with total and free serum concentrations of indoxyl sulphate (IXS), a protein bound uraemic toxin. Further in vitro evaluation showed that IXS had direct physiological effects on cardiomyocytes and was shown to act through pathway involving protein kinase-A akin to the mechanism of action of sympathomimetics. In conclusion, this reverse translational research has demonstrated for the first time that CKD per se causes impairment of peak cardiac power output and thereby cardiac functional reserve in vivo, and unravelled a novel mechanism of cardiotoxicity mediated by a protein-bound uraemic toxin in vitro.
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