Abstract
Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5-monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil gender-specific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource.
Highlights
Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF)
We determined the perturbations in ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) at the protein and metabolite pathway level using an unbiased and comprehensive screen of a large number of heart failure samples matched to histopathologically-normal donor controls for age, gender, and body-mass index (BMI)—a total of 51 left ventricular myocardial samples from 44 human hearts (Table 1; Fig. 1a–c)
Gender distribution was evenly matched in donors, whereas both ICM and DCM groups had increased percentages of males in keeping with the epidemiology of these diseases (Fig. 1c)
Summary
Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. A more extensive understanding as to whether upstream perturbations are propagated downstream via translation to the protein level, and further via enzymatic processing to the metabolite level, are required Such analyses require large sample sizes, in addition to matched control (non-diseased) groups to adequately address the major confounders of age, gender, and body-mass index (BMI). We determined the perturbations in ICM and DCM at the protein and metabolite pathway level using an unbiased and comprehensive screen of a large number of heart failure samples matched to histopathologically-normal donor controls for age, gender, and BMI—a total of 51 left ventricular myocardial samples from 44 human hearts (Table 1; Fig. 1a–c). We provide all proteomic and metabolomic results via an interactive online repository (https://mengboli.shinyapps. io/heartomics/) as a publicly available resource, thereby enabling researchers without access to human cardiac tissue
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