Evaluation of Acute Cardiorespiratory Disease: Integrating Metabolite-wide Analysis and Lung Mechanics Pathophysiology

Challenges in studying acute life-threatening events and a knowledge gap in biomarker exploration for overlapping cardio-respiratory conditions necessitate further investigation. This thesis aims to bridge the gap by identifying additional biomarkers using metabolomics and physiological measures in acute cardio-respiratory conditions. Our hypotheses aim to test the differentiation power of plasma metabolomic profiles, characterize ventilation heterogeneity, and identify of metabolic dysfunction in lipid mediators in acute cardiorespiratory conditions.

Methods: We employed a multidimensional approach using LC-MS and GC-MS platforms to analyze plasma, breath, and sputum samples from the same population. The following studies were conducted: (1) Metabolite analysis in blood plasma samples of n = 54, in which n = 20 acquired from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients and n = 20 acquired from acute heart failure (AHF) patients, compared to n = 14 samples acquired from healthy volunteers. (2) Breath data analysis for ventilation heterogeneity involved 310 subjects using the FOT test, with a subgroup of 208 with published VOC measurements (1, 2), The analysis aimed to investigate the association between identified VOC metabolomics disturbances and respiratory impedance. (3)Prospective study using n = 141 sputum samples of AECOPD, acute asthma, pneumonia patients, and healthy control group targeting 13 metabolomic markers of inflammation resolution and comparing the results to a sub-cohort of n = 45 during stable status.

Results: (I) Mass spectral analysis identified 2193 compounds in plasma samples of AECOPD, AHF, and healthy subjects. Biomarker scores of 19 metabolites (9 features associated with AECOPD and 10 with AHF) demonstrated ≥70% sensitivity and specificity in distinguishing between ACOPD, AHF, and health. (II) Resistance at 5 and 5-19 Hz as well as reactance at 5 Hz, area under the reactance AX, and resonant frequency were significantly different (p <0.000) between all groups; moreover, (p <0.05) indicated the significant impact of respiratory system compliance on the recovery of O, N, and S VOCs in exhaled breath. (III) Group comparisons revealed significant differences in lipid mediator PGE2 levels (p <0.01), with no significant differences observed in stable cohorts. Correlation analysis showed a negative association between eosinophil count and PGE2 levels (coefficient = -0.21, p <0.05) and a positive association between neutrophil count and PGE2 levels (coefficient = 0.24, p <0.05).

Conclusion: This research highlights the potentials of metabolomics, both in targeted and untargeted approaches, along with the integration of bioinformatic statistical models in effectively differentiating between conditions with an overlapping pathology in an acute exacerbation’s events and healthy volunteers. Additionally, the study demonstrates the feasibility of utilizing handheld FOT as a valuable tool for assessing respiratory system mechanics in the acute care setting. Furthermore, examining the relationships between the analysed metabolites and other clinical observations adds to our understanding of acute cardio-respiratory conditions. These findings provide valuable insights that can contribute to the development of improved diagnostic strategies in the future.