Higher Serum Lysophosphatidic Acids Predict Left Ventricular Reverse Remodeling in Pediatric Dilated Cardiomyopathy

Abstract

Background: The prognosis of pediatric dilated cardiomyopathy (PDCM) is highly variable, ranging from death to cardiac function recovery. Left ventricular reverse remodeling (LVRR) represents a favorable prognosis in PDCM. Disturbance of lipid metabolism is associated with the change of cardiac function, but no studies have examined lipidomics data and LVRR.Methods: Discovery analyses were based on 540 targeted lipids in an observational, prospective China—AOCC (An Integrative-Omics Study of Cardiomyopathy Patients for Diagnosis and Prognosis in China) study. The OPLS-DA and random forest (RF) analysis were used to screen the candidate lipids. Associations of the candidate lipids were examined in Cox proportional hazards regression models. Furthermore, we developed a risk score comprising the significant lipids, with each attributed a score of 1 when the concentration was above the median. All significant findings were replicated in a validation set of the China-AOCC study.Results: There were 59 patients in the discovery set and 24 patients in the validation set. LVRR was observed in 27 patients (32.5%). After adjusting for age, left ventricular ejection fraction (LVEF), and left ventricular end-diastolic dimension (LVEDD) z-score, lysophosphatidic acids (LysoPA) 16:0, LysoPA 18:2, LysoPA 18:1, and LysoPA 18:0 were significantly associated with LVRR in the discovery set, and hazard ratios (HRs) were 2.793 (95% CI, 1.545–5.048), 2.812 (95% CI, 1.542–5.128), 2.831 (95% CI, 1.555–5.154), and 2.782 (95% CI, 1.548-5.002), respectively. We developed a LysoPA score comprising the four LysoPA. When the LysoPA score reached 4, LVRR was more likely to be observed in both sets. The AUC increased with the addition of the LysoPA score to the LVEDD z-score (from 0.693 to 0.875 in the discovery set, from 0.708 to 0.854 in the validation set) for prediction of LVRR.Conclusions: Serum LysoPA can predict LVRR in PDCM patients. When the LysoPA score was combined with the LVEDD z-score, it may help in ascertaining the prognosis and monitoring effects of anti-heart failure pharmacotherapy.

A Comprehensive Insight and Mechanistic Understanding of the Lipidomic Alterations Associated With DCM

“…The levels of lysophosphatidic acids have been shown to predict LV reverse remodeling (LVRR) in these pediatric DCM cases, and when combined with LV end-diastolic dimension (LVEDD) score, its levels could monitor the effects of anti-heart failure pharmacotherapy. 45 The beneficial role of n-3 polyunsaturated fatty acids (PUFAs) was assessed using fat-1 transgenic mice in which pressure overload was induced by transverse aortic constriction for 8 weeks. The fat-1 gene codes for the enzyme n-3 fatty acid desaturase, which converts n-6 PUFAs to n-3 PUFAs.…”

“…Modulation in the activity of key kinases involved in this pathway has been estimated to be interfered with by a dual specificity phosphatase, namely mitogen-activated protein kinase phosphatase 1 (MKP1), that ultimately leads to LV reverse remodeling in pediatric DCM cases. 45

Figure 2 Dynamics of CL and Cytochrome C in Stressed Myocardium In stressed myocardium, cardiolipin (CL) first flips from the inner leaflet of the inner mitochondrial membrane (IMM) to the outer leaflet and then are carried to the outer mitochondrial membrane (OMM) by mitochondrial creatine kinase (MtCK) and nucleoside diphosphate kinase (NDPK-D). CLs provide room for the incorporation of B-cell lymphoma 2-associated X protein (Bax)/B-cell lymphoma 2 antagonist/killer (Bak), which acts as a channel for the release of cytochrome c (cyt c).

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“…Wen et al 45 has shown that levels of 4 lysophosphatidic acids (lysoPAs), namely lysoPA 16:0, lysoPA 18:0, lysoPA 18:1, and lysoPA 18:2, have been significantly associated with LVRR in the case of pediatric DCM. The mechanistic background of these lysoPAs has remained elusive.…”