Using Literature Based Discovery to Gain Insights Into the Metabolomic Processes of Cardiac Arrest

In this paper, we describe how we applied LBD techniques to discover lecithin cholesterol acyltransferase (LCAT) as a druggable target for cardiac arrest. We fully describe our process which includes the use of high-throughput metabolomic analysis to identify metabolites significantly related to cardiac arrest, and how we used LBD to gain insights into how these metabolites relate to cardiac arrest. These insights lead to our proposal (for the first time) of LCAT as a druggable target; the effects of which are supported by in vivo studies which were brought forth by this work. Metabolites are the end product of many biochemical pathways within the human body. Observed changes in metabolite levels are indicative of changes in these pathways, and provide valuable insights toward the cause, progression, and treatment of diseases. Following cardiac arrest, we observed changes in metabolite levels pre- and post-resuscitation. We used LBD to help discover diseases implicitly linked via these metabolites of interest. Results of LBD indicated a strong link between Fish Eye disease and cardiac arrest. Since fish eye disease is characterized by an LCAT deficiency, it began an investigation into the effects of LCAT and cardiac arrest survival. In the investigation, we found that decreased LCAT activity may increase cardiac arrest survival rates by increasing ω-3 polyunsaturated fatty acid availability in circulation. We verified the effects of ω-3 polyunsaturated fatty acids on increasing survival rate following cardiac arrest via in vivo with rat models.

MEDI6012: Recombinant Human Lecithin Cholesterol Acyltransferase, High‐Density Lipoprotein, and Low‐Density Lipoprotein Receptor–Mediated Reverse Cholesterol Transport

Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate‐limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double‐blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment‐emergent adverse events that were similar to those of placebo. Dose‐dependent increases in high‐density lipoprotein cholesterol were observed with area under the concentration‐time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high‐density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non‐ATP‐binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low‐density lipoprotein particles by 41%, 88%, and 79% at the 80‐, 240‐, and 800‐mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high‐density lipoprotein cholesterol, endogenous apoA1, and non‐ATP‐binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low‐density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high‐density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02601560.

High-Density Lipoprotein Modifications: A Pathological Consequence or Cause of Disease Progression?

High-density lipoprotein (HDL) is well-known for its cardioprotective effects, as it possesses anti-inflammatory, anti-oxidative, anti-thrombotic, and cytoprotective properties. Traditionally, studies and therapeutic approaches have focused on raising HDL cholesterol levels. Recently, it became evident that, not HDL cholesterol, but HDL composition and functionality, is probably a more fruitful target. In disorders, such as chronic kidney disease or cardiovascular diseases, it has been observed that HDL is modified and becomes dysfunctional. There are different modification that can occur, such as serum amyloid, an enrichment and oxidation, carbamylation, and glycation of key proteins. Additionally, the composition of HDL can be affected by changes to enzymes such as cholesterol ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and phospholipid transfer protein (PLTP) or by modification to other important components. This review will highlight some main modifications to HDL and discuss whether these modifications are purely a consequential result of pathology or are actually involved in the pathology itself and have a causal role. Therefore, HDL composition may present a molecular target for the amelioration of certain diseases, but more information is needed to determine to what extent HDL modifications play a causal role in disease development.

LCAT deficiency and pregnancy: Case report

Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive condition affecting lipid metabolism with a prevalence of less than 1:1,000,000. Described here is the case of a 29-year-old pregnant woman with a diagnosis of LCAT deficiency (c.140G>A in exon 4), who had three episodes of hypertriglyceridemia-induced pancreatitis and nephrotic-range proteinuria throughout the pregnancy. Furthermore, fetal ultrasounds carried out during the second and third trimester revealed a steady reduction in fetal growth rate, and fetal growth restriction (FGR) was diagnosed. The woman underwent an elective caesarean section at 33 weeks of gestation and delivered a healthy neonate. This case report adds knowledge of the natural history of LCAT deficiency during pregnancy and will be useful in future patient management.