Mutation could hint at heart disease therapeutic target

Researchers have found a potential therapeutic target for clogged arteries and other health risks that stem from an excess of harmful fats in the bloodstream. "Cardiovascular disease occurs when lipids from the blood plasma are deposited in the walls of blood vessels, ultimately restricting blood flow," explained Steve Farber, who specializes in elucidating how cells process lipids. "This complex disease affects about a third of the world's population, so improving our understanding of the mechanisms that regulate the levels of blood lipids has important public health implications." Farber, Meredith Wilson and colleagues focused on a protein that is crucial for the synthesis of ApoB-containing lipoproteins. This protein, microsomal triglyceride transfer protein (MTP), is highly conserved in animals, from insects to humans. MTP loads lipids onto ApoB, a key initial step in the synthesis of ApoB-containing lipoproteins. Normally, MTP can transfer different types of lipids to ApoB, including triglycerides. However, the researchers found a mutation in MTP that blocks the loading of triglycerides, but not phospholipids, onto ApoB. MTP long has been considered a possible therapeutic target to help lower triglyceride levels in the blood and prevent cardiovascular disease. However, the existing chemical inhibitors of MTP are too effective and block all MTP function, which can cause intestinal fat malabsorption and a dangerous accumulation of fat in the liver. "Our study opens the door for the design of more specific MTP inhibitors that mimic this new mutation and selectively block triglyceride transfer to ApoB," concluded Wilson. "Our data suggests that this type of inhibitor could reduce circulating triglyceride levels without the risk of unpleasant and serious side effects in the intestine and liver." Their findings were published in PLOS Genetics Aug. 6, 2020.

Nanoparticle system captures heart-disease biomarker

Researchers at the University of Wisconsin (UW)–Madison have developed a method combining sticky nanoparticles with high-precision protein measurement to capture and analyze a marker of heart disease. Specifically, nanoproteomics captures and measures various forms of the protein cardiac troponin I (cTnI) a biomarker of heart damage used to help diagnose heart attacks and other diseases of that organ. Currently, doctors use an ELISA test to help diagnose heart attacks based on elevated levels of cTnI in the patient’s blood sample. This test is sensitive; however, patients can have high levels of cTnI in the blood without having heart disease. The result can be expensive, unnecessary treatments. “So, we want to use our nanoproteomics system to look into more details at various modified forms of this protein rather than just measuring its concentration,” said Ying Ge, director of the Human Proteomics Program in the UW School of Medicine and Public Health. “That will help reveal molecular fingerprints of cTnI from each patient for precision medicine.” To that end, the researchers designed nanoparticles of magnetite, linking them to a peptide of 13 amino acids long designed to specifically bind to cTnI. The peptide latches onto cTnI in a blood sample, and the nanoparticles can be collected together using a magnet. Using the nanoparticles, the researchers were able to effectively enrich cTnI in samples of human heart tissue and blood. They subsequently used advanced mass spectrometry to obtain an accurate measurement of cTnI and assess the various modified forms of the protein. The work was published Aug. 6, 2020, in the journal Nature Communications.

Helping predict chest pain in those with heart disease

Stress-induced activity in the brain’s inferior frontal lobe may have a direct correlation with chest pain in those with coronary artery disease. That’s according to research that appeared Aug. 10, 2020, in Circulation: Cardiovascular Imaging. “Our study sought to understand the degree to which health care providers should incorporate stress and other psychological factors when evaluating and treating angina,” explained lead investigator Amit Shah, assistant professor of epidemiology at Emory University’s Rollins School of Public Health in Atlanta. “Although brain imaging during a mental stress challenge is not a test that can be ordered in clinical settings, the study shows an important proof-of-concept that shows the brain’s reactivity to stress is an important consideration when considering angina treatment.” Of note, 148 people with coronary artery disease participated in the three-year study. The group underwent both testing of mentally stressful events in a clinical setting and brain and cardiac imaging. The researchers assessed participants with three tests performed over a two-week period: a mental stress test with brain imaging; a mental stress test with heart imaging; and an exercise or chemical stress test with heart imaging. Researchers monitored participants for chest pain. Additional questionnaires for chest pain and cardiovascular events were assessed after two years. Among the findings was that participants who reported having monthly, weekly or daily angina symptoms had higher inferior frontal lobe activity in response to mental stress. In addition, those who reported angina during mental stress testing with cardiac imaging also had higher inferior frontal lobe activation vs. those who did not have active chest pain during mental stress testing.

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