Scientists at the Cedars-Sinai Heart Institute have identified a heart-specific form of the BIN1 protein, which is responsible for sculpting tiny folds in pockets (T-tubules) that are present on the surface of heart muscle cells. The study provides the first direct evidence of a previously theoretical “fuzzy space” or “slow diffusion zone” that protects against irregular heartbeats by maintaining an ideal concentration of electrochemical molecules, according to the researchers.
“The findings help us understand how heart cells are organized, but more importantly, they give us insight into the way heart cells change when hearts start to fail,” said Robin Shaw, M.D., Ph.D., cardiologist and expert in heart failure and rhythm abnormalities at the Heart Institute.
“In addition, the results have diagnostic implications and eventually could lead to therapeutic options,” said Dr. Shaw, senior author of an article (“Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia”) in Nature Medicine that describes the study, which was conducted in laboratory mice. “By measuring the BIN1 level in the heart or in the bloodstream, we believe we can approximate the health of the heart and prognosticate patient outcome because we know BIN1 is decreased in heart failure. This gives us a target: If we can restore or replace the BIN1, perhaps we can rescue failing hearts.”
Dr. Shaw's group, which has studied BIN1 for seven years, previously found that BIN1 allowed calcium channels to localize to the T-tubules, establishing pathways for calcium to get into the cell. They also found that BIN1 could be detected in the bloodstream as well as in the heart, that heart BIN1 is decreased by 50% in advanced stages of the most common forms of heart failure, and that low levels of BIN1 in the blood are a predictor of heart rhythm disturbances.
Heart researchers used to speculate that the BIN1 protein was responsible for making the T-tubules themselves, but Dr. Shaw's group found that the pockets exist even in the absence of the protein.
“In this study, using specialized microscopes, we could see that even though the T-tubules were still there, they looked very different. We discovered that although BIN1 does not create the tubule, it shapes it. The tubule was thought to be a very smooth dip of the membrane, but we now know there is a very complex folding, where BIN1 sculpts microfolds within the tubule,” explained Dr. Shaw.
“We…found that T-tubule inner folds are rescued by expression of the BIN1 isoform BIN1+13+17, which promotes N-WASP–dependent actin polymerization to stabilize the T-tubule membrane at cardiac Z discs,” wrote the investigators. “BIN1+13+17 recruits actin to fold the T-tubule membrane, creating a 'fuzzy space' that protectively restricts ion flux. When the amount of the BIN1+13+17 isoform is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered, and arrhythmia can result.”
The tiny folds are very important because they can trap the chemicals that control heart rhythm, noted Dr. Shaw.
“A little bit of trapping of calcium and potassium ions slightly changes the concentration of the environment just outside the cell, and these subtle changes are very protective for the heart. They actually alter the electrophysiology, protecting against arrhythmias like those that occur in heart failure. About 300,000 people die each year of heart failure, and rhythm abnormalities are the dominant cause of death,” he continued.
Cardiologists now use ultrasound images and estimates of the amount of blood pumped out of the left ventricle with each heartbeat to gauge the health of a patient's heart, but cardiologists long have known that this “ejection fraction” is a poor indicator of patient wellbeing or outcome.
“The membranes of heart cells, like other cells, recycle, and thus heart cell membranes and their associated BIN1 gets into the bloodstream,” said Dr. Shaw. “By taking a simple blood sample, we can measure what's going on in the heart. As we refine this BIN1 blood test, we believe we will be able to do a biochemical assessment of the heart cell, the myocyte.”