All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- NOTE: You can make the print bigger with the font button on your browser! (It's usually a big "A") ---------------------------------------------------------- Drug May Help Prevent Irregular Heartbeat April 9, 2004 - A calcium leak inside heart cells may trigger an irregular heart beat. An experimental drug to plug the leak seems to prevent it but has only been tried in mice. Researchers hope to start human testing next year. The arrhythmia mentioned is VT or ventricular tachycardia - fast irregular beating of the heart's lower chambers. If it gets worse, the heart stops beating and quivers instead, called ventricular fibrillation. This is deadly. Many CHFers have these arrhythmias. Sufferers have a leak in a tiny channel that controls calcium levels inside their heart cells. That leak triggers the deadly irregular heartbeat, says Dr. Andrew Marks. An experimental drug called JTV519 can plug the calcium leak and prevent the irregular heart beats. Dr. Marks bred mice to have the same leak defect. He gave half the mice the new drug. Stressing them with exercise pushed all the untreated mice into ventricular arrhythmias and 89% died. None of the treated mice went into irregular heartbeats. This calcium leak seems to worsen heart failure too, so plugging it may help CHFers. In other not yet published animal studies, Marks found that fixing the leak improves overall heart function. Calcium causes heart muscles to contract. The question was, exactly how? Small calcium channels on the surface of heart cells play a role. Marks discovered a bigger calcium channel that works inside heart cells, one he thinks is the key to controlling the heart's beating. This is called the "ryanodine-receptor channel." In this channel is a protein called calstabin2. Between heart beats, it should keep the channel closed so calcium can't leak out. In heart failure, calstabin2 doesn't do its job well enough. The calcium that leaks, worsens an already weakened heart and messes up the heart's electrical activity so that an arrhythmia may happen. The experimental new drug improves the natural protein's ability to close the channel. Source: Columbia University Press Release ========================================================= This is from Dr. Andrew Marks, Center for Molecular Cardiology - paraphrased by me: Our research focused on the body's molecular control of calcium release between heart cells through channels. We reported a not-before-known process called "coupled gating." This helps regulate heart muscle cell contraction. Coupled gating explains how groups of calcium release channels are activated and deactivated in a coordinated way to make skeletal and heart muscle contract. We have related these newly found cell signaling mechanisms to the molecular mechanisms underlying human heart failure, and more recently with fatal heart arrhythmias that cause sudden cardiac death. We have pioneered study of defective regulation of cell-to-cell calcium release channels in human heart failure. In 2000 we reported the discovery of a defect in the calcium release channel (ryanodine receptor) in human heart failure. We showed that this defect is due to over- stimulation of the "flight or fight" response, which is harmful in failing hearts, but can be corrected with oral beta-blockers. Source: www.cumc.columbia.edu/dept/cardiology/research.html#marks ============================================================ More on calcium channels and your heart beat: The membrane around a normal heart cell contains a small calcium channel that is stimulated by electrical impulses that drive heart rhythm. When stimulated, this calcium channel triggers another, larger calcium channel within the cell, called the ryanodine receptor or RyR2. This larger channel releases calcium ions. This rush of calcium ions signals the heart muscle to forcefully contract. RyR2 sits at the surface of the sarcoplasmic reticulum. That is a sac full of calcium ions, and it is the major gatekeeper for calcium ion release. The more calcium released through RyR2, the stronger the heart beat. In a previous study, Dr. Marks found that CHFers' calcium channels don't work right. This causes a calcium leak that can weaken heart beating even more, and possibly trigger fatal heart arrhythmias. A protein called calstabin2 usually holds the large RyR2 channel closed when it should be closed. When the cycle of RyR2 and calstabin2 is disrupted, the channel leaks calcium ions, triggering arrhythmia. The experimental drug JTV519 improves calstabin2- ryanodine receptor binding. The drug reduces diastolic calcium leakage in animals with heart failure. It increases binding of the protein calstabin2 to the ryanodine receptor. Dr. Marks' experiments show that if no calstabin2 is present, the drug won't work. Source: www.thedoctorslounge.net/cardiolounge/articles/jtv519/ ======================================================= Beta-blockers do more than we thought: (see www.chfpatients.com/glossary.htm for definitions) Dr. Marks discovered that one of the ways the ryanodine calcium receptor can be activated to release more calcium (thus increasing the heart's pumping power) is stimulating the nervous system to produce more catecholamines (like adrenaline) into the blood. CHFers have high levels of catecholamines in their blood, but their calcium release system doesn't respond properly to these neurohormones. This causes the nervous system to release even more catecholamines, with little response from the heart muscle. Dr. Marks found that the weak link in the calcium release system is the RyR2. In heart failure, RyR2 is unable to answer signals calling for release of more calcium ions. Because not enough ions are released, the heart muscle can't contract hard enough to do its job right. Dr. Marks’ animal study showed that beta-blockers prevent this RyR2 problem, letting them respond correctly to cell signaling so they can release calcium ions as needed. This suggests that *ALL* heart failure patients could benefit to some extent from beta-blockers. In a previous study, Dr. Marks studied human hearts before and after CHF treatment. They took tissue samples from the hearts of patients getting heart transplants. They discovered that calcium channels in the hearts of patients on LVADs had less problems with the RyR2 channels. Giving the heart muscle a rest had helped restore normal function. Dr. Marks also removed individual calcium channels from the old hearts of transplant recipients, put them in artificial membranes, and tested their function in the lab. Calcium channels from these CHFers didn't work right, not responding to stimulation by catecholamines. They also had a calcium leak that weakened heart contraction. The research was supported by grants from the National Institutes of Health and the American Heart Association. Source: www.globaltechnoscan.com/9thJan-15thJan02/heart_failure.htm