Columbia team finds treatment that corrects cellular defect at the root of heart failure

December 11, 2001

NEW YORK - Researchers at Columbia University have shown for the first time that beta blockers - drugs used to treat cardiovascular disease - can correct a specific defect in failing hearts.

"Up until now we have been treating symptoms but not the cause of heart failure," says Dr. Andrew R. Marks, Clyde and Helen Wu Professor of Molecular Cardiology at Columbia University College of Physicians & Surgeons and principal investigator of the study. "Our research shows that we can treat the cause." Dr. Marks also serves as director of Columbia's Center for Molecular Cardiology and is professor of medicine and pharmacology. The findings will be published in the Dec. 4 issue of the journal Circulation.

Heart failure, the leading cause of death in the developed world, occurs when the heart is too weak to sustain proper circulation. Some patients in heart failure receive left-ventricular assist devices (LVADs), which are implanted in the chest to help pump the blood and give the patient's own heart a rest as he or she waits for a heart transplant. Patients in heart failure may also be given drugs to improve symptoms. But heart transplant is the only way to cure heart failure.

Dr. Marks' research demonstrates that defects in the calcium channel controlling heart muscle function occur in heart failure. The membrane surrounding a cell contains a small calcium channel stimulated by the electrical impulses driving heart rhythm. When stimulated, this calcium channel triggers another, larger calcium channel within the cell, called the ryanodine receptor, to release calcium ions. The rush of calcium ions then signals the heart muscle to contract powerfully. The ryanodine receptor sits at the surface of the sarcoplasmic reticulum, a sac containing calcium ions, and is the major gatekeeper for calcium ion release.

The more calcium released through the ryanodine receptor, the stronger the contraction of the heart. Dr. Marks and his colleagues have discovered that one of the ways in which the ryanodine receptor can be activated to release more calcium involves stimulation of the nervous system to generate increased levels of catecholamines (adrenaline) in the blood.

Patients with heart failure have high levels of catecholamines in their blood, but their calcium ion release system does not respond properly to these neurotransmitters. This causes the nervous system to release even more catecholamines, with little or no response from the heart muscle.

Dr. Marks discovered that the weak link in the calcium channel release system, which causes the body to respond to catecholamines, is the ryanodine receptor. In heart failure, Dr. Marks found, the ryanodine receptor is excessively phosphorylated, making it unable to answer signals calling for the release of more calcium ions. When these ions are not released, the heart muscle cannot contract with the strength needed to pump blood through the body.

Dr. Marks' study used animal models to show that beta blockers prevent excess phosphorylation of the ryanodine receptor, allowing it to respond to cellular signaling and release calcium ions as needed. While beta blockers are not normally used in patients in the late stages of heart failure, Dr. Marks suggests that they should be and that many more heart failure patients could benefit from beta blockers than now receive them.

In a previous study published in the journal Cell, Dr. Marks and his colleagues were able to examine human hearts before and after heart failure treatment. They took tissue samples from the hearts of patients who were about to receive LVADs. These patients were eventually given heart transplants, after which Dr. Marks and his colleagues studied the patients' old hearts. They noted that the calcium channels in the heart muscle tissue of patients who were on LVADs exhibited less excess phosphorylation. Giving the heart muscle a rest apparently helped restore normal function.

"It's really an incredible opportunity to measure in humans at the molecular level the effect of treating heart failure," says Dr. Marks. "There's no other way to do that." Dr. Marks and his colleagues also removed individual calcium channels from the heart muscle, placed them in artificial membranes, and tested their function in the lab. They found that the calcium channels from patients with heart failure have defective function that, in addition to making them unresponsive to further stimulation by catecholamines, also causes a calcium leak that can weaken heart muscle contraction and possibly trigger fatal heart arrhythmias. These arrhythmias, known as ventricular fibrillation, are the cause of death in about 50 percent of patients with heart failure.

"Heart failure is an extremely complex disease that is caused by problems involving multiple systems both in the heart and in other organs of the body," Dr. Marks notes. "While it is unlikely that any one treatment will cure heart failure, understanding the basic defects in failing hearts should pave the way for multiple new forms of treatment."
The research was supported by grants from the National Institutes of Health and the American Heart Association.

Columbia University Medical Center

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