Columbia University Medical Center

Columbia Team Finds Cellular Defect At The Root Of Heart Failure

New York, NY – May 11, 2000 – A Columbia cardiologist has identified a molecular-level malfunction in patients with heart failure that can be repaired with existing treatments and may point the way toward new therapies for heart failure and heart arrhythmia.
“Up until now we’ve been treating symptoms but not the cause of heart failure. Our research suggests that there may be a way to treat the cause,” says Dr. Andrew R. Marks, Clyde and Helen Wu Professor of Molecular Cardiology at the College of Physicians and Surgeons. Dr. Marks directs Columbia’s Center for Molecular Cardiology and is a professor of medicine and pharmacology. The report of Dr. Marks’ discovery will be published in the May 12 issue of the journal Cell.
Heart failure, a leading cause of death worldwide, 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 that the ryanodine receptor releases, the stronger the contraction of the heart. Dr. Marks and his colleagues have discovered that increased levels of catecholamines, chemicals such as adrenaline that help transmit nerve impulses, can trigger the ryanodine receptor to release more calcium.
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 a malfunctioning ryanodine receptor is the weak link in the calcium channel release system that causes this failure in catecholamine response. In heart failure, Dr. Marks found, the ryanodine receptor is excessively phosphorylated, rendering it unable to answer signals calling for the release of more calcium ions. When these ions aren’t released, the heart muscle cannot contract with the strength needed to pump blood through the body.
Dr. Marks work suggests that beta blockers, drugs used to treat cardiovascular disease, may prevent or even reverse the development of excess phosphorylation on 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 considered as a means of helping more heart failure patients.

In the study, Dr. Marks and his colleagues examined 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 the 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 had defects that, in addition to making them unresponsive to catecholamine stimulation, caused 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, the American Heart Association, the Whitaker Foundation, and the Richard and Lynne Kaiser Family Foundation.

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