Heart valve holds key to organ survival

A Johns Hopkins-led research team has identified an ion channel within the heart that can be useful in helping the organ survive a heart attack. This channel, a type of control valve in heart cell mitochondria offers new perspectives on how energy supplies are maintained in the heart.

According to The National Institute of Health, heart attacks are unfortunately a common occurrence. The heart works 24 hours a day, pumping oxygen and nutrients in the blood to the body. Blood is supplied to the heart through its coronary arteries.

In coronary heart disease (CHD), plaques or fatty substances build up inside the walls of the arteries, the body's main transport system. The plaques also attract blood components, which stick to the artery wall lining. Called atherosclerosis, the process develops gradually, over many years, often beginning in the early stages of human development.

The fatty buildup or plaque can rupture and lead to the beginning of a blood clot that covers the break. The clot reduces blood flow, and the process of fatty buildup, plaque rupture and blood clot formation causes the coronary arteries to narrow, severely reducing blood flow.

When too little blood reaches the heart, the condition is called ischemia. Chest pain, or angina, may occur as a result. The pain ranges from mild and intermittent, to more pronounced and consistent.

The pain is severe enough that a normal daily routine is difficult to execute. Inadequate blood supply consequently causes no symptoms, a condition called silent ischemia.

If a blood clot suddenly cuts off most or all blood supply to the heart, a heart attack results. Cells in the heart muscle that do not receive enough oxygen-carrying blood begin to die off. The greater damage is produced as more and more cardiovascular cells die off.

The channel studied by the Hopkins research team, mitoKCa, is a potassium-activated calcium channel. It was discovered on the inner membrane of heart cell mitochondria, tiny structures packed inside cells. These powerhouses continuously pump out ATP, a chemical storage form of energy for cells.

The ATP is used by other parts of the cell to perform tasks like muscle contraction. Mitochondria are finely tuned to adapt to changing demands on their activity. Ultimately, it is this adaptability that determines whether cells, and thus the individual, lives or dies after experiencing a heart attack.

The discovery of mitoKCa could lead to new therapies for heart disease.

"Our results suggest that activating this channel optimizes energy production to improve the heart's overall strength," said senior author Brian O'Rourke, Ph.D., an associate professor of medicine at Johns Hopkins. "Interestingly, this beneficial effect can be activated by a drug to help the heart cell resist stumbling down the slippery slope to cell death when the blood supply is cut off, reducing the damage caused by a cardiac arrest."

The channel allows potassium ions to flow, especially when cellular concentrations of calcium rise. Four types of experiments were used by researchers to observe these functions. Lead scientist Wenhong Xu, Ph.D., isolated mitochondria from heart cells of guinea pigs and used fine-tipped glass pipettes and a high-magnification lens to record the electrical activity of the channel in patches of mitochondrial membrane.

When a potassium channel inhibitor, charybdotoxin, derived from scorpions, was added to the pipette, the channel's activity stopped. Channel activity increased when calcium was added in place of the toxin.

In a third experiment, researchers were able to confirm that the potassium channel contributed to mitochondrial potassium uptake. Canadian collaborators from Queens College in Ontario helped to find the channel protein in purified mitochondrial membrane preparations. Using fluorescent indicators in whole cardiac cells, researchers confirmed that the potassium channel contributed to this central process.

Finally, researchers at Otsuka Maryland Research Institute in Rockville, Md. tested whether an opener of mitoKCa could protect against blood flow blockage similar to that which is experienced during a heart attack. Using rabbits, they found that animals given the drug had heart attacks that were half the size of untreated animals.

According to the American Heart Association, among Americans aged 20 and older, the incidence of Coronary Heart Disease, the disease which leads to Angina and heart attacks, is 6.9 percent for non-Hispanic white males and 5.4 percent for non-Hispanic white females.

These numbers are slightly higher for black Americans, among whom 7.1 percent of males and 9 percent of females suffer from Coronary Heart Disease. In 1999, 529,659 Americans -- one in every five -- died of heart disease.

The research done by Johns Hopkins therefore is integral to the development of new medications and solutions for heart disease.

"We're at a new frontier of discovery," O'Rourke said in a recent interview with Quadnet magazine.

"If we can determine how mitochondrial ion channels regulate energy in heart cells, we may be able to protect the heart against life-threatening arrhythmias and other cardiac diseases."