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Angina drug potentially useful against heart rhythm disorders

April 01, 2008

Rare genetic syndromes provide insights into post-heart attack electrophysiology

A recently approved angina drug may also represent a powerful new treatment for a rare hereditary syndrome that places teens at risk for sudden cardiac death, according to research presented to today at the 57th Annual Scientific Sessions of the American College of Cardiology (ACC) in Chicago.

Cardiac arrhythmias are electrical malfunctions that throw the heart out of rhythm, causing many of the 330,000 sudden cardiac deaths each year in the United States. Most fatal arrhythmias occur in aging patients when scar tissue left by a heart attack interferes with the heart's electrical system. As many as 1,000 deaths each year, however, are caused by Long QT Syndrome (LQTS), which occurs mostly in teens with otherwise healthy hearts. While rare, LQTS is yielding insights into the much more common post-heart attack arrhythmias, researchers said.

The QT interval is part of the heart's electrical signature as recorded by an electrocardiogram (ECG). The QT represents the time it takes for the heart's lower chambers to "reset" electrically after each heartbeat. QTc is QT corrected for heart rate, a more accurate measure. In LQTS patients, QTc reset time is prolonged, which makes the heart more susceptible to fatal arrhythmias. The condition may go unnoticed until sports, strong emotions or even loud noises knock the heart out of rhythm, causing loss of pulse and consciousness (syncope). Sudden death will then occur if the heart is not restarted with a defibrillator. Given the current state of awareness, some families have lost a second child before realizing all the children have the syndrome.

In the current, pilot study, researchers found that a drug, ranolazine (brand name Ranexa, CV Therapeutics) shortens the QT interval by about 5 percent; just enough to reduce symptoms and risks associated with one form of LQTS (LQT3-deltaKPQ). It is one of three forms of the disease that together make up 90 percent of LQTS cases. Past studies have shown that patients with angina, severe chest pain caused by inadequate blood flow to the heart, are also more likely to experience arrhythmias. Researchers got a clue that ranolazine, approved in January 2006, might influence QTc during its angina clinical trials, where it was found to have electrophysiological side effects.

"Past studies have shown that people with angina are also at risk for rhythm disorders," said Arthur Moss, M.D., professor of Medicine in the Department of Medicine at the University of Rochester Medical Center and lead author on the ranolazine abstract. "Our study found that we may be able to treat two conditions for the price of one with this drug. Specifically, Ranolazine shortens the QTc interval and improves myocardial relaxation in patients with the LQT3 mutation."

In a carefully controlled setting, and with informed consent, researchers gave five patients with the LQT3 mutation an 8-hour intravenous infusion of ranolazine, with ECG and ECHO evaluation before, during, and after treatment. Over the infusion period, the mean reduction in QTc from baseline was 26 +/- 3ms (p<0.0001). This represents about a five percent reduction in the QTc duration, researchers said.

In addition, researchers observed a significant 13 percent shortening in left ventricular isovolumic relaxation time and a significant 25 percent increase in mitral E-wave velocity during the infusion. Both are measures of how well an important chamber of the heart, the left ventricle, relaxes after each heartbeat, enabling it to fill with blood before the next contraction. Past studies have shown that the ability of the ventricle to relax is lessened, not just in Long QT, but also in more common post-heart attack arrhythmias and in conditions including hypertension, coronary artery disease and diabetes. Researchers said that ranolazine was the first treatment to bring about improved ventricular relaxation. No adverse effects of ranolazine were observed.

Cell Circuitry

Atoms and molecules have an undefined property called charge that explains how they behave. Like charges repel each other and opposites attract. Pulling apart two particles that are attracted to each other (separation of charge) creates potential energy that can be put to work. Cells have harnessed charge and potential energy to drive life processes by pumping charged particles into or out of cells.

The buildup of charged particles on one side of a cell membrane (membrane potential) means those particles will rush back if given the chance. That chance comes, under carefully regulated circumstances, with the opening of channel proteins that enable charged particle flow. The flow serves as a switch, kicking on cell functions. In heart muscle cells, for instance, signaling mechanisms coordinate the flow of sodium, potassium and calcium ions to create the potential energy needed for the cells to contract. By contracting in unison, many heart muscle cells bring about the heartbeat. After each heart muscle cell contracts in response to a rush of charged particles, those particles must be pumped back across the membrane to re-create separation of charge (repolarize it), and get it ready for the next contraction, all within milliseconds.

Changes to ion channels, whether caused by disease, aging or LQTS, can cause channel proteins to leak charged particles, which alters the timing of the heartbeat. Ranolazine was found to block late sodium ion current in those patients with mutations of the LQT3 type examined in the current study. The net effect was a significant shortening/improvement of repolarization as measured by QTc duration.



University of Rochester Medical Center