Angina drug ranolazine potentially useful against heart rhythm disorders

Apr 9 2008

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 on April 1st 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.

Life Stages, Medications and LQTS Risk

In 1979, Moss helped to launch the International LQTS Registry, a database of families with the LQTS trait. By following generations of sufferers, gene hunters used the registry to track down more than 300 genetic mutations involving seven genes that cause versions of LQTS. By following the outcomes of patients in the registry over many years, researchers are now drawing accurate conclusions about risk. In addition to Moss' paper on renolazine, his fellow researchers from the Medical Center presented three papers on different aspects of LQTS risk at ACC this year, each an analyses of data collected from the registry.

The first study, led by Princy Thottathil, found that patients with LQTS that also have asthma, and that receive standard asthma treatment with stimulants to clear airways (e.g. beta-agonist therapy), have approximately twice the risk of having their first LQTS-related cardiac event (fainting, aborted cardiac arrest or sudden death) as the average patient. Conversely, those treated with beta-blocker therapy to address their arrhythmia risk, along with beta-agonist therapy for their asthma, enjoyed an 80 percent reduction in cardiac events (HR = 0.14; P = 0.05).

Past studies have suggested that treatment with beta-blockers, widely used hypertension drugs, is prudent as a preventive measure in all LQTS patients. The study examined 3,287 patients enrolled in the International LQTS Registry. Statistical analysis used to assess the independent contribution of clinical factors for first cardiac events from birth through age 40. Beta-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio [HR] = 2.00, 95% confidence interval 1.26-3.15, p = 0.003) after adjustment for relevant covariates including time-dependent beta-blocker use, sex, QTc, and history of asthma. This risk was augmented within the first year after the initiation of beta-agonist therapy (HR = 3.53; p = 0.006). The combined use of beta-agonist and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66; p < 0.01).

In the second study led by Jehu S. Mathew, researchers found that going through menopause provided LQTS patients with a four-fold reduction in risk of cardiac events, providing further evidence that estrogen levels affect event risk. Past studied have determined that the risk of events is highest for women during child-bearing years, when estrogen levels are, on average, higher, and highest during the year a woman gives birth.
The study involved 1,624 women, with 560 having undergone menopause (average age: 47). The primary endpoint was the occurrence of any cardiac event between the ages of 20 and 70 years. When assessing annualized cardiac event rates, meaningfully lower cardiac event rates were seen after menopause. This held true when patients were grouped by prior syncope, by QTc length and by genotype.

The last study, led by Edward Y. Sze, observed the effects of combining inherited risk for cardiac created by the LQTS syndrome with inevitable age-related heart disease. While most previous studies have focused on the course of LQTS on patients within the first four decades of life, the current study looked at risk in 641 patients aged 40 and older (with a QTc of greater than 449ms). Patients were identified as having coronary disease if they had a history of hospitalization for myocardial infarction, coronary angioplasty, coronary artery bypass graft surgery, or were treated with medication for angina. LQTS-related cardiac events included the first occurrence of syncope, aborted cardiac arrest, or sudden cardiac death without evidence suggestive of an acute coronary event.

The study found that coronary disease, developed with age, was associated with a more than two-fold increase in risk of LQTS-related cardiac events (hazard ratio 2.24, 95% confidence interval 1.24-4.04, p=0.008) after adjustment for syncopal history before age 40, QTc, and gender.

“This is the first study to demonstrate that coronary disease augments the risk for LQTS-related cardiac events in LQTS,” Moss said. “The findings highlight the need for more focused preventive therapy in LQTS patients above the age of 40. Inherited plus acquired disease is a bad combination.”