Ideal treatment for potentially fatal heart condition changes with age

Doctors now make more informed decisions on how to treat an electrical disorder of the heart - be it with drugs, an implanted device or nothing - thanks to a series of decades-long, Rochester-based studies.

The two latest studies in the series, published recently in the journal Circulation, further defined the ideal treatments for the youngest and oldest of patients with Long QT syndrome (LQTS) and concluded that they are not the same. Another conclusion is that the risk of fatal events in children is relatively low, and that implanted devices, while clearly important for some high-risk patients, may create more risk than the condition itself in some cases. That may change, however, if that patient survives past 40, when the same device becomes a lifesaver.

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 behind by a heart attack interferes with the heart's electrical system. As many as 1,000 deaths each year, however, are caused by LQTS.

The QT interval is part of the heart's electrical signature as recorded by an electrocardiogram (ECG). It represents the time it takes for the heart's lower chambers to "electrically recover" after each heartbeat. QTc is the QT interval 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 rapid, chaotic heart rhythm with loss of consciousness (syncope). In some cases, the dangerous heart rhythm stops on its own, but in others, it deteriorates into a fatal rhythm (ventricular fibrillation). Sudden death will then occur if the heart is not restarted with a defibrillator.

The LQTS syndromes were discovered 50 years ago, but researchers are still fine-tuning treatment recommendations. When is a drug or device warranted? If so, which procedures are right for which patients, and when is the best time to intervene? The competing risks of the disease itself, versus those created by invasive treatments, often complicate decision-making.

"Even when effective treatment is available, it doesn't always translate immediately into use by the affected patients, if the awareness is not there," said Ilan Goldenberg, M.D., research assistant professor of Cardiology in the Department of Medicine at the University of Rochester Medical Center, and first author of the Circulation paper. "Our study found surprisingly that just one in five children diagnosed with LQTS received appropriate drug treatment, beta blockers, known for years to cut their risk of death by 50 percent or more."

Arthur Moss, M.D., professor of Medicine at the University of Rochester Medical Center, and an author on the current paper, in 1979 helped to launch the International LQTS Registry, a database of families with the LQTS trait. By following generations of affected families, gene hunters used the registry to track down more than 500 genetic mutations involving ten genes that cause versions of LQTS. By following the outcomes of patients in the registry over many years, and by identifying groups of patients at high risk, researchers are closing in on more accurate ways to reduce the risk. In the current issue of Circulation, separate studies looked at risk of fainting or sudden cardiac death in two groups of registry patients, the youngest (under 13) and the oldest (over 40).

Risk in Children

For the current report about LQTS in children, the authors reviewed data on more than 3000 children who were enrolled in the registry before their teenage years, focusing predominantly on fatal or near-fatal events. The team reaffirmed that abnormally long QTc period (greater than 500 ms) in boys and fainting spells (syncope) in both boys and girls are significant predictors of aborted cardiac arrest or sudden cardiac death during childhood.

The syncope association with risk was time-dependent: the more recent the syncope, the greater the risk for a cardiac event. Girls accounted for 63 percent of the children in the registry, and they had a slightly but statistically significant longer baseline QTc. That said, boys had a higher rate of events (5 percent for boys, 1 percent for girls).

Doctors often recommended that LQTS patients be treated with beta-adrenergic blocking medications, which reduce the symptoms connected with hypertension and other disorders related to the sympathetic nervous system. Beta-blockers interfere with the action of epinephrine, lowering blood pressure and heart rate and stopping some arrhythmias.

Somewhat surprisingly, although the vast majority of the patients in the registry were already diagnosed with LQTS, and beta-blockers have been shown to be safe and effective, only 21 percent of the children were being treated with a beta-blocker. Treatment with a beta-blocker reduced the risk of aborted cardiac arrest or sudden cardiac death by 50 percent or more in this pediatric cohort. A very small number of children received other therapies.

While beta blocker therapy is established as effective therapy in most patients, specialists also have to decide which patients require additional, more invasive therapy beyond drugs. Aggressive LQTS interventions include implantation of a permanent pacemaker or a cardioverter defibrillator (ICD), or the use of a surgical procedure to eliminate stimulating nerves to the heart. An ICD shocks the heart back into proper rhythm when it detects a dangerous heart rhythm disorder. The surgical procedure cuts certain sympathetic nerves that control heartbeat rate and can reduce the risk of fainting or sudden death in young people with LQTS, according to a 2004 paper in Circulation.

In way of good news, the report confirmed a low mortality rate, with only 53 events (not all fatal) during nearly 12 years of follow-up in 3015 children in the LQTS registry (annual serious event rate of 0.15 percent).

"When the low rate of rate of fatal events is measured against the potential for failure of implanted devices, the negatives of device therapy in low-risk LQTS children may outweigh the plusses," Goldenberg said. "This only emphasizes the importance of the present report and highlights the continued need for improved risk stratification. Although the ICD clearly has life-saving value, it is not for everyone, and the majority of patients with LQTS can be treated effectively with beta-blocker therapy."

Life After 40

In a companion report, the team looked at data from 2759 subjects 41 to 75 years old, stratified by QTc, gender, and age sub-group (41 to 60 compared to 61 to 75 years). Even after age 40 years, patients with LQTS and a prolonged QTc continued to have a substantial risk of aborted cardiac arrest or sudden cardiac death, particularly from ages 41 to 60 years old.

Women with higher QTc intervals had more events than those without significant QTc prolongation, whereas the event rate was similar among men regardless of QTc range. Similar to the data in the children, recent syncope was a predictor of serious adverse events in affected patients, with a nearly 10-foldincreased risk. Beta-Blockers were used in 25 percent of patients, more so in those with a longer QTc. A trend toward lower mortality was observed in the older patients treated with beta-blockers, which could obviously be due to several different protective mechanisms (e.g. lowered blood pressure).

Among patients receiving ICD therapy, 15 percent had experienced their ICD to fire in response to an arrhythmia, possibly saving their lives. The authors concluded that ICD implantation in LQTS patients over age 40 should be considered for primary prevention in those who have still symptoms despite beta-blocker therapy. Surgical denervation was performed in just 9 patients in this adult LQTS population, so conclusions were hard to draw. Overall, the results show continuing risk for patients over age 40.

"LQTS is clearly not the same in all patients," Moss said. "We welcome the recognition by a colleague who wrote an editorial accompanying our articles in Circulation that decades of work involved in building the International LQTS Registry have paid off in better treatment for LQTS patients, young and old."