The Johns Hopkins Gazette: January 24, 2000
January 24, 2000
VOL. 29, NO. 19


'Stunning' News About Heart Failure

Molecular glitch causes stop after open-heart surgery

By Marjorie Centofanti

Johns Hopkins Gazette Online Edition

Scientists at Johns Hopkins and Queen's University in Ontario have shown that a small molecular glitch is responsible for the sudden heart failure that almost universally strikes after open heart surgery and that costs the United States an estimated $10 billion in postoperative medical care every year.

It's the first time scientists have demonstrated that a problem at a molecular level can lead to any type of acquired heart failure. Acquired heart failures are the common ones, the researchers say, in contrast to those that are inherited, far rarer forms of the disorder.

In their study, the scientists focused on molecules linked to heart muscle contraction, in particular, an abnormal form of a protein called troponin I, known as TnI, that's part of a heart muscle cell's contractile "machinery" and that appears in certain patients with weakened hearts. The work, reported in the Jan. 20 edition of the journal Science, shows just how TnI goes awry and explains how that leads to the heart failure known as "cardiac stunning."

The study not only points to new ways to prevent and treat this specific heart problem, but, says team director Eduardo Marban, "understanding cardiac stunning moves us much closer to explaining the more common garden variety of heart failure, the chronic type that affects thousands in this country."

"Cardiac stunning affects virtually all patients who've had open heart surgery or have been placed on a heart/lung machine," says Hopkins Children's Center cardiologist Anne Murphy, who led the research team. "It's the reason heart patients must spend an entire day in intensive care following surgery," Marban adds. "Stunning exacts a high cost because of the added need for specialized patient care and the worry patients and their families experience with a prolonged recovery." Marked by a general weakness in the heart muscle, the disorder lasts from a few hours to days. "A stunned heart won't contract with the proper intensity," Murphy says. Cardiologists quickly place patients on adrenalin or a similar drug that strengthens heart beat.

Though stunning normally passes, some patients require life support, and some, especially those with complications, die. "I've seen children with very good surgical repair of an underlying heart defect have a rocky time postoperatively because of this," Murphy says.

The conditions that trigger stunning are specific, Murphy says. "You commonly see it after blood supply to the heart has temporarily shut down and then gets restored," she says. So patients--especially children--who have to switch to a heart/lung machine during open heart surgery are prime targets. Adult heart attack victims who've had blood supply restored through drugs or angioplasty also are prone.

Team researchers knew from their earlier experiments that animal models of stunning have damaged TnI. The protein is short: It contains fewer amino acid "building blocks" than normal. The scientists also found the shorter TnI in heart muscle samples from patients with weakened hearts.

But to see if faulty TnI causes cardiac stunning, Murphy explains, the team cloned genes for abnormal human TnI and inserted them into mice. Some 20 percent of the TnI in the mice turned out to be the shortened form. These mice developed enlarged hearts, a classic response to weakened muscle. "The force their heart muscles exerted was also far below normal," Murphy says. "The mice resembled humans with cardiac stunning in any way we could measure.

"What we've done," Murphy says, "is produce, artificially, what normally can happen in heart muscle when blood supply gets interrupted." A major part of the study also explains, step-by-step, what the scientists believe goes awry in cardiac stunning, a feat that's taken the team 14 years of research. Basically, they've shown, Murphy says, that heart cells deprived of oxygen experience a sudden increase in calcium. High calcium, in turn, trips the production of enzymes that cleave proteins. "And when the protein troponin I gets shortened," Marban says, "that somehow gums up the contractile machinery."

Marban says it's likely that in chronic heart failure, patients' hearts are subjected to many small cutoffs of blood supply over a period of time, due to blood vessel disease. They may have mini-bouts of cardiac stunning that take their toll. "That's an ongoing area of study for our lab," he says. Other work will be to find some way to anticipate stunning, Murphy says. "Then, perhaps we could pre-treat surgery patients with something that keeps troponin I shortening to a minimum or avoids it altogether."

The American Heart Association picked this research in December for its list of Top 10 Research Advances in Heart Disease and Stroke in 1999.

Other Hopkins researchers in the study were Harald Kogler, David Kass and doctoral student Dimitrios Georgakopoulos. The research was funded by grants from the American Heart Association, the National Institutes of Health, the Deutsche Forschunungsgemeinschaft, the Heart and Stroke Foundation of Canada, the Medical Research Council of Canada and internal university contributions.