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Cardiovascular Report - Looking back for better heart care

Cardiovascular Report Winter 2011

Looking back for better heart care

Date: February 28, 2011


David Kass
David Kass wonders if asynchrony is “druggable.”
photo by Keith Weller

When David Kass tells people what’s going on in his Johns Hopkins lab, he invokes a bit of Hollywood. To further improve researchers’ mastery over electrical malfunctions of the heart, he says, “we’ve gone back in time. It’s a bit like the Benjamin Button story, where we can only learn the truth by reviewing our past.”

The quest of the moment, Kass explains, is to know the underlying mechanisms behind one of Hopkins’ strongest areas. In what he describes as “an amazingly fast history,” Kass and others over the past decade developed ways to resynchronize a failing heart’s discordant beats with a form of biventricular pacing known as cardiac resynchronization therapy, or CRT.

But Kass says CRT’s rapid deployment has hindered the deeper understanding of how it works. He explains that CRT’s trailblazers found ways to introduce the new technology directly into human beings without pausing over its basic science. “We never had an animal model,” Kass says. So while CRT has helped many, Kass and fellow researchers still want to know why it won’t work in all heart failure patients with poor ventricular function.

“We usually start with the basic science,” Kass says, “But this process started at the end. At first we thought it was working in everybody and it’s great. But it didn’t.”

Up to a third of heart failure patients showed no response to CRT, which led Kass’s team to explore a simple “responder, nonresponder problem.” How could they know in advance which patients would respond and which would not, and was there a way to adapt CRT to broaden its benefits?

Kass’s team has used tools in search of the details that separate responders from nonresponders—including ECG monitors to track whether placement of leads in heart tissue should be more site-specific—and they’ve used noninvasive imaging to get a better sense of the wall motion between the two ventricles in hearts that suffer from dyssynchrony. These new bits of data are helpful, says Kass, but they’re still not quite basic enough.

Still, these newer questions were beginning to center on whether CRT “is doing something to patients that we never imagined,” says Kass. What if the asynchrony stems from a problem at the biochemical signaling level? “This might be druggable,” says Kass. “We might find a way to get CRT in a bottle.”

Joined by research associates Gordon Tomaselli, Jennifer Van Eyk and Brian O’Rourke, Kass et al are studying how CRT alters the sympathetic nervous system. They have homed in on the adrenergic receptors in heart muscle cells, where they can see that CRT is “doing something very fundamental to the motors.” Something about CRT helps those motors generate more force for less energy.

Tomaselli thinks key secrets of the CRT puzzle may reside in the signaling pathways. “This doesn’t happen by magic. It happens by well-defined signaling pathways that change in the body. If you know what the pathways are, you can develop agonists or antagonists.”

Kass wonders if the answer is already out there. “There may be an existing drug that can do the same thing. So we’re chasing that down right now,” he says.

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