The poet Tennyson said it first, in 1847: "All thy heart lies open unto me." Eight years later, in 1855, Browning weighed in: "Open my heart and you will see ..."
Obviously, these great British bards of the mid-19th century could not have been invoking the cardiac muscle laid bare in the operating room for surgical repair or transplantation. Yet modern open-heart surgery triggers a form of heart failure that goes back centuries.
The cardiology trade knows it as "myocardial stunning," or "heart stunning." "It was first recognized in 1976," said research and clinical cardiologist Eduardo Marb n, "and given this sexy, stunning name in 1980. Stunning has probably been going on for a long time. Coronary artery disease has been around for several centuries at least – ever since people have been eating rich diets, and living well."
Marb n said that the heart-stun syndrome "is probably getting more and more common" for two reasons: First of all, more and more patients undergo heart surgery every year. Secondly, the established goal of therapy now in acute ischemic syndrome, unstable angina, heart attack, is prompt restoration of blood flow to the heart muscle. So patients are routinely rushed in to intensive care, and given clot-busting drugs, or direct mechanical revascularization therapy – angioplasty – to restore blood flow.
"Patients sometimes get their blood flow back pretty quickly," Marb n said, "but they are left with this stunned heart muscle, and initially perhaps with a falsely pessimistic view of what their ultimate functional recovery is going to be. This change in medical strategy, with its new emphasis on very prompt reperfusion at any cost, has made for more of this stunning syndrome. This postoperative care costs the U.S. economy some $10 billion a year."
Stunning usually follows, as the night does the day, a surgical session on a heart/lung machine, which makes it in a sense iatrogenic – that is, surgery-induced.
Inevitable feature of intensive care
"It is iatrogenic in a sense," Marb n noted, "but it's also inevitable in the sense that the consequences of not starting the reperfusion, or not starting the surgery, would be infinitely worse. But now that we recognize the molecular mechanism of stunning, we may be able to prevent it, using new therapies.
"This is not something that strikes a patient on the street," he explained. "Rather, it happens after some kind of injury to the heart that in itself doesn't kill the heart, but leaves behind this kind of reversible insult. It happens in the setting of an aborted heart attack, or of cardiac surgery, during which time the heart needs to be stopped for a while. The rest of the body is on a bypass machine. The heart itself is not having normal blood flow – by design – so the surgeons can operate on it.
"But during this timeout," Marb n said, "even if there's a technical success, the patient may undergo this form of reversible injury that's called stunning. It usually occurs immediately after the previous insult, lasts for a day to several weeks, then the heart recovers. That's the fascinating thing about stunning; the patient eventually recovers completely from this common, reversible, acquired form of heart failure. It's not something you're born with. This isn't genetically programmed, like some forms of heart failure are. You can acquire stunning just by getting the right hit in a clinical setting.
"Stunned myocardium," he added, "is a form of heart failure that follows brief ischemic injury to the heart – so brief that it doesn't kill the cells of that organ, but nevertheless leaves behind this syndrome of abnormal contraction. It can be quire severe; the signs are an indication of the inability of the heart to pump blood normally. The symptoms are low blood pressure, congestion of fluid in the lungs, decreased exercise tolerance – and in the extreme, circulatory collapse and death."
Marb n, who directs the Institute of Molecular Cardiobiology at Johns Hopkins University (Baltimore, Maryland), has strived for the past 14 years to lay bare the molecular triggers of stunning. In his cross-hairs is a well-known cardiac-muscle protein called troponin, which leaks from the heart into the blood – where it's not normally found – within minutes after myocardial damage occurs.
"During my previous studies of protein injury in stunned myocardium," Marb n said, "we had found partial degradation of troponin I, and determined where the site of this injury in the protein sequence was. We were able to mimic that mutated protein very simply, using a gene truncation. What happens in the protein injury is that the sequence is clipped by proteolytic enzymes, so it loses the last 17 amino acids of its normal 210 amino acid length, and now is only 103 residues long."
Marb n is senior author of a paper in the current issue of Science, dated Jan. 21, 2000. Its title: "Transgenic mouse model of stunned myocardium."
For transgenic mice, no recovery
"This article," he said, "describes how we made a gene fragment that reproduced that proteolytic fragment of troponin I, and injected it into the germ line of embryonic animals to make transgenic mice. When born, they developed myocardial stunning. Unlike the reversible human syndrome, in mice it's not something that goes away, because they have the truncated protein in their genes.
"Mice can live for two years or more," Marb n pointed out. "We've had these transgenic heart-stun mice up to 16 months without any evidence of premature mortality. They appear to be perfectly compensated clinically, in the sense that their hearts are enlarged, and they're not contracting well, but just enough to maintain a normal cardiac output at baseline.
"We suspect that if we stress these mice – we haven't done those experiments yet – by exercise and so on, that we will see inability to maintain the supply of blood in the face of increased demand, and thus premature death."
He made the added point that "this is the first genetically determined model of a common form of heart failure. So it may be a very useful platform for drug testing and proof-of-principle experiments."
Marb n concluded: "We're open to discussions either for collaborative research or commercial exploitation, depending on avoidance of overlap with experiments we already have planned."
This article first appeared in the Jan. 25, 2000, issue of BioWorld Today, a sister publication to Cardiovascular Device Update.