When arterial blood stops flowing to the heart, the heart stops beatingand dies. If the stoppage results from clotting of the coronary arteries,the final curtain of atherosclerosis, it may take the heart muscleanywhere from 30 minutes to four hours, as a rule, to shut down.

On the death certificate, the cause of the heart failure will usuallyread "cardiac ischemia." That's what kills more people every year inthe industrial world than any other single cause of death.

"The term `ischemia' means inadequate blood supply;" explainedmolecular cardiologist R. Sanders Williams, "that is, when the bloodsupply is reduced below the normal level. Global or total ischemiameans the flow is reduced to zero."

Ischemia is only the most lethal of the myriad stresses that ceaselesslyassail the cells of the human body. Cancer is another death-dealingstress. Viral infection may or may not kill, but certainly stresses outthe cells. So does inflammation, and extremes of cold and heat.

The body doesn't take these insults lying down _ at least, not atfirst. To mitigate these cellular stresses, nature deploys a family ofgenes, which encode the so-called `heat-shock proteins.' So-called,because they were first studied in the thermal response of the fruit fly,whence so many gene discoveries flow.

"The human cell responds to excessive heat and to ischemia in asomewhat similar way," Williams told BioWorld Today. "The heat-shock genes are a very interesting gene family. The proteins theyencode are expressing to some degree in all living cells that we knowabout, from bacteria to humans."

But they aren't just posted to damp down the effects of stress."These proteins are necessary for normal housekeeping functions inunstressed cells," Williams added. "They are molecular chaperones,guiding newly synthesized proteins to form their correct shape withinthe cell."

At the start of the 90s, Williams' lab began studying ischemia as astress, as opposed to thermal stress. "We found that ischemiaactivated many of the same heat-shock genes in the heart," heobserved.

Human Gene Beefs Up Mouse Hearts

Williams, who is chief of cardiology at the University of TexasSouthwestern Medical Center, in Dallas, is senior author of a paper intoday's Proceedings of the National Academy of Sciences (PNAS).Its title: "Cardioprotective effects of 70-kDa heat shock protein intransgenic mice."

His laboratory constructed a strain of mice whose hearts, whenstressed by ischemia, expressed human heat-shock proteins alongwith their own murine ones.

The researchers began by removing the beating hearts fromtransgenic animals and hooking them up to a surrogate blood supply,consisting of a physiological nutrient solution bubbled through anoxygen generator to mimic normal circulation.

"We showed that when the perfusion flow is maintained," Williamsrecounted, "the heart accumulates normal levels of ATP and otherhigh-energy phosphates, and that it beats normally. Next, we stop theflow for a period of time," he continued, "and then restart it. Duringthat period of zero flow, which mimics a human coronary occlusion,or heart attack, the mouse heart will be injured.

"If that type of ischemia is prolonged, the cells will die. In a mouse,we found that very short periods of total ischemia _ on the order of10 minutes _ sufficed to induce irreversible injury."

Because the transgenic mice carried additional heat-shock DNA,specifically, the human 70kD gene, the experiment asked "whetherthe presence of higher-than-normal concentration of heat-shockprotein would allow a complete recovery." Which is what Williamsand his co-authors saw happen.

This model of ischemia, he said, "has been used for many years inlarger animals, to study the hearts of rats or rabbits. It was a bit novelfor us to do it in mice, since their hearts are so much smaller."

He went on, "And what was totally novel was to do all of this withinthe nuclear magnetic resonance [NMR] magnet, so we could measurehigh-energy phosphate concentrations."

`Ultimate Clinical Applications' In Far Offing

He made the point that "if you can re-open an occluded coronaryvessel within two to four hours, and sometimes as late as six hours,heart-attack patients will do much better than if you're unable to openit until a little longer time has elapsed."

He thinks that "the ultimate clinical implication of this [PNAS-reported] work is that we might be able to extend that window of timea physician might have to restore blood flow to the heart beforeirreversible injury has occurred."

Williams stressed that "This clinical perspective is speculative, andwe're way away from accomplishing it, but I imagine that efforts tomanipulate stress proteins would first come in high-risk settings likecardiac surgery and invasive procedures such as angioplasty." Hesuggested:

* Designing small-molecule drugs to stimulate the body's ownproduction of heat-shock proteins, prior to cardiac surgery, or morebroadly in individuals at high risk of coronary disease. "A number oflaboratories are working on that right now," Williams observed.

* Mimic the transgenic-mouse model, by putting an extra copy of aheat-shock protein gene into the genomes of susceptible people, toaugment their own endogenous production of heat-shock proteins.

Meanwhile, Williams and his colleagues are now "studying otherstress proteins [besides 70kD], and also observing protective effects.So it may be that by combining more than one gene, we can produceeven higher levels of protection against ischemia.

"The real question we asked in this experiment," he concluded, was:"As nature fine-tunes this system, is it the best that the cell can do?Or can we go nature one better and modulate it a little bit?" n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.