When arterial blood stops flowing to the heart, the heart stops beating and dies. If the stoppage results from clotting of the coronary arteries, the final curtain of atherosclerosis, it may take the heart muscle anywhere from 30 minutes to four hours, as a rule, to shut down.
On the death certificate, the cause of the heart failure will usually read "cardiac ischemia." That's what kills more people every year in the industrial world than any other single cause of death.
"The term `ischemia' means inadequate blood supply;" explained molecular cardiologist R. Sanders Williams, "that is, when the blood supply is reduced below the normal level. Global or total ischemia means the flow is reduced to zero."
Ischemia is only the most lethal of the myriad stresses that ceaselessly assail the cells of the human body. Cancer is another death-dealing stress. Viral infection may or may not kill, but certainly stresses out the cells. So does inflammation, and extremes of cold and heat.
The body doesn't take these insults lying down _ at least, not at first. To mitigate these cellular stresses, nature deploys a family of genes, 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 a somewhat similar way," Williams told BioWorld Today. "The heat- shock genes are a very interesting gene family. The proteins they encode are expressing to some degree in all living cells that we know about, 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 in unstressed cells," Williams added. "They are molecular chaperones, guiding newly synthesized proteins to form their correct shape within the cell."
At the start of the 90s, Williams' lab began studying ischemia as a stress, as opposed to thermal stress. "We found that ischemia activated many of the same heat-shock genes in the heart," he observed.
Human Gene Beefs Up Mouse Hearts
Williams, who is chief of cardiology at the University of Texas Southwestern Medical Center, in Dallas, is senior author of a paper in today's Proceedings of the National Academy of Sciences (PNAS). Its title: "Cardioprotective effects of 70-kDa heat shock protein in transgenic mice."
His laboratory constructed a strain of mice whose hearts, when stressed by ischemia, expressed human heat-shock proteins along with their own murine ones.
The researchers began by removing the beating hearts from transgenic animals and hooking them up to a surrogate blood supply, consisting of a physiological nutrient solution bubbled through an oxygen generator to mimic normal circulation.
"We showed that when the perfusion flow is maintained," Williams recounted, "the heart accumulates normal levels of ATP and other high-energy phosphates, and that it beats normally. Next, we stop the flow for a period of time," he continued, "and then restart it. During that 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 of 10 minutes _ sufficed to induce irreversible injury."
Because the transgenic mice carried additional heat-shock DNA, specifically, the human 70kD gene, the experiment asked "whether the presence of higher-than-normal concentration of heat-shock protein would allow a complete recovery." Which is what Williams and his co-authors saw happen.
This model of ischemia, he said, "has been used for many years in larger animals, to study the hearts of rats or rabbits. It was a bit novel for 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 within the nuclear magnetic resonance [NMR] magnet, so we could measure high-energy phosphate concentrations."
`Ultimate Clinical Applications' In Far Offing
He made the point that "if you can re-open an occluded coronary vessel 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 open it 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 time a physician might have to restore blood flow to the heart before irreversible injury has occurred."
Williams stressed that "This clinical perspective is speculative, and we're way away from accomplishing it, but I imagine that efforts to manipulate stress proteins would first come in high-risk settings like cardiac surgery and invasive procedures such as angioplasty." He suggested:
* Designing small-molecule drugs to stimulate the body's own production of heat-shock proteins, prior to cardiac surgery, or more broadly in individuals at high risk of coronary disease. "A number of laboratories are working on that right now," Williams observed.
* Mimic the transgenic-mouse model, by putting an extra copy of a heat-shock protein gene into the genomes of susceptible people, to augment their own endogenous production of heat-shock proteins.
Meanwhile, Williams and his colleagues are now "studying other stress proteins [besides 70kD], and also observing protective effects. So it may be that by combining more than one gene, we can produce even 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.