By David N. Leff
What caused deaths from heart attack to drop by half between 1970 and 1990 - from 600,000 a year to 300,000?
Were these new leases on life due to better cardiovascular therapies? To people quitting cigarettes? Exercising more? Adopting "lite," low-cholesterol dietary lifestyles? Presumably all of the above, plus curbing other, less obvious risk factors. Why, for example, are the wealthy more prone to heart disease than the poor? And the better educated less prone?
Yet, despite the improvement in survival, heart failure remains the top killer in industrialized countries. This taunting challenge inspires cardiovascular researchers to explore newer potential modi operandi for combating heart attack and cardiac failure.
Thus, the April 2001 issue of Nature Medicine reports: "Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function." The article's senior author is clinical immunologist Silviu Itescu, director of transplantation immunology at Columbia University's Presbyterian Medical Center in New York.
Fatal heart failure is the culmination of a one-two punch: (1) The initial acute ischemic attack and (2) its sequel, chronic congestive heart failure.
"In heart attack," Itescu told BioWorld Today, "you've occluded one of your major coronary arteries, and end up having some death of heart tissue that doesn't get perfused with oxygen within six hours. But I would say 95 percent of such people," he continued, "are able to survive ischemic heart attacks because their loss of heart tissue is seldom that large. Generally the amount of cardiomyocytes - heart-muscle cells - lost in an acute heart attack is not sufficient to cause mortality."
Swollen Cells Gasp In Vain For Oxygen
"But then what happens," Itescu went on, "is that the rim of normal heart tissue surrounding the dead tissue tries to compensate for its loss. Because if you've lost a bit of tissue, your heart just doesn't pump well enough any more. Those cells - the cardiomyocytes - just swell up inside with compensatory hypertrophy. They enlarge three to four times, adjacent to the infarcted area, which allows them to pump harder.
"At some point," Itescu recounted, "those cardiomyocytes that have hypertrophied and grown in size exhaust themselves and die from oxygen starvation. Then that area becomes ischemic, so your heart-attack zone enlarges from the middle out, takes over the area that previously was cardiomyocytes, and keeps enlarging like a wave that just goes on and on.
"The next neighboring area then enlarges," he went on, "trying to compensate, until those cardiomyocytes give out and die. In the end, what happens is progression of tissue death, and replacement with scar tissue. That process is called remodeling, and leads clinically to fatal heart failure."
Itescu pointed out, "What was not appreciated until our study in Nature Medicine was that the reason these enlarged cells give out and die is that they're not adequately supplied with oxygen. Tissue death begins almost immediately, within days, causing swelling of cardiomyocytes to compensate. And then this process goes on throughout the duration of the patient's life."
To forestall an acute heart attack, the heart surgeon performs a coronary bypass operation - an end run around the clot-blocked artery - and hooks up replacement blood vessels to supply oxygen-rich blood to the starved heart. Itescu and his co-authors carried out the cellular equivalent of a bypass by introducing stem cells to the heart that endowed the damaged cardiomyocyte areas with new blood capillaries - the process of angiogenesis.
"We conducted our in vivo experiments," Itescu recounted, "with nude rats that don't have an immune system. That's how we were able to put our human stem cells into them. And we hypothesized that we wouldn't need new cardiomyocytes in order to improve cardiac function.
"Initially, we identified a very homogeneous stem-cell population in adult human bone marrow," he went on. "Those were cells that in embryos are known to become blood vessels. We found that such embryonic angioblast cells are also present in the adult bone marrow."
Next, the team "purified a homogeneous population of stem cells that looked like endothelial [blood vessel] precursors. However," Itescu observed, "we specifically did not want to have any cardiomyocyte precursors. Then we injected these stem cells into the tail veins of rats that had a major coronary artery clamped shut, to simulate an acute heart attack."
Those stem cells went exclusively to the damaged heart tissue, where they triggered the formation of new blood capillaries. These found their way to the cardiac target because the infarct produced special signals, chemotactic ligands, which the angioblasts recognized through receptors on their surfaces. Like micro-controls, they also spurred the development of the rats' own vessels in the immediate intact vicinity.
The treatment led to sustained 30 percent to 40 percent improvement in heart function, and less than one-third the amount of scar tissue, compared with untreated control animals. These ameliorations continued throughout the four months of the experiment.
Heart Cells Turn Back From Death's Door
"The most important finding, I think," Itescu commented, "is that if we simply improve microvascular blood supply to the endogenous cardiac cardiomyocytes that have hypertrophied in compensation for the loss of tissue after a heart attack, we can allow them to survive, not to die through an apoptotic pathway, and thereby enable the heart to improve its function by about 40 percent."
Last week, Itescu and his co-authors started to plan the beginnings of designing human trials. "I would think," he predicted, "that within 12 months we will have developed a protocol, and be ready to start some early safety or clinical trials.
"Meanwhile," he added, "what we need to understand a bit more is the timing, the kinetics of these cells. We can do all that in our animal models. Our in vivo experiments showed that in human trials, we can give these stem cells back from two days to two weeks after an acute heart attack, and prevent the cardiac failure progression.
"We might go to primates for fancier questions," Itescu allowed. "But in terms of the fundamental clinical protocol," he concluded, "based on what we've done in the rat, there should be no down side to using this sort of approach in humans." n