Cardiovascular Spare Parts 
by Ricki Lewis, Ph.D.

The human cardiovascular system is highly efficient, yet enormously complex. A
thousand times each day, the muscular heart pumps five quarts of blood through
the arteries, to the smaller arterioles and finally the microscopic 
capillaries, and then through ever larger venules and veins, back to the heart. 

The journey of blood through the capillaries alone covers more than 60,000
miles! In such an intricate and interconnected system, it's easy to see how a 
single glitch can profoundly affect health. 

Medical researchers have devised some ingenious ways to replace malfunctioning
cardiovascular parts.  Substitute heart valves have been in use for three 
decades, and replacement blood, blood vessels, and even a heart are being 
developed.

Many of these inventions are carefully crafted combinations of synthetic
materials and biological substances, designed to hopefully equal nature, yet
at the same time mimic the body closely enough so that the immune system does 
not reject the new part. Plus, these products must present a smooth surface 
for blood to flow over. Even the tiniest uneven surface can rupture a passing 
platelet, triggering the chemical cascade of clotting that can obstruct blood 
flow to a vital organ.

                          Red Blood Cell Substitutes

Blood is a complex mixture of red cells, white cells, and platelets, suspended
in a watery, protein-rich plasma. Because these components must be present in 
specific proportions, duplicating nature's recipe is a daunting task. But the 
rise in blood-borne infections, such as hepatitis and AIDS, has made the idea 
of a blood substitute quite appealing. The next best thing, many researchers
think, is a substance that can do the work of red blood cells in transporting 
and delivering oxygen to the body's tissues and removing wastes. The
hemoglobin protein in red blood cells normally carries out this function. 

A safe and effective red cell substitute must meet strict criteria. "It must
be absolutely disease-free, have a long storage life, and it must do the job
for an extended period of time," says Joseph Stocks, M.D., a blood banking
expert at the Maine Medical Center in Portland. 

Several types of chemicals can carry oxygen. In 1965, Leland Clark, Ph.D., at 
the University of Cincinnati, showed that some chemicals soak up so much
oxygen that they could supply the vital gas to an animal immersed in it. He 
dropped a mouse into a beaker filled with silicone oil. The animal's lungs
quickly filled and it sank--but kept breathing!  Silicone oil proved too
toxic, so Clark next worked with the perfluorochemicals (PFCs), organic 
compounds containing the element fluorine.

Clinical trials with PFCs began in 1978, and the first red cell replacement 
using these chemicals was approved by the Food and Drug Administration in 
January 1990.  The product, Fluosol, is a mixture of two PFCs, a mild 
detergent, and lipid molecules from egg yolk. Its use is very restricted. 

"Fluosol was approved as an oxygen-carrying drug in limited amounts, to be
used during balloon angioplasty in the coronary arteries," explains Joseph
Fratantoni, M.D., of FDA's Center for Biologics Evaluation and Research.

With balloon angioplasty, an inflated balloon is used to press plaque against 
artery walls, opening up the blocked vessel. Blood flow to the neighboring
area is temporarily impeded during the procedure, which may cause chest pain
and change in heart muscle function. But Fluosol, infused through a narrow
tube in the balloon, keeps the area oxygenated. 

Previous attempts to deliver blood through the balloon failed because a very
small tube must be used, and the red cells are too large to squeeze through.
But a Fluosol particle is only 1/900th the volume of a red blood cell, and the
preparation is half as thick as blood. With the protective effect of Fluosol, 
it may be possible to extend the angioplasty technique to more patients.

Fluosol may have other applications. Clinical trials are under way to examine 
its use following administration of "clot-busting" drugs such as streptokinase
and tissue-plasminogen activator. After a clot is dissolved, the rush of blood
through the opened region can damage tissue. Fluosol may stem this tide by
allowing a steadier trickle of fluid past as the clot breaks apart. It may
also help to save heart muscle normally deprived of oxygen during a heart 
attack and to oxygenate donated organs awaiting transplant. 

An obvious red cell substitute is the hemoglobin molecule itself, which would 
probably not trigger an immune reaction if freed from the red blood cells that
normally contain it. (Such an immune reaction can occur if a mismatched blood 
transfusion, containing cells from incompatible blood types, is given.) 

There would be no compatability problem with freed hemoglobin, but it could 
carry disease, unless purified. Researchers at Somatogen Inc. in Broomfield,
Colo., have circumvented these problems by mass-producing human hemoglobin in 
genetically engineered bacteria and yeast, providing a pure and abundant
source of the molecule, much as human insulin is supplied to diabetics. 

But use of single hemoglobin molecules outside of their red cell carriers 
presents several problems. The molecules are broken in two in the body, and 
can then squeeze through the one-cell-thick walls of the capillaries and
easily enter the kidney tubules to be excreted before delivering oxygen where 
it's needed. In addition, without co-factors contained in the red cell, 
hemoglobin cannot efficiently bind oxygen delivered by the lungs, and also
loses antioxidant biochemicals that normally protect surrounding cells from 
damage by too much oxygen.

Fortunately, clever chemists have already overcome these technological
hurdles. They link individual hemoglobin molecules together, or chemically
augment them.  This provides the bulk the molecules need to stay in 
circulation.  The molecule can even be further modified so that it not only 
binds and transports oxygen, but relinquishes it easily to oxygen-depleted
tissues.

Several companies are applying these chemical manipulations to human
hemoglobin derived from donated blood, starting with a "crosslinking" 
technique developed by Quest Blood Substitute, Inc., in Detroit. Werner Wahl, 
Ph.D., vice president for science and technology at Quest, explains: "When you
crosslink hemoglobin molecules, you add a chemical reagent to tie two or more 
of them together. There are lots of kinds of chemicals you can use, but some
are better than others. Exactly how you crosslink determines the
characteristics of the hemoglobin." 

Each company then introduces its own chemical modifications. One substitute,
for example, follows crosslinking with a special pasteurization process to
eliminate viral contaminants. 

A compromise between a free, "naked" hemoglobin molecule and nature's red cell
packaging is to enclose hemoglobin in a fatty bubble called a liposome, 
forming a structure called a "neohemocyte." Biologically, this makes sense. 
"Evolution spent an awful lot of time and energy wrapping hemoglobin in a 
membrane. So, maybe it isn't surprising that when you unwrap the package, 
there is trouble," says Fratantoni. 

At the University of California at San Francisco, pharmaceutical chemist C. 
Anthony Hunt, Ph.D., is wrapping hemoglobin in the same type of capsules used 
to enclose ink in "carbonless carbon" paper and scents in "scratch 'n sniff"
papers. But so far in animal studies, the immune system rapidly seeks and 
destroys these neohemocytes.

                            Brave New Blood Vessels 

Delivery of blood through open vessels is crucial to cardiovascular function. 
Block a vessel with plaque or a clot, and blood flow backs up, robbing nearby 
tissues of vital oxygen.  Blood can only flow through a smooth conduit.  So 
far, none of the several methods to unclog or replace blocked arteries keeps
them smooth indefinitely. Plaque that is scraped away or pressed against the
artery wall recurs. A transplanted blood vessel may provoke the recipient's 
immune system to reject it, and taking a vessel from the patient's own body 
involves surgery at two sites rather than just one. 

Synthetic blood vessels cause problems too. "There is a great need for a
living artery equivalent that has the properties of an actual artery," says 
Eugene Bell, Ph.D., chief scientific officer of Organogenesis, Inc., in 
Cambridge, Massachusetts. "No small-caliber, synthetic vascular graft 
presently exists that will remain unplugged by blood clots."

That company's "living blood vessel equivalent," now being tested in animals, 
is a flexible yet strong tubule mimicking the triple-decker structure of real 
blood vessels. It is built of an inner layer of tile-like cells (called 
endothelium), a middle layer of smooth muscle, and an outer layer of
connective tissue. The cells, which come from human cadaver arteries, are 
grown in the laboratory and then molded into the tubules.  A very important 
step is the removal of molecules on the cells that are most likely to trigger 
an immune attack.  A woven-in Dacron mesh lends strength to the tubules.

The blood vessel equivalent can be made in any length or width, and can 
tolerate the pressure exerted by blood hurtling through the circulatory 
system. The vessel replacements can be stitched to their natural counterparts 
so seamlessly that blood clots are not likely to form. Bell foresees eventual 
use of the living blood vessel equivalent in cardiac bypass surgery, and in 
replacing damaged arteries in the brain and legs. 

Another possible blood vessel replacement is Dacron vessels coated with the 
patient's own endothelial cells. Because the body recognizes these cells as 
"self," it does not reject the replacement vessel. By adding certain growth 
factors, the cells are coaxed to knit a one-cell-thick endothelial lining on
the interior of the Dacron tubules smooth enough to prevent clotting. In cell 
culture experiments conducted by Stuart Williams, Ph.D., and co-workers at
Jefferson Medical College in Philadelphia, the lining began to form 
immediately.

                                    Valves

Heart valves are flaps of tissue embedded in thin sheets of connective
tissue.  Located at strategic points in the heart, the valves keep blood
flowing in one direction.  About seven different types of artificial valves 
are approved for use by FDA.  Some are similar to the first device, which 
resembled a ball in a cage. It was implanted in a 52-year-old man in 1961 by
Albert Starr, M.D., and M.L. Edwards, M.D.

"It's hard to beat the original Starr-Edwards model," says John  Watson, chief
of the devices and technology branch of the National Heart, Lung, and Blood 
Institute. "Claude Pepper was one of the original people in Congress who
helped form the institute, and he subsequently received a Starr-Edwards valve.
He lived for 20 years and died from something unrelated.  The fundamental 
design has been refined in terms of surgical technique and clinical 
management, but really there have been no significant breakthroughs." 

But opinion varies. Says William Letsing, M.D., of FDA's Office of Device 
Evaluation, "The Starr-Edwards is a 1960s type valve.  Many newer models, such
as the St. Jude, have much better hemodynamics and a higher state of
technology."

When natural heart valves do not close properly, are abnormally thick, or are 
damaged by rheumatic endocarditis (a complication of rheumatic fever that can 
also sometimes follow strep throat), replacement valves are lifesaving. After 
open-heart surgery became possible in the 1950s, surgeons first tried to treat
valve disease by scraping away the calcium deposits causing the problem. But
it was clear that replacing, rather than repairing, the valve would be more 
effective. Today mechanical prosthetic heart valves are built of a ceramic and
a metal (such as titanium). Pig valves and cow pericardium (outer heart 
muscle) are also fashioned into valves that are mounted on synthetic bases
called stents.

About 75,000 people receive replacement heart valves in the United States each
year. Mechanical models are generally used for those under 65 because of
superior long-term durability, and for children, who tend to deposit calcium
on biological valves. Older patients are usually given animal models that do
not last as long because they are less likely to calcify or be blocked by 
clots and may not require replacement. Many patients with mechanical
replacement valves must take anti-clotting drugs because they otherwise would 
have a considerably increased risk of a dangerous clot forming. 

But even a medical device as successful as heart valves can be improved.
Charles Peskin, Ph.D., a mathematician at New York University, uses computer
modeling to design better valves. Depicting the heart and its circulation in
three dimensions, he alters the curvatures of the discs and angles of the 
pivot points so that the smoothest possible blood flow is achieved. 

"We think of clotting purely as a chemical process, but it also depends on
fluid mechanics," Peskin says." If the blood stagnates in a pool, a clot will 
form. We're trying to design a valve so there will be no regions of 
stagnation." One of Peskin's heart valve designs is being patented, but his 
device is still a long way from an FDA application. 

                             The Artificial Heart 

In the 1980s, four men lived for varying amounts of time with artificial
hearts. But problems were rampant. The plastic, metal and Velcro of the heart 
attracted bacteria to areas inaccessible to many antibiotics. The device also 
caused blood clots, triggering strokes. 

As a result, life for the "permanent" artificial heart recipient was
difficult. Recipient William Schroeder, for example, suffered from strokes, 
seizures, fever, and depression on many of his record-setting 620 days with 
the Jarvik-7 device, which was then used predominantly as a short term "bridge
to transplant." But even this temporary use was halted in January 1990. 

The attachment of the Jarvik device to the bulky exterior equipment is thought
to be a route of infection.  So many scientists hope a fully implantable, 
electrically driven artificial heart can be developed. Other artificial hearts
are under development at the University of Arizona in Phoenix, the University 
of Utah in Salt Lake City, Pennsylvania State University in Hershey with 3M 
Corp., the Cleveland Clinic Foundation with Nimbus, Inc., Temple University in
Philadelphia with Abiomed, Inc., the Minneapolis Heart Institute, and the 
Texas Heart Institute in Houston. 

                          Ventricular Assist Devices

A currently more fruitful area of research is the electrically powered
implantable ventricular assist device, a pump used to support the patient's 
left ventricle, the chamber that must work most vigorously to send blood on 
its way throughout the body. The 1970s and 1980s saw a variety of experimental
left ventricular assists, all tethered to outside support equipment. Used as a
bridge to transplant, the device is promising.

In a study reported by R. Gaykowski, L. Barker, and W. Yates at the 34th
annual meeting of the American Society for Artificial Internal Organs, 92 
heart patients received Jarvik-7 devices while awaiting a heart transplant. Of
these 92, 63 received donor hearts, and 35 of these survived, a survival rate 
after transplant of 56. In a similar evaluation of patients using the 
ventricular assist to sustain them until a donor heart became available,
survival after transplant was 82. 

The difference in performance between the two devices may be anatomical 
location or technology complexity. "The technology for both devices is
similar.  But control of the total artificial heart is more difficult, because
there are both left and right ventricles that must be integrated," says the 
National Heart, Lung, and Blood Institute's Watson. 

One type of totally implantable ventricular assist device is a blood pump 
about the size of a softball, inserted beneath the heart in the muscles of the
abdomen. Blood from the left ventricle is diverted to the pump, which then
sends it to the aorta, the largest artery in the body. The pump senses when to
boost the blood by way of an electrically driven control unit that monitors 
the cardiac cycle.

The control unit, about the size of a deck of cards, is also implanted in 
muscle. The implanted miniature electrical engine and rechargeable battery are
charged from the outside by a coil and battery pack worn by the patient. The
external coil is coupled to a second coil implanted under the skin of the 
abdomen.

"We expect to begin implanting the device in people for clinical study in the 
fall of 1991.  We are now in the process of fabricating the systems, selecting
clinical centers, and developing protocols that will require an IDE 
[investigational device exemption] from the FDA," says Watson.

Many cultures have regarded the heart as the center of a person's being. In 
the coming century, scientists hope to beat heart disease by a prudent
combination of prevention and an arsenal of cardiovascular spare parts. n 

Ricki Lewis has a Ph.D. in genetics and teaches biology at the State
University of New York at Albany. 

                       Blood's Journey Through the Heart

The human heart is built of four chambers. The upper chambers--right and left 
atria--receive blood from the veins. The lower chambers--right and left 
ventricles--pump blood into the arteries. Valves keep blood flowing in the
proper direction. 

Blood that has given up its oxygen to the tissues enters the heart at the 
right atrium. It passes through a valve to enter the right ventricle, from
which it crosses a valve to enter the pulmonary artery. The blood then travels
through the lungs, picking up oxygen and losing carbon dioxide. The newly 
oxygenated blood then flows through the pulmonary vein to the left atrium of
the heart. The blood passes through another valve to enter the left ventricle,
from which it exits the heart through a valve into the aorta, the largest 
artery. From the branches of the aorta, the blood travels in increasingly 
narrow arterial vessels, releasing its oxygen to the tissues along the way. 
The deoxygenated blood travels back to the heart in vessels that gradually
increase in diameter, until the blood is in the two branches of the venae 
cavae, the veins that empty back into the right atrium. 

--R.L.