快猫短视频

PEER inside the major artery鈥攖he aorta鈥攐f even the healthiest
adult and the chances are you will see the beginnings of heart disease. At any
of dozens of junctions where the artery branches off to deliver blood to the
arms, the liver or the legs, you will find faint streaks of fat that may one day
build into vessel-obstructing plaque. Disturbing as this is, the tendency of
blood vessels to accumulate crud has led researchers to look at the circulatory
system in an entirely new way.

As scientists are now learning, those little fatty harbingers of heart
disease and stroke belie a much more sophisticated and sensitive plumbing system
than anyone had realised. It turns out there鈥檚 a lot more to heart disease than
biochemistry.

Your arteries can 鈥渇eel鈥� the blood flowing, and respond to how hard it pushes
and pulls. The cells that line them can change shape, move around and switch
genes on and off in response to changes in pressure. They are so sensitive to
the mechanical stress of blood flow that your circulatory system has evolved
tricks of fluid dynamics to help spread the forces and avoid dangerous
extremes.

By thinking of blood vessels as smart pipes, scientists are learning how
their complex behaviour conspires to produce heart disease or stroke and how
some people may be more susceptible than others, simply because of the shape of
their arteries. Now researchers are using this new knowledge to improve heart
bypass surgery, and to build a novel artificial heart to replace those damaged
by disease.

Atherosclerosis, or hardening of the arteries, occurs when fat, proteins and
cholesterol accumulate at one spot, usually a junction in a large artery. This
accumulation forms a plaque which weakens the vessel and disturbs the normal
chemical exchange between the vessel lining, called the endothelium, and the
blood. Signals that prevent clotting are blocked, and platelets, the blood cells
that initiate clots, sometimes grab other platelets from the passing flow,
congealing on top of the plaque into a hard, pale clump called a thrombus.
Eventually, the artery can block entirely, rupture, or a chunk of thrombus can
break off and lodge in a smaller artery, potentially causing a heart attack or
stroke.

Fluid dynamics has long been thought to play a role in this process of
atherosclerosis. In 1969, a team led by Colin Caro, a physiologist at Imperial
College in London, proposed that the locations where plaque usually develops
were 鈥渄ead spots鈥� in the bloodstream, analogous to stagnant pools in a creek.
They were broadly right, but only recently has the endothelium鈥檚 sensitivity to
fluid dynamics come to light, complicating the story. 鈥淭he lining of every blood
vessel is a sensory organ,鈥� says Michael Gimbrone, a pathologist at Harvard
Medical School in Boston. 鈥淓veryone once thought of the endothelium as a passive
layer, but in fact it is very responsive.鈥�

The peculiar thing about fluid dynamics at arterial branches is how the shear
stress changes. Shear stress, the force acting parallel to the endothelium, is
the tug that the blood exerts on the walls of your arteries as it flows through.
It鈥檚 one of the forces that rolls pebbles along a river bed and pulls sand off a
beach as a wave recedes. When blood reaches a bend in your arteries, it slams
against the far wall as it changes its course. Like the outside of a bend in a
river, the flow is faster here than on the inside. The corresponding shear
stress is higher too. On the inside of bends and near branches in the
circulatory system, on the other hand, the shear stress can get quite low.

Gimbrone and his colleagues discovered that the cells lining the artery walls
can sense changes in shear stress and respond by switching on important genes.
They grew human endothelial cells in culture dishes and pumped growth medium
across them at different speeds. By making the growth medium flow smoothly or by
forcing it to churn chaotically, Gimbrone was able to subject the cells to an
even or a turbulent shear stress. The researchers then monitored several genes
known to play a role in atherosclerosis.

Good stress

They discovered that the smooth shear stress caused three genes to become more active
(快猫短视频, Science, 5 October 1996, p 17).
Two of these code for enzymes that reduce blood clotting and protect cells from damage.
The third gene produces a protein vital for the synthesis of nitric oxide, which
inhibits the development of thrombi鈥攂lood clots鈥攁nd prevents the
surrounding layer of smooth muscle cells from overgrowing the endothelial layer.
But the activities of these genes were barely detectable in cells that felt
turbulent shear stress or no stress at all. Some stress, it seems, is a good
thing.

While these experiments reveal that cells can respond to large changes in
shear stress, they may not mimic exactly the situation in our arteries. Here,
the differences in shear stress that the endothelium senses are more subtle. In
straight sections of arteries, the blood flows smoothly and all the vessel walls
feels roughly the same shear stress. But where the vessel wall follows a
complicated shape, such as at junctions or around bumps made by atherosclerotic
plaques, the flow becomes slightly disturbed. Downstream of a large plaque, for
instance, the blood may reverse to form an eddy
(see Diagram). Can endothelial
cells really spot these small differences in shear stress?

To find out, Gimbrone鈥檚 graduate student Tobi Nagel took a closer look at the
cells downstream of a bump in one of the culture dishes. She discovered that
another set of genes suspected of involvement in atherosclerosis were more
active in cells located in the disturbed flow than in the smooth flow. She
concluded that some genes really can respond to the tiny changes in shear stress
that occur at arterial junctions and sclerotic lumps. Exactly which genes are
switched on or off is still up in the air, but researchers are beginning to
believe that the changes in gene activity in regions with low shear stress could
be the body鈥檚 attempt to correct what it senses to be a flow problem. In the
long run, the strategy seems to backfire as more plaque builds up. And once a
deposit begins to build up at a branch, the effect may snowball as the plaque
thickens.FIG-mg21724901.JPG

But why does plaque begin to develop in the first place? Forbes Dewey, a
mechanical engineer at the Massachusetts Institute of Technology may have part
of the answer. Not only do endothelial cells in disturbed flows shut down
protective genes, they actually crawl around, apparently trying to escape from
areas where shear stress changes abruptly.

Using a time-lapse video camera, Dewey鈥檚 group spied on endothelial cells as
they grew inside a transparent plastic model of an artery. Rather than blood,
they pumped growth medium through it. The video reveals that for some of the
time, the cells extended their pseudopodia鈥攖emporary cell projections used
for movement鈥攁nd crawled around. Most of the cells moved in random
directions. But just beyond a branch in their model artery, where flow is
disturbed, the cells tended to move in one direction, away from the region of
turbulence.

Dewey believes that this movement of cells ultimately leads to thinning of
the vessel wall near branches, precisely where atherosclerosis tends to occur.
The artery wall can produce new endothelial cells only for so long, he says.
Eventually, the emigrating cells leave gaps. Then other cells such as immune
cells called leucocytes from the blood try to fill the holes, creating a sticky
surface where fat and cholesterol can adhere.

This remarkable sensitivity to shear forces begs a question: How do cells
measure the stresses exerted by the blood? 鈥淭hat鈥檚 very up in the air,鈥� says
Dewey. 快猫短视频s understand how cells sense their chemical environment. Roughly
speaking, proteins protruding from the cell鈥檚 surface sample the surroundings
and transmit chemical signals to the nucleus. There, genes become active or shut
down in response. But now biologists must think of ways for cells to sense
mechanical force. 鈥淚t鈥檚 sort of like looking for a quark,鈥� Dewey says. 鈥淚t鈥檚
very difficult.鈥�

Perhaps the best clue so far comes from the work of a former graduate student
of Dewey鈥檚, Natacha DePaola. She found that communication between cells breaks
down in regions of turbulent flow. Normally, neighbouring endothelial cells
constantly send signals to each other through connecting pores called gap
junctions. These signals help to maintain consistency among groups of cells so
they can form a coherent layer of endothelium. If the signalling is disrupted,
some cells may break ranks and switch off genes they really should keep on, or
vice versa.

Shape matters

To test the idea, DePaola grew cells in environments with both steady and
turbulent flows of growth medium and recorded the transmission of signals
between cells. As expected, signalling was steady between the cells in regions
with steady flow. But in areas where the shear stress varied rapidly from cell
to cell, just beyond a bump in the wall or near an arterial branch, for
instance, communication dropped off.

DePaola suspects that cells sitting in a region of smooth blood flow are
pushed downstream to the same degree, so their junctions remain intact. But
other cells, sited in regions of turbulence, experience large changes in shear
stress from one cell to the next. Where these changes are particularly sudden,
the gap junctions between cells are pulled apart and the connections
break鈥攚hich is exactly what DePaola observed.

Large changes in shear stress are so bad for our health that the circulatory
system seems to have evolved a clever trick to minimise the dangers. The secret,
says Caro who is still actively involved in the field, lies in the shape of your
arteries.

Caro uses what looks like a twisted tree branch with lots of stubby twigs to
explain the process. It鈥檚 a plastic cast of a human aorta. The twigs are what鈥檚
left of branching arteries, and the curve is where the aorta once emerged from
the top of someone鈥檚 heart and turned south to carry blood to the lower body.
鈥淧opular conception is that the arch is shaped like an umbrella handle. But you
can see it鈥檚 far from that,鈥� he says, as he lays the aorta on the table. It
doesn鈥檛 lie flat as an umbrella handle would, but wobbles. 鈥淚t鈥檚 actually a
screw thread. It鈥檚 a helix.鈥�

This helical geometry may be more common than anyone realised. Every large
vessel Caro and his colleagues have examined possesses some sort of spiral
shape. In fact, he suspects the geometry of almost every large bend and branch
in the circulatory system is helical or 鈥渘on-planar鈥�.

Caro and Denis Doorly, an aeronautical engineer at Imperial College, first
realised the significance of non-planar geometry while making models of arteries
using flexible plastic tubing. When they bent the tubing like an umbrella handle
and injected blue dye into the water flowing through it, they found that, as
expected, the water flowed fastest on the outside of the curve and slowest on
the inside. But when they added a second bend in a different plane by simply
pushing the tubing off to one side, the dye swirled round as it raced through
the curve, like water whirling down a plughole.

What good is swirling blood? In crude terms, it scours the arteries of
deposits that could cause disease. Just as sediments tend to build up on the
inside of a bend in a river, so they would in arteries if it weren鈥檛 for helical
flow. 鈥淪tagnant regions are bad news,鈥� Caro says. 鈥淵ou want to clean things
out.鈥� But on a more subtle level, swirling seems to spread out the shear forces
which might otherwise disrupt the sensitive endothelial cells.

When Caro and his colleagues measured the shear stresses in their models,
they found that on the outside of a planar bend the shear stress is high, while
on the inside the shear stress is low. Nothing unexpected there. But in a spiral
bend, the swirling flow reduces the extremes of shear鈥攖he lows are less
low and the highs less high. It鈥檚 as if the helical arteries are set up to keep
shear stress in large blood vessels within reasonable bounds.

Caro鈥檚 group has also shown that non-planar geometry limits shear stress at
arterial branches. Swirling motion, it seems, is one way in which evolution has
improved the flow of blood, perhaps with the benefit of postponing heart
disease.

It now appears that non-planarity varies between individuals, and Caro and
others believe that the geometry of arteries could be used to assess a person鈥檚
risk of heart disease. In 1997, Morton Friedman and Zhaohua Ding at Ohio State
University in Columbus compared magnetic resonance images from 20 people. They
studied a location where the aorta splits into two and found that the
non-planarity of arteries varies substantially from person to person. Caro and
Friedman hope that further studies will show whether people with more planar
aortas are at greater risk of disease. If the correlation is confirmed, an MRI
scan could identify those with the greatest risk and give them a chance to take
preventive measures such as eating a low-cholesterol diet, taking more
exercise or giving up smoking.

One of the worst arterial arrangements for extremes of shear stress doesn鈥檛
occur naturally, yet millions of people are walking around with it. It鈥檚 a
bypass graft鈥攁 section of blood vessel spliced on to a coronary artery,
for instance, to divert blood around a blockage. Where the bypass rejoins the
artery, the blood slams up against the far wall like a bobsleigh entering a
tight turn, leaving backflows and eddies along the wall
(see Diagram). Caro
believes these extremes are worse than they need to be because at the moment
surgeons do not install non-planar bends. A computer simulation developed by
Imperial College aeronautical engineer Spencer Sherwin and his colleagues shows
that adding a slight twist to the graft reduces the extremes of shear stress by
more than threefold.

Non-planar bypasses could prevent graft failure in two ways. First, they
would eliminate the dead spots where the graft meets the artery, so the blood
could scour out the inside of the bend, preventing plaque development. In
addition, many grafts fail after muscle cells in the arterial wall divide
excessively and block up the junction. Friedman has found that this
over-proliferation of cells is a response to very high shear stress, probably to
protect against ballooning or rupture. Eliminating both the highs and the lows
may be good for graft survival.

From a surgical standpoint, introducing such a non-planar bend would be
simple. But before recommending such a procedure, Caro and his colleagues want
to ensure it doesn鈥檛 create more problems than it solves. 鈥淵ou may have to
expose more of the artery, or you may get kinking with too much twist,鈥� Doorly
says. The team is now collaborating with surgeons at the Bristol Heart Institute
in Britain to test non-planar grafts. At the same time, researchers in the US
are using swirling blood flow to develop an artificial heart (see 鈥淗eart in a
飞丑颈谤濒鈥�).

Caro even speculates that we may be able to adjust our vascular geometry by
changing posture. Hunching over, for example, might straighten out some
non-planar curves. Or it could conceivably do the opposite. Without careful
studies, he says, there is no way to know whether slouching is good, bad or
irrelevant. But considering the sensitivity of your arteries, your doctor may
one day admonish you to stand up straight to keep your blood swirling.

Without clotting, every bruise and scrape would be life-threatening, as it is
for haemophiliacs whose blood clots only slowly. But clotting operates on such a
hair trigger that it can also kill, as it does in heart disease, making this
vital property of blood the biggest challenge in the development of an
artificial heart.

So David Lederman and his colleagues at ABIOMED Cardiovascular near Boston
have worked out the precise parameters of thrombus formation with an eye to
developing a permanent replacement heart that won鈥檛 clot up.

The key, he says, is to keep the blood鈥檚 shear stress within certain limits.
鈥淚f you do that, you鈥檙e home free.鈥� Whenever the shear exceeds a certain level,
blood cells begin to break apart. Conversely if the shear drops too far, thrombi
form.

Clotting comes down to 鈥渞esidence times鈥�, or how long the clotting factors in
the blood stay close to one another and to the potential clotting site. Normally
when blood leaks from a cut vessel, it stops moving. Residence times go up, a
clot forms and the vessel regains its integrity. Residence times can also get
too high in undamaged vessels if the shear pressure along the wall is too low.
So arteries and veins secrete substances that inhibit clotting, helping to keep
the blood fluid even if it gets a bit slow on the inside of a bend. But plaques
on the walls of arteries block the secretion, making them potential sites for
the growth of thrombi. And plastic鈥攅ven the high-tech sort used in medical
implants鈥攕ecretes nothing.

So rather than relying on anti-clotting drugs, ABIOMED鈥檚 replacement heart,
due to enter clinical trials this year, uses a natural method of controlling
clots: swirling blood. Blood enters the device through a tube positioned
off-centre. This starts a vortex that continues to whirl even when the valves
are closed. Then, when the exit valve opens, the blood swirls out of the top
(see Diagram).
The shear stress stays within the desired range in most of the
heart for most of the time.

Even this design leaves small areas with low flow. 鈥淵ou cannot avoid having
some region that might violate the shear stress rule,鈥� says Lederman. But as
long as such regions are small, he says, the thrombi will break down as fast as
they form.

THE story of swirling fluids may not end with the blood. As Colin Caro points
out, the respiratory system also has non-planar bends. As you breathe in, the
air turns a corner from your mouth into the throat, then turns again when it
enters the lungs. One possible benefit of swirling airflow is that it might
lessen the impact of particles in the airstream on any one point in your lungs.
And what about the urinary system? Caro admits that this is pure speculation,
but swirling flow could operate there too. Just as plaque can form in arteries,
without swirling flow, nasty bacteria could accumulate in the urinary tract.